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
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Time (days) Patent Application Publication Nov. 1, 2012 Sheet 2 of 28 US 2012/0277199 A1
Figure 2
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10 Patent Application Publication Nov. 1, 2012 Sheet 6 of 28 US 2012/0277199 A1
Figure 6
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Figure 7
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Dextromethorphan NMDA antagonist Eliprodi NMDA antagonist L-701324 NMDA antagonist
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Figure 8
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Patent Application Publication Nov. 1, 2012 Sheet 9 of 28 US 2012/0277199 A1
Figure 9
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Patent Application Publication Nov. 1, 2012 Sheet 10 of 28 US 2012/0277199 A1
Figure 10
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Figure 11
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Figure 12
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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
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Figure 14
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Figure 17 (A) 15-18% P407+ water Ciprofloxacin Dexamethansone
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Figure 18
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Figure 19 (A) 15-18% P407+ water Ciprofloxacin Dexamethansone
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Figure 20
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Figure 21
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Figure 22
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Figure 23
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Figure 24
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Figure 25
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Figure 26
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Figure 27
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Figure 28
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MODULATION OF GEL TEMPERATURE OF weight of the formulation and further comprises one or POLOXAMER-CONTAINING more gelation temperature increasing or gelation tem FORMULATIONS perature decreasing agents. 0013. In some embodiments, the formulation provides an CROSS-REFERENCE in vivo sustained release of atherapeutically effective amount of the active agent for a period of at least 5 days. In some 0001. This patent application claims the benefit of U.S. embodiments, the formulation provides an in vivo Sustained Provisional Application Ser. No. 61/253,782 filed Oct. 21, release of a therapeutically effective amount of the active 2009; U.S. Provisional Application Ser. No. 61/255,379 filed agent for a period of at least 7 days. In some embodiments, the Oct. 27, 2009; U.S. Provisional Application Ser. No. 61/255, formulation provides an in Vivo Sustained release of a thera 780 filed Oct. 28, 2009; U.S. Provisional Application Ser. No. peutically effective amount of the active agent for a period of 61/255,783 filed Oct. 28, 2009: U.S. Provisional Application at least 10 days. In some embodiments, the formulation pro Ser. No. 61/297,138 filed Jan. 21, 2010; U.S. Provisional vides an in vivo sustained release of a therapeutically effec Application Ser. No. 61/297,170 filed Jan. 21, 2010; U.S. tive amount of the active agent for a period of at least 14 days. Provisional Application Ser. No. 61/364,288 filed Jul. 14, 0014. In some embodiments, the formulation is adminis 2010; and U.S. Provisional Application Ser. No. 61,366,677 tered at or in the vicinity of the round window membrane of filed Jul. 22, 2010; allot which are incorporated by reference the ear. In some embodiments, the in vivo Sustained release herein in their entirety. occurs in the inner ear. 0015. In some embodiments, the formulation is adminis BACKGROUND OF THE INVENTION tered in the middle ear, away from the round window mem brane. In some embodiments, the in vivo Sustained release 0002 Sustained release formulations that gel upon contact occurs in the middle ear. with the body are used in a variety of therapeutic applications. 0016. In some embodiments, the formulation is adminis tered into or in the vicinity of one or more sinonasal cavities. SUMMARY OF THE INVENTION In some embodiments, the in vivo Sustained release occurs in 0003. Described herein are sustained release formulations one or more sinonasal cavities or in the vicinity of one or more comprising thermosensitive polymers. Also described herein sinonasal cavities. are methods wherein gelation temperature of formulations 0017. In some embodiments, the thermosensitive polymer comprising thermosensitive polymers is manipulated with is P407. In some embodiments, the formulation is substan the addition of one or more gel temperature modifying agents tially free of additional preservatives. In some embodiments, to achieve a desired therapeutically relevant gelation tem the formulation is Substantially free of pyrogens. In some perature (e.g., a formulation that gels upon contact with the embodiments, the formulation comprises less than about 5 body). endotoxin units (EU) per kg of body weight of a subject. In some embodiments, the formulation is substantially free of 0004 Provided herein, in some embodiments, are pharma additional tonicity agents. ceutical formulations comprising an active agent, a ther 0018. In some embodiments, the formulation comprises a mosensitive polymer comprising polyoxyethylene and poly Suspension of one or more multiparticulate active agents. In oxypropylene copolymers, and Some embodiments, the multiparticulate active agent is a 0005 a) having a syringable viscosity at time of admin micronized active agent sterilized by dry-heat, irradiation or istration Suitable for administration via a 25-31 gauge steam sterilization. needle; 0019. In some embodiments, the formulation has any indi 0006 b) having a gelation temperature between about vidual product related impurity of no more than 1% by weight 14° C. and about 42°C. of the formulation. In some embodiments, the formulation 0007 c) providing in vivo sustained release of a thera has total product related impurities of no more than 2% by peutically effective amount of the active agent for a weight of the formulation. period of at least 3 days; and 0020. In some embodiments, the active agent is a corticos 0008 (d) having less than 50 cfu of microbial agents per teroid, or a salt or prodrug or Solvate thereof. grant of the formulation; provided that 0021. In some embodiments, the corticosteroid is 21-ac 0009 (i) the formulation comprises less than 14.5% of etoxypregnenolone, alclometasone, algestone, amcinonide, the thermosensitive polymer by weight of the formula beclomethasone, betamethasone, budesonide, chloropred tion and further comprises one or more gelation tem nisone, clobetasol, clobetaSone, clocortolone, cloprednol, perature increasing agents; or corticosterone, cortisone, cortivaZol, deflazacort, desonide, 0010 (ii) the formulation comprises more than 25% of desoximetaSone, dexamethasone, diflorasone, diflucor the thermosensitive polymer by weight of the formula tolone, difluprednate, enoXolone, fluazacort, flucloronide, tion and further comprises one or more gelation tem flumethasone, flunisolide, fluocinolone acetonide, fluocino perature decreasing agents; or nide, fluocortin butyl, fluocortolone, fluorometholone, flu 0011 (iii) the formulation comprises between about 5% perolone acetate, fluprednidene acetate, fluprednisolone, flu and about 20% of the thermosensitive polymer by randrenolide, fluticasone propionate, formocortal, weight of the formulation, wherein the thermosensitive halcinonide, halobetasol propionate, halometasone, halopre polymer has been purified, and optionally further com done acetate, hydrocortamate, hydrocortisone, loteprednol prises one or more gelation temperature increasing or etabonate, maZipredone, medrysone, meprednisone, methyl gelation temperature decreasing agents; or prednisolone, mometasone furoate, paramethasone, predni 0012 (iv) the formulation comprises between about carbate, prednisolone, prednisolone 25-diethylamino-ac 14.5% and about 25% of the thermosensitive polymer by etate, prednisolone sodium phosphate, prednisone, prednival, US 2012/0277199 A1 Nov. 1, 2012
prednylidene, rimexolone, tiXocortol, triamcinolone, triamci herbicolacin, brevicin, halocin, agrocin, alveicin, carnocin, nolone acetonide, triamcinolone benetonide, or triamcino curvaticin, divercin, enterocin, enterolysin, erwiniocin, gly lone hexacetonide, or salt or prodrug thereof. cinecin, lactococin, lacticin, leucoccin, mesentericin, pedio 0022. In some embodiments, the corticosteroid is dexam cin, plantaricin, Sakacin, Sulfolobicin, vibriocin, warneri ethasone, prednisolone, methylprednisolone, triamcinolone, nand, nisin, or a salt or cocrystal, or prodrug or Solvate or a salt or prodrug or Solvate thereof, or a combination thereof, or a combination thereof. thereof. In some embodiments, the corticosteroid is dexam 0027. In some embodiments, the antibiotic agent is cipro ethasone, or a salt or prodrug or Solvate thereof. In some floxacin, amoxicillin, amoxicillin+clavulanic acid, moxi embodiments, the dexamethasone is dexamethasone sodium floxacin or ofloxacin. In some embodiments, the antibiotic phosphate or dexamethasone acetate. agent is ciprofloxacin or ciprofloxacin hydrate. In some 0023. In some embodiments, the dexamethasone, or salt or embodiments, the ciprofloxacin or ciprofloxacin hydrate is prodrug or Solvate thereof, is present in an amount from about present in an amount between about 0.1 to about 20% by 0.05% to about 40% by weight of the formulation. In some weight of the formulation. embodiments, the dexamethasone, or salt or prodrug or Sol 0028. In some embodiments, the formulation provides an vate thereof, is present in an amount from about 0.1% to about in vivo sustained release of atherapeutically effective amount 30% by weight of the formulation. In some embodiments, the of ciprofloxacin for a period of at least 5 days. In some dexamethasone, or salt or prodrug or Solvate thereof, is embodiments, the formulation provides an in vivo Sustained present in an amount from about 0.5% to about 15% by release of a therapeutically effective amount of ciprofloxacin weight of the formulation. for a period of at least 7 days. In some embodiments, the 0024. In some embodiments, the formulation provides an formulation provides an in Vivo Sustained release of a thera in vivo sustained release of a therapeutically effective amount peutically effective amount of ciprofloxacin for a period of at of dexamethasone for a period of at least 5 days. In some least 10 days. In some embodiments, the formulation pro embodiments, the formulation provides an in vivo Sustained vides an in vivo sustained release of a therapeutically effec release of a therapeutically effective amount of dexametha tive amount of ciprofloxacin for a period of at least 14 days. Sone for a period of at least 7 days. In some embodiments, the 0029. In some embodiments, the gel temperature increas formulation provides an in vivo Sustained release of a thera ing agent or gel temperature decreasing agent is selected from peutically effective amount of dexamethasone for a period of P188, P338, cyclodextrin, Tween 20, Tween 40, Tween 65, at least 10 days. In some embodiments, the formulation pro Tween 80, Tween 85, sodium oleate, sodium caprate, sodium vides an in vivo Sustained release of a therapeutically effec caprylate and PEG. tive amount of dexamethasone for a period of at least 14 days. 0030. Also provided herein are kits comprising (a) steril 0025. In some embodiments, the active agent is an antimi ized multiparticulate active agent powder and (b) a solution crobial agent. In some embodiments, the antimicrobial agent comprising a thermosensitive polymer, wherein (a) and (b). is an antibiotic. when combined, form a formulation described above. 0026. In some embodiments, the antibiotic is amikacin, 0031. In some embodiments, the formulations described gentamicin, kanamycin, neomycin, netilmicin, Streptomycin, above comprise a higher concentration of an active agent than tobramycin, paromycin, geldanamycin, herbimycin, loracar the actual administered dose. In some of Such embodiments, bef, ertapenem, doripenem, imipenem, meropenem, cefaclor, the formulation is diluted prior to administration. Accord cefamandole, cefotoxin, cefprozil, cefuroxime, cefixime, cef ingly, in some embodiments, the percentage by weight dinir, cefditoren, cefpodoxime, ceftazidime, ceftibuten, cefti amount of active agent in the administered formulation is Zoxime, ceftriaxone, cefepime, ceftobirprole, Vancomycin, different from the percentage by weight amount of active azithromycin, clarithromycin, dirithromycin, erythromycin, agent in the prepared formulation. roXithromycin, troleandomycin, tellithromycin, spectinomy 0032. In one aspect, provided herein are pharmaceutical cin, aztreonam, amoxicillin, amplicillin, azociling, carbenicil formulations comprising lin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, 0033 (a) less than 14.5% of a thermosensitive polymer meticillin, nafcillin, oxacillin, peperacillin, ticarcillin, baci by weight of the formulation and further comprising one tracin, colistin, polymyxin B, ciprofloxacin, clavulanic acid, or more gelation temperature increasing agents; enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxi 0034 (b) water; floxacin, nonfloxacin, ofloxacin, trovafloxacin, grepafloxa 0035 (c) between about 0.2% and about 20% of cin, sparfloxacin, AL-15469A, AL-38905, OP-145, afenide, micronized dexamethasone by weight of the adminis prontosil, Sulfacetamide, Sulfamethiazole, Sulfanilimide, Sul tered formulation; fasalazine, Sulfisoxazole, trimethoprim, cotrimoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, 0.036 (d) having a gelation temperature between about tetraycline, lineZolid, arsogebanubem chloramphenicol, clin 14° C. and about 42°C.; damycin, lincomycin, ethambutol, fosfomycin, fusidic acid, 0037 (e) having less than 50 cfu of microbial agents per furazolidone, isoniazid, lineZolid, metronidazole, mupirocin, gram of the formulation; and nitrofurantoin, platensimycin, pyrazinamide, quinupristin, 0.038 (f) having a syringable viscosity at time of admin dalfopristin, rifampicin, thamphenicol, timidazole, amoxicil istration Suitable for administration via a 25-31 gauge lin+clavulanic acid, Maximin H5, Dermcidin, Cecropins, needle. andropin, moricin, ceratotoxin, melittin, Magainin, der 0039. In one aspect, provided herein are pharmaceutical maseptin, bombinin, brevinin-1, esculentins and buforin II, formulations comprising CAP18, LL37, abaecin, apidaecins, prophenin, indolicidin, 0040 (a) more than 25% of a thermosensitive polymer brevinins, protegrin, tachyplesins, defensins, drosomycin, by weight of the formulation and further comprising one alamethicin, pexiganan or MSI-78, MSI-843, MSI-594, or more gelation temperature decreasing agents; polyphemusin, colicin, pyocin, klebicin, Subtilin, epidermin, 0041 (b) water; US 2012/0277199 A1 Nov. 1, 2012
0042 (c) between about 0.2% and about 20% of 0068 (a) more than 25% of a thermosensitive polymer micronized dexamethasone by weight of the adminis by weight of the formulation and further comprising one tered formulation; or more gelation temperature decreasing agents; 0043 (d) having a gelation temperature between about 0069 (b) water; 14° C. and about 42°C.; 0070 (c) between about 0.2% and about 20% of cipro 0044 (e) having less than 50 cfu of microbial agents per floxacin by weight of the administered formulation; gram of the formulation; and 0071 (d) having a gelation temperature between about 0045 (f) having a syringable viscosity at time of admin 14° C. and about 42°C.; istration Suitable for administration via a 25-31 gauge 0.072 (e) having less than 50 cfu of microbial agents per needle. gram of the formulation; and 0046. In one aspect, provided herein are pharmaceutical 0.073 (f) having a syringable viscosity at time of admin formulations comprising istration Suitable for administration via a 25-31 gauge 0047 (a) between about 5% to about 20% of a purified needle. thermosensitive polymer by weight of the formulation, 0074. In one aspect, provided herein are pharmaceutical and optionally further comprising one or more gelation formulations comprising temperature increasing agents: 0075 (a) between about 5% to about 20% of a purified 0048 (b) water; thermosensitive polymer by weight of the formulation, 0049 (c) between about 0.2% and about 20% of and optionally further comprising one or more gelation micronized dexamethasone by weight of the adminis temperature increasing agents: tered formulation; 0.076 (b) water; 0050 (d) having a gelation temperature between about 0.077 (c) between about 0.2% and about 20% ciprof 14° C. and about 42°C.; loxacin by weight of the administered formulation; 0051 (e) having less than 50 cfu of microbial agents per 0078 (d) having a gelation temperature between about gram of the formulation; and 14° C. and about 42°C.; 0.052 (f) having a syringable viscosity at time of admin 0079 (e) having less than 50 cfu of microbial agents per istration Suitable for administration via a 25-31 gauge gram of the formulation; and needle. 0080 (f) having a syringable viscosity at time of admin 0053. In one aspect, provided herein are pharmaceutical istration suitable for administration via a 25-31 gauge formulations comprising needle. 0054 (a) between about 14.5% and about 25% of a I0081. In one aspect, provided herein are pharmaceutical thermosensitive polymer by weight of the formulation formulations comprising and further comprising one or more gelation tempera I0082 (a) between about 14.5% and about 25% of a ture increasing or gelation temperature decreasing thermosensitive polymer by weight of the formulation agents: and further comprising one or more gelation tempera 0.055 (b) water; ture increasing or gelation temperature decreasing 0056 (c) between about 0.2% and about 20% of agents; micronized dexamethasone by weight of the adminis I0083) (b) water; tered formulation; I0084) (c) between about 0.2% and about 20% of cipro 0057 (d) having a gelation temperature between about floxacin by weight of the administered formulation; 14° C. and about 42°C.; 0085 (d) having a gelation temperature between about 0.058 (e) having less than 50 cfu of microbial agents per 14° C. and about 42°C.; gram of the formulation; and I0086 (e) having less than 50 cfu of microbial agents per 0059 (f) having a syringable viscosity at time of admin gram of the formulation; and istration Suitable for administration via a 25-31 gauge 0.087 (f) having a syringable viscosity at time of admin needle. istration Suitable for administration via a 25-31 gauge 0060. In one aspect, provided herein are pharmaceutical needle. formulations comprising I0088. In one aspect, provided herein are pharmaceutical 0061 (a) less than 14.5% of a thermosensitive polymer formulations comprising by weight of the formulation and further comprising one 0089 (a) less than 14.5% of a thermosensitive polymer or more gelation temperature increasing agents; by weight of the formulation and further comprising one 0062 (b) water; or more gelation temperature increasing agents; 0063 (c) between about 0.2% and about 20% of cipro 0090 (b) water; floxacin by weight of the administered formulation; (0.091 (c) between about 0.001% and about 5% of 0064 (d) having a gelation temperature between about micronized dexamethasone by weight of the adminis 14° C. and about 42°C.; tered formulation; 0065 (e) having less than 50 cfu of microbial agents per 0092 (d) between about 0.1% and about 10% of cipro gram of the formulation; and floxacin, moxifloxacin or ofloxacin by weight of the 0.066 (f) having a syringable viscosity at time of admin administered formulation. istration Suitable for administration via a 25-31 gauge 0.093 (e) having a gelation temperature between about needle. 14° C. and about 42°C.; 0067. In one aspect, provided herein are pharmaceutical 0094 (f) having less than 50 cfu of microbial agents per formulations comprising gram of the formulation; and US 2012/0277199 A1 Nov. 1, 2012
0.095 (g) having a syringable viscosity at time of I0120) Further provided herein is the use of any formula administration suitable for administration via a 25-31 tion described above in the manufacture of a medicament for gauge needle. treatment of any otic and/or sinonasal and/or nasopharyngeal 0096. In one aspect, provided herein are pharmaceutical disorder described herein. formulations comprising 0121 Provided herein, in some embodiments, are meth 0097 (a) more than 25% of a thermosensitive polymer ods for treating an otic disorder selected from Meniere's by weight of the formulation and further comprising one disease, Sudden sensorineural hearing loss, noise induced or more gelation temperature decreasing agents; hearing loss, age-related hearing loss, Vertigo, tinnitus, oto (0098 (b) water; Sclerosis, autoimmune ear disease (AIED), otitis media, and (0099 (c) between about 0.001% and about 5% of otitis externa comprising administration of any formulation micronized dexamethasone by weight of the adminis described herein to an individual in need thereof. tered formulation; 0.122 Provided herein, in some embodiments, are meth 0100 (d) between about 0.1% and about 10% of cipro ods for treating a sinonasal or nasopharyngeal disorder floxacin, moxifloxacin or ofloxacin by weight of the selected from sinonasal polyposis, allergic fungal sinusitis, administered formulation. nasal polyps, paranasal sinus cancers, nasopharyngeal can 0101 (e) having a gelation temperature between about cers, epistaxis, anoSmia, repiratory papilloma, papilloma 14° C. and about 42°C.; virus induced tumors (e.g., inverting papillomas), recurrent 0102 (f) having less than 50 cfu of microbial agents per respiratory papillomas, reduction of post-Surgical complica gram of the formulation; and tions associated with sinonasal Surgery (inferior turbinate 0103 (g) having a syringable viscosity at time of removal), chronic sinusitis, and/or chronic rhinosinusitis administration suitable for administration via a 25-31 comprising administration of any formulation described gauge needle. herein to an individual in need thereof. 0104. In one aspect, provided herein are pharmaceutical formulations comprising BRIEF DESCRIPTION OF FIGURES 0105 (a) between about 5% to about 20% of a purified I0123 FIG. 1. is an illustrative comparison of non-sus thermosensitive polymer by weight of the formulation, tained release and Sustained release formulations. and optionally further comprising one or more gelation 0.124 FIG. 2 are illustrative predicted tunable releases of temperature increasing agents: an active agent from four compositions. 0106 (b) water; I0125 FIG. 3 are illustrative inner ear pharmacokinetics 0107 (c) between about 0.001% and about 5% of with increasing concentrations of a steroid drug in Sustained micronized dexamethasone by weight of the adminis release formulations. tered formulation; 0.126 FIG. 4 is an illustration of in vitro mean dissolution (0.108 (d) between about 0.1% and about 10% of cipro time with increasing concentrations of Steroid drug in Sus floxacin, moxifloxacin or ofloxacin by weight of the tained release formulations. administered formulation. 0127 FIG. 5 is an illustration of in vitro mean dissolution 0109 (e) having a gelation temperature between about time of high versus low solubility drug Substances and solu 14° C. and about 42°C.; tion versus gel formulations. 0110 (f) having less than 50 cfu of microbial agents per I0128 FIG. 6 is an illustrative comparison of in vitro gram of the formulation; and release of Zoledronate from a formulation comprising Zoledr 0111 (g) having a syringable viscosity at time of onate versus a formulation comprising a Zoledronate-calcium administration suitable for administration via a 25-31 complex. I0129 FIG. 7 illustrates the mean dissolution time (MDT) gauge needle. for certain formulations. 0112. In one aspect, provided herein are pharmaceutical 0.130 FIG. 8 illustrates the MRT for dexamethasone formulations comprising (Dex), dexamethasone sodium phosphate (DSP), and dexam 0113 (a) between about 14.5% and about 25% of a ethasone acetate (DA) from certain formulations following thermosensitive polymer by weight of the formulation intratympanic injection in guinea pigs. and further comprising one or more gelation tempera 0131 FIG. 9 illustrates the MRT for soluble form or meth ture increasing or gelation temperature decreasing ylprednisolone (MPS) and insoluble form of methylpredniso agents: lone (MP) from certain formulations following intratympanic 0114 (b) water; injection in guinea pigs. 0115 (c) between about 0.001% and about 5% of (0132 FIG. 10 illustrates the MRT for 0.6% L-701324 in micronized dexamethasone by weight of the adminis 17% poloxamer 407 formulation following intratympanic tered formulation; injection in guinea pigs. 0116 (d) between about 0.1% and about 10% of cipro 0.133 FIG. 11 illustrates the MRT for 0.5% SP-600125 in floxacin, moxifloxacin or ofloxacin by weight of the 17% poloxamer 407 formulation following intratympanic administered formulation. injection in guinea pigs. 0117 (e) having a gelation temperature between about 0.134 FIG. 12 illustrates the MRT for 2% meclizine in 14° C. and about 42°C.; 17% poloxamer 407 formulation following intratympanic 0118 (f) having less than 50 cfu of microbial agents per injection in guinea pigs. gram of the formulation; and 0.135 FIG. 13 illustrates a substantially uniform distribu 0119 (g) having a syringable viscosity at time of tion of dexamethasone in the chochlea from a formulation administration suitable for administration via a 25-31 comprising a thermosensitive polymer and the uneven distri gauge needle. bution of dexamethasone in the cochlea from a dexametha US 2012/0277199 A1 Nov. 1, 2012
Sone solution not containing a thermosensitive polymer fol (50 ul). Free drug levels in the middle ear were quantified at lowing intratympanic injection. the indicated times. Data are presented as meant SEM. Polox 0.136 FIG. 14 illustrates the effect of poloxamer 407 for amer concentrations are as follows: 16% poloxamer (dia mulations comprising varying concentrations of dexametha mond), 17% poloxamer (square), 19% poloxamer (triangle) Sone on the ABR hearing thresholds in guinea pigs following and 21% poloxamer (circle). intratympanic administration. Hearing was tested by record 0145 FIG. 23 illustrates middle ear pharmacokinetics fol ing the brainstem activity in response to a known auditory lowing intratympanic administration of various doses of P407 stimulus, under general anesthesia, in a sound isolation booth. formulations. Guinea pigs (n=4) received a single intratym An earphone (EC1, Tucker Davis Technologies) was fitted panic injection (50 ul) of either 0.5% Cipro 0.1% DSP (circle) into the ear just above the external auditory canal orifice. or 1% Cipro 0.1% DSP (square). Free drug levels in the Three subcutaneous needle electrodes were used to measure middle ear were quantified at the indicated times. Data are the brainstem activity, placed in the postauricular area of the presented as mean-SEM. ear (reference), on the vertex of the skull (active) and in the 0146 FIG. 24 illustrates middle ear pharmacokinetics fol hind leg (ground). The acoustic stimulus was generated using lowing intratympanic administration of various doses of P407 the SigGen System (Tucker Davis Technologies) and con formulations. Guinea pigs (n=4) received a single intratym sisted of 10 ms auditory clicks (frequency range 100 HZ-30 panic injection (50 ul) of either 0.3% Cipro 0.1% DEX (dia KHZ). Responses were averaged from 512 presentations with mond), 0.6% Cipro 0.2% DEX (circle), 2% Cipro 0.7% DEX sound level up to 90 dB SPL with increments of 5 dB SPL. (triangle) or 6% Cipro, 2% DEX (square). Free drug levels in Responses were acquired using BioSig (Tucker Davis Tech the middle ear were quantified at the indicated times. Data are nologies) and threshold was determined as the average presented as mean-SEM. between the non observable and smallest observable inten 0147 FIG. 25 illustrates tissue-bound middle ear drug S1ty. levels following intratympanic administration of P407 for 0.137 FIG. 15 illustrates a comparison of in vitro release mulations. Guinea pigs (n=4) received a single intratympanic characteristics of otic agents from 15-18% poloxamer formu injection (50 ul) of 0.3% Cipro 0.1% DEX. Tissue-bound lations comprising water and 50% poloxamer formulation drug levels in the middle ear epithelium were quantified at the comprising water+ethanol as solvent upon administration to indicated times. Data are presented as meant SEM. Black the middle ear in guinea pigs. bars: ciprofloxacin, white bars: dexamethasone. 0138 FIG. 16 illustrates a comparison of in vivo release 0148 FIG. 26 illustrates middle ear pharmacokinetics fol characteristics of otic agents from 15-18% poloxamerformu lowing intratympanic administration of various volumes of a lations comprising water and 50% poloxamer formulation formulation. Guinea pigs (n 4) received a single intratym comprising water+ethanol as solvent upon administration to panic injection of either 25ul (circle), 50 ul (square) or 75 ul the middle ear in guinea pigs. (triangle) of 0.3% Cipro 0.1% DEX. Drug levels in the middle 0139 FIG. 17 illustrates middle ear drug concentration of ear were quantified at the indicated times. Data are presented ciprofloxacin and dexamethasone from 15-18% poloxamer as mean-SEM. formulations comprising water and 50% poloxamer formu 0149 FIG. 27 illustrates Hearing evaluation of P407 for lation comprising water+ethanol as solvent upon administra mulations administered intratympanically. Guinea pigs (n=4) tion to the middle ear in guinea pigs in dry ear conditions. received a single intratympanic administration (50 ul) of 0140 FIG. 18 illustrates middle ear drug concentration of 0.2% CiproHCl, 0.2% DEX. Hearing evaluation was con ciprofloxacin and dexamethasone from 15-18% poloxamer ducted using Auditory Brainstem Response across frequen formulations comprising water and 50% poloxamer formu cies. Data are presented as meant-SEM (n=4) of ABR thresh lation comprising water+ethanol as solvent upon administra old. tion to the middle ear in guinea pigs in wet ear conditions. 0150 FIG. 28 A-G illustrates the hemolysis in guinea pig 0141 FIG. 19 illustrates middle ear fluid levels of ciprof red blood cells when exposed to serially diluted poloxamer loxacin and dexamethasone from 15-18% poloxamer formu Solutions. lations comprising water and 50% poloxamer formulation comprising water+ethanol as solvent upon administration to the middle ear in guinea pigs in dry ear conditions. DETAILED DESCRIPTION OF THE INVENTION 0142 FIG. 20 is a comparison of release profile for for 0151. Local administration of active agents reduces tox mulations described herein and Ciprodex (R. Otic solution. icities and/or side effects associated with systemic adminis 0143 FIG. 21 illustrates effect of formulations described tration. The ability to provide sustained release of active herein and Ciprodex(R) Otic solution on auditory function in agents at localized sites in the body is desirable for current guinea pigs following intratympanic administration in guinea treatment modalites that require multiple daily dosing and/or pigs. Administration of CiprodeXR Otic causes transient prolonged dosing because Such Sustained release treatment hearing shift of 20-25 dB, improving by day 7. Administra regimens reduce dosing frequency thereby improving patient tion of a formulation comprising dexamethasone, ciprofloxa compliance. Provided herein are sustained release active cin, 15-18% P407 and water causes minimal hearing shift agent pharmaceutical formulations that gel upon contact with (5-10 dB), resolved by day 7. Administration of a formulation the body. Such formulations are suitable for local administra comprising dexamethasone, ciprofloxacin, 50% P407 and tion at various target sites in the body, including and not water--ethanol causes transient hearing shift of 40-50 dB. limited to the ear, the eye, the sinonasal cavities, the gas resolved by day 3. trointestinal tract, the buccal cavity, the intrathecal and/or 014.4 FIG.22 illustrates middle ear pharmacokinetics fol intracranial cavities, synovial cavities or the like. lowing intratympanic administration of varying poloxamer 0152 Provided herein are formulations that are manufac concentrations all containing 0.5% Cipro and 0.1% DEX. tured with low bioburden or sterilized with stringent sterilty Guinea pigs (n=4) received a single intratympanic injection requirements and are Suitable for administration in vivo. In US 2012/0277199 A1 Nov. 1, 2012
Some embodiments, the biocompatible compositions body. In certain instances, even trace amounts of pyrogens described herein are substantially free of pyrogens and/or and/or microbes can triggerinfections and related physiologi microbes. cal changes in the isolated microenvironment of the inner 0153. Where the current standard of care requires multiple and/or middle ear. The compositions described herein are administrations of drops or injections (e.g. intratympanic sterile compositions suitable for administration to the isolated injections) over several days (e.g., up to two weeks), includ environment of the inner ear and/or into the middle ear and ing schedules of receiving multiple injections per day, formu provide Sustained release of an active agent at the target site. lations described herein are administered at reduced dosing 0159. In some embodiments, for application to the inner frequency compared to the current standard of care. In certain ear, the formulations described herein are administered (e.g., instances, a reduced frequency of administration alleviates via intratympanic injection, as ear drops in the ear canal, discomfort caused by multiple injections in individuals direct perfusion during otic Surgery) behind and/or through undergoing treatment for a disease, disorder or condition the tympanic membrane at or near the round window mem and/or improves patient compliance during long-term brane and/or the ossicular chain. In some embodiments, Sus therapy. In some embodiments, the formulations described tained release formulations described herein are injected as a herein are administered locally at a target site and prolong liquid into the tympanic cavity in the vicinity of the round residence time of an active agent at the site of administration. window membrane and gel and/or form thickened liquids 0154 Localized administration allows an active agent to upon contact with auditory Surfaces. reach a target organ (e.g., inner ear) and reduces or eliminates 0160. In some other embodiments, for application to the systemic accumulation of the active agent. In some instances, middle ear, the formulations described herein are adminis local administration provides a higher therapeutic index for tered (e.g., via intratympanic injection, as ear drops in the ear an active agent that would otherwise have dose-limiting sys canal, direct perfusion during otic Surgery) behind and/or temic toxicity. In addition, localized treatment also affords through the tympanic membrane so that they are not in con the use of previously undesired therapeutic agents, including tact with the round window membrane and/or the ossicular agents with poor pK profiles, poor uptake, low systemic chain. In some embodiments, Sustained release formulations release, and/or toxicity issues. described herein are administered in the tympanic cavity, 0155. In some instances, a disadvantage of liquid formu away from the round window membrane. In some embodi lations is their propensity to wash way in physiological media ments, the formulations are deposited, by injection, on the and cause rapid clearance of the formulation from the site of walls of the middle ear and gel and/or form thickened liquids administration. Provided herein, in certain embodiments, are upon contact with auditory Surfaces. formulations comprising polymers that gel at about body 0.161. In other embodiments, the formulations are admin temperature and remain in contact with the target Surfaces istered as a paint (e.g., the formulations are Smeared on the (e.g., the sinonasal epithelium) for extended periods of time. walls of the tympanic cavity using a cotton-tipped Stick). In Formulations described herein avoid attenuation of therapeu Some embodiments, the formulations are sprayed (e.g., as a tic benefit due to drainage or washing away of active agents. fluid, a foam or the like) into the middle ear cavity (e.g., when 0156 Accordingly, provided herein are pharmaceutical the tympanic membrane has ruptured). In some embodi formulations that meet stringent criteria including pH, ionic ments, the formulations are administered on the auditory balance, and/or sterility. Such formulations are designed to be walls and not on auditory bones (e.g., the ossicles). In some isotonic with biological fluids. In some embodiments, the embodiments, the compositions described herein are admin biocompatible compositions described herein are formulated istered in the outer ear, e.g., in the ear canal. with minimum excipients and thus reduce or eliminate irrita (0162. In some embodiments, formulations described tion or toxicity at the site of administration. Further, the herein are low viscosity liquid compositions suitable for formulations comprise thermosensitive polymers that are administration as ear drops. Following administration, the biocompatible and/or otherwise non-toxic. In some embodi formulations form thickened liquids and/or gels that do not ments, the thermosensitive gel is biodegradable and/or bioe wash away from the middle ear and/or the round window liminated (e.g., the copolymer is eliminated from the body by membrane and provide Sustained release of active agents, a biodegradation or bioelimination process, e.g., elimination even in the presence of biological fluids such as middle ear in the urine, the feces or the like). fluids present in individuals suffering from otitis media with effusion. By way of example, when formulations comprising Administration in the Ear a copolymer of polyoxyethyelene and polyoxypropylene are O157. In some embodiments, the sustained release formu administered to an individual suffering from otitis media with lations described herein are suitable for administration to the effusion, the formulations do not wash away, and remain in ear for the treatment of otic disorders including and not lim contact with the walls of the middle ear preventing infection ited to Meniere's disease, Sudden sensorineural hearing loss, and/or further accumulation of mucus. In certain other noise induced hearing loss, age-related hearing loss, Vertigo, embodiments, the formulations are deposited on auditory tinnitus, otosclerosis, autoimmune ear disease (AIED), otitis bones (e.g., as a treatment for otosclerosis). media, otitis externa, ear infections and the like. Administration in Sinonasal Structures 0158. The environment of the inner ear is an isolated envi ronment. The endolymph and the perilymph are static fluids (0163. In some embodiments, the sustained release formu and are not in contiguous contact with the circulatory system. lations described herein are suitable for instrasinusoidal, In certain instances, even trace amounts of pyrogens and/or intranasal, and/or intranasopharyngeal administration for the microbes can trigger infections and related physiological treatment of sinusoidal, nasal, and/or nasopharynx disorders changes in the isolated microenvironment of the inner ear. including and not limited, sinonasal polyposis, allergic fungal When the tympanic membrane is intact, the air of the middle sinusitis, nasal polyps, paranasal cancers, nasopharyngeal ear is not in direct contact with the atmosphere outside the cancers, epistaxis, anoSmia, respiratory papilloma, papilloma US 2012/0277199 A1 Nov. 1, 2012
virus induced tumors (e.g., inverting papillomas), recurrent position. In some embodiments, a formulation described respiratory papillomas, reduction of post-Surgical complica herein comprises at least about 12% and not more than about tions associated with sinonasal Surgery (inferior turbinate 20% of a thermosensitive polymer (e.g., polyoxyethylene removal), chronic sinusitis, chronic rhinosinusitis and the polyoxypropylene triblock copolymer) by weight of the com like. position. In some of Such embodiments, the thermosensitive 0164. In some embodiments, sustained release formula polymer is a purified polymer. In other embodiments, the tions described herein are administered in a sinusoidal cavity thermosensitive polymer is un-purified. In any of the afore and/or in the vicinity of the sinusoidal cavities, including the mentioned embodiments, the formulations further comprise a ethmoid, maxillary, frontal and/or sphenoid sinusoidal cavi gel temperature modulating agent. ties and other anatomical or physiological structures located (0167. In some embodiments, a formulation described within the sinonasal cavities such as nasal polyps, turbinates, herein comprises at least about 5% and not more than about site of surgical wound or the like. There is considerable ana 20% of a thermosensitive polymer (e.g., polyoxyethylene tomical variation in sinuses amongst individuals. Current polyoxypropylene triblock copolymer) by weight of the com treatment regimens for sinusodial conditions include nasal position. In some embodiments, a formulation described sprays and/or nasal irrigation for topical drug administration herein comprises at least about 10% and not more than about into the paranasal sinuses. However, nasal sprays and/or nasal 20% of a thermosensitive polymer (e.g., polyoxyethylene irrigation are not effective in delivering a solution in the polyoxypropylene triblock copolymer) by weight of the com paranasal sinuses and/or the sinusoidal cavities. Moreover, position. In some embodiments, a formulation described the solutions drain out of the nasal passages. In some other herein comprises at least about 10% and not more than about embodiments, the sustained release formulations described 18% of a thermosensitive polymer (e.g., polyoxyethylene herein are administered in nasal cavities and provide Sus polyoxypropylene triblock copolymer) by weight of the com tained release without attenuation of therapeutic benefit due position. In some embodiments, a formulation described to drainage of formulation via nasal passages. In yet other herein comprises at least about 10% and not more than about embodiments, the sustained release formulations described 16% of a thermosensitive polymer (e.g., polyoxyethylene herein are administered in the nasopharyngeal region. polyoxypropylene triblock copolymer) by weight of the com 0165. In some embodiments, sustained release formula position. In some embodiments, a formulation described tions described herein are administerd in conjunction with a herein comprises at least about 10% and not more than about Surgical procedure, e.g., in combination with tympanostomy, 15% of a thermosensitive polymer (e.g., polyoxyethylene sinonasal polypectomy, balloon rhinoplasty or the like. In polyoxypropylene triblock copolymer) by weight of the com Some embodiments, Sustained release formulations described position. In some embodiments, a formulation described herein are suitable for use with certain devices such as Adva herein comprises at least about 12% and not more than about CoatTM Sinus Dressing and the AdvaCoatTM RX for chronic 14% of a thermosensitive polymer (e.g., polyoxyethylene rhinosinusitis (available from Carbylan BioSurgery, Inc), polyoxypropylene triblock copolymer) by weight of the com catheter-based tools such as the Balloon SinuplastyTM devices position. In some embodiments, a formulation described available from Acclarent, or bioabsorbable drug eluting stents herein comprises at least about 10% and not more than about such as a stent available from Intersect ENT, Inc. 13% of a thermosensitive polymer (e.g., polyoxyethylene 0166 In some embodiments, a formulation described polyoxypropylene triblock copolymer) by weight of the com herein comprises at least about 5.0% and not more than about position. In some embodiments, a formulation described 50% of a thermosensitive polymer (e.g., polyoxyethylene herein comprises at least about 5% and not more than about polyoxypropylene triblock copolymer) by weight of the com 15%, 16%, 17%, 18%, 19% or 20% of a thermosensitive position. In some embodiments, a formulation described polymer (e.g., polyoxyethylene-polyoxypropylene triblock herein comprises at least about 5.0% and not more than about copolymer) by weight of the composition. In some of Such 40% of a thermosensitive polymer (e.g., polyoxyethylene embodiments, the thermosensitive polymer is a purified poly polyoxypropylene triblock copolymer) by weight of the com mer. In other embodiments, the thermosensitive polymer is position. In some embodiments, a formulation described un-purified. In any of the aforementioned embodiments, the herein comprises at least about 10.0% and not more than formulations further comprise a gel temperature modulating about 35% of a thermosensitive polymer (e.g., polyoxyethyl agent. ene-polyoxypropylene triblock copolymer) by weight of the (0168. In some embodiments, a formulation described composition. In some embodiments, a formulation described herein comprises at least about 5.0%, 10.0%, 10.5%, 11.0%, herein comprises at least about 10.0% and not more than 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, about 30% of a thermosensitive polymer (e.g., polyoxyethyl 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, or 18.0% and not more ene-polyoxypropylene triblock copolymer) by weight of the than about 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, composition. In some embodiments, a formulation described 17.5%, 18.0%, 18.5%, 19.0%, 20.0%, 21.0%, 25.0%, 30%, herein comprises at least about 10.0% and not more than 40% or 50% of P407 by weight of the composition. about 25% of a thermosensitive polymer (e.g., polyoxyethyl (0169. In some embodiments, formulations described ene-polyoxypropylene triblock copolymer) by weight of the above have a gelation temperature between about 5° C. and composition. In some embodiments, a formulation described about 42°C. and comprise between about 5% to about 50% of herein comprises at least about 12.0% and not more than a thermosensitive polymer by weight of the composition. In about 25% of a thermosensitive polymer (e.g., polyoxyethyl some embodiments, formulations described above have a ene-polyoxypropylene triblock copolymer) by weight of the gelation temperature between about 14°C. and about 42°C. composition. In some embodiments, a formulation described and comprise between about 5% to about 40% of a ther herein comprises at least about 10% and not more than about mosensitive polymer by weight of the composition. In some 20% of a thermosensitive polymer (e.g., polyoxyethylene embodiments, the about 5% to about 40% of a thermosensi polyoxypropylene triblock copolymer) by weight of the com tive polymer comprises a polyoxyethylene-polyoxypropy US 2012/0277199 A1 Nov. 1, 2012
lene triblock copolymer by weight of the composition. In sal. In some embodiments, a formulation disclosed herein Some embodiments, the thermosensitive polymer (e.g., poly comprises less than about 1 ppm of each of benzethonium oxyethylene-polyoxypropylene triblock copolymer) is puri chloride, benzalkonium chloride, and thiomersal. fied. In some embodiments, the thermosensitive polymer (0173. In some embodiments, the formulations described (e.g., polyoxyethylene-polyoxypropylene triblock copoly herein are free or substantially free of additional tonicity mer) is un-purified (e.g., commercially available P407 NF agents that cause irritation and/or toxicity. Examples of addi from BASF). In some embodiments, the about 5% to about tional tonicity agents include propylene glycol. Thus, in some 40% of a thermosensitive polymer comprises a polyoxyeth embodiments, a formulation described herein is free or sub ylene-polyoxypropylene triblock copolymer and the formu stantially free of propylene glycol. In some embodiments, a lation further comprises a gel temperature modulating agent. formulation disclosed herein comprises less than about 50 By way of example, in certain embodiments, a gel tempera ppm of propylene glycol. In some embodiments, a formula ture modulating agent is selected from, for example, cyclo tion disclosed herein comprises less than about 25 ppm of dextrin, PEG, P188, P338, carboxymethyl cellulose, hyalu propylene glycol. In some embodiments, a formulation dis ronic acid, Carbopol R, chitosan, or the like. closed herein comprises less than about 20 ppm of propylene 0170. In some embodiments of the formulations described glycol. In some embodiments, a formulation disclosed herein above, the formulations comprise purified poloxamer. In comprises less than about 10 ppm of propylene glycol. In Some embodiments, a formulation comprising a purified Some embodiments, a formulation disclosed herein com poloxamer contains a lower poloxamer concentration com prises less than about 5 ppm of propylene glycol. In some pared to a formulation comprising non-purified poloxamer embodiments, a formulation disclosed herein comprises less while retaining the ability to gel at a temperature between than about 1 ppm of propylene glycol. about 14°C. and about 42°C. By way of example, a micron 0.174. In some embodiments, the formulations described ized dexamethasone formulation comprising between about herein are free or substantially free of additional moisture 10% and about 12% of fractionated poloxamer 407 gels at a retention agents. Examples of moisture retention agents temperature between about 14° C. and about 42°C., and a include glycerin. Thus, in some embodiments, a formulation micronized dexamethasone formulation comprising between described herein is free or substantially free of glycerin. In about 14.5% and about 25% of un-purified poloxamer 407 Some embodiments, a formulation disclosed herein com also gels at a temperature between about 14°C. and about 42 prises less than about 50 ppm of glycerin. In some embodi C. Thus use of purified poloxamer allows for use of a lower ments, a formulation disclosed herein comprises less than amount of the thermosensitive polymer while retaining the about 25 ppm of glycerin. In some embodiments, a formula gel temperature and Sustained release properties of the for tion disclosed herein comprises less than about 20 ppm of mulation. glycerin. In some embodiments, a formulation disclosed 0171 Accordingly, also contemplated within the scope of herein comprises less than about 10 ppm of glycerin. In some embodiments described herein are active compositions com embodiments, a formulation disclosed herein comprises less prising primarily a thermosensitive polymer comprising than about 5 ppm of glycerin. In some embodiments, a for polyoxyethylene and polyoxyethylene copolymers as a major mulation disclosed herein comprises less than about 1 ppm of component polymer and a gel temperature modifying agent glycerin. as a minor component polymer Such that the formulation 0.175. The formulations described herein are substantially retains the ability to gel attemperatures between about 14°C. free of degradation products of the active agent and/or the and about 42°C. By way of example, a composition compris polymer components. As used herein, “substantially free of ing about 30% of non-purified P407 by weight of the com degradation products' means less than 5% by weight of the position, and about 3% P188 by weight of the composition active agent and/or the polymer components are degradation gels at about body temperature. products of the active agent and/or the polymer components. 0172. In some embodiments, the formulations described In further embodiments, the term means less than 3% by herein are free or substantially free of additional preservatives weight of the active agent and/or the polymer components are that cause irritation and/or toxicity. Additional preservatives degradation products of the active agent and/or the polymer do not include trace amounts of antioxidants (e.g., Butylated components. In yet further embodiments, the term means less hydroxytoluene (BHT)) that stabilize thermosensitive poly than 2% by weight of the active agent and/or the polymer mers, and which are typically provided commercially with components are degradation products of the active agent and/ thermosensitive polymers. Examples of additional preserva or the polymer components. In further embodiments, the term tives include benzethonium chloride, benzalkonium chloride, means less than 1% by weight of the active agent and/or the and thiomersal. In some embodiments, a formulation dis polymer components are degradation products of the active closed herein comprises less than about 50 ppm of each of agent and/or the polymer components. benzethonium chloride, benzalkonium chloride, and thiomer (0176). In some embodiments, the formulations described sal. In some embodiments, a formulation disclosed herein herein are free or substantially free of additional thickening comprises less than about 25 ppm of each of benzethonium agents. Examples of additional thickening agents include chi chloride, benzalkonium chloride, and thiomersal. In some tosan, or polyethylene glycol (PEG). In some embodiments, a embodiments, a formulation disclosed herein comprises less formulation disclosed herein comprises less than about 5% by than about 20 ppm of each of benzethonium chloride, benza weight of chitosan. In some embodiments, a formulation Ikonium chloride, and thiomersal. In some embodiments, a disclosed herein comprises less than about 4% by weight of formulation disclosed herein comprises less than about 10 chitosan. In some embodiments, a formulation disclosed ppm of each of benzethonium chloride, benzalkonium chlo herein comprises less than about 3% by weight of chitosan. In ride, and thiomersal. In some embodiments, a formulation Some embodiments, a formulation disclosed herein com disclosed herein comprises less than about 5 ppm of each of prises less than about 2% by weight of chitosan. In some benzethonium chloride, benzalkonium chloride, and thiomer embodiments, a formulation disclosed herein comprises less US 2012/0277199 A1 Nov. 1, 2012
than about 1% by weight of chitosan. In some embodiments, closed herein comprises less than about 10 ppm of each of a formulation disclosed herein comprises less than about acetic acid, iodine, merbromin, and chlorhexidene. In some 0.5% by weight of chitosan. embodiments, a formulation disclosed herein comprises less 0177. In some embodiments, the formulations described than about 5 ppm of each of acetic acid, iodine, merbromin, herein are free or substantially free of additional mucoadhe and chlorhexidene. In some embodiments, a formulation dis sives. Examples of additional mucoadhesives include hyalu closed herein comprises less than about 1 ppm of each of ronic acid. In some embodiments, a formulation described acetic acid, iodine, merbromin, and chlorhexidene. herein comprises less than about 5% by weight of hyaluronic 0180 Further, certain preparations (e.g., preparations for acid. In some embodiments, a formulation disclosed herein inner ear administration, intrathecal administration) require comprises less than about 4% by weight of hyaluronic acid. In particularly low concentrations of several potentially-com Some embodiments, a formulation disclosed herein com mon contaminants that are known to be toxic. Other dosage prises less than about 3% by weight of hyaluronic acid. In forms, while seeking to limit the contamination attributable to Some embodiments, a formulation disclosed herein com these compounds, do not require the stringent precautions prises less than about 2% by weight of hyaluronic acid. In that Such preparations require. For example, in Some embodi Some embodiments, a formulation disclosed herein com ments, the formulations described herein are free or substan prises less than about 1% by weight of hyaluronic acid. In tially free of contaminants such as arsenic, lead, mercury, and Some embodiments, a formulation disclosed herein com tin. Thus, in some embodiments, a formulation disclosed prises less than about 0.5% by weight of hyaluronic acid. herein is free or Substantially free of arsenic, lead, mercury, 0178. In some embodiments, the formulations described and tin. In some embodiments, a formulation disclosed herein herein are free or substantially free of additional common comprises less than about 50 ppm of each of arsenic, lead, Solvents that cause irritation and/or toxicity. Examples of mercury, and tin. In some embodiments, a formulation dis additional Solvents include ethanol, propylene glycol, closed herein comprises less than about 25 ppm of each of DMSO, N-Methyl-2-pyrrolidone, and cyclohexane. Thus, in arsenic, lead, mercury, and tin. In some embodiments, a for some embodiments, a formulation described herein is free or mulation disclosed herein comprises less than about 20 ppm substantially free of ethanol, propylene glycol, DMSO, of each of arsenic, lead, mercury, and tin. In some embodi N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi ments, a formulation disclosed herein comprises less than ments, a formulation disclosed herein comprises less than about 10 ppm of each of arsenic, lead, mercury, and tin. In about 50 ppm of each of ethanol, propylene glycol, DMSO, Some embodiments, a formulation disclosed herein com N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi prises less than about 5 ppm of each of arsenic, lead, mercury, ments, a formulation disclosed herein comprises less than and tin. In some embodiments, a formulation disclosed herein about 25 ppm of each of ethanol, propylene glycol, DMSO, comprises less than about 1 ppm of each of arsenic, lead, N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi mercury, and tin. ments, a formulation disclosed herein comprises less than about 20 ppm of each of ethanol, propylene glycol, DMSO, CERTAIN DEFINITIONS N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi 0181 “Thermosensitive polymers' or “thermosetting ments, a formulation disclosed herein comprises less than polymers' are polymers that undergo a reversible tempera about 10 ppm of each of ethanol, propylene glycol, DMSO, ture-dependent phase transtion (e.g., a liquid to gel transition, N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi a gel to liquid transition, or the like). Example of thermosen ments, a formulation disclosed herein comprises less than sitive polymers that form thermosensitive gels include and are about 5 ppm of each of ethanol, propylene glycol, DMSO, not limited to poloxamers (e.g., Pluronics F68(R), F88(R), and N-Methyl-2-pyrrolidone, and cyclohexane. In some embodi F108(R), F127(R), or the like) or any other thermosetting poly ments, a formulation disclosed herein comprises less than mer described herein. about 1 ppm of each of ethanol, propylene glycol, DMSO, 0182. As used herein, a “purified thermosensitive poly N-Methyl-2-pyrrolidone, and cyclohexane. mer is a commercially purchased thermosensitive polymer 0179. In some embodiments, the formulations described that is subjected to further steps prior to preparation of for herein are free or substantially free of additional antiseptics mulations described herein. A purified thermosensitive poly that are commonly used to disinfect any component of an mer has lower polydispersity (i.e., a narrower distribution of active preparation and that are potentially toxic. Examples of molecular weights amongst the individual polymer chains additional antiseptics that are known to be toxic include acetic therein) and/or lower ethylene content and/or less unsatura acid, iodine and merbromin. Additionally, chlorhexidene, a tion and/or weight% oxyethylene values compared to a com commonly used antiseptic, that is used to disinfect compo mercially available sample of the same polymer. Purification nents of an active preparation (including devices used to is carried out using any Suitable technique including and not administer the preparation) is highly toxic in minute concen limited to fractionation, chromatography, washing and/or trations (e.g., 0.05%). Thus, in some embodiments, a formu decantation, purification using Supercritical fluid (See, for lation disclosed herein is free or substantially free of acetic example, U.S. Patent Appl. Pub. No. 2008/02694.49, disclo acid, iodine, merbromin, and chlorhexidene. In some sure of purification of polymers by use of supercritical fluid embodiments, a formulation disclosed herein comprises less described therein is incorporated herein by reference), than about 50 ppm of each of acetic acid, iodine, merbromin, reverse precipitation (See, for example, U.S. Pat. No. 7,148, and chlorhexidene. In some embodiments, a formulation dis 320, disclosure of reverse precipitation described therein is closed herein comprises less than about 25 ppm of each of incorporated herein by reference), Salt extraction and liquid acetic acid, iodine, merbromin, and chlorhexidene. In some phase separation (See for example, U.S. Pat. No. 5,800,711, embodiments, a formulation disclosed herein comprises less disclosure of poloxamer purification described therein is than about 20 ppm of each of acetic acid, iodine, merbromin, incorporated herein by reference), or the like. Other processes and chlorhexidene. In some embodiments, a formulation dis for purification and/or fractionation of polymers are US 2012/0277199 A1 Nov. 1, 2012
described in, for example, U.S. Pat. No. 6,977.045 and U.S. expected to relieve to some extent one or more of the Symp Pat. No. 6,761,824 which processes described therein are toms of the disease or condition being treated. For example, incorporated herein by reference the result of administration of an active agent disclosed herein 0183 By way of example, in some embodiments, purified is reduction and/or alleviation of the signs, symptoms, or poloxamer 407 is fractionated P407 having a lower polydis causes of tinnitus or balance disorders. For example, an persity index compared to a commercially purchased batch of “effective amount” for therapeutic uses is the amount of P407 grade NF from BASF. By way of example, the commer active agent, including a formulation as disclosed herein cially purchased P407 has a polydispersity index of about 1.2. required to provide a decrease or amelioration in disease In some embodiments, the polydispersity index of fraction symptoms without undue adverse side effects. The term ated P407 as described herein is between about 1 and about “therapeutically effective amount' includes, for example, a 1.15. In other embodiments, the polydispersity index of frac prophylactically effective amount. An “effective amount of tionated P407 as described herein is between about 1 and an active agent disclosed herein is an amount effective to about 1.1. In yet other embodiments, the polydispersity index achieve a desired pharmacologic effect or therapeutic of fractionated P407 as described herein is between about 1 improvement without undue adverse side effects. It is under and about 1.05. As used herein, the calculated polydispersity stood that “an effective amount’ or “a therapeutically effec index (PDI) is the weight average molecular weight divided tive amount varies, in some embodiments, from Subject to by the number average molecular weight of polymeric chains Subject, due to variation in metabolism of the compound (M/M). It indicates the distribution of individual molecular administered, age, weight, general condition of the Subject, masses in a batch of polymers. the condition being treated, the severity of the condition being 0184. A “syringable viscosity' is a viscosity that is low treated, and the judgment of the prescribing physician. It is enough Such that a pharmaceutical formulation described also understood that “an effective amount” in an extended herein is a liquid that is capable of being administered (e.g., release dosing format may differ from “an effective amount Syringed) via a narrow gauge needle or cannula or catheter in an immediate release dosign format based upon pharma using normal finger pressure (e.g., by a physician using nor cokinetic and pharmacodynamic considerations. malfingerpressure on the plunger of the Syringe. Such that the 0187. As used herein, the term “active agent” refers to needle of the Syringe can accurately and stably deliver the active agents that treat, or reduce orameliorate severity of any pharmaceutical formulation at the targeted site (e.g., round active disorder described herein. Suitable “active agents' window membrane of inner ear, sinonasal cavities or the like). may be antimicrobial agents (e.g., antibacterial agents (effec Thus in some embodiments, formulations described herein tive against bacteria), antiviral agents (effective against are dispensed through a 18-31 gauge needle or cannula or viruses), antifungal agents (effective against fungi), antipro catheter. In some embodiments, formulations described toZoal (effective against protozoa), and/orantiparasitic to any herein are dispensed through a 20-26 gauge needle or cannula class of microbial parasites), corticosteroids, or any other or catheter. In some embodiments, formulations described active agent described herein. “Active agents’ may work by herein are dispensed through a 25-31 gauge needle or cannula any Suitable mechanism, non-limiting examples of which or catheter. In some embodiments, formulations described include by being anti-inflammatory, antimicrobial, toxic, herein are dispensed through a 27-31 gauge needle or cannula cytostatic, immunomodulatory agents, ion channgel modula or catheter. In some embodiments, formulations described tors, anti-angiogenic agents and the like. herein are syringable through a 27 gauge needle or cannula or 0188 The mean residence time (MRT) is the average time catheter. In some embodiments, formulations described that molecules of an active agent reside in an active structure herein are syringable through a 29 gauge needle or cannula or after administration of a dose. catheter. In some embodiments, formulations described 0189 A "prodrug” refers to an active agent that is con herein are syringable through a 31 gauge needle or cannula or Verted into the parent drug in vivo. In certain embodiments, a catheter. prodrug is enzymatically metabolized by one or more steps or 0185. A “gelation temperature modifying agent” or a “gel processes to the biologically, pharmaceutically or therapeu temperature modifying agent' is an additive added to any tically active form of the compound. To produce a prodrug, a formulation described herein, and changes the gelation tem pharmaceutically active compound is modified Such that the perature of the formulation such that the gel temperature of active compound will be regenerated upon in vivo adminis the formulation is maintained, in some embodiments, tration. In one embodiment, the prodrug is designed to alter between about 5° C. and about 42°C. In some other embodi the metabolic stability or the transport characteristics of a ments, a gel temperature modifying agent changes the gela drug, to mask side effects or toxicity, or to alter other charac tion temperature of the formulation Such that the gel tempera teristics or properties of a drug. Compounds provided herein, ture of the formulation is maintained, in Some embodiments, in some embodiments, are derivatized into Suitable prodrugs. between about 14°C. and about 42°C. In some embodiments, 0190. Other objects, features, and advantages of the meth a gel temperature modifying agent increases the gelation ods and compositions described herein will become apparent temperature of the formulation compared to the gelation tem from the following detailed description. It should be under perature in the absence of the gel temperature modifying stood, however, that the detailed description and the specific agent. In some embodiments, a gel temperature modifying examples, while indicating specific embodiments, are given agent decreases the gelation temperature of the formulation by way of illustration only. compared to the gelation temperature in the absence of the gel temperature modifying agent. Active Agents 0186. The terms “effective amount” or “therapeutically effective amount, as used herein, refer to a sufficient amount 0191 Provided herein are active agent compositions and of the active agent or active agent (e.g., an active agent, an formulations that are suitable for localized administration and anti-inflammatory agent) being administered that would be provide Sustained release of an active agent at the target site. US 2012/0277199 A1 Nov. 1, 2012
0.192 Antimicrobial Agents Examples of quinolones include and are not limited to cipro 0193 In some embodiments, the active agent suitable for floxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, use in the formulations and methods disclosed herein is an moxifloxacin, nonfloxacin, ofloxacin, trovafloxacin, grepa antimicrobial agent including an antibacterial agent, an anti floxacin, sparfloxacin, AL-15469A, AL-38905 or the like. In fungal agent, an antiviral agent, an antiprotozoal agent, and/ Some embodiments, the antibiotic is a Sulfonamide. or an antiparasitic agent. In some embodiments, the antimi Examples of suflonamides include and are not limited to crobial agent is a protein, a peptide, an antibody, DNA, an afenide, prontosil, Sulfacetamide, Sulfamethiazole, Sulfanil siRNA, a carbohydrate, an inorganic molecule, oran organic imide, Sulfasalazine, Sulfisoxazole, trimethoprim, cotrimox molecule. In certain embodiments, the active agents are anti azole or the like. In some embodiments, the antibiotic is a microbial Small molecules. tetracycline antibiotic. Examples of tetracyclines include and 0194 Antibacterial Agents are not limited to demeclocycline, doxycycline, minocycline, 0.195. In some embodiments, the active agent is an anti oxytetracycline, tetraycline or the like. In some embodi bacterial agent. In some embodiments, the antibacterial agent ments, the antibiotic is an oxazolidinone antibiotic. Examples treats infections caused by gram positive bacteria. In some of oxazolidinone antibiotics include and are not limited to embodiments, the antibacterial agent treats infections caused linezolid or the like. In some embodiments, the antibiotic is by gram negative bacteria. In some embodiments, the anti arsogebanubem chloramphenicol, clindamycin, lincomycin, bacterial agent treats infections caused by mycobacteria. In ethambutol, fosfomycin, fusidic acid, furazolidone, iso Some embodiments, the antibacterial agent treats infections niazid, lineZolid, metronidazole, mupirocin, nitrofurantoin, caused by giardia. platensimycin, pyrazinamide, quinupristin, dalfopristin, 0196. In some embodiments, the antibacterial agent treats infections by inhibiting bacterial protein synthesis. In some rifampicin, thamphenicol, timidazole or the like. embodiments, the antibacterial agent treats infections by dis 0.198. In some embodiments, an antibiotic compatible rupting synthesis of bacterial cell wall. In some embodi with the compositions described herein is a broad spectrum ments, the antibacterial agent treats infections by changing antibiotic. In some embodiments, an antibiotic compatible permeability of bacterial cell membranes. In some embodi with the compositions described herein is effective in treating ments, the antibacterial agent treats infections by disrupting infections that are resistant to other classes of antibiotics. For DNA replication in bacteria. example, in Some instances, Vancomycin is effective in treat 0197) In some embodiments, the antibacterial agent is an ing infections caused by methicillin resistant staphyloccocus antibiotic. In some embodiments, the antibiotic is an ami aureus bacteria. noglycoside. Examples of aminoglycoside antibiotics 0199. In some embodiments, an active antibacterial agent include and are not limited to amikacin, gentamicin, kanamy is a peptide or a lantibiotic including, by way of non-limiting cin, neomycin, netilmicin, Streptomycin, tobramycin, paro example, Maximin H5, Dermcidin, Cecropins, andropin, mycin or the like. In some embodiments, the antibiotic is an moricin, ceratotoxin, melittin, Magainin, dermaseptin, bom ansamycin. Examples of ansamycins include and are not limited to geldanamycin, herbimycin or the like. In some binin, brevinin-1, esculentins and buforin II, CAP 18, LL37, embodiments, the antibiotic is a carbacephem. Examples of abaecin, apidaecins, prophenin, indolicidin, brevinins, prote carbecephems include and are not limited to loracarbefor the grin, tachyplesins, defensins, drosomycin, alamethicin, pexi like. In some embodiments, the antibiotic is a carbapenem. ganan or MSI-78, and other MSI peptides like MSI-843 and Examples of carbapenems include and are not limited to MSI-594, polyphemusin, Class III and III bacterocins like: ertapenem, doripenem, imipenem (cilostatin), meropenem or colicin, pyocin, klebicin, Subtilin, epidermin, herbicolacin, the like. In some embodiments, the antibiotic is a cepha brevicin, halocin, agrocin, alveicin, carnocin, curvaticin, losporin (including, for example, first, second, third, fourth or divercin, enterocin, enterolysin, erwiniocin, glycinecin, lac fifth generation cephalosporins). Examples of cephalosporins tococin, lacticin, leucoccin, mesentericin, pediocin, plantari include and are not limited to cefaclor, cefamandole, cefo cin, Sakacin, Sulfolobicin, vibriocin, warnerinand, nisin or the toxin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, like. In some embodiments, the antibiotic is a polypeptide or cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriax peptide. Examples of polypeptide antibiotics include and are one, cefepime, ceftobirprole or the like. In some embodi not limited to bacitracin, colistin, polymyxin B or the like. ments, the antibiotic is a glycopeptide. Examples of glyco Examples of peptide antibacterial agents include and are not peptides include and are not limited to Vancomycin or the like. limited to OP-145 (Octoplus). In some embodiments, the antibiotic is a macrollide antibiotic. 0200. In specific embodiments, an antibiotic used in for Examples of macrollides include and are not limited to azithromycin, clarithromycin, dirithromycin, erythromycin, mulations described herein is ciprofloxacin (Cipro(R). In spe roXithromycin, troleandomycin, tellithromycin, spectinomy cific embodiments, an antibiotic used in formulations cin, or the like. In some embodiments, the antibiotic is a described herein is amoxicillin. In specific embodiments, an monobactam. Examples of monobactams include and are not antibiotic used informulations described herein is, amoxicil limited to aztreonam or the like. In some embodiments, the lin+clavulanic acid (Augmenting). In specific embodiments, antibiotic is a beta-lactamase inhibitor and/or penicillin. an antibiotic used in formulations described herein is moxi Examples of beta-lactamase inhibitors include clavulanic floxacin. acid and/or pencillins and/or beta-lactams. Examples of peni 0201 Localized administration of antibiotic compositions cillins include and are not limited to amoxicillin, amplicillin, reduces the risk of development of resistance to antibiotics azociling, carbenicillin, cloxacillin, dicloxacillin, fluclox compared to the risk for development of antibiotic resistance acillin, mezlocillin, meticillin, nafcillin, oxacillin, peperacil when an antibiotic is administered systemically. The compo lin, ticarcillin, amoXcillin+clavulanic acid (Augmenting), or sitions described herein are effective for recurring active dis the like. In some embodiments, the antibiotic is a quinolone. eases or conditions including, for example, recurring ear US 2012/0277199 A1 Nov. 1, 2012
infections in children without the need for changing treatment lone. In another embodiment the active pharmaceutical ingre regimens (e.g., in response to development of antibiotic resis dient of the formulation described herein is dexamethasone. tance). In an additional embodiment, the active pharmaceutical ingredient of the formulation described herein is beclometha Antiviral Agents Sone. In an additional embodiment, the active pharmaceutical 0202 In some embodiments, the active agent is an antivi ingredient of the formulation described herein is triamcino ral agent. In some embodiments, the antiviral agents include lone. In a further embodiment, the active pharmaceutical but are not limited to acyclovir, famciclovir and valacyclovir. ingredient of the formulation described herein is selected Other antiviral agents include abacavir, aciclovir, adfovir, from 21-acetoxypregnenolone, alclometaSone, algestone, amantadine, amprenavir, arbidol, atazanavir, artipla, brivu amcinonide, beclomethasone, betamethasone, budesonide, dine, cidofovir, combivir, edoxudine, efavirenz, emtricitab chloroprednisone, clobetasol, clobetasone, clocortolone, clo ine, enfuVirtide, entecavir, fomvirsen, foSamprenavir, foscar prednol, corticosterone, cortisone, cortivaZol, deflazacort, net, foSfonet, ganciclovir, gardasil, ibacitabine, immunovir, desonide, desoximetaSone, dexamethasone, diflorasone, idoxuridine, imiquimod, indinavir, inosine, integrase inhibi diflucortolone, difluprednate, enoxolone, fluazacort, fluclo tors, interferons, including interferon type III, interferon type ronide, flumethasone, flunisolide, fluocinolone acetonide, II, interferon type I, lamivudine, lopinavir, loviride, fluocinonide, fluocortin butyl, fluocortolone, fluo MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, rometholone, fluperolone acetate, fluprednidene acetate, flu nexavir, nucleoside analogues, oseltamivir, penciclovir, per prednisolone, flurandrenolide, fluticaSone propionate, for amivir, pleconaril, podophyllotoxin, protease inhibitors, mocortal, halcinonide, halobetasol propionate, reverse transcriptase inhibitors, ribavirin, rimantadine, halometaSone, halopredone acetate, hydrocortamate, hydro ritonavir, saquinavir, stavudine, tenofovir, tenofovir diso cortisone, loteprednol etabonate, maZipredone, medrysone, proxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, meprednisone, methylprednisolone, mometaSone furoate, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitab paramethasone, prednicarbate, prednisolone, prednisolone ine, Zanamivir, Zidovudine, and combinations thereof. 25-diethylamino-acetate, prednisolone sodium phosphate, Antifungal Agents prednisone, prednival, prednylidene, rimexolone, tiXocortol, triamcinolone, triamcinolone acetonide, triamcinolone bene 0203. In some embodiments, the active agent is an anti tonide, triamcinolone hexacetonide, or combinations thereof. fungal agent. In some embodiments, the antifungal agents 0209 Anti-inflammatory agents that are not disclosed include but are not limited to ammolfine, utenafine, naftifine, herein but which are useful in sustained release formulations terbinafine, flucytosine, fluconazole, itraconazole, ketocona described herein are expressly included and intended within Zole, posaconazole, ravuconazole, Voriconazole, clotrima the scope of the embodiments presented. Zole, econazole, miconazole, oxiconazole, Sulconazole, ter conazole, tioconazole, nikkomycin Z, caspofungin, 0210 Bisphosphonates micafungin, anidulafungin, amphotericin B, liposomal nys 0211. In some embodiments, bisphosphonates are used in tastin, pimaricin, griseofulvin, ciclopiroX olamine, halopro the formulations disclosed herein, including for the treatment gin, tolnaftate, undecylenate, clioquinol, and combinations of otosclerosis. Bisphosphonates are contemplated as modu thereof. lators of bone remodeling in the active capsule (e.g., in the 0204 Antiparasitic agents include amitraz, amoscanate, treatment of otosclerosis). Examples of bisphosphonates avermectin, carbadox, diethylcarbamizine, dimetridazole, include and are not limited to etidronate (DIDRONELR): diminaZene, ivermectin, macrofilaricide, malathion, mitaban, clodronate (BONEFOS(R); tiludronate (SKELID(R); pamidr oxamniquine, permethrin, praziquantel, prantel pamoate, sel onate (APD, AREDIAR); neridronate; olpadronate; alendr amectin, sodium Stibogluconate, thiabendazole, and combi onate (FOSFAMAX(R): ibandronate (BONIVAR); risedr nations thereof. onate (ACTONEL(R); Zoledronate (ZOMETAR), or the like. 0205 Antimicrobial agents also include antibacterial, In certain embodiments, a bisphosphonate is Zoledronatae or antiviral, antifungal, antiprotozoal and/or anti-parasitic risedronatae. agents described in U.S. application Ser. Nos. 12/427,663, 0212 Relative potency of bisphosphonates is shown in 12/466,310, 12/472,034, 12/486,697, 12/493,611, 12/494, Table A below: 156, 12/500,486, 12/504,553, 12/506,091, 12/506,127, 12/506,573, 12/506,616, and 12/506,664, the disclosure of TABLE A antimicrobial agents described therein is incorporated herein by reference. Antimicrobial agents that are not disclosed Bisphosphonate Relative Potency to Etidronate herein but which are useful in sustained release formulations Pamidronate (APD, Aredia) 100 Neridironate 100 described herein are expressly included and intended within Olpadronate 500 the scope of the embodiments presented. Alendronate (Fosamax) 500 0206 Anti-Inflammatory Agents Ibandronate (Boniva) 1OOO 0207 Corticosteroids (including agents that act at gluco Risedronate (Actonel) 2OOO corticoid receptors) or other anti-inflammatory Steroids are Zoledronate (Zometa, Aclasta) 1OOOO compatible with the formulations disclosed herein. One advantage of the use of a formulation described herein is the 0213 Bisphosphonates and/or other bone-remodeling greatly reduced systemic exposure to anti-inflammatory glu agents that are not disclosed herein but which are useful in cocorticoid steroids. Sustained release formulations described herein are expressly 0208. In one embodiment is the active pharmaceutical included and intended within the scope of the embodiments ingredient of the formulation described herein is predniso presented. US 2012/0277199 A1 Nov. 1, 2012
Immunomodulating Agents BN-50730 (tetrahedra-4,7,8,10 methyl-1 (chloro-1 phenyl)- 6(methoxy-4 phenyl-carbamoyl)-9 pyrido4',3'-4,5thieno3, TNF-C. Modulators 2-f triazolo-1.2.4 4.3-adiazepine-1,4), BN 50739, 0214 Contemplated for use with the formulations dis SM-12502, RP-55778, Ro 24-4736, SR27417A, CV-6209, closed herein are active agents which reduce or ameliorate WEB 2086, WEB 2170, 14-deoxyandrographolide, CL symptoms or effects as a result of an autoimmune disease 184005, CV-3988, TCV-309, PMS-601, TCV-309 or the like. and/or inflammatory disorder. Accordingly, Some embodi ments of the methods and compositions described herein Toll Like Receptor Inhibitors incorporate the use of agents which block the effects of TNF 0219. Examples of toll like receptor inhibitors include and C., including anti-TNF agents for treatment of sinonasal and/ are not limited to E5531 ((6-O-2-deoxy-6-O-methyl-4-O- or otic conditions associated with autoimmune disease and/or phosphono-3-O-(R)-3-Z-dodec-5-endoyloxydecl-2-3- inflammation. By way of example only, anti-TNF agents OXO-tetradecanoylamino-B-O-phosphono-C-D-glucopyra include protein-based therapeutics, such as etanercept (EN nose tetrasodium salt); E5564 (C.-D-Glucopyranose.3-O- BREL(R), infliximab (REMICADE(R), adalimumab (HU decyl-2-deoxy-6-O-2-deoxy-3-O-(3R)-3- MIRAR) and golimumab (CNTO 148), and small molecule methoxydecyl-6-O-methyl-2-(11Z)-1-oxo-11 therapeutics, such as TACE inhibitors, IKK inhibitors or cal octadecenylamino-4-O-phosphono-B-D-glucopyranosyl cineurin inhibitors or combinations thereof. Calcineurin 2-(1,3-dioxotetradecyl)amino-1-(dihydrogen phosphate), inhibitors are a group of structurally diverse Small molecule tetrasodium salt); compound 4a (hydrocinnamoyl-L-Valyl immunomodulators which function through the inhibition of pyrrolidine; see PNAS, Jun. 24, 2003, vol. 100, no. 13, 7971 calcineurin function. Examples of calcineurin modulators 7976 which is herein incorporated by reference for disclo include tacrolimus, pimecrolimus, cyclosporine or the like. sures related to compound 4a); CPG 52364 (Coley Pharma IKK inhibitors are yet another structurally diverse group of ceutical Group); LY294.002 (2-(4-Morpholinyl)-8-phenyl Small molecule immunomodulators, examples of which 4H-1-benzopyran-4-one); PD98059 (2-(2-amino-3- include and are not limited to PC-839, PS-1145, BMS methoxyphenyl)-4H-1-Benzopyran-4-one); chloroquine or 345541, SC-514 or the like. the like. 0215. Other immunomodulator agents suitable for use in the methods and compositions described herein include and Progesterone Receptor Modulators are not limited to: 0220 Examples progesterone receptor modulators TACE Inhibitors: include and are not limited to RU-486 (11b, 17 b)-11-4- (Dimethylamino)phenyl-17-hydroxy-17-(1-propyn y1)-es 0216 Examples of TACE inhibitors include and are not tra-4,9-dien-3-one); CDB-2914 (17O-acetoxy-11 B-4-N,N- limited to Nitroarginine analog A, GW3333, TMI-1, BMS dimethylaminophenyl-19-norpregna-4,9-diene-3,20 561392, DPC-3333, TMI-2, BMS-566394, TMI-005, aprat dione); CDB-4124 (17O-acetoxy-21-methoxy-113-4-N,N- astat, GW4459, W-3646, IK-682, GI-5402, GI-2454.02, dimethylaminophenyl-19-norpregna-4,9-diene-3,20 BB-2983, DPC-A38088, DPH-067517, R-618, CH-138 or dione); CDB-4453 (17O-acetoxy-21-methoxy-11 B-4-N- the like. methylaminophenyl-19-norpregna-4.9-diene-3,20-dione); RTI3021-022 (Research Triangle Institute); ZK 230211 (11 Interleukin Inhibitors (4-acetylphenyl)-17-hydroxy-17-(1,1,2,2,2-pentafluoroet 0217 Examples of Interleukin inhibitors include and are hyl)estra-4,9-dien-3-one); ORG 31710 (11-(4-dimethylami not limited to WS-4 (an antibody against IL-8), SB 265610 nophenyl)-6-methyl-4,5-dihydro(estra-4,9-diene-17,2'- (N-(2-Bromophenyl)-N'-(7-cyano-1H-benzotriazol-4-yl) (3H)-furan)-3-one): ORG33628 (Organon); onapristone (ZK urea); SB 225002 (N-(2-Bromophenyl)-N'-(2-hydroxy-4-ni 98299); asoprisnil; ulipristal; a anti-progesterone antibody; trophenyl)urea); SB203580 (4-(4-Fluorophenyl)-2-(4-meth an anti-progesterone receptor antibody or the like. ylsulfinyl phenyl)-5-(4-pyridyl) 1H-imidazole); SB272844 (GlaxoSmithKline); SB517785 (GlaxoSmithKline); Prostaglandins SB656933 (GlaxoSmithKline); Sch527123 (2-hydroxy-N, 0221 Examples of prostaglandins and/or analogs thereof N-dimethyl-3-2-((R)-1-(5-methyl-furan-2-yl)-propyl include and are not limited to naturally occurring prostaglan aminol-3,4-dioxo-cyclobut-1-enylamino-benzamide); dins, Prostaglandin analogues. Such as latanoprost, tra PD98059(2-(2-amino-3-methoxyphenyl)-4H-1-Benzopy voprost, unoprostone, minprostin F2 alpha and bimtoprost, ran-4-one); reparixin: N-4-chloro-2-hydroxy-3-(piperazine SQ29548, JB004/A or the like. 1-sulfonyl)phenyl)-N'-(2-chloro-3-fluorophenyl)urea p-tolu enesulfonate, basiliximab; cyclosporin A; SDZ RAD (40-O- Adenosine Receptor Modulators (2-hydroxyethyl)-rapamycin); FR235222 (Astellas Pharma); 0222 Examples of adenosine receptor modulators include daclizumab; anakinra. AF12198 (Ac-Phe-Glu-Trp-Thr-Pro and are not limited to ATL313 (4-(3-(6-amino-9-(5-cyclopro Gly-Trp-Tyr-Gln-L-azetidine-2-carbonyl-Tyr-Ala-Leu-Pro pylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-pu Leu-NH2) or the like. rin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester); GW328267X ((2R,3R,4S.5R)-2-6-amino-2-(1-ben Platelet Activating Factor Antagonists Zyl-2-hydroxyethyl)amino-9H-purin-9-yl)-5-(2-ethyl-2H 0218. Examples of platelet activating factor antagonists tetrazol-5-yl)tetrahydrofuran-3,4-diol); CGS 21680 hydro include and are not limited to kadsurenone, phomactin G, chloride (4-2-6-Amino-9-(N-ethyl-b-D- ginsenosides, apafant (4-(2-chlorophenyl)-9-methyl-23 (4- ribofuranuronamidosyl)-9H-purin-2-yl)aminoethyl morpholinyl)-3-propanol-1-yl6H-thieno3.2-f 1.2.4 tria benzenepropanoic acid hydrochloride); CV 1808 Zolo4.3-11.4 diazepine), A-85783, BN-52063, BN-52021, (2-Phenylaminoadenosine); p-DITC-APEC (2-4-2-[2-(4- US 2012/0277199 A1 Nov. 1, 2012
Isothiocyanatophenyl)thiocarbonylaminoethylaminocarbo mercaptopurine, mitomycin, mitotane, mitoxantrone, nelara nylethylphenethylamino-5'-N-ethylcarboxamidadenos bine, nilotinib, oblimersen, oxaliplatin, PAC-1, paclitaxel, ine); SDZ WAG994 (N-Cyclohexyl-2'-O-methyladenosine); pemetrexed, pentostatin, pipobroman, pixantrone, plicamy CVT-3146 (regadenoson: 1-(9-(3,4-dihydroxy-5-(hy cin, procarbazine, proteasome inhibitors (e.g., bortezomib), droxymethyl)oxolan-2-yl)-6-aminopurin-2-yl)pyrazol-4- raltitrexed, rebeccamycin, Revlimid(R), rubitecan, SN-38, yl)-N-methylcarboxamide); ATL-146e (4-3-6-Amino-9- salinosporamide A, satraplatin, streptozotocin, Swainsonine, (5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)- tariquidar, taxane, tegafur-uracil, temozolomide, testolac 9H-purin-2-yl)-prop-2-ynyl)-cyclohexanecarboxylic acid tone, thioTEPA, tioguanine, topotecan, trabectedin, tretinoin, methyl ester); 5'-n-Ethyl-carboxamidoadenosine; tecadeno triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, son; CVT-510 (N-(3(R)-tetrahydrofuranyl)-6-aminopurine uracil mustard, valrubicin, vinblastine, Vincristine, Vinorel riboside); CCPA (2-Chloro-N-6-cyclopentyladenosine); bine, Vorinostat, ZoSuquidar. or the like. CPA (N-6-Cyclopentyladenosine); GR79236 (N-(1S,2S)-2- 0226. Other cytotoxic agents are described in, for Hydroxycyclopentyl)adenosine); 2'-MeCCPA; PD 81723 example, U.S. application Ser. No. 12/493,611, which agents ((2-Amino-4,5-dimethyl-3-thienyl)-3-(trifluoromethyl) are incorporated herein by reference. phenyl)methanone); PSB 36 (1-Butyl-8-(hexahydro-2,5- methanopentalen-3a(1H)-yl)-3,7-dihydro-3-(3-hydroxypro Estrogen Receptors Modulators pyl)-1H-purine-2,6-dione); ribavirin; CHA (N6 cyclohexyladenosine); GW493.838 (GSK): (-)-N-6-(2- 0227 Contemplated for use with the formulations dis phenylisopropyl)adenosine; GW684067 (2R,3R,4S.5R)-5- closed herein are active agents which modulate estrogen ethynyl-2-6-tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- receptors. Accordingly, Some embodiments of the methods yltetrahydrofuran-3,4-diol); CVT-3619 (2-(6-((2- and compositions described herein incorporate the use of hydroxycyclopentyl)amino)purin-9-yl)-5-((2- estrogen receptor modulators for treatment of sinonasal and/ fluorophenylthio)methyl)oxolane-3,4-diol): 2-Cl-IB-MECA or otic conditions including and not limited to polyps and/or (CF102; 2-chloro-N'-(3-iodobenzyl)-5'-N-methylcarbam cancers in the sinonasal and/or otic structures. Examples of oyladenosine); HEMADO; IB-MECA (CF101; N'-(3-iodo estrogen receptor modulators include and are not limited to, benzyl)-5'-N-methylcarbamoyladenosine); CP-532903 (N- PPT (4,4',4'-(4-Propyl-1H-pyrazole-1,3,5-triyl)trisphe (2,5-Dichlorobenzyl)-3'-aminoadenosine-5'-N- nol); SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl methylcarboxamide); CF502 (Can-Fite BioPharma); LJ-529 2,3,4,5-tetrahydro-1H-3-benzazepine); estrogen; estradiol; (2-chloro-N(6)–(3-iodobenzyl)-5'-N-methylcarbamoyl-4- estradiol derivatives, including but not limited to 17-13 estra thioadenosine); BAA (8-butylaminoadenosine); 6-Amino-2- diol, estrone, estriol, synthetic estrogen compositions or com chloropurine riboside: 2-Chloroadenosine; NECA (5'-N-eth binations thereof. In some embodiments, the ERB agonist is ylcarboxamidoadenosine); APNEA (N6-2-(4-aminophenyl) ERB-131, phytoestrogen, MK 101 (bioNovo); VG-1010 (bioNovo); DPN (diarylpropiolitrile); ERB-041: WAY ethyladenosine); or the like. 202196; WAY-214156; genistein; estrogen; estradiol or the 0223 Other immunomodulating agents are described in, like. for example, U.S. application Ser. Nos. 12/472,034 and 12/427,663, which agents are incorporated herein by refer Growth Factors ence and are contemplated as being within the scope of embodiments presented herein. 0228 Contemplated for use with the formulations dis Cytotoxic Agents and/or Chemotherapeutic Agents closed herein are agents which modulate epithelial cell growth. Accordingly, Some embodiments of the methods and 0224 Contemplated for use with the formulations dis compositions described herein incorporate the use of growth closed herein are active agents which reduce or ameliorate factors and/or modulators of growth factors for treatment of symptoms or effects as a result of a cell proliferation disorder. sinonasal and/or otic conditions associated with aberrant Accordingly, some embodiments of the methods and compo growth in otic, sinonasal and/or nasopharyngeal regions. sitions described herein incorporate the use of cytotoxic Examples of growth factors contemplated for incorporation agents for treatment of sinonasal and/or otic conditions in compositions described herein include, for example, fibro including and not limited to cancers. blast growth factor (FGF), insulin-like growth factor (IGF), 0225. Examples of cytotoxic agents include and are not epidermal growth factor (EGF), a platlet-derived growth fac limited to methotrexate (RHEUMATREX(R), Amethopterin) tor (PGF), agonists of epidermal growth factor (EGF) recep cyclophosphamide (CYTOXANR), thalidomide (THALI tor, hepatocyte growth factor (HGF). Transforming growth DOMID(R), acridine carboxamide, Actimid(R), actinomycin, 17-N-allylamino-17-demethoxygeldanamycin, aminopterin, factor alpha (TGF-C.), Transforming growth factor beta amsacrine, anthracycline, antineoplastic, antineoplaston, (TGF-3), modulators of Vascular endothelial growth factor 5-azacytidine, azathioprine, BL22, bendamustine, biricodar, (VEGF), neutorophic factors or the like. bleomycin, bortezomib. bryostatin, buSulfan, calyculin, camptothecin, capecitabine, carboplatin, chlorambucil, cispl Apoptosis Modulators atin, cladribine, clofarabine, cytarabine, dacarbazine, dasat 0229 Contemplated for use with the formulations dis inib, daunorubicin, decitabine, dichloroacetic acid, discoder closed herein are agents which reduce or ameliorate symp mollide, docetaxel, doxorubicin, epirubicin, epothilone, toms or effects as a result of apoptosis. Accordingly, some eribulin, estramustine, etoposide, exatecan, exisulind, fer embodiments of the methods and compositions described ruginol, floxuridine, fludarabine, fluorouracil, fosfestrol, herein incorporate the use of apoptosis modulators for treat fotemustine, gemcitabine, hydroxyurea, IT-101. idarubicin, ment of sinonasal and/orotic conditions associated with aber ifosfamide, imiquimod, irinotecan, irofulven, ixabepilone, rant apoptosis. Inhibitors of apoptosis include inhibitors of laniquidar, lapatinib, lenalidomide, lomustine, lurtotecan, the MAPK/JNK signaling cascade AKT inhibitors, IKK mafosfamide, masoprocol, mechlorethamine, melphalan, inhibitors, JAK inhibitors, PI3 kinase inhibitors, NF-KB US 2012/0277199 A1 Nov. 1, 2012
inhibitors, p38 inhibitors, ERK inhibitors, Src inhibitors or orthostericantagonist of NF-kB. In some embodiments, the the like that are involved in apoptotic pathways. Other modu NF-kB transcription factor agonist, partial agonist, and/or lators of apoptotic pathways included modulators of caspases positive allosteric modulatoris PamCys ((S)-(2,3-bis(palmi or sirtuin. toyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)- Lys4-OH, trihydrochloride); Act 1 (NF-kB activator 1); JNK Modulators Acetyl-1'-keto-b-Boswellic Acid; Andrographolide; Caffeic 0230. In some embodiments, the anti-apoptotic agent is an Acid Phenethyl Ester (CAPE); Gliotoxin: Isohelenin: agent which inhibits (partially or fully) the activity of the NEMO-Binding Domain Binding Peptide (DRQIKIWFQN MAPK/JNK signaling cascade. In some embodiments, the RRMKWKKTALDWSWLQTE); NF-kB Activation Inhibi anti-apoptotic agent is minocycline; SB-203580 (4-(4-Fluo tor (6-Amino-4-(4-phenoxyphenylethylamino)quinazoline); rophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridyl) NF-kB Activation Inhibitor II (4-Methyl-N1-(3-phenylpro 1H-imidazole); PD 169316 (4-(4-Fluorophenyl)-2-(4-nitro pyl)benzene-1,2-diamine); NF-kB Activation Inhibitor III phenyl)-5-(4-pyridyl)-1H-imidazole); SB 202190 (4-(4- (3-Chloro-4-nitro-N-(5-nitro-2-thiazolyl)-benzamide); Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imi NF-kBActivation Inhibitor IV ((E)-2-Fluoro-4'-methoxy stil dazole); RWJ 67657 (4-4-(4-fluorophenyl)-1-(3- bene); NF-kB Activation Inhibitor V (5-Hydroxy-(2,6-diiso phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl)-3-butyn propylphenyl)-1H-isoindole-1,3-dione); NF-kB SN50 (AAVALLPAVLLALLAPVQRKRQKLMP): Oridonin; Par 1-ol); SB 220025 (5-(2-Amino-4-pyrimidinyl)-4-(4- thenolide; PPM-18 (2-Benzoylamino-1,4-naphthoduinone); fluorophenyl)-1-(4-piperidinlyl)imidazole); or combinations Ro'-9920; Sulfasalazine; TIRAP Inhibitor Peptide thereof. In some embodiments, the agent which antagonizes (RQIKIWFNRRMKWKKLQLRDAAPGGAIVS); Witha the MAPK/JNK signaling cascade is D-JNKI-1 (D)-h.JIPs. ferin A: Wogonin; BAY 1 1-7082 (E)3-(4-Methylphenyl) 157-DPro-DPro-(D)-HIV-TATs, as), AM-111 (Auris), sulfonyl)-2-propenenitrile); BAY 1 1-7085 ((E)3-(4-t-Bu SP600 125 (anthra 1.9-cdpyrazol-6(2H)-one), JNK Inhibitor tylphenyl)sulfonyl-2-propenenitrile); (E)-Capsaicin; or I(L)-HIV-TATss-PP-JBD), JNK Inhibitor III ((L)-HIV TAT-s7-gaba-c-Junosz), AS601245 (1,3-benzothiazol-2- combinations thereof y1 (2-2-(3-pyridinyl)ethylamino-4 pyrimidinyl)acetoni trile), JNK Inhibitor VI (HN-RPKRPTTLNLF-NH), JNK p38 Modulators Inhibitor VIII (N-(4-Amino-5-cyano-6-ethoxypyridin-2-yl)- 0235 Some embodiments incorporate the use of active 2-(2,5-dimethoxyphenyl)acetamide), JNK Inhibitor IX (N- agents that modulate p38. In some embodiments, the agent (3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)-1-naphtha that modulates p38 is a p38 antagonist, partial agonist, inverse mide), dicumarol (3,3'-Methylenebis(4-hydroxycoumarin)), agonists, neutral or competitive antagonists, allosteric SC-236 (4-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H antagonists, and/or orthostericantagonists. In some embodi pyrazol-1-ylbenzene-sulfonamide), CEP-1347 (Cephalon), ments, the p38 antagonist, partial agonist, inverse agonists, CEP-11004 (Cephalon); or combinations thereof. In some neutral or competitive antagonist, allosteric antagonist, and/ embodiments, the anti-apoptotic agent is AM-111 (Auris). or orthosteric antagonist is ARRY-797 (Array BioPharma); SB-220025 (5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophe JAK (Janus Kinase) Modulators nyl)-1-(4-piperidinlyl)imidazole); SB-239063 (trans-4-4- 0231 Contemplated for use with the formulations dis (4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imida closed herein are active agents that fully or partially inhibit Zol-1-yl)cyclohexanol); SB-202190 (4-(4-Fluorophenyl)-2- JAK kinases. In some embodiments, the anti-apoptotic agent (4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole); JX-4O1 is VX-680, TG 101348, TG101209, INCBO18424, XL019, (-2-Methoxy-4-(methylthio)benzoyl-4-(phenylmethyl)pi CEP-701, AT9283, or combinations thereof. peridine): PD-169316 (4-(4-Fluorophenyl)-2-(4-nitrophe nyl)-5-(4-pyridyl)-1H-imidazole); SKF-86002 (6-(4-Fluo Akt Modulators rophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo[2.1-b thiazole dihydrochloride); SB-200646 (N-(1-Methyl-1H 0232. In some embodiments, the anti-apoptotic agent is an indol-5-yl)-N'-3-pyridinylurea); CMPD-1 (2'-Fluoro-N-(4- agent that inhibits (partially or fully) the activity of Akt1. In hydroxyphenyl)-1,1'-biphenyl-4-butanamide); EO-1428 Some embodiments, the anti-apoptotic agent is a growth fac ((2-Methylphenyl)-4-(2-amino-4-bromophenyl)amino-2- tor. In some embodiments, the growth factor is EGF. chlorophenylmethanone); SB-253080 (4-5-(4-Fluorophe nyl)-2-[4-(methylsulfonyl)phenyl)-1H-imidazol-4-ylpyri PI3 Kinases Modulators dine); SD-169 (1H-Indole-5-carboxamide); SB-203580 (4- 0233. In some embodiments, the anti-apoptotic agent is an (4-Fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridyl) agent that inhibits (partially or fully) the activity of PI3 1H-imidazole); or combinations thereof. kinases. In some embodiments, the anti-apoptotic agent is 740Y-P:SC3036 (KKHTDDGYMPMSPGVA); PI 3-kinase Src Modulators Activator (Santa Cruz, Biotechnology, Inc.), wortmannin, 0236 Contemplated for use in the methods and composi wortmannin analogs (e.g., PX-866); or combinations thereof tions described herein are Src modulators. In some embodi ments, the Src antagonist, partial agonist, inverse agonist, NF-kB Modulators neutral or competitive antagonist, allosteric antagonist, and/ 0234 Some embodiments incorporate the use of active or orthostericantagonist is 1-Naphthyl PP1 (1-(1,1-Dimeth agents that modulate an NF-kB transcription factor. In certain ylethyl)-3-(1-naphthalenyl)-1H-pyrazolo 3,4-dpyrimidin instances, the agent that modulates an NF-kB transcription 4-amine); Lavendustin A (5-(2,5-Dihydroxyphenyl) factoris an antagonist, partial agonist, inverse agonist, neutral methyl(2-hydroxyphenyl)methy 1 amino-2- or competitive antagonist, allosteric antagonist, and/or hydroxybenzoic acid); MNS (3.4-Methylenedioxy-b- US 2012/0277199 A1 Nov. 1, 2012
nitrostyrene); PP1 (1-(1,1-Dimethylethyl)-1-(4- tetrahydroxyflavone; 4'-hydroxyflavone; 5-hydroxyflavone: methylphenyl)-1H-pyrazolo 3,4-dpyrimidin-4-amine); PP2 5,4'-dihydroxyflavone; 5,7-dihydroxyflavone; or combina (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo 3,4- tions thereof. dpyrimidin-4-amine); KX1-004 (Kinex); KX1-005 (Kinex): 0239. Other pro-apoptotic and anti-apoptotic agents are KX1-136 (Kinex); KX1-174 (Kinex); KX1-141 (Kinex): described in U.S. application Ser. No. 12/500,486 which KX2-328 (Kinex); KX1-306 (Kinex); KX1-329 (Kinex): agents are incorporated herein by reference and are contem KX2-391 (Kinex); KX2-377 (Kinex); ZD4190 (Astra Zen plated as being within the scope of embodiments presented eca; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-(1H-1.2. herein. 3-triazol-1-yl)ethoxy)guinazolin-4-amine); AP22408 (Ariad Pharmaceuticals); AP23236 (Ariad Pharmaceuticals); Antihistamines AP23451 (Ariad Pharmaceuticals); AP23464 (Ariad Phar maceuticals); AZD0530 (Astra Zeneca); AZM475271 0240 Contemplated for use with the formulations dis (M475271; Astra Zeneca); Dasatinib (N-(2-chloro-6-meth closed herein are agents which reduce or ameliorate symp ylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-meth toms or effects as a result of wheal and flare in sinonasal ylpyrimidin-4-ylamino) thiazole-5-carboxamide); GN963 passages. Accordingly, some embodiments of the methods (trans-4-(6,7-dimethoxyquinoxalin-2ylamino)cyclohexanol and compositions described herein incorporate the use of sulfate); Bosutinib (4-((2,4-dichloro-5-methoxyphenyl) antihistamines for treatment of Sinonasal conditions, amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)- Examples of antihistamines Suitable for methods and compo 3-quinolinecarbonitrile); or combinations thereof. sitions described herein include, but are not limited to, meclizine, diphenhydramine, loratadine, levocetirizine, fex Caspase Modulators ofenadine, quetiapine, mepyramine, piperoxan, antazoline, carbinoxamine, doxylamine, clemastine, dimenhydrinate, 0237. In some embodiments, an antagonist, partial ago pheniramine, chlorphenamine, chlorpheniramine, dexchlor nist, inverse agonist, neutral or competitive antagonist, allos pheniramine, brompheniramine, triprolidine, cyclizine, chlo teric antagonist, and/or orthosteric antagonist of a caspase rcyclizine, hydroxyzine, promethazine, alimemazine, trime target, including but not limited to caspase-8 and/or caspase prazine, cyproheptadine, azatadine, ketotifen, oxatomide, 9, is suitable for use in methods and compositions described meclizine hydrochloride, promethazine hydrochloride, herein. In some embodiments, the caspase inhibitor is hydroxyZine pamoate, chlorperazine, or the like. Z-VAD-FMK (Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluo romethylketone); Z-LEHD-FMK (benzyloxycarbonyl-Leu 0241. Other antihistamines are described in U.S. applica Glu(OMe)-His-Asp(OMe)-fluoromethylketone); B-D-FMK tion Ser. Nos. 12/472,034 and 12/427,663, which agents are (boc-aspartyl (Ome)-fluoromethylketone); Ac-LEHD-CHO incorporated herein by reference and are contemplated as (N-acetyl-Leu-Glu-His-Asp-CHO); Ac-IETD-CHO(N- being within the scope of embodiments presented herein. acetyl-Ile-Glu-Thr-Asp-CHO): Z-IETD-FMK (benzyloxy carbonyl-Ile-GlucOMe)-Thr-Asp(OMe)-fluoromethy Ion Channel Modulators lketone); FAM-LEHD-FMK (benzyloxycarbonyl Leu-Glu NMDA Receptor Modulators His-Asp-fluoromethyl ketone); FAM-LETD-FMK (benzy loxycarbonyl Leu-Glu-Thr-Asp-fluoromethyl ketone); 0242 Contemplated for use with the formulations dis Q-VD-OPH (Quinoline-Val-Asp-CH-O-Ph); or combina closed herein are agents which reduce or ameliorate symp tions thereof. toms or effects as a result of aberrant ion channel activity in epithelial cells lining sinusoidal cavities and/or in auris hair Sirtuin Modulators Modulators cells. In some instances, aberrant NMDA receptor activity is associated with influx of Ca" and/or Na" ions in epithelial 0238. Some embodiments incorporate the use of one or cells. Accordingly, Some embodiments of the methods and more antagonists, partial agonists, inverse agonists, neutral or compositions described herein incorporate the use of NMDA competitive antagonists, allostericantagonists, and/or orthos receptor antagonists or NMDA receptor agonists for treat tericantagonists of sirtuins as active agents. In some embodi ment of sinonasal and/orotic conditions associated with aber ments, the agonist, partial agonist, and/or positive allosteric rant ion channel activity. Examples of NMDA receptor modulator of sirtuin activity is a stilbene, flavone, isoflavone, antagonists include and are not limited to aminoadamantane, flavanone, catechin, free radical protective compound, isoni dextromethorphan, dextrorphan, ibogaine, ketamine (includ cotinamide, dipyridamole, ZM 336372 (3-(dimethylamino)- ing R or Sketamine), nitrous oxide, phencyclidine, riluzole, N-3(4-hydroxybenzoyl)-amino-4-met hylphenylbenza tiletamine, memantine, neramexane, dizocilpine, aptiganel, mide), camptothecin, coumestrol, nordihydroguaiaretic acid, remacimide, 7-chlorokynurenate, DCKA (5,7-dichlo esculetin, SRT1720 (Sirtris), SRT-1460 (Sirtris), SRT2183 rokynurenic acid), kynurenic acid, 1-aminocyclopropanecar (Sirtris), resveratrol, piceatannol, rhapontin, deoxyrhapontin, boxylic acid (ACPC), AP7 (2-amino-7-phosphonoheptanoic butein, a chalcone (e.g., chalcon; isoliquirtigen; butein; 4.2, acid), APV (R-2-amino-5-phosphonopentanoate), CPPene 4'-trihydroxychalcone; 3.4.2',4',6'-pentahydroxychalcone); (3-(R)-2-carboxypiperazin-4-yl-prop-2-enyl-1-phospho morin, fisetin; luteolin; quercetin; kaempferol; apigenin; gos nic acid); (+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy Sypetin; myricetin; 6-hydroxyapigenin; 5-hydroxyflavone; 4-phenylpiperidino)-1-pro-panol: (1S,2S)-1-(4-hydroxy-3- 5.7.3',4',5'-pentahydroxyflavone; 3.7.3',4',5'-pentahydroxy methoxyphenyl)-2-(4-hydroxy-4-phenylpiperi-dino)-1- flavone; 3.6.3',4'-tetrahydroxyflavone; 7.3',4',5'-tetrahy propanol: (3R,4S)-3-(4-(4-fluorophenyl)-4- droxyflavone; 3.6.2',4'-tetrahydroxyflavone; 7,4'-dihydroxy hydroxypiperidin-1-yl-)-chroman-4,7-diol: (1R*, 2R)-1- flavone; 7,8.3',4'-tetrahydroxyflavone; 3,6,2',3'- (4-hydroxy-3-methylphenyl)-2-(4-(4-fluoro-phenyl)-4- US 2012/0277199 A1 Nov. 1, 2012 hydroxypiperidin-1-yl)-propan-1-ol-mesylate; AM-101, some embodiments, a Na" channel blocker is vinpocetine L-701324, dextrometorphan, eliprodil, and/or combinations ((3a, 16a)-Eburnamenine-14-carboxylic acid ethyl ester); thereof. sipatrigine (2-(4-Methylpiperazin-1-yl)-5-(2,3,5-trichlo rophenyl)-pyrimidin-4-amine); amiloride (3,5-diamino-N- ENaC Receptor Modulators (aminoiminomethyl)-6-chloropyrazinecarbox amide hydro 0243 In some embodiments, an active agent modulates chloride); carbamazepine (5H-dibenzob.fazepine-5- ion channel activity (e.g., in auris hair cells, in Sinonasal carboxamide); TTX (octahydro-12-(hydroxymethyl)-2- imino-5,9:7.10a-dimethano-10aH-1.3dioxocino 6.5-d epithelia) and is a modulator of ENaC channels. The epithe pyrimidine-4,7,10,11,12-pentol); RS1 OO642 (1-(2,6- lial sodium channel (ENaC, sodium channel non-neuronal 1 dimethyl-phenoxy)-2-ethylaminopropane hydrochloride); (SCNN1) oramiloride sensitive sodium channel (ASSC)) is a mexiletine ((1-(2,6-dimethylphenoxy)-2-aminopropane membrane-bound ion-channel that is permeable for Li-ions, hydrochloride)); QX-314 (N-(2,6-Dimethylphenylcarbam protons and Na'-ions. The ENaC is located in the apical oylmethyl)triethylammonium bromide); phenyloin (5.5- membrane of polarized epithelial cells and is involved in diphenylimidazolidine-2,4-dione); lamotrigine (6-(2,3- transepithelial Na'-ion transport. Na/K+-ATPase is also dichlorophenyl)-1,2,4-triazine-3,5-diamine); 4030W92 (2,4- involved in Na' transport and ion homeostasis. Examples of diamino-5-(2,3-dichlorophenyl)-6- modulators of the activity of ENaC include, by way of fluoromethylpyrimidine); BW 10O3C87 (5-(2,3,5- example, the mineralcorticoid aldosterone, triamterene, and trichlorophenyl)pyrimidine-2.4-1.1 ethaneSulphonate); amiloride. QX-222 (2-(2,6-dimethylphenyl)amino-N.N.N-trimethyl Calcium Channel Modulators 2-oxoethaniminium chloride); ambroXol (trans-4-(2- Amino-3,5-dibromophenyl)methylaminocyclo hexanol 0244. In some embodiments, an active agent modulates hydrochloride); R56865 (N-1-(4-(4-fluorophenoxy)butyl ion channel activity (e.g., in auris hair cells, in Sinonasal 4-piperidinyl-N-methyl-2-benzo-thiazolamine); lubeluzole; epithelia) and is a calcium channel agonist or antagonist. In ajmaline ((17R.21alpha)-ajmalan-17,21-diol); procainamide Some embodiments, the calcium channel antagonist is cin (4-amino-N-(2-diethylaminoethyl)benzamide hydrochlo narizine, flunarizine, or nimodipine. Other calcium channel ride); flecamide; riluzoleor; or combinations thereof. blockers include and are not limited to Verapamil, diltiazem, omega-conotoxin, GVIA, amlodipine, felodipine, lacidipine, AMPA Receptor Modulators mibefradil, NPPB (5-Nitro-2-(3-phenylpropylamino)ben Zoic Acid), flunarizine, and/or combinations thereof. 0248. In some embodiments, an active agent modulates ion channel activity (e.g., in auris hair cells, in sinonasal Potassium Channel Modulators epithelia) and is an AMPA receptor antagonist. In some embodiments, the agent which antagonizes the AMPA recep 0245. In some embodiments, an active agent modulates tors is CNQX (6-cyano-7-nitroquinoxaline-2,3-dione); ion channel activity (e.g., in auris hair cells, in Sinonasal NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzof dui epithelia) and is a potassium channel agonist orantagonist. In noxaline-2,3-dione); DNQX (6,7-dinitroquinoxaline-2,3-di Some embodiments, the agonist of a potassium channel is one); kynurenic acid; 2,3-dihydroxy-6-nitro-7-sulfamoyl nicorandil; minoxidil, levcromakalim, lemakalim, cro makalim; L-735,334 (14-hydroxy CAF-603 oleate); retigab benzo-fcquinoxaline; or combinations thereof. ine; flupirtine; BMS-204352 (3S)-(+)-(5-Chloro-2-methox yphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H Metabotropic Glutamate Receptor Modulators indole-2-one); DMP-543 (10,10-bis((2-fluoro-4-pyridinyl) 0249. In some embodiments, an active agent modulates methyl)-9(1OH)-anthracenone); or combinations thereof. ion channel activity (e.g., in auris hair cells, in sinonasal 0246. In some embodiments, an active agent modulates epithelia) and indirectly controls the opening of ion channels potassium channel activity (e.g., in auris hair cells, in Sinona by the activation of biochemical cascades. In some of Such sal epithelia) and is an antagonist of a potassium channel (e.g. embodiments, the agent is a modulator of mGlu receptors. a potassium channel blocker). In some embodiments, the 0250 Examples of agents that are group II mGlu receptor antagonist of a potassium channel is linopirdine: XE991 (10. agonists include and are not limited to LY389795 ((-)-2-thia 10-bis(4-pyridinylmethyl)-9(1OH)-anthracenone); 4-AP 4-aminobicyclo-hexane-4,6-dicarboxylate); LY379268 ((-)- (4-aminopyridine): 3,4-DAP (3,4-Diaminopyridine); E-4031 2-oxa-4-aminobicyclo-hexane-4,6-dicarboxylate); (4-1-2-(6-methyl-2-pyridyl)ethyl-4-piperidinylcarbo LY354740 ((+)-2-aminobicyclo-hexane-2,6dicarboxylate); nyl-methanesulfonanilide); DIDS (4,4'-diisothiocyanostil DCG-IV ((2S,2R,3R)-2-(2',3'-dicarboxycyclopropyl)gly bene-2,2'-disulfonic acid); Way 123,398 (N-methyl-N-(2- cine): 2R,4R-APDC (2R,4R-4-aminopyrrolidine-2,4-dicar (methyl(1-methyl-1H-benzimidazol-2-yl)amino)ethyl)-4- boxylate), (S)-3C4HPG ((S)-3-carboxy-4-hydroxyphenylg ((methylsulfonyl)amino)benzenesulfonamide HCl); CGS lycine); (S)-4C3HPG ((S)-4-carboxy-3- 12066A (7-Trifluoromethyl-4-(4-methyl-1-piperazinyl) hydroxyphenylglycine); L-CCG-I ((2S,1'S,2S)-2- pyrrolo-1,2-aquinoxaline); dolfetilide; Sotalol; apamin; (carboxycyclopropyl)glycine); or the like. Example of agents amiodarone; azimilide; bretylium; clofilium; tedisamil; that are group III mGlu receptoragonists include and are not ibutilide; sematilide; nifekalant; tamulus toxin and combina limited to ACPT-I ((1S,3R.4S)-1-aminocyclopentane-1,3,4- tions thereof. tricarboxylic acid); L-AP4 (L-(+)-2-Amino-4-phosphonobu tyric acid): (S)-3,4-DCPG ((S)-3,4-dicarboxyphenylgly Sodium Channel Modulators cine); (RS)-3,4-DCPG ((RS)-3,4-dicarboxyphenylglycine); 0247. In some embodiments, an active agent modulates (RS)-4-phosphonophenylglycine ((RS)PPG); AMN082 (N'- ion channel activity (e.g., in auris hair cells, in Sinonasal bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride); epithelia) and is a Sosium channel agonist or antagonist. In DCG-IV ((2S,2R,3R)-2-(2',3'-dicarboxycyclopropyl)gly US 2012/0277199 A1 Nov. 1, 2012
cine); or the like. Other mGlu receptor modulators include limited to Hydrocortisone, Cortisone, Prednisone, Predniso and are not limited to is 3,5-Dimethylpyrrole-2,4-dicarboxy lone, Methylprednisolone, Dexamethasone, Betamethasone, lic acid 2-propyl ester 4-(12.2-trimethyl-propyl)ester (3.5- Triamcinolone. Beclometasone, Fludrocortisone acetate, dimethyl PPP): 3,3'-difluorobenzaldazine (DFB), 3,3'-dim Aldosterone or the like). lethoxybenzaldazine (DMeOB), 3,3'-dichlorobenzaldazine (DCB) and other allosteric modulators of mGluRs disclosed RNAi in Mol. Pharmacol. 2003, 64,731-740; (E)-6-methyl-2-(phe 0255. In some embodiments, where inhibition or down nyldiazenyl)pyridin-3-ol (SIB 1757); (E)-2-methyl-6- regulation of a target is desired (e.g. genes encoding one or styrylpyridine (SIB 1893): 2-methyl-6-(phenylethynyl)pyri more calcineurins, IKKs, TACEs, TLRs, or cytokines), RNA dine (MPEP), 2-methyl-4-((6-methylpyridin-2-yl)ethynyl) interference are utilized. In some embodiments, the agent that thiazole (MTEP): 7-(Hydroxyimino)cyclopropabchromen inhibits or down-regulates the targetisan siRNA molecule. In 1C-carboxylate ethyl ester (CPCCOEt), N-cyclohexyl-3- certain instances, the siRNA molecule inhibits the transcrip methylbenzodthiazolo 3.2-aimidazole-2-carboxamide tion of a target by RNA interference (RNAi). In some embodi (YM-298198), tricyclo[3.3.3.1 nonanyl quinoxaline-2-car ments, a double stranded RNA (dsRNA) molecule with boxamide (NPS 2390); 6-methoxy-N-(4-methoxyphenyl) sequences complementary to a target is generated (e.g. by quinazolin-4-amine (LY 456239), piracetam, Oxiracetam, PCR). In some embodiments, a 20-25 bp siRNA molecule Aniracetam, Pramiracetam, Phenylpiracetam (Carphedon), with sequences complementary to a target is generated. In Etiracetam, Levetiracetam, Nefiracetam, Nicoracetam, some embodiments, the 20-25bp siRNA molecule has 2-5bp Rolziracetam, Nebracetam, Fasoracetam, Coluracetam, overhangs on the 3' end of each Strand, and a 5' phosphate Dimiracetam, Brivaracetam, Seletracetam, Rolipram or the terminus and a 3' hydroxyl terminus. In some embodiments, like. the 20-25bp siRNA molecule has blunt ends. For techniques for generating RNA sequences see Molecular Cloning: A TRPV1 Modulators Laboratory Manual, second edition (Sambrook et al., 1989) 0251. In some embodiments, an active agent modulates and Molecular Cloning: A Laboratory Manual, third edition ion channel activity (e.g., in auris hair cells, in Sinonasal (Sambrook and Russel, 2001), jointly referred to herein as epithelia) and is a TRPV1 agonist or antagonist. In some “Sambrook”); Current Protocols in Molecular Biology (F. M. embodiments, an agonist of one or more of the TRPV recep Ausubel et al., eds., 1987, including Supplements through tors is capsaicin, resiniferatoxin, or combinations thereof. 2001); Current Protocols in Nucleic Acid Chemistry John 0252). Other ion channel modulators include purinergic Wiley & Sons, Inc., New York, 2000) which are hereby incor receptor modulators, GABA receptor modulators or the like. porated by reference for such disclosure. Ion channel modulators described in U.S. application Ser. 0256 In some embodiments, the dsRNA or siRNA mol Nos. 12/506,664, 12/427,663, and 12/494,156 are incorpo ecule is incorporated into a Sustained-release formulation rated herein by reference and are contemplated as being described herein and is injected into or in the vicinity of the within the scope of embodiments presented herein. sinonasal and/or otic cavity or structure. 0257. In certain instances, after administration of the Anti-Angiogenesis Agents dsRNA or siRNA molecule, cells at the site of administration (e.g. the cells of Sinonasal passages, auris hair cells) are 0253 Contemplated for use with the formulations dis transformed with the dsRNA or siRNA molecule. In certain closed herein are agents which are anti-angiogenesis agents. instances following transformation, the dsRNA molecule is In some embodiments, the formulations provided herein cleaved into multiple fragments of about 20-25 bp to yield allow for Sustained release of anti-angiogenic in the intrasi siRNA molecules. In certain instances, the fragments have nusoidal and/or nasal and/or nasopharyngeal regions. In some about 2 bp overhangs on the 3' end of each strand. embodiments, the anti-angiogenesis agent is a modulator of 0258. In certain instances, an siRNA molecule is divided the VEGF1 and/or VEGF2 receptor(s). Examples of anti into two strands (the guide Strand and the anti-guide Strand) angiogenic agents that are suitable for use in the methods by an RNA-induced Silencing Complex (RISC). In certain described herein include and are not limited to bevacizumab, instances, the guide strand is incorporated into the catalytic thalidomide, linomide, TNP-470, matrix metalloprotease component of the RISC (i.e. argonaute). In certain instances, inhibitors, VEGFR antagonists, and the like. the guide strand binds to a complementary target mRNA Immunosuppressants sequence. In certain instances, the RISC cleaves the target mRNA. In certain instances, the expression of the target gene 0254 Contemplated for use with the formulations dis is down-regulated. closed herein are agents which are immunosupressants. In 0259. In some embodiments, a sequence complementary some embodiments, the formulations provided herein allow to a target is ligated into a vector. In some embodiments, the for Sustained release of immunosuppressants in an affected sequence is placed between two promoters. In some embodi area for long term treatment of condition Such as, for ments, the promoters are orientated in opposite directions. In example, Wegerner's granulomatosis. Further, the intrasinu Some embodiments, the vector is contacted with a cell. In soidal and/or nasal and/or nasopharyngeal formulations certain instances, a cell is transformed with the vector. In described herein are administered with reduced dosing fre certain instances following transformation, sense and anti quency thereby improving patient compliance and comfort sense Strands of the sequence are generated. In certain where long term therapy is indicated. Examples of immuno instances, the sense and anti-sense Strands hybridize to form Suppressants include and are not limited to Cyclosporine, a dsRNA molecule which is cleaved into siRNA molecules. In 6-MP, and Methotrexate. In some embodiments, an immuno certain instances, the strands hybridize to form an siRNA Suppresant is an agent that acts at glucocorticoid receptors molecule. In some embodiments, the vector is a plasmid (e.g (e.g., any glucocorticoid described herein, including and not pSUPER: pSUPER.neo; pSUPER.neo-gfp). US 2012/0277199 A1 Nov. 1, 2012
0260. In some embodiments, the vector is incorporated 12/494,156, 12/500,486, 12/504,553, 12/506,091, 12/506, into a Sustained release microsphere or microparticle, hydro 127, 12/506,573, 12/506,616, and 12/506,664, the disclosure gel, liposome, or thermoreversible gel. of active agents described therein is incorporated herein by reference. Other Agents Combination Therapy 0261. In some embodiments, agents that are suitable for 0265 Antimicrobial Agents and Anti-Inflammatory use in formulations described herein include agents that Agents modulate activity of epithelial cells lining the sinonasal cavi 0266 Contemplated within the scope of the embodiments ties and/or nasal passages and/or auris hair cells. Examples of presented herein are compositions that comprise an antimi agents that modulate the activity of epithelial cells include crobial agent in combination with an anti-inflammatory and are not limited to modulators of the PTEN pathway; agent. In specific embodiments, a formulation described modulators of PPAR; modulators of EGFR: growth factors herein comprises an antimicrobial agent (e.g., any antimicro bial agent described herein) in combination with an anti including and not limited to TGF-beta, and fibroblast growth inflammatory agent (e.g., any anti-inflammatory agent factor; and/or modulators of epithelial cell adhesion. described herein). In certain embodiments, a formulation 0262. In some embodiments, agents suitable for use in described herein comprises an antibiotic (e.g., any antibiotic formulations described herein include agents that modulate described herein) in combination with a corticosteroid. synthesis and/or activity of keratin (e.g., actinomycin D. Vita 0267 In some embodiments, a composition comprising an min A, or the like). In some embodiments, agents that are antibiotic and a corticosteroid has different release profiles suitable for use in intrasinusoidal formulations described for each of the active agents. In other embodiments, a com herein include agents that modulate eosinophils and/or position comprising an antibiotic agent and a corticosteroid inflammatory cytokines. Examples of agents that modulate agent has substantially similar release profiles for each of the the activity of eosinophils and/or inflammatory cytokines active agents. include and are not limited to leukotriene blockers (e.g., mon 0268. In certain embodiments, a formulation described teleukast, SingulairR), prostaglandin D receptor (PGD2) herein comprises an antibiotic in combination with dexam modulators, lipophosphatidic acid receptor (LPA) modula ethasone. In certain embodiments, a formulation described tors, 5-lipoxygenase activating protein (FLAP) modulators, herein comprises an antibiotic in combination with methyl CRTH2 (DP2) modulators, or the like. In some embodiments, prednisolone or prednisolone. In certain embodiments, a for agents suitable for use in intrasinusoidal formulations mulation described herein comprises ciprofloxacin in combi described herein include agents that modulate cadherins (e.g., nation with dexamethasone. In certain embodiments, a Trichostatin A, ADH1 (Molecular and Cellular Neuro formulation described herein comprises ciprofloxacin in science, 28, 2005, 253-263), Antibody sc-59778 or the like). combination with methylprednisolone or prednisolone or tri 0263. In some embodiments, active agents compatible amcinolone. with the formulations described herein include neurotoxins 0269. In some embodiments, a composition comprising an for the treatment of active nerve disorders. Such neurotoxins antibiotic and a corticosteroid contains one or both active include venoms, channel agents and/or nerve agents includ agents as multiparticulates (e.g., as micronized active agents). ing but not limited to Botulinum Toxin Type A (BotoxR), By way of example, in some embodiments, a composition erabutoxin, tetrodotoxin, batrachotoxin, maurotoxin, agi comprising water Soluble dexamethasone and multiparticu toxin, charybdotoxin, margatoxin, slotoxin, Scyllatoxin, lates of a form of ciprofloxacin with poor water solubility hefutoxin, calciseptine, taicatoxin, calcicludine, PhTx3 or the provides extended release of dexamethasone for at least 3 like. In some embodiments, active agents compatible with the days and extended release of ciprofloxacin for at least 10 formulation described herein include vascular and/or vesti days. By way of example, in some embodiments, a composi bular Suppressants. Examples of vestibular suppressants tion comprising multiparticulates (e.g., micronized particles) include and are not limited to meclizine, amytriptyline, dro of a form of dexamethasone with poor water solubility, and a peridol and other vascular and/or vestibular suppressants water soluble form of ciprofloxacin provides extended release described in U.S. application Ser. No. 12/486,697, vascular of ciprofloxacin for at least 3 days and extended release of and/or vestibular Suppressants described therein are incorpo dexamethasone for at least 10 days. By way of example, in rated herein by reference). In some embodiments, active Some embodiments, a composition comprising multiparticu agents compatible with the formulations described herein lates (e.g., micron-sized particles, nanoparticles, non-sized include agents that modulate re-growth of damaged auris particles) of a form of dexamethasone with poor water solu sensory hair cells. In some instances, modulation of the WNT bility and mulitparticulates (e.g., micron-sized particles, pathway promotes morphogenesis and/or re-growth of dam nanoparticles, non-sized particles) of a form of ciprofloxacin aged auris sensory hair cells. WNT signalling proteins with poor water solubility provides an extended release of include protein products encoded by genes such as WNT1, each active agent for at least 7 days. WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, 0270. Other active agents suitable for combination WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, therapy include and are not limited to agents described in U.S. WNT9A, WNT9B, WNT10A, WNT10B, WNT11, or application Ser. Nos. 12/427,663, 12/466,310, 12/472,034, WNT16. Modulators of the WNT pathway include, and are 12/486,697, 12/493,611, 12/494,156, 12/500,486, 12/504, not limited to, 2-amino-4-3,4-(methylenedioxy)benzyl 553, 12/506,091, 12/506,127, 12/506,573, 12/506,616, and amino-6-(3-methoxyphenyl)pyrimidine, the signalling mol 12/506,664, agents described therein are incorporated herein ecule Cerberus, or the like. by reference. 0264. Other active agents that are compatible with the formulations described herein include and are not limited to Imaging Devices active agents described in U.S. application Ser. Nos. 12/427, 0271 In some embodiments, any formulation described 663, 12/466,310, 12/472,034, 12/486,697, 12/493,611, herein is used in combination with a mechanical or imaging US 2012/0277199 A1 Nov. 1, 2012 20 device to monitor or survey the condition being treated. For herein comprising an anti-microbial agent (e.g., an antibiotic example, magnetic resonance imaging (MRI) devices are Such as ciprofloxacin) or an anti-inflammatory agent (e.g., a contemplated within the scope of the embodiments described corticosteroid such as dexamethasone, triamcinolone or the herein, wherein the MRI devices (for example, 3 Tesla MRI like), or a combination thereof, is administered in combina devices) are capable of evaluating disease progression, and tion with Surgery (e.g., ear Surgery for cholesteatoma or Glue Subsequent treatment with the pharmaceutical formulations ear). disclosed herein. In some embodiments, formulations described herein comprise Gadolinium-based dyes, iodine Sterilization based dyes, barium-based dyes, or the like and are used in the 0275 Included within the embodiments disclosed herein treatment of any active disorder described herein and/or with are means and processes for sterilization of a pharmaceutical any mechanical or imaging device or method described formulation disclosed herein for use in humans. The goal is to herein (e.g., a CAT scan). Such formulations allow for visu provide a safe pharmaceutical product, relatively free of alization of disease progression and/or formulation penetra infection causing micro-organisms. The U.S. Food and Drug tion (e.g., penetration across round window membrane into Administration has provided regulatory guidance in the pub the inner ear and/or therapeutic effectiveness of the formula lication “Guidance for Industry: Sterile Drug Products Pro tion. In certain embodiments, an imaging agent (e.g., gado duced by Aseptic Processing available at: http://www.fda. linium hydrate injection) is used in combination with three gov/cder/guidance/5882fn1.htm, which is incorporated dimensional real inversion recovery (3D-real IR) and/three herein by reference in its entirety. dimensional fluid-attenuated inversion recovery (3D 0276. As used herein, sterilization means a process used to FLAIR) magnetic resonance imaging (MRI), and/or any destroy or remove microorganisms and/or pyrogens that are formulation described herein to evaluate disease severity present in a product or packaging. Available methods for the (e.g., size of nasal polyps), formulation penetration at the site inactivation of microorganisms include, but are not limited to, or administration, and/or therapeutic effectiveness of the for the application of extreme heat, lethal chemicals, or gamma mulation. In some instances, a formulation described herein radiation. facilitates delivery of a sufficient amount of an imaging agent (0277 Heat sterilization methods include the use of a satu to the site of treatment and allows for visualization of disease rated steam autoclave at a temperature of at least 121°C., or progression and/or formulation penetration and/or therapeu dry heat sterilization (e.g., heating a dry powder for about tic effectiveness of the formulation. 3-11 hours at internal powder temperatures of 130-140°C., or 0272. In some embodiments, the compositions described for 1-2 hours at internal temperatures of 150-180° C.). Filtra herein include a dye to help enhance the visualization of tion sterilization is a method used to remove microorganisms penetration of the formulation targeted sites of administration from solutions. and/or treatment. In some of such embodiments, dyes that are 0278. In some embodiments, a formulation is subjected to compatible with the compositions described herein include terminal sterilization. In other words, the formulation that is and are not limited to Evans blue, Methylene blue, Isosulfan autoclaved comprises the active agent and all the excipients. blue, Trypan blue, indocyanine green or the like. In other embodiments, all the excipients are subjected to heat sterilization and the active agent is sterilized separately; the Surgery and Implants active agent and the excipients are then mixed aseptically. In 0273. In some embodiments, the pharmaceutical formula yet other embodiments, the active agent is sterilized sepa tions described herein are used in combination with (e.g., rately (e.g., dry-heat sterilized, irradiated, steam-sterilized) implantation, short-term use, long-term use, or removal of) and the other excipients are sterile-filtered; the sterile active implants (e.g., cochlear implants). As used herein, implants agent and the sterile-filtered solution are then mixed asepti include medical devices, examples of which include cochlear cally. In further embodiments, a sterile Suspension of active implants, hearing sparing devices, hearing-improvement agent in a solution comprising a thermosetting polymer is devices, short electrodes, tympanostomy tubes, micro-pros aseptically mixed with a second solution comprising a ther theses or piston-like prostheses; needles; stem cell trans mosetting polymer and optionally a second active agent. plants; drug delivery devices; any cell-based therapeutic; 0279. In some instances, conventionally used methods of drug delivery stent; catheter, ballon rhinoplasty; or the like. sterilization (e.g., heat treatment (e.g., in an autoclave), 0274. In some embodiments, administration of an phar gamma irradiation, filtration) lead to irreversible degradation maceutical formulation described herein in combination with of polymeric components (e.g., thermosetting polymer com Surgery delays or prevents collateral damage, e.g., irritation, ponents) and/or the active agent in the formulation. In some inflammation and/or infection, caused by the external active instances, sterilization of a pharmaceutical formulation by intervention (e.g., installation of an external device or Sur filtration through membranes (e.g., 0.2 um membranes) is not gery). In some embodiments, administration of an pharma possible if the formulation comprises thixotropic polymers. ceutical formulation described herein in combination with an 0280 Accordingly, provided herein are methods for ster active intervention reduces or eliminates post-Surgical and/or ilization of pharmaceutical formulations that prevent degra post-implantation complications (e.g., inflammation, cell dation of polymeric components and/or the active agent dur damage, infection, osteoneogenesis or the like). In some ing the process of sterilization. In some embodiments, the use instances, perfusion of a Surgical area with a formulation of an appropriate thermosetting polymer in combination with described herein reduces post-Surgery or post-implantation a specific buffer and/or pH range for the formulation allows recuperation time. In one aspect, formulations described for high temperature terminal sterilization of formulations herein, and modes of administration thereof, are applicable to described herein with substantially low degradation of the methods of direct perfusion at the site of Surgery, during therapeutic agent and/or the polymeric excipients. Surgery, before Surgery or after Surgery, or a combination 0281 Any appropriate buffer is used depending on the thereof. In specific embodiments, formulations described active agent used in the formulation. In some instances, since US 2012/0277199 A1 Nov. 1, 2012 pKa of TRIS decreases as temperature increases at approxi 0287. The practical osmolality of an pharmaceutical for mately -0.03/°C. and pKa of PBS increases as temperature mulation disclosed herein is from about 100 mOsm/kg to increases at approximately 0.003/C., autoclaving at 250°F. about 1000 mOsm/kg, from about 200 mOsm/kg to about 800 (121°C.) results in a significant downward pH shift (i.e. more mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, acidic) in the TRIS buffer whereas a relatively much less or from about 250 mOsm/kg to about 320 mOsm/kg, or from upward pH shift in the PBS buffer and therefore much about 250 mOsm/kg to about 350 mOsm/kg or from about increased hydrolysis and/or degradation of an active agent in 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, TRIS than in PBS. Degradation of an active agent and/or a formulation described herein has a practical osmolarity of polymeric components is reduced by the use of an appropriate about 100 mOsm/L to about 1000 mOsm/L, about 200 combination of a buffer and concentration of thermosensitive mOsm/L to about 800 mOsm/L, about 250 mOsm/L to about polymer. 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L. 0282. In certain embodiments, any sustained release for about 250 mOsm/L to about 320 mOsm/L, or about 280 mulation described herein has less than about 100 colony mOsm/L to about 320 mOsm/L. In some embodiments, the forming units, less than about 60 colony forming units, less practical osmolality is estimated as an additive combination than about 50 colony forming units, less than about 40 colony of buffer osmolality and the osmolality of the supernatant of forming units, or less than about 30 colony forming units of the gelled poloxamer in water. microbial agents per gram of formulation. The Sterile formu 0288. In specific embodiments, the practical osmolality of lations described herein are substantially free of microbes. a formulation described herein is measured in a cell-based 0283 An additional aspect of the sterilization process is assay. The osmolality experienced by red blood cells isolated the removal of by-products from the killing of microorgan from guinea pigs was determined as a function of the hemoly isms. The process of depyrogenation removes such pyrogens sis index. RBCs were placed in poloxamer solutions of vary from the sample. Because the molecular size of endotoxins ing concentrations. 0.5 mL of 10% guinea pig red blood cells can vary widely, the presence of endotoxins is expressed in in saline was added into a 2.5 mL solution of poloxamer 407 “endotoxin units” (EU). One EU is equivalent to 100 pico in buffer. The resulting suspension was serially diluted and grams of E. coli LPS. Humans can develop a response to as the hemolysis index of RBCs was recorded for each solution. little as 5 EU/kg of body weight. In certain embodiments, The hemolysis index is defined as the ratio of absorbance of a active compositions described herein contain lower endot sample at 540 nm to the absorbance of a 0.9% saline solution oxin levels (e.g. <5 EU/kg of body weight of a subject, <4 at 540 nm. A hemolysis index of 1 indicates that the “practical EU/kg of body weight of a subject) when compared to con osmolality” experienced by the RBCs is suitable for inner ear ventionally acceptable endotoxin levels (e.g., 5 EU/kg of administration. The RBCs are intact in media with a suitable body weight of a subject). In certain embodiments, the for practical osmolality (FIG. 28). The osmolality of the polox mulations described herein are substantially free of pyrogens. amer Solution was also measured by freezing point depres sion method or vapor pressure methods. The practical osmo pH and Practical Osmolarity lality of the formulation is measured using commercially available osmometers and the value is confirmed by the 0284. In some embodiments, an pharmaceutical formula hemolysis assay. tion disclosed herein is formulated to provide an ionic balance 0289 Table 10 shows a comparison of osmolality as deter that is compatible biological fluids (e.g., endolymph and/or mined by the serial dilution cell-based assay and a direct perilymph in an inner ear environment, spinal fluid in the measurement using freezing point depression or vapor pres intrathecal space or the like). sure methods. The serial dilution method is predictive of 0285. As used herein, “practical osmolarity/osmolality” practical osmolality that is compatible with the inner ear or “deliverable osmolarity/osmolality” means the osmolarity/ environment. osmolality of a formulation as determined by measuring the osmolarity/oSmolality of the active agent and all excipients TABLE 10 except the thermosensitive polymer agent (e.g., polyoxyeth ylene-polyooxypropylene copolymers, or the like). The prac Osmolality per “Direct tical osmolarity of a formulation disclosed herein is measured Hemolysis Measurement' (mCSM by any suitable method, e.g., a freezing point depression Sample Index per FP/VP) RBC in DIWater 360 50,55 method as described in Viegas et al., Int. J. Pharm., 1998, RBC in 0.45% Saline 5 170,161 160, 157-162. In some instances, the practical osmolarity of a RBC in 0.9% Saline 1 293,293 formulation disclosed herein is measured by vapor pressure RBC in 2% Saline 2 611619 oSmometry (e.g., vapor pressure depression method) that RBC in 10% Saline 155 >QL/2674 RBC in P4O7-in-DI water 19 245,114 allows for determination of the osmolarity of a formulation at RBC in P4O7-in-50 mM 1 458,310 higher temperatures. In some instances, vapor pressure TRIS O.3% NaCl depression method allows for determination of the osmolarity RBC in P4O7-in-50 mM 1 523,377 of a formulation comprising a a thermosensitive polymer at a TRIS O.45% NaCl higher temperature Such as for example the gelation tempera FP: freezing-point osmometry; ture of the thermosensitive polymer. VP: vapor-pressure osmometry Sample preparation: 0.5 mL of 10% guinea pig red blood cells in saline was added into 2.5 0286. In some embodiments, the osmolarity at a target site mL of P407 in buffer solution of action (e.g., the perilymph in the inner ear, spinal fluid, emolysis Index is defined as the 540 nm Absorbance ratio of sample: 0.9% saline sinonasal fluids or the like) is about the same as the practical osmolarity (i.e., osmolarity of materials that cross or pen 0290. In some embodiments, useful formulations also etrate the round window membrane in the ear) of a formula include one or more pH adjusting agents or buffering agents. tion described herein. Suitable pH adjusting agents or buffers include, but are not US 2012/0277199 A1 Nov. 1, 2012 22 limited to acetate, bicarbonate, ammonium chloride, citrate, (e.g., micrometer-sized particles, nanometer-sized particles phosphate, pharmaceutically acceptable salts thereof and or the like) for any formulation described herein. In some combinations or mixtures thereof. In certain embodiments of embodiments, any formulation described herein comprises the present disclosure, the amount of buffer included in the multiparticulates, i.e., a plurality of particle sizes (e.g., gel formulations are an amount Such that the pH of the gel micronized particles, nano-sized particles, non-sized par formulation does not interfere with the body's natural buff ticles, colloidal particles); i.e., the formulation is a multipar ering system and/or the osmolarity of physiological fluids. In ticulate formulation. In some embodiments, any formulation some embodiments, the pH of a formulation described herein described herein comprises one or more multiparticulate is between about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0 and (e.g., micronized) therapeutic agents. In some embodiments, about 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, or 12.0. any formulation described herein comprises micronized In some embodiments, the pH of a formulation described therapeutic agents. Micronization is a process of reducing the herein is between about 3.0 and about 12.0. In some embodi average diameter of particles of a solid material. In some ments, the pH of a formulation described herein is between embodiments, the average diameter of particles in a micron about 4.5 and about 10.0. In some embodiments, the pH of a ized solid is from about 0.5 um to about 500 um. In some formulation described herein is between about 3.5 and about embodiments, the average diameter of particles in a micron 8.5. In some embodiments, the pH of a formulation described ized solid is from about 1 um to about 200 um. In some herein is between about 5.5 and about 8.0. In some embodi embodiments, the average diameter of particles in a micron ments, the pH of a formulation described herein is between ized solid is from about 2 um to about 100 um. In some about 6.5 and about 8.0. In some embodiments, the pH of a embodiments, the average diameter of particles in a micron formulation described herein is between about 7.0 and about ized solid is from about 3 um to about 50 um. In some 7.8. In some embodiments, the pH of a formulation described embodiments, the use of multiparticulates of active agent herein is between about 7.0 and about 7.6. In some embodi allows for extended and/or sustained release of the active ments, the pH of a formulation described herein is between agent from any formulation described herein compared to a about 7.0 and about 7.4. In some embodiments, the pH of a formulation comprising non-multiparticulate or a water formulation described herein is between about 7.4 and about soluble active agent. 7.8. 0294. In specific embodiments, upon administration of a 0291. In some embodiments, the formulations described Sustained release pharmaceutical formulation comprising herein have a pH and/or practical osmolarity as described micronized active agent to an individual in need thereof, the herein, and have a concentration of active pharmaceutical micronized active agent particles serve as a depot for further ingredient between about 1 uM and about 10 uM, between extended release of the active agent even after the gel has about 1 mM and about 100 mM, between about 0.1 mM and eroded. In some of Such embodiments, the micronized par about 100 mM, between about 0.1 mM and about 100 nM. In ticles remain adhered to active surfaces. Accordingly, in some some embodiments, the formulations described herein have a embodiments, Sustained release pharmaceutical formulations pH and/or practical osmolarity as described herein, and have suitable for methods described herein comprise substantially a concentration of active pharmaceutical ingredient between high concentrations of micronized active agent. In some of about 0.01%-about 40%, between about 0.01%-about 20%, Such embodiments, Sustained release pharmaceutical formu between about 0.01%-about 10%, between about 0.01%- lations are suspensions comprising micronized active agents. about 7.5%, between about 0.01%-6%, between about 0.01 0295. In some instances, any particle in any formulation 5%, between about 0.1%-about 40%, between about 0.1%- described herein is a coated or uncoated particle (e.g., a about 30%, between about 0.1%-about 20%, between about coated micronized particle, nano-particle) and/or a micro 0.1-about 10%, or between about 0.1-about 6% of the active sphere and/or a liposomal particle. Particle size reduction ingredient by weight of the formulation. In some embodi techniques include, by way of example, grinding, milling ments, formulations described herein have a pH and/or prac (e.g., air-attrition milling (jet milling), ball milling), coacer tical osmolarity as described herein, and have a concentration Vation, complex coacervation, high pressure homogeniza of active pharmaceutical agent between about 1%-about tion, spray drying and/or Supercritical fluid crystallization. In 40%, between about 5%-about 40%, between about 10%- Some instances, particles are sized by mechanical impact about 40%, between about 15%-about 40%, between about (e.g., by hammer mills, ball mill and/or pin mills). In some 10%-about 30%, between about 10%-20%, between about instances, particles are sized via fluid energy (e.g., by spiral 15%-about 25%, or between about 20%-30%, of the active jet mills, loop jet mills, and/or fluidized bedjet mills). ingredient by weight of the formulation. In some embodi 0296. In some embodiments formulations described ments, the formulations described herein have a pH and/or herein comprise crystalline particles and/or isotropic par practical osmolarity as described herein, and have a concen ticles. In some embodiments, formulations described herein tration of active pharmaceutical ingredient between about 1 comprise amorphous particles and/oranisotropic particles. In pg/mL and about 500 g/mL, between about 1 g/mL and Some embodiments, formulations described herein comprise about 250 ug/mL, between about 1 Jug and about 100 ug/mL, therapeutic agent particles wherein the therapeutic agent is a between about 1 g/mL and about 50 lug/mL, or between free base, or a salt, or a Solvate, or a prodrug of a therapeutic about 1 lug/mL and about 20 ug/mL of the active agent by agent, or any combination thereof. Volume of the formulation. 0297 As illustrated in FIG. 2, compositions comprising multiparticulate (e.g., micronized) active agents provide Tunable Release Characteristics extended release over a longer period of time compared to 0292 Particle Size compositions comprising non-particulate and/or water 0293 Size reduction is used to increase surface area and/ soluble active agents. In some instances, the multiparticulate or modulate formulation dissolution properties and/or to and/or less water-soluble active agent provides a steady Sup maintain a consistent average particle size distribution (PSD) ply (e.g., +/-20%) of active agent via slow degradation and US 2012/0277199 A1 Nov. 1, 2012 serves as a depot for the active agent. Such a depot effect Such a drug from a mineral acid salt (e.g., hydrochloric acid or increases residence time of the active agent in the ear. In Sulfuric acid salts) to a salt of a small to medium sized organic specific embodiments, selection of an appropriate particle acid (e.g., a citrate, maleate, nicotinate, or besylate salt or the size of the active agent (e.g., micronized active agent) and like). By way of example, dexamethasone acetate is less solubility of the active agent is water, in combination with the soluble than dexamethasone hydrochloride in biological and/ amount of thermosensitive polymer component in the com or aqueous fluids. By way of example, a water Soluble active position, provides tunable extended release characteristics agent has a solubility of 210 mg/mL. An active agent that has that allow for release of an active agent overa period of hours, been rendered less soluble or insoluble in aqueous and/or days, weeks or months. biological media has a water solubility of less than 10 mg/mL, 0298 Solubility less than 1 mg/mL or less than 0.1 mg/mL. The release profile 0299 The release characteristics of an active agent from a of an active agent and/or any salts thereof is compared using formulation described herein are tuned by modifying the solubility of the active agent in biological and/or aqueous in vitro and in vivo procedures described herein. media. One approach to extend release of an active agent is to 0304. A second approach for controlling the dissolution desolubilize the soluble active agent. Solubility of the drug in and/or release profile of an active agent is to form a complex biological and/or aqueous fluids is modified by selection of a of an active agent with a complexation agent that hinders pharmacologically acceptable salt that is insoluble or has a dissolution of the active agent in biological and/or aqueous lower solubility than the drug alone or a different salt of the media. Examples of Such complexation agents include and drug. In certain instances, solubility of the drug in biological are not limited to cryptands (e.g., 2.2.2cryptand, diaza-18 and/or aqueous fluids is modified by selection of crystalline crown-6), cyclodextrins, crown ethers (e.g., 12-crown-4,15 salt forms (polymorphs) that are insoluble or have lower crown-5,18-crown-6, dibenzo-18-crown-6 or the like), or the solubility than other salt forms or the drug alone. like. In further instances, by way of example, anionic active 0300. By way of example, in the case of anionic drugs agents, cationic (e.g., amine based) active agents and Zwitte (e.g., active agents bearing acidic moieties like carboxylic rionic active agents are rendered insoluble or less soluble in acids, phosphates, Sulfates, or the like) a soluble drug is biological and/or aqueous media by complexation with poly rendered insoluble or less soluble in biological and/or aque mers (e.g., hyaluronic acid), insoluble organic compounds ous fluids by exchanging the counterion from a Group I metal (e.g., Surfactants such as phospholipids), or polyvalent metal ion (e.g., Sodium or potassium), to a counterion from group II ions (e.g., multimeric complexes with cesium, calcium, mag of the periodic table (e.g., calcium or magnesium) or any nesium, iron, zinc, or the like). By way of example, complex other polyvalent cation (e.g., iron, Zinc, barium, cesium or the coacervation of proteins (e.g., insulin) with bovine serum like). By way of example, an oligonucleotide anionic drug albumin (BSA) or gelatin modifies the dissolution and/or (e.g., alicaforsen) is rendered insoluble or less soluble in release profile of a protein from a formulation described biological and/or aqueous media by formation of a calcium herein. salt thereof. By way of example, a protein (e.g., insulin) is 0305. By way of example, the amount of a systemically rendered insoluble or less soluble in biological and/or aque administered (e.g., oral or intravenously administered) bis ous fluids by formation of a zinc salt thereof. phosphonate reaching the perilymph in the inner ear and/or 0301 By way of example, for cationic drugs (e.g., active otic bone structure is about 0.6 ng/day for rosidronate, and agents containing primary, secondary, or tertiary aliphatic or about 0.1 ng/day for Zoledronic acid and alters cochlear func aromatic amines), a soluble drug is rendered insoluble or less tion. The formulations described herein deliver a more thera soluble in biological and/or aqueous fluids by formulating at peutically effective amount of a bisphosphonate to the peri or above the pKa of at least one of the amine moieties. By way lymph and/or active capsule compared to a bisphosphonate of example, for a pKa of ~5 for an amine moiety in a drug, a that is administered via a systemic route thus reducing toxic formulation at a pH>5 reduces the solubility of the drug in ity of bisphosphonates. By way of example, an extended biological and/or aqueous fluids. By way of example, mecliz release formulation of Zoledronate (e.g., a formulation com ine is insoluble in water with two amine groups (pKa of ~5 prising a complex of Zoledronate with calcium ions) releases and 9), however it is readily solubilized in a poloxamer for a therapeutically effective amount of Zoledronate reducing mulation when the pH of the solution is maintained below a any toxicity caused by higher amounts of Zoledronate that pH of 5.5, and it is insoluble in a poloxamer formulation could altercochlearfunction (e.g., by calcium depletion in the above a pH of 6. By way of example, when an active agent is delivery site). FIG. 6 illustrates a comparison of the in vitro a cationic drug (e.g., an agent bearing at least one amine mean dissolution time (MDT) for a 16% P407 formulation moiety with a pKa ~5), apoloxamer gel formulation at a pH of comprising Zoledronate versus a 16% P407 formulation com 4.5 has a lower mean dissolution time (MDT) compared to a prising a complex of Zoledronate with calcium. Complex poloxamer formulation at a pH of 7.4. ation with calcium increases the mean dissolution time of 0302) In addition, modifying the solubility of the active Zoledronate from 2 hours to 8 hours. agent can also have an effect on the properties of the ther 0306 Yet another approach to tune the release profile of an mosensitive gel. By way of example, amitriptyline is water active agent from a formulation described herein is to com soluble (greater than 100 mg/mL) and increases the gelation plex a salt or free base of an active agent with a polyelectro temperature of a poloxamer formulation. Reducing the solu lyte (e.g., poly(sodium styrene Sulfonate), polyacrylic acid, bility of amitriptyline (e.g., by formation of a prodrug) allows polyamines or the like). The ionic interactions between the fortuning of the gelation temperature of a poloxamer formu polyelectrolyte and the salt or free base of the active agent lation. modify the dissolution characteristics of the active agent in 0303. Further, cationic drugs (e.g., drugs with one or more biological and/or aqueous fluids. By way of example, solu amine moieties) are rendered insoluble or less soluble in bility of genetic material in biological and/or aqueous media biological and/or aqueous media by exchanging the Salt of is modified by addition of cationic polymers and/or formation US 2012/0277199 A1 Nov. 1, 2012 24 of cationic micelles. The release profile of an active agent and n=1 characterizes an erosion controlled mechanism. The a complex thereof is compared using in vitro and in vivo mean dissolution time (MDT) is the sum of different periods procedures described herein. of time the drug molecules stay in the matrix before release, 0307 A further approach to extend the release profile of an divided by the total number of molecules and is optionally active agent from a formulation described herein is to use calculated by: prodrugs of an active agent. An active agent (anionic, cat ionic, Zwitterionic or neutral) is rendered insoluble or less soluble in biological and/or aqueous media by formation of a DT = klin prodrug that is insoluble or less soluble in biological and/or n + 1 aqueous media than the drug alone. Such prodrugs are formed by covalent attachment of a moiety (e.g., an ester, or amide of a bulky or waterinsoluble group Such as benzoic acid, amines, 0313. In some embodiments, the MDT for an active agent fatty acids, cyclic or aromatic acids or alcohols, polymeric from a formulation described herein is from about 30 hours to chains, or the like) to the parent drug. The release profile of an about 1 week. In some embodiments, the MDT for a formu active agent and a prodrug thereof is compared using in vitro lation described herein is from about 1 week to about 6 weeks. and in vivo procedures described herein. 0314. In some embodiments, the mean residence time 0308 A further approach to tuning the dissolution prop (MRT) for an active agent in a formulation described herein is erties and/or release profile of an active agent is to coat from about 20 hours to about 48 hours. In some embodiments, particles of the active agent with certain Sustained release the MRT for an active agent from a formulation described excipients (e.g., hydroxypropylmethyl cellulose, carboxym herein is from about 20 hours to about 96 hours. In some embodiments, the MRT for an active agent from a formula ethylcellulose or the like). By way of example, an active agent tion described herein is from about 20 hours to about 1 week. is micronized and the micronized particles are coated with In some embodiments, the MRT for an active agent from a Sustained release excipients; the coated active agent particu formulation described herein is from about 1 week to about 6 lates are then formulated in any of the compositions described weeks. herein. 0315. In some embodiments, middle or external ear for 0309 Active Agent Concentration mulations described herein allow for maintenance of thera 0310. The release profile of an active agent is tuned by peutic levels of active agent in dry ear conditions or wet ear changing the concentration of an active agent in the formu conditions. By way of example, a formulation described lation. By way of example, at increased concentration of an herein comprising ciprofloxacin, about 40-60% of a thermor active agent, a) initial drug levels reached in the inner ear (as eversible polymer, a buffer and an additional solvent such as measured in perilymph) are high and b) there is an increase in ethanol provides a Sustained release of ciprofloxacin for at the duration of exposure. FIG.3 illustrates a dose proportion least 7 days and the drug levels detected in middle ear fluids ality effect of the drug when formulated in a poloxamer gel. are about the same as or higher than the minimum inhibitory FIG. 4 illustrates the dose proportionality effect in vitro in a concentration (MIC), i.e., such a formulation provides cipro release kinetic assay in which increasing the drug concentra floxacin concentrations of > 1 g/mL in the middle ear fluids tion is associated with an increase in the mean dissolution (MEF) for at least 7 days. In an other example, a formulation time. An increase in active agent concentration in the formu comprising dexamethasone, about 40-60% of a thermor lation prolongs residence time and/or MDT of the active eversible polymer, a buffer and an additional solvent such as agent in the ear. ethanol provides a Sustained release of dexamethasone for at 0311. In some embodiments, the MDT for an active agent least 7 days and the drug levels detected in middle ear fluids from a formulation described herein is from about 30 hours to are >1-40mcg/mL for at least 7 days. FIG.15-19 illustrate the about 48 hours. In some embodiments, the MDT for an active Sustained release profiles of otic agents from formulations agent from a formulation described herein is from about 30 described herein when the formulations are administered in hours to about 96 hours. A linear relationship between the the middle ear. FIG. 20 illustrates the sustained release char formulations mean dissolution time (MDT) and the P407 acteristics of the formulations described herein when com (also known as PF-127, Pol-407. Pluronic-127) concentration pared with release characteristics of Ciprodex(R). FIG. 21 is a indicates that the active agent is released due to the erosion of comparison of therapeutic efficacy for an otic Solution the polymer gel (poloxamer) and not via diffusion. A non (Ciprodex(R) and formulations described herein and illus linear relationship indicates release of active agent via a com trates the minimal hearing shifts that occur upon administra bination of diffusion and/or polymer gel degradation. tion of gel formulations described herein. 0312 The MDT is inversely proportional to the release 0316 Gel Strength rate of an active agent from a composition described herein. 0317. The gel strength and concentration of the active Experimentally, the released active agent is optionally fitted agent affects release kinetics (e.g., mean dissolution time) of to the Korsmeyer-Peppas equation: an active agent from the composition. For example, at low poloxamer concentration, elimination rate is accelerated (Mean Dissolution time (MDT) is lower). FIG. 5 illustrates in 9 = k + b vitro mean dissolution time of high versus low solubility drug Substances and Solution versus gel formulations. 0318. In some embodiments, the MDT for poloxamer where Q is the amount of active agent released at time t, Q is from a formulation described herein is at least 6 hours. In the overall released amount of active agent, k is a release some embodiments, the MDT for poloxamer from a formu constant of the nth order, n is a dimensionless number related lation described herein is at least 10 hours. In some embodi to the dissolution mechanism and b is the axis intercept, ments, the MDT for poloxamer from a formulation described characterizing the initial burst release mechanism wherein herein is at least 24, 48, 60, 100, 150, 200 or 250 hours. The US 2012/0277199 A1 Nov. 1, 2012
MDT is determined using techniques described herein in, for least 7 days. In some embodiments, pharmaceutical formula example, Example 6. FIG. 7 illustrates the MDT for certain tions provided herein provide Sustained release of an active formulations. agent (e.g., a corticosteroid, an antibiotic) for a period of at 0319. In some embodiments, the Mean Residence Time least 8 days. In some embodiments, pharmaceutical formula (MRT) of an active agent in the perilymph for any formulation tions provided herein provide Sustained release of an active described herein is between about 5, 7, 10, 15, 20, 24, 36, 48, agent (e.g., a corticosteroid, an antibiotic) for a period of at 60, 70 or 80 hours and about 100, 200, 300, 400, 500 or 600 least 9 days. In some embodiments, pharmaceutical formula hours. FIG. 8 illustrates the MRT for dexamethasone (Dex), tions provided herein provide Sustained release of an active dexamethasone sodium phosphate (DSP), and dexametha agent (e.g., a corticosteroid, an antibiotic) for a period of at Sone acetate (DA) from certain formulations following least 10 days. In some embodiments, pharmaceutical formu intratympanic injection in guinea pigs. FIG. 9 illustrates the lations provided herein provide Sustained release of an active MRT for soluble form or methylprednisolone (MPS) and agent (e.g., a corticosteroid, an antibiotic) for a period of at insoluble form of methylprednisolone (MP) from certain for least 2 weeks. In some embodiments, pharmaceutical formu mulations following intratympanic injection in guinea pigs. lations provided herein provide Sustained release of an active FIG.10 illustrates the MRT for 0.6%L-701324 in 17% polox agent (e.g., a corticosteroid, an antibiotic) for a period of at amer 407 formulation following intratympanic injection in least 3 weeks. In some embodiments, pharmaceutical formu guinea pigs. FIG.11 illustrates the MRT for 0.5% SP-600125 lations provided herein provide Sustained release of an active in 17% poloxamer 407 formulation following intratympanic agent (e.g., a corticosteroid, an antibiotic) for a period of at injection in guinea pigs. FIG. 12 illustrates the MRT for 2% least 4 weeks. In some embodiments, pharmaceutical formu meclizine in 17% poloxamer 407 formulation following lations provided herein provide Sustained release of an active intratympanic injection in guinea pigs. agent (e.g., a corticosteroid, an antibiotic) for a period of at 0320 In some embodiments, a composition described least 5 weeks. In some embodiments, pharmaceutical formu herein is a solution of microparticulates or micronized active lations provided herein provide Sustained release of an active agent and is Substantially free of thermosensitive polymer agent (e.g., a corticosteroid, an antibiotic) for a period of at components. In some of Such embodiments, the composition least 7 days. In some embodiments, pharmaceutical formula provides essentially immediate release of an active agent. In tions provided herein provide Sustained release of an active other embodiments, a Suspension of microparticulates or agent (e.g., a corticosteroid, an antibiotic) for a period of at micronized active agent that is substantially free of ther least 6 weeks. In some embodiments, pharmaceutical formu mosensitive polymer components provides intermediate sus lations provided herein provide sustained release of an active tained release of active agent. In certain other embodiments, agent (e.g., a corticosteroid, an antibiotic) for a period of at a formulation comprising microparticulates or micronized least 7 weeks. In some embodiments, pharmaceutical formu active agent and a thermosensitive polymer provides an lations provided herein provide Sustained release of an active extended Sustained release of active agent. As used herein, agent (e.g., a corticosteroid, an antibiotic) for a period of at immediate release of an active agent refers to Substantially least 8 weeks. In some embodiments, pharmaceutical formu complete release of an active agent from the formulation in lations provided herein provide Sustained release of an active less than about 5 hours. As used herein, Sustained release agent (e.g., a corticosteroid, an antibiotic) for a period of at refers to extended release of an active agent from a formula least 3 months. In some embodiments, pharmaceutical for tion Such as, for example, a Sustained release of active agent mulations provided herein provide Sustained release of an over at least 2, 3, 5, 7, 14, 21, 28 days, or at least 1, 2, 3, 4, 5 active agent (e.g., a corticosteroid, an antibiotic) for a period or 6 months or 1 year. of at least 4 months. In some embodiments, pharmaceutical 0321. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 5 months. In some embodiments, pharmaceutical least 1 day. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 6 months. In some embodiments, pharmaceutical least 2 days. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 7 months. In some embodiments, pharmaceutical least 2 days. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 8 months. In some embodiments, pharmaceutical least 3 days. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 10 months. In some embodiments, pharmaceutical least 4 days. In some embodiments, pharmaceutical formula formulations provided herein provide sustained release of an tions provided herein provide Sustained release of an active active agent (e.g., a corticosteroid, an antibiotic) for a period agent (e.g., a corticosteroid, an antibiotic) for a period of at of at least 12 months. least 5 days. In some embodiments, pharmaceutical formula 0322 The release profile can also be modified by the for tions provided herein provide Sustained release of an active mation of cocrystals (norfloxacin is known to form cocrystal, agent (e.g., a corticosteroid, an antibiotic) for a period of at Crystal Growth & Design, Vol. 6, No. 12, 2006 Basavoju et least 6 days. In some embodiments, pharmaceutical formula al.) As an example ciprofloxacin free base forms cocrystals tions provided herein provide Sustained release of an active with dexamethasone that will modify the release profile of the agent (e.g., a corticosteroid, an antibiotic) for a period of at cocrystals. The MDT of ciprofloxacin (Cipro)/dexametha US 2012/0277199 A1 Nov. 1, 2012 26 sone (Dex) or dexamethasone phosphate (DSP) suspensions used in the formulation. By way of example, intratympanic in 16% P407 are manipulated by the formation of cocrystal or administration of DSP in either an aqueous or hydrogel inclusion-crystal as seen in the table below vehicle in guinea pigs resulted in limited inner ear exposure (AUC values ranging from 28 to 57 ugh/ml) and rapid elimi nation from inner ear compartment (MRT of 4-7h). However, administration of a less soluble form of the drug, i.e., DEX or Crystal DA in either aqueous or hydrogel vehicle led to higher dex Sample MDT Cipro MDT Dex Structure amethasone exposure in the perilymph (AUC of 84-359 ug.h/ 2% Cipro/0.67% Dex in 16% P407 187 83 Needles ml) and prolonged residence time (MRT 17-82 h). 2% Cipro/0.67% Dex in 16% P407 93 37 Plates 2% Cipro in 16% P407 187 Needles 0329. By way of example, the inner ear profile of methyl 0.6% Dex in 16% P407 17 prednisolone is tunable via the use of soluble (MPS) and 2% Cipro/0.67% DSP in 16% 169 11 Needles water insoluble (MP) forms. Methylprednisolone levels in the P4O7 perilymph peaked rapidly following intratympanic adminis O.67% DSP in 16% P4O7 Less tration of the MPS hydrogel in guinea pigs at 6.5 ug/ml and than 3 decreased to a fraction of the peak levels (0.8-1.0%) within 3 days. In contrast, administration of a formulation comprising 0323. The release profile of an active agent from a solution the less soluble MP resulted in higher peak levels (19.2 ug/ml) or Suspension or gel formulation is tunable as described that decreased slowly over 10 days. above. Accordingly, in certain embodiments, a Suspension of 0330. Thus, in certain embodiments, the nature and the microparticulates or micronized active agent provides inter composition of the vehicle and the degree of aqueous solu mediate Sustained release or extended Sustained release. In bility of the drug present in the formulation affects pharma certain embodiments, a composition comprising a ther cokinetic parameters such as the mean residence time and/or mosensitive polymer and microparticulate or micronized exposure in the target area. active agent provides intermediate Sustained release or 0331 In certain instances, once drug exposure (e.g., con extended Sustained release. In certain embodiments, a solu centration in perilymph, sinonasal fluid, spinal fluid or the tion of an active agent provides immediate release or inter like) of a drug reaches steady State, the concentration of the mediate Sustained release. drug stays at or about the therapeutic dose for an extended 0324 Biodistribution period of time (e.g., one day, 2 days, 3 days, 4 days, 5 days, 6 0325 In some embodiments, in vivo distribution of drugs days, or 1 week, 3 weeks, 6 weeks, 2 months). In some from formulations described herein is governed by passive embodiments, the steady state concentration of active agent diffusion. In some embodiments, a formulation comprising a released from a sustained release formulation described thermosensitive gel described herein advantageously allows herein is about 5 to about 20 times the steady state concen for Substantially uniform distribution of an active agent and tration of an active agent released from a formulation that is reduces variability in drug exposure in vivo. For example, not a Sustained release formulation. In some embodiments, Solutions of dexamethasone that do not contain thermosensi the steady state concentration of active agent released from a tive polymers provide uneven distribution (large gradient) of sustained release formulation described herein is about 20 to active agents in the cochlea. FIG. 13 illustrates a substantially about 50 times the steady state concentration of an active uniform distribution of dexamethasone in the chochlea upon agent released from a formulation that is not a Sustained administration of a formulation comprising athermosensitive release formulation. polymer and the uneven distribution of dexamethasone in the 0332. In specific embodiments, any formulation described cochlea upon administration of a dexamethasone solution not herein provides extended release of an active agent for at least containing a thermosensitive polymer-following intratym 7 days, at least 10 days, at least 2 weeks, at least 4 weeks, at panic injection. least 6 weeks, at least 8 weeks, at least 12 weeks, or at least 16 0326 Pharmacokinetics weeks. 0327. The pharmacokinetic profile of active agents released from formulations described herein is dependent on Pharmaceutical Formulations the nature of the vehicle (for example, aqueous solution com prising a thermosensitive polymer versus aqueous Solution 0333 Provided herein are pharmaceutical formulations that does not contain athermosensitive polymer). In addition, that include at least one active agent and a pharmaceutically the pharmacokinetic profile of active agents also depends on acceptable diluent(s), excipient(s), or carrier(s). the physicochemical properties of the active agent as described above. Thus, a combination of an appropriate ther Thermosensitive Gels mosensitive polymer vehicle and physicochemical properties 0334 Polymers composed of polyoxypropylene and poly of a drug provides an optimized release profile. By way of oxyethylene form thermosensitive gels when incorporated example, for a 17% Poloxamer 407 formulation, when either into aqueous solutions. These polymers have the ability to dexamethasone or methylprednisolone is present as a water change from the liquid state to the gel State attemperatures soluble salt, i.e. DSP and MPS, respectively, MDT values are close to body temperature, therefore allowing useful formu about 3 h. However, the MDT values of waterinsoluble forms lations that are applied to the targeted structure(s). The liquid of dexamethasone and methylprednisolone (e.g., DEX, DA state-to-gel state phase transition (gelation temperature) is and MP) range from 40 to 71 h. By way of example, a DSP dependent on the polymer concentration, buffer concentra aqueous solution has a MDT of 0.3 h whereas a micronized tion and the ingredients in the Solution. In some embodi DEX suspension in water has a MDT value of 44 h. ments, a thermosensitive gel Suitable for compositions 0328. In some embodiments, the solubility of the drug described herein is an aqueous gel comprising of a polymer of modulates the pharmacokinetics regardless of the vehicle polyoxypropylene and polyoxyethylene. US 2012/0277199 A1 Nov. 1, 2012 27
0335 Poloxamer is a synthetic block polymer of ethylene described in U.S. Pat. Nos. 6,004,573, 6,117949, 6,201,072, oxide and propylene oxide. Poloxamer 407 (PF-127, P407) is and 6,287,588. It also includes biodegradable polymeric drug a theroreversible polymer composed of polyoxyethylene carriers disclosed in pending U.S. patent application Ser. Nos. polyoxypropylene copolymers. Other poloxamers include 09/906,041, 09/559,799 and 10/919,603. The biodegradable 124, 188 (F-68 grade), 237 (F-87 grade), and 338 (F-108 drug carrier comprises ABA-type or BAB-type triblock grade). Aqueous solutions of poloxamers are stable in the copolymers or mixtures thereof, wherein the A-blocks are presence of acids, alkalis, and metalions. PF-127 (or P407) is relatively hydrophobic and comprise biodegradable polyes a commercially available polyoxyethylene-polyoxypropy ters or poly(orthoester)s, and the B-blocks are relatively lene triblock copolymer, with an average molar mass of hydrophilic and comprise polyethylene glycol (PEG), said 13,000. The polymer can be further purified by suitable meth copolymers having a hydrophobic content of between 50.1 to ods that will enhance gelation properties of the polymer. It 83% by weight and a hydrophilic content of between 17 to contains approximately 70% ethylene oxide, which accounts 49.9% by weight, and an overall block copolymer molecular for its hydrophilicity. It is one of the series of poloxamer ABA weight of between 2000 and 8000 Daltons. block copolymers, whose members share the chemical for 0340. In some embodiments, other thermosensitive poly mula shown below. mers are useful depending upon the particular active agent, other pharmaceutical agent or excipients/additives used, and as such are considered to fall within the scope of the present hydrophilic hydrophilic disclosure. For example, other commercially-available glyc -- -- erin-based gels, glycerin-derived compounds, conjugated, or crosslinked gels, matrices, hydrogels, and polymers, as well as gelatins and their derivatives, alginates, and alginate-based i-to-ch-cro-it-cis-to-ch-cis-rot gels, and even various native and synthetic hydrogel and CH3 hydrogel-derived compounds are all expected to be useful in N--/ the pharmaceutical formulations described herein. In some embodiments, bioacceptable gels include, but are not limited hydrophobic to, alginate hydrogels SAF(R)-Gel (ConvaTec, Princeton, N.J.), Duoderm R. Hydroactive Gel (ConvaTec), Nu-gel(R) 0336 Poloxamers are available in several types, and with (Johnson & Johnson Medical, Arlington, Tex.); CarrasynR varying molecular weights ranging from about 2000 to about (V) Acemannan Hydrogel (Carrington Laboratories, Inc., 15000. The O.-hydro-co-hydroxypoly(oxyethylene), poly(ox Irving, Tex.); glyceringels Elta R. Hydrogel (Swiss-American ypropylene), poly(oxyethylene) block copolymers com Products, Inc., Dallas, Tex.), K-YR) Sterile (Johnson & prise varying ratios of a and b as shown below: Johnson), gelatin hydrogels, chitosan, silicon-base gels (e.g., Medgel(R) or the like. Other thermosensitive and/or bioac ceptable gels suitable for compositions described herein include acrylic acid-based polymers (e.g., CarbopolR), cel poloxamer 8. b lulose based polymers (e.g., hydroxypropylmethyl cellulose, 124 12 2O carboxymethyl cellulose, or the like), alkyl aryl polyether 188 8O 27 alcohol-based polymer (e.g., TyloxapolR), or the like. 237 64 37 Purification poly(oxyethylene)/poly(oxypropylene) Triblock 338 141 44 407 101 56 Polymers 0341. In some embodiments, any active composition described herein comprises purified thermosensitive poly 0337. In certain embodiments, a thermosensitive gel for mer. In some embodiments, any active composition described mulation described herein comprises apoloxamer. In specific herein comprises fractionated a purified thermosensitive embodiments, a thermosensitive gel formulation described polymer composed of polyoxyethylene-polyoxypropylene herein comprises P407. When placed in contact with the copolymers. In some of Such embodiments, the thermosensi body, Such a gel preparation will form a semi-solid structure tive polymer is a poloxamer. and a Sustained release depot. Furthermore, poloxamers (e.g., 0342. The purification of poloxamers is based on the P407) have good solubilizing capacity, low toxicity, and are removal of low molecular weight components (e.g., oligo biocompatible. mers, unreacted material and/or other unwanted impurities 0338. In an alternative embodiment, the thermosensitive that are produced during manufacturing or storage) and/or gel comprises a PEG-PLGA-PEG triblock copolymer (Jeong large molecular weight components (components from et al, Nature (1997), 388:860-2: Jeong et al., J. Control. unwanted polymer-polymer reactions). The resulting purified Release (2000), 63:155-63; Jeong et al. Adv. Drug Delivery product has a narrower PDI with approximately the same Rev. (2002), 54:37-51). The polymer exhibits sol-gel behav molecular weight as the original material. In some embodi ior over a concentration of about 5% w/w to about 40% w/w. ments, a purified poloxamer has better gelling characteristics Depending on the properties desired, the lactide/glycolide (e.g., a lower Tgel for the same '% poloxamer concentration molar ratio in the PLGA copolymer ranges from about 1:1 to while providing a higher viscosity in the gel State). about 20:1. The resulting copolymers are soluble in water and 0343 As used herein, a purified thermosensitive polymer form a free-flowing liquid at room temperature, but form a gel has low polydispersity (i.e., a narrow distribution of molecu at body temperature. lar weights amongst the individual polymer chains therein). 0339 ReGel R is a tradename of MacroMed Incorporated For example, commercially available poloxamers contain for a class of low molecular weight, biodegradable block certain impurities such as poly(oxyethylene) homopolymer copolymers having reverse thermal gelation properties as and poly(oxyethylene)/poly(oxypropylene) diblock poly US 2012/0277199 A1 Nov. 1, 2012 28 mers due to the nature of the manner in which they are (oxyethylene)/poly(oxypropylene) triblock polymers com produced. The relative amounts of these byproducts increase pared to active compositions that comprise non-fractionated as the molecular weights of the component blocks increase. In poly(oxyethylene)/poly(oxypropylene) triblock polymers. Some instances, in commercially available poloxamer 407, 0350 Advantageously, such compositions comprising byproducts may constitute from about 15 to about 50% by lower concentrations of fractionated poly(oxyethylene)/poly weight of the polymer depending upon the manufacturer, (oxypropylene) triblock polymers (e.g., poloxamers) retain thereby resulting in high polydispersity. Example 15 illus gelation properties (e.g., gelation between about 15° C. and trates a procedure for fractionation of P407 that reduces poly about 42°C.) and Sustained release characteristics (e.g., Sus dispersity in commercially available P407. tained release of dexamethasone over at least 3 days, 5 days or 0344. In some embodiments, super critical fluid extraction 7 days) despite having a lower concentration of the poly technique is used to fractionate polyoxyalkylene block (oxyethylene)/poly(oxypropylene) triblock polymer (e.g., copolymers. See, U.S. Pat. No. 5,567,859, the disclosure for poloxamer). fractionation of polymers described therein is incorporated 0351. Accordingly, by way of example, a formulation herein by reference. In this technique, lower molecular comprising micronized dexamethasone and lower concentra weight fractions in commercially purchased polymer are tions of fractionated P407 (e.g., between about 5% to about removed in a stream of CO maintained at a pressure of 2200 14% P407) has gelation properties and/or sustained release pounds per square inch (psi) and a temperature of 40° C. characteristics that are substantially the same or better than thereby providing purified polymer having low polydisper the gelation properties and/or Sustained release characteris S1ty. tics of a formulation comprising micronized dexamethasone 0345. In some embodiments, gel permeation chromatog and non-fractionated P407 (e.g., between about 14.5% to raphy allows for isolation of fractions of polymers. See, Euro about 25% of P407 NF from BASF). pean Patent Application WO92/16484; the use of gel perme ation chromatography to isolate a fraction of poloxamer Gelation Temperature Modifying Agents having low polydispersity and Saturation described therein is 0352. In some embodiments, pharmaceutical formula incorporated herein by reference. tions described herein comprise gelation temperature modi 0346. In some embodiments, one or more of the blocks is fying agents. A 'gelation temperature modifying agent' or a purified prior to manufacture of the copolymer. By way of 'gel temperature modifying agent' is an additive added to any example, purifying either the polyoxypropylene center block formulation described herein, and changes the gelation tem during synthesis of the copolymer, or the copolymer product perature of the formulation such that the gel temperature of itself (See, U.S. Pat. Nos. 5,523,492, and 5,696.298, incor the formulation is maintained between about 14°C. and about porated herein by reference for such disclosure) allows for 42° C. A gel temperature modifying agent increases or manufacture of purified poloxamers. decreases the gelation temperature of any formulation 0347 In some embodiments, fractionation of polyoxy described herein such that the formulation maintains a gela alkylene block copolymers is achieved by batchwise removal tion temperature of between about 14°C. and about 42°C. of low molecular weight species using a salt extraction and 0353. In some embodiments, a gel temperature modifying liquid phase separation technique (See, U.S. Pat. No. 5,800, agent is a gel temperature increasing agent. For example, 711, which process of purification of polymers described where a formulation comprising a thermosensitive polymer therein is incorporated herein by reference). Such fraction has a gelation temperature below 14° C., addition of a gel ation produces polyoxyalkylene block copolymers (e.g., temperature increasing agent (e.g., P188, P388, cyclodextrin, poloxamer 407, poloxamer 188 or the like) having improved carboxymethyl cellulose, hyaluronic acid, Carbopol R, physical characteristics including increased gel strength, Tween 20, Tween 40, Tween 60, Tween 80, Tween 81, Tween decreased polydispersity, higher average molecular weight, 85, n methylpyrrolidone, short chain fatty acid salts (e.g., decreased gelling concentration and/or extended gel dissolu Sodium oleate, sodium caprate, sodium caprylate or the like) tion profiles compared to commercially available poloxamers increases the gelation temperature of the formulation to above (e.g., P407 NF grade from BASF). Other processes for puri 14°C., to between about 14° C. and about 42°C. fication and/or fractionation of polymers are described in, for 0354. In some embodiments, a gel temperature modifying example, U.S. Pat. No. 6,977.045 and U.S. Pat. No. 6,761,824 agent is a gel temperature decreasing agent. For example, which processes are incorporated herein by reference. where a formulation comprising a thermosensitive polymer 0348. In some instances, low molecular weight contami has a gelation temperature above 42°C., addition of a gel nants of polymers (e.g., poloxamers) cause deleterious side temperature decreasing agent (e.g., P188, P388, cyclodextrin, effects in Vivo: the use of purified poloxamers in pharmaceu carboxymethyl cellulose, hyaluronic acid, Carbopol R, tical formulations described herein reduces such in vivo side Tween 20, Tween 40, Tween 60, Tween 80, Tween 81, Tween effects. 85, in methylpyrrolidone, fatty acid salts (e.g., sodium oleate, 0349 Accordingly, also contemplated within the scope of Sodium caprate, Sodium caprylate or the like) decreases the embodiments presented herein are formulations comprising gelation temperature of the formulation to below 42°C., to purified poly(oxyethylene)/poly(oxypropylene) triblock between about 14° C. and about 42°C. polymers that are substantially free of the poly(oxyethylene) 0355. In some embodiments, a gel temperature modifying homopolymers and/or poly(oxypropylene)/poly(oxyethyl agent is a pH sensitive polymer (e.g., chitosan). In some ene) diblock byproducts, thereby narrowing the molecular embodiments, a gel temperature modifying agent is a ther weight distribution of block copolymers, (i.e., providing low mosensitive polymer. In some embodiments, a gel tempera polydispersity). In some embodiments, such purified poly ture modifying agent is an ion-sensitive polymer (e.g., algi (Oxyethylene)/poly(oxypropylene) triblock polymers (e.g., nates gel in the presence of calcium ions). In some fractionated poloxamers) allow for formulation of active embodiments, agel temperature modifying agent is an acrylic compositions that comprise lower concentrations of the poly acid-based polymer (e.g., CarbopolR). In some embodi US 2012/0277199 A1 Nov. 1, 2012 29 ments, a gel temperature modifying agent is a cellulose based 0359 Since the polymer systems of thermosensitive gels polymer (e.g., hydroxypropylmethyl cellulose, carboxym dissolve more completely at reduced temperatures, methods ethyl cellulose, or the like). In some embodiments, a gel of solubilization include adding the required amount of poly temperature modifying agent is an alkyl aryl polyether alco mer to the amount of water to be used at reduced tempera hol-based polymer (e.g., TyloxapolR). tures. Generally after wetting the polymer by shaking, the 0356. In some embodiments, a gel temperature modifying mixture is capped and placed in a cold chamber or in a agent is a poloxamer. By way of example, addition of not thermostatic container at about 0-10°C. in order to dissolve more than about 5% poloxamer 188 to a formulation com the polymer. In some embodiments, the dissolution is carried prising about 16% P407 increases the gelation temperature of out a temperature between about 10° C. and about 20°C. The a 16% P407 formulation by about 5° C. mixture is stirred or shaken to bring about a more rapid dissolution of the thermosensitive polymer. In some instances Gelation Temperature the active agent and/or other pharmaceutically active agent is suspended if it is insoluble in water. The pH/osmolarity of the 0357. In one embodiment, a pharmaceutical formulation formulation is modulated by the addition of appropriate buff described herein is a liquid at about room temperature. In ering agents. certain embodiments, the pharmaceutical formulation is characterized by a phase transition between about room tem Viscosity perature and about body temperature (including an individual with a serious fever, e.g., up to about 42°C.). In some embodi 0360. In some embodiments, a formulation described ments, the phase transition occurs between at least about 1° C. herein contains a thermosensitive polymer Sufficient to pro below body temperature and body temperature, between at vide a viscosity of between about 10,000 and about 1,000,000 least about 2°C. below body temperature and body tempera centipoise. In some embodiments, a formulation described ture, between at least about 3°C. below body temperature and herein contains a thermosensitive polymer Sufficient to pro body temperature, between at least about 4°C. below body vide a viscosity of between about 50,000 and about 1,000,000 temperature and body temperature, between at least about 6° centipoise. In some embodiments, a formulation described C. below body temperature and body temperature, between at herein contains a thermosensitive polymer Sufficient to pro least about 8°C. below body temperature and body tempera vide a viscosity of between about 150,000 and about 1,000, ture, between at least about 10° C. below body temperature 000 centipoise. In some embodiments, a formulation and body temperature, between at least about 15° C. below described herein contains a thermosetting polymer sufficient body temperature and body temperature, or between at least to provide a viscosity of between about 50,000 and about about 20°C. below body temperature and body temperature. 600,000 centipoise. In some embodiments, a formulation 0358. In some embodiments, a formulation described described herein contains a thermosensitive polymer suffi herein has a gelation temperature of between about 5°C., 10° cient to provide a viscosity of between about 100,000 and C., 14°C., 15°C., 16°C., 17°C., 18°C., 19°C., or 20°C., and about 500,000 centipoise. In some embodiments, a formula about 25°C., 28°C., 30° C., 33°C., 35° C., 37° C., 40° C. or tion described herein contains athermosensitive polymer Suf 42°C. In some embodiments, a formulation described herein ficient to provide a viscosity of between about 150,000 and has a gelation temperature of between about 5° C. and about about 400,000 centipoise. By way of example, a thermosen 42°C. In some embodiments, a formulation described herein sitive polymer concentration of about 15.5% in a composition has a gelation temperature of between about 10°C. and about described herein provides an apparent viscosity of about 270, 42°C. In some embodiments, a formulation described herein 000 cp. By way of example, a thermosensitive polymer con has a gelation temperature of between about 14°C. and about centration of about 16% in a composition described herein 42°C. In some embodiments, a formulation described herein provides an apparent viscosity of about 360,000 cp. By way of has a gelation temperature of between about 14°C. and about example, a thermosensitive polymer concentration of about 40°C. In some embodiments, a formulation described herein 17% in a composition described herein provides an apparent has a gelation temperature of between about 14°C. and about viscosity viscosity of about 480,000 cp. 37°C. In some embodiments, a formulation described herein 0361. In some embodiments, the formulations described has a gelation temperature of between about 14°C. and about herein are low viscosity formulations at body temperature. In 35°C. In some embodiments, a formulation described herein Some embodiments, a low viscosity formulation described has a gelation temperature of between about 16°C. and about herein provides an apparent viscosity of from about 100 cp to 35°C. In some embodiments, a formulation described herein about 10,000 cP. has a gelation temperature of between about 18°C. and about 0362. In some embodiments, a formulation described 35°C. In some embodiments, a formulation described herein herein contains a viscosity enhancing polymer Sufficient to has a gelation temperature of between about 20° C. and about provide a viscosity of between about 1,000 and about 1,000, 42°C. In some embodiments, a formulation described herein 000 centipoise at body temperature. In some embodiments, a has a gelation temperature of between about 20° C. and about formulation described herein contains a viscosity enhancing 37°C. In some embodiments, a formulation described herein polymer sufficient to provide a viscosity of between about has a gelation temperature of between about 20° C. and about 1,000 and about 500,000 centipoise at body temperature. In 35°C. In some embodiments, a formulation described herein Some embodiments, a formulation described herein contains has a gelation temperature of between about 20° C. and about a viscosity enhancing polymer Sufficient to provide a viscos 30°C. In some embodiments, a formulation described herein ity of between about 1,000 and about 250,000 centipoise at has a gelation temperature of between about 20° C. and about body temperature. In some embodiments, a formulation 28°C. In some embodiments, a formulation described herein described herein contains a viscosity enhancing polymer Suf has a gelation temperature of between about 20° C. and about ficient to provide a viscosity of between about 1,000 and 250 C. about 100,000 centipoise at body temperature. US 2012/0277199 A1 Nov. 1, 2012 30
0363. In one embodiment, administration of any formula herein comprises between about 15% and about 75% of a tion described herein at about room temperature (e.g., Viscosity enhancing polymer by weight of the composition. In between about 18° C. to about 28°C.) reduces or inhibits Some embodiments, a formulation described herein com Vertigo associated with intratympanic administration of cold prises between about 30% and about 75% of a viscosity (e.g., temperature below about 18°C.) otic formulations. enhancing polymer by weight of the composition. In some 0364. In some embodiments, use of a higher concentration embodiments, a formulation described herein comprises of active agent results informulations having higher viscosity between about 35% and about 75% of a viscosity enhancing compared to formulations have lower concentration of active polymer by weight of the composition. In some embodi agents. As shown in Example 15, increase in concentration of ments, a formulation described herein comprises between drug in the formulation, and use of purified poloxamer, allows about 40% and about 75% of a viscosity enhancing polymer for use of lower concentrations of thermosensitive polymer by weight of the composition. In some embodiments, a for by weight of the formulation. mulation described herein comprises between about 45% and 0365. The viscosity is measured at a shear rate of 0.31 s' about 75% of a viscosity enhancing polymer by weight of the using a cone/plate viscometer (Brookfield DVII+Pro viscom composition. In some embodiments, a formulation described eter with a CP50 spindle at 0.08 rpm as a reference). herein comprises between about 45% and about 65% of a 0366. In some embodiments, a formulation described Viscosity enhancing polymer by weight of the composition. In herein comprises between about 0.1%, 0.5%, 1%, 2%, 3%, Some embodiments, a formulation described herein com 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, prises between about 40% and about 60% of a viscosity 40%, 45%, 50%, or 55% and about 0.5%, 1%, 5%, 10%, 15%, enhancing polymer by weight of the composition. In some of 20%. 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, Such embodiments, a viscosity enhancing polymer is a hydro 70%, 75% 80% or 89% of a viscosity enhancing polymer. In gel, a thermoreversible polymer, an acrylic acid based poly Some embodiments, a formulation described herein com mer, a pH sensitive polymer, a polymer sensitive to concen prises between about 0.1% and about 50% of a viscosity tration of ions (e.g., alginate gels in the presence of Calcium enhancing polymer by weight of the composition. In some ions) and the like. embodiments, a formulation described herein comprises 0367. In some embodiments, a formulation described between about 0.5% and about 30% of a viscosity enhancing herein comprises between about 10%, 15%, 20%, 25%, 30%, polymer by weight of the composition. In some embodi 35%, 40%, 45%, 50%, or 55% and about 25%, 20%, 25%, ments, a formulation described herein comprises between 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or about 0.1% and about 20% of a viscosity enhancing polymer 89% of athermoreversible polymer. In some of such embodi by weight of the composition. In some embodiments, a for ments, a thermoreversible polymer is a poloxamer. In some mulation described herein comprises between about 0.1% embodiments, the resulting formulation is a thermoreversible and about 10% of a viscosity enhancing polymer by weight of gel, but it need not be thermoreversible; that is, depending on the composition. In some embodiments, a formulation the amount of thermoreversible polymer in the composition, described herein comprises between about 0.1% and about the resulting gel may be thermoreversible or not thermor 1% of a viscosity enhancing polymer by weight of the com eversible. The classification “thermoreversible polymer position. In some embodiments, a formulation described refers to polymers that are capable of forming thermorevers herein comprises between about 0.1% and about 0.5% of a ible gels in the range 15-42 degrees Celsius. In some of Such Viscosity enhancing polymer by weight of the composition. In embodiments, the poloxamer is Pluronic-127 (PF-127, Pol Some embodiments, a formulation described herein com 407). By way of example, a buffered poloxamer 407 solution prises between about 1% and about 30% of a viscosity comprising between about 15-25% of poloxamer exhibits enhancing polymer by weight of the composition. In some thermoreversible gelation properties and degrades in an aque embodiments, a formulation described herein comprises ous environment. By way of example, a buffered poloxamer between about 1% and about 10% of a viscosity enhancing 407 solution comprising between about 35% and about 80% polymer by weight of the composition. In some embodi of poloxamer by weight of the composition and an additional ments, a formulation described herein comprises between solvent such as ethanol exhibits substantially reduced ther about 10% and about 80% of a viscosity enhancing polymer moreversible gelation properties and is substantially stable in by weight of the composition. In some embodiments, a for an aqueous environment. In some of Such embodiments, a mulation described herein comprises between about 10% and formulation comprising between about 35% and about 80% about 50% of a viscosity enhancing polymer by weight of the of poloxamer by weight of the composition, an alcohol (e.g. composition. In some embodiments, a formulation described ethanol) and water exhibits high viscosity (e.g., 5000-8000 herein comprises between about 10% and about 30% of a cP) at about room temperature (e.g., about 25°C.) or about Viscosity enhancing polymer by weight of the composition. In body temperature (e.g., about 37°C.-42°C., including indi Some embodiments, a formulation described herein com viduals with a fever). prises between about 20% and about 75% of a viscosity 0368. In some embodiments, a formulation described enhancing polymer by weight of the composition. In some herein comprises between about 10% and about 80% of embodiments, a formulation described herein comprises PF-127 by weight of the composition. In some embodiments, between about 20% and about 65% of a viscosity enhancing a formulation described hereincomprises between about 10% polymer by weight of the composition. In some embodi and about 75% of PF-127 by weight of the composition. In ments, a formulation described herein comprises between Some embodiments, a formulation described herein com about 20% and about 50% of a viscosity enhancing polymer prises between about 15% and about 75% of PF-127 by by weight of the composition. In some embodiments, a for weight of the composition. In some embodiments, a formu mulation described herein comprises between about 25% and lation described herein comprises between about 20% and about 75% of a viscosity enhancing polymer by weight of the about 75% of PF-127 by weight of the composition. In some composition. In some embodiments, a formulation described embodiments, a formulation described herein comprises US 2012/0277199 A1 Nov. 1, 2012
between about 25% and about 75% of a thermoreversible profiles of otic agents in middle ear fluids from compositions polymer of PF-127 by weight of the composition. In some comprising water and a mixture of water and ethanol as embodiments, a formulation described herein comprises solvent. FIG. 16 shows a comparison of in vivo release pro between about 30% and about 75% of a thermoreversible files of otic agents in middle ear fluids from compositions polymer of PF-127 by weight of the composition. In some comprising water and a mixture of water and ethanol as embodiments, a formulation described herein comprises solvent. between about 35% and about 75% of PF-127 by weight of 0373. In some embodiments, in a formulation described the composition. In some embodiments, a formulation herein, the solvent is water. In some embodiments, a formu described herein comprises between about 40% and about lation described herein comprises a mixture of solvents (e.g., 75% of PF-127 by weight of the composition. In some a mixture of water and an alcohol, or the like). In some embodiments, a formulation described herein comprises embodiments, in a formulation described herein the solventis between about 45% and about 75% of PF-127 by weight of a mixture of ethanol and water. the composition. In some embodiments, a formulation described herein comprises between about 45% and about Additional Excipients 65% of PF-127 by weight of the composition. In some 0374. In some embodiments, a formulation described embodiments, a formulation described herein comprises herein further comprises additional biocompatible excipi between about 40% and about 60% of PF-127 by weight of ents. Example of additional excipients include agents for the composition. imaging and/or visualization, penetration enhancers, includ ing and not limited to alkyl saccharides (e.g., dodecyl malto Buffers side, or the like), hyaluronic acid, (including and not limited 0369. In some embodiments, formulations described to Hyalastine(R), HyalectinR), HyaloftilR), and/or partial herein comprise buffers. In one embodiment is a buffer such esters and/or salts thereof (e.g., barium salt of hyaluronic as acetate or citrate buffer at slightly acidic pH. In one acid, or any other salt of hyaluronic acid described in embodiment the buffer is a sodium acetate buffer having a pH WO/1998/017285, salts described therein are incorporated of about 4.5 to about 6.5. In one embodiment the buffer is a herein by reference), hyaluronidase (e.g., PH-20 (Hal sodium citrate buffer having a pH of about 5.0 to about 8.0, or Zoyme)) or any other excipient that modulates release profile about 5.5 to about 7.0. and/or stability and/or permeability and/or drug uptake and/ 0370. In an alternative embodiment, the buffer used is or bioavailability and/or toxicity and/or immunogenicity and/ tris(hydroxymethyl)aminomethane, bicarbonate, carbonate or gelation characteristics of any formulation described or phosphate at slightly basic pH. In one embodiment, the herein. Additional excipients are described in U.S. applica buffer is a sodium bicarbonate buffer having a pH of about 6.5 tion Ser. Nos. 12/427,663, 12/466,310, 12/472,034, 12/486, to about 8.5, or about 7.0 to about 8.0. In another embodiment 697, 12/493,611, 12/494,156, 12/500,486, 12/504,553, the buffer is a sodium phosphate dibasic buffer having a pH of 12/506,091, 12/506,127, 12/506,573, 12/506,616, and about 6.0 to about 9.0. 12/506,664, the disclosure of excipients described therein is 0371. In some embodiments, the concentration of the incorporated herein by reference. buffer component is adjusted to bring the practical osmolarity of any formulation described herein within a biocompatible Dosing Methods range. 0375. In some embodiments, formulations described herein are perfused in auditory and/or sinonasal structures. In Solvents Some embodiments, formulations described herein are administered via needle or cannula or catheter in intrasinu 0372. In some embodiments, the release profile of a thick soidal cavities or in the vicinity of sinusoidal structures (e.g., ened formulation is modified by selection of an appropriate nasal polyps, Swollen turbinates), in intrathecal space, in Syn Solvent or combination of Solvents. In some embodiments in ovial spaces, in the ear (e.g., via intratympanic injection, or at a formulation described herein, the solvent is water. In some or near the round window membrane of the ear) or the like. In embodiments, a formulation described herein comprises a Some embodiments, formulations described herein are mixture of solvents (e.g., a mixture of water and an additional administered as drops, paint, foam, in situ Sponge or the like. Solvent Such as an alcohol, or the like). In some embodiments, a formulation described herein comprises additional solvents Frequency of Administration including and not limited to ethanol, propylene glycol, PEG 400, DMSO, N-methylpyrrolidone or any other auris-suitable 0376. In some embodiments, a composition disclosed Solvent. In some embodiments, the additional solvent is a herein is administered to an individual in need thereof once. water-miscible solvent. In some embodiments, following In some embodiments, a composition disclosed herein is administration of a formulation comprising a mixture of sol administered to an individual in need thereof more than once. vents, the additional Solvent diffuses out into the aqueous 0377 The number of times a composition is administered and/or biological fluids thereby thickening the composition. to an individual in need thereof depends on the discretion of In some embodiments, an additional Solvent comprises a medical professional, the disorder, the severity of the dis between about 5% to about 50%, between about 10% to about order, and the individuals's response to the formulation. In 40%, between about 10% to about 30%, or between about Some embodiments, a formulation described herein is admin 10% to about 20% of the solvent present in a formulation istered as prophylactically, therapeutically or as a chronic described herein. By way of example, a formulation treatment over an extended period of time. described herein in comprises water (including water present 0378. In the case wherein the patient's status does in the buffer solution) as the solvent and ethanol as an addi improve, upon the doctor's discretion the administration of tional solvent. FIG. 15 shows a comparison of in vitro release the active agent compounds may be given continuously; alter US 2012/0277199 A1 Nov. 1, 2012 32 natively, the dose of drug being administered may be tempo Formulation B rarily reduced or temporarily Suspended for a certain length of time (i.e., a “drug holiday'). The length of the drug holiday 0383 varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, Quantity (mgg of 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, Ingredient formulation) 250 days, 280 days, 300 days, 320 days, 350 days, and 365 dexamethasone 2O.O BHT O.OO2 days. The dose reduction during a drug holiday may be from Purified Poloxamer 407 12O.O 10%-100%, including by way of example only 10%, 15%, PBS buffer (0.1M) 9.0 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. 0384. A 10-g batch of gel formulation containing 2.0% 0379. Once improvement of the patient's active conditions micronized dexamethasone is prepared. 13.8 mg of Sodium has occurred, a maintenance active agent dose is administered phosphate dibasic dihydrate USP (Fisher Scientific.)+3.1 mg if necessary. Subsequently, the dosage or the frequency of of sodium phosphate monobasic monohydrate USP (Fisher administration, or both, is optionally reduced, as a function of Scientific.)+74 mg of sodium chloride USP (Fisher Scien tific.) is dissolved with 8.2 g of sterile filtered DI water and the the symptoms, to a level at which the improved disease, pH is adjusted to 7.4 with 1M NaOH. The buffer solution is disorder or condition is retained. In certain embodiments, chilled down and a suitable amount of poloxamer 407 (BASF patients require intermittent treatment on a long-term basis Corp., containing approximately 100 ppm of BHT) or puri upon any recurrence of symptoms. fied poloxamer (See Example 15 below) is sprinkled into the chilled PBS solution while mixing, the solution is mixed until Kits/Articles of Manufacture all the poloxamer is dissolved. The poloxamer is sterile fil tered using a 33 mm PVDF 0.22 um sterile syringe filter 0380. In some embodiments, pharmaceutical formula (Millipore Corp.) and delivered to 2 mL sterile glass vials tions described herein are manufactured as ready to use single (Wheaton) in an aseptic environment, the vials are closed component Solutions that are administered to an individual in with sterile butyl rubber stoppers (Kimble) and crimped need thereof. In other embodiments, pharmaceutical formu sealed with 13 mm Al seals (Kimble). 20 mg of micronized lations described herein are manufactured as multi-compo dexamethsone is placed in separate clean depyrogenated nent kits comprising dry-heat sterilized multiparticulate (e.g., vials, the vials are closed with sterile butyl rubber stoppers micronized, nanoparticles, non-sized particles) active agent (Kimble) and crimped sealed with 13 mm Al seals (Kimble), vials are dry heat sterilized (Fisher Scientific Isotemp oven) powder, a medium for reconstitution of the dry powder (e.g., for 7 hours at 140° C. Before administration for the experi sterile water or buffer or saline) and/or a solution comprising ments described herein, 1 mL of the cold poloxamer solution the thermosensitive polymer and a buffer. The dry powder is is delivered to a vial containing 20 mg of Sterile micronized reconstituted with the sterile medium and/or the solution dexamethasone using a 21 G needle (Becton Dickinson) comprising the thermosensitive polymer and buffer just prior attached to a 1 mL sterile Syringe (Becton Dickinson), Sus to administration of the pharmaceutical formulation to an pension mixed well by shaking to ensure homogeneity of the individual in need thereof. suspension. The suspension is then withdrawn with the 21 G syringe and the needle is switched to a 27 G needle for EXAMPLES administration. 0381 Example 1 Examples 2-5 Formulations Comprising Amoxicillin, Moxifloxa Preparation of a Thermosensitive Gel cin, Triamcinolone, and Prednisolone Respectively Dexamethasone Composition Comprising are Prepared Using the Above Procedure Micronized Dexamethasone Powder Example 6 Preparation of a Thermosensitive Gel Zoledronate Formulation A Composition 0382 0385) 16% poloxamer 407 NF in 50 mM TRIS buffer: 0386 Weigh 0.4518 g of sodium chloride (Fisher scien tific)+0.6034 g of tromethamine (Fisher scientific) dissolve with 82 g of DI water, then add 850 uL of5 NHCl to adjust pH Quantity (mgg of to 7.5, osmolality of solution is 277 mOsm/kg. Weigh 67.3 g Ingredient formulation) of above buffer cool down buffer then sprinkle 12.8 g of dexamethasone 2O.O poloxamer 407 NF (Spectrum chemicals) while mixing. Mix BHT O.OO2 until a clear translucid solution is obtained. The solution is Poloxamer 407 16O.O filter-sterilized using a 0.2 um sterilizing filter. PBS buffer (0.1M) 9.0 (0387. A 3.4 mM formulation of Zoledronic acid in 16% P407 in 50 mM TRIS buffer was prepared by dissolving 17.6 mg of Zoledronic acid monohydrate (Betapharma) into 17 g US 2012/0277199 A1 Nov. 1, 2012
of a 16% poloxamer 407 in 50 mM TRIS buffer, and the pH was adjusted to 7.3 with 5N NaOH. TABLE 1 0388 A 3.4 mM formulation of Zoledronic acid com Meclizine formulations in 16% poloxamer 407. plexed with Calcium in 16% P407 in 50 mMTRIS buffer was prepared by dissolving 17.6 mg of Zoledronic acid monohy % Meclizine mg Meclizine QS to with 16% IL of 5N drate (Betapharma) into 17 g of a 16% poloxamer 407 in 50 di-HCI di-HCI P4O7 in TRIS NaOH Final pH mM TRIS buffer, and the pH was adjusted to 7.3 with 5N O.S 26 S.O 12.5 5.5 NaOH. Then 2 mg of calcium chloride dehydrate was added 1 50 S.O 25 S.1 to 2 mL of the above solution, and the mixture was stirred 2 102 S.O 60 7.5 until it was homogeneous. 0389 Dissolution was performed at 37°C. in Snapwells 0394 2% Meclizine di-HCl in 16% Poloxamer 407/2% (6.5 mm diameter polycarbonate membrane with a pore size Poloxamer 188 in TRIS Buffer (Final pH of 4.7): of 0.4 um). 0.2 mL of the formulation was placed into Snap 0395. 100.5g of meclizine di-HCl (MP biomedicals) was well and left to harden, then 0.5 mL of 0.9% saline is placed QS to 5,023 g with a 16% poloxamer 407/2% poloxamer 188 into reservoir and shaken using a Labline orbit shaker at 70 solution in 50 mM TRIS buffer. Twenty microliters of a 5 N rpm. Samples were taken every hour (0.1 mL withdrawn and NaOH was added to adjust pH to 4.7 mixed until clear, filtered replaced with warm buffer). Samples were analyzed for through a 0.22 Lum PES syringe filter. Gelation temperature of Zoledronic acid concentration by UV at 215 nm using an this formulation was 26°C. Evolution 160 UV/Vis spectrophotometer (Thermo Scien tific). Quantitation was performed against an external calibra 0396 2% Meclizine di-HCl in 16% Poloxamer 407/1% tion standard. Poloxamer 188 in TRIS Buffer (Final pH of 6.8). 0397 102.5g of meclizine di-HCl (MP biomedicals) was QS to 5,023 g with a 16% poloxamer 407/1%poloxamer 188 Solution in 50 mM TRIS buffer. Take 1 mL of the above Sample MDT (hr) solution and add 7 ul of a 5 N NaOH was added to adjust pH Zoledronic acid in 16% P407 2 to 6.8, the resulting Suspension was mixed to ensure homo Zoledronic acid-Calcium in 16% P407 8 geneity. Gelation temperature of this formulation was 24°C.
TABLE 2 Example 7 Mean dissolution time in 10 nM PBS buffer pH 7.4 Preparation of a Thermosensitive Gel JNK Inhibitor Sample MDT (hours) Composition 2% Amitriptyline in 16% P407 3 0.5% Meclizine in 16% Poloxamer 407 5 0390. A formulation comprising 0.5% w/w SP600125 in 1% Meclizine in 16% Poloxamer 407 9 16% Poloxamer 407 was made by dispersing 5.3 mg of 2% Meclizine in 16% Poloxamer 407 70 SP600 125 (LC Labs) in 994.7 mg of a 16% P407 in 50 mM Tris buffer. Solubility in the gel was measured to be ~190 ug/mL. The reported water solubility of SP600 125 is 11 TABLE 3 ug/mL with a LogD (7.4) of 3.2 and amp of 183° C. Mean dissolution time in 0.9% sodium chloride (Switched from 0391 Dissolution testing was performed as above. MDT 10 nM PBS to eliminate the effect of buffer on release profile). for a 0.5% SP600 125 in 16% poloxamer 407 gel was calcu Sample MDT (hours) lated to be 60 hours. 2% Meclizine in 16% Poloxamer 407 3.5 2% Poloxamer 188 (pH 4.7) 2% Meclizine in 16% Poloxamer 407 >100 Example 8 1% Poloxamer 188 (pH 6.8) Preparation of a Thermosensitive Gel Vascular Sup pressant Compositions Comprising Poloxamer 407 Alone or in Combination with Poloxamer 188 Example 9 0392) 2% Amitriptyline HCl in 16% Poloxamer 407: Preparation of Thermosensitive Gel Compositions 0393 102 mg of amitriptyline HCl (MP biomedicals) was Comprising Micronized Ciprofloxacin Hydrate Pow QS to 5g with a 16% poloxamer 407 in 50 mM TRIS buffer, der or Ciprofloxacin Powder and Micronized Dex pH of 6.8-; the mixture was stirred until amitriptyline was amethasone Powder dissolved. Tgel measurements were performed using a Brookfield viscometer RVDV-II+P with a CP-51 spindle 0398. The procedure in Example 1 is used to prepare the rotated at 0.08 rpm (shear rate of 0.31 s) equipped with a following formulations, formulations comprising a gel tem temperature control unit (temperature ramped from 15–37°C. perature modifying agent (Formulations A and C) and one at 1.6°C/min). Tgel was measured at 30.7°C. comprising P407 alone (Formulation B). US 2012/0277199 A1 Nov. 1, 2012 34
Formulation A CHEMICALS) is sprinkled into the cold solution while mix ing. The mixture is further mixed until the poloxamer is 0399 completely dissolved. The pH for this solution is measured. 04.05 17% Poloxamer 407/2% Active Agent in PBS pH of 5.3 Quantity (mgg of Ingredient formulation) 0406 Take an aliquot (approximately 30 mL) of the above solution and adjust the pH to 5.3 by the addition of 1 MHC1. Ciprofloxacin hydrate, micronized 1S.O dexamethasone 1S.O (0407 17% Poloxamer 407/2% Active Agent in PBS pH of BHT O.OO2 8.0 Poloxamer 407 18O.O Poloxamer 188 2O.O 0408. Take an aliquot (approximately 30 mL) of the above PBS buffer (0.1M) 9.0 stock solution and adjust the pH to 8.0 by the addition of 1 M NaOH. 04.09. A PBS buffer (pH 7.3) is prepared by dissolving Formulation B 805.5 mg of sodium chloride (Fisher Scientific), 606 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 247 04.00 mg of Sodium phosphate monobasic anhydrous (Fisher Sci entific), then QS to 200 g with sterile filtered DI water. 0410 A 2% solution of an active agent in PBS pH 7.3 is Quantity (mgg of prepared by dissolving an appropriate amount of the active Ingredient formulation) agent in the PBS buffer and QS to 10 g with PBS buffer. ciprofloxacin 1S.O 0411 One mL samples are individually placed in 3 mL dexamethasone 1S.O screw cap glass vials (with rubber lining) and closed tightly. BHT O.OO2 The vials are placed in a Market Forge-sterilmatic autoclave Poloxamer 407 18O.O (settings, slow liquids) and sterilized at 250 F. for 15 min PBS buffer (0.1M) 9.0 utes. After the autoclave the samples are left to cool down to room temperature and then placed in refrigerator. The samples are homogenized by mixing the vials while cold. Formulation C 0412 Appearance (e.g., discoloration and/or precipita tion) is observed and recorded. HPLC analysis is performed 04.01 using an Agilent 1200 equipped with a Luna C18(2) 3 um, 100 A, 250x4.6 mm column) using a 30-80 acetonitrilegra dient (1-10 min) of (water-acetonitrile mixture containing Quantity (mgg of 0.05%TFA), for a total run of 15 minutes. Samples are diluted Ingredient formulation) by taking 30 uL of sample and dissolved with 1.5 mL of a 1:1 Ciprofloxacin 1S.O acetonitrile water mixture. Purity of the active agent in the dexamethasone 1S.O autoclaved samples is recorded. BHT O.OO2 Poloxamer 407 12O.O 0413 Formulations comprising gentamicin, ciprofloxacin Carboxymethylcellulose 6O.O and micronized dexamethasone, prepared according to the PBS buffer (0.1M) 9.0 procedure above, are tested using the above procedure to determine the effect of pH on degradation during the auto claving step. 0402. The gel temperature of Formulations A, B and Care compared. Formulation A is expected to gel at about body temperature, Formulation B is expected to gel at higher than Example 11 body temperature, Formulation C is expected to gel at about body temperature. Thus P188 is expected to be a gel tempera Effect of Buffer Type on the Degradation Products ture lowering agent in Formulation A, and for Formulations Containing Poloxamer 407NF after 0403. Carboxymethylcellulose is expected to be a gel tem Heat Sterilization (Autoclaving) perature increasing agent in Formulation C. 0414 ATRIS buffer is made by dissolving 377.8 mg of Example 10 sodium chloride (Fisher Scientific), and 602.9 mg of Effect of pH on Degradation Products for Auto Tromethamine (Sigma Chemical Co.) then QS to 100 g with claved 17% Poloxamer 407NF/2% Active Agent in sterile filtered DI water, pH is adjusted to 7.4 with 1M HC1. PBS Buffer Stock Solution Containing 25% Poloxamer 407 Solution in 0404 Astock solution of a 17% poloxamer 407/2% active TRIS Buffer: agent is prepared by dissolving 351.4 mg of sodium chloride (Fisher Scientific), 302.1 mg of sodium phosphate dibasic 0415 Weigh 45 g of TRIS buffer, chill in an ice chilled anhydrous (Fisher Scientific), 122.1 mg of sodium phosphate bath then sprinkle into the buffer, while mixing, 15 g of monobasic anhydrous (Fisher Scientific) and an appropriate poloxamer 407 NF (Spectrum Chemicals). The mixture is amount of an active agent with 79.3 g of sterile filtered DI further mixed until all the poloxamer is completely dissolved. water. The solution is cooled down in a ice chilled water bath 0416 A series of formulations is prepared with the above and then 17.05 g of poloxamer 407NF (SPECTRUM stock solution. An appropriate amount of active agent (or salt US 2012/0277199 A1 Nov. 1, 2012
or prodrug thereof) and/or active agent as micronized/coated/ room temperature. The vials are placed in the refrigerator and liposomal particles (or salt or prodrug thereof) is used for all mixed while cold to homogenize the samples. experiments. 0421 HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2) 3 m, 100 A, 250x4.6 mm column) using a 30-80 acetonitrile gradient (1-10 min) of Stock Solution (pH 7.3) Containing 25% Poloxamer 407 (water-acetonitrile mixture containing 0.05% TFA), for a Solution in PBS Buffer: total run of 15 minutes. Samples are diluted by taking 300 uL. 0417 PBS buffer described above is used. Dissolve 704 of sample and dissolving with 1.5 mL of a 1:1 acetonitrile mg of sodium chloride (Fisher Scientific), 601.2 mg of water mixture. Purity of the active agent in the autoclaved sodium phosphate dibasic anhydrous (Fisher Scientific), samples is recorded. The stability of formulations in TRIS and PBS buffers is compared. 242.7 mg of sodium phosphate monobasic anhydrous (Fisher 0422 Viscosity measurements are performed using a Scientific) with 140.4 g of sterile filtered DI water. The solu Brookfield viscometer RVDV-II+P with a CPE-51 spindle tion is cooled down in an ice chilled water bath and then 50 g rotated at 0.08 rpm (shear rate of 0.31 s), equipped with a of poloxamer 407NF (SPECTRUM CHEMICALS) is water jacketed temperature control unit (temperature ramped sprinkled into the cold solution while mixing. The mixture is from 15-34°C. at 1.6°C./min). Tgel is defined as the inflec further mixed until the poloxamer is completely dissolved. tion point of the curve where the increase in Viscosity occurs 0418. A series of formulations is prepared with the above due to the sol-gel transition. Only formulations that show no stock Solution. An appropriate amount of active agent (or salt change after autoclaving are analyzed. or prodrug thereof) and/or active agent as micronized/coated/ 0423 Formulations comprising gentamicin, ciprofloxacin liposomal particles (or salt or prodrug thereof) is used for all and dexamethasone, are tested using the above procedure to experiments. determine the degradation products and Viscosity of a formu 0419 Tables 4 and 5 list samples prepared using the pro lation containing 2% active agent and 17% poloxamer 407NF cedures described above. An appropriate amount of active after heat sterilization (autoclaving). Stability of formula agent is added to each sample to provide a final concentration tions containing micronized active agent is compared to non of 2% active agent in the sample. micronized drug formulation counterparts.
TABLE 4 Example 12 Preparation of samples containing TRIS buffer Modulation of Gel Temperature 25% Stock 0424 The effect of Poloxamer 188 and Dexamethasone Solution TRIS Buffer Sodium phospahate (DSP) on the gelation temperature and Sample pH (g) (g) viscosity of Poloxamer 407 formulations was evaluated with 20% P407.2% active 7.45 8.01 1.82 the purpose of manipulating the gelation temperature. agent TRIS 0425 A 25% Poloxamer 407 stock solution in PBS buffer 18% P407.2% active 7.45 7.22 2.61 and the PBS solution from Example 11 were used. Poloxamer agent TRIS 188NF from BASF was used. 16% P407.2% active 7.45 6.47 3.42 agent TRIS 18% P407.2% active 7.4 7.18 2.64 TABLE 6 agent TRIS 4% active agentTRIS 7.5 9.7 Preparation of samples containing poloxamer 407/poloxaner 188 2% active agentTRIS 7.43 5 1% active agentTRIS 7.35 5 25% P407 Stock Poloxamer PBS Buffer 2% active agentTRIS 7.4 4.9 Sample Solution (g) 188 (mg) (g) (Suspension) 16% P4O7.10% P188 3.2O7 5O1 1.3036 17% P4O7.10% P188 3.4089 500 1.1056 18% P4O7.10% P188 3.61S6 502 O.9072 1990 P4O7.10% P188 3.8183 500 0.7050 TABLE 5 20% P4O7.10% P188 4.008 5O1 OSO32 20% P4O7.5% P188 4.01 256 0.770 Preparation of samples containing PBS buffer (pH of 7.3 25% Stock Solution PBS Buffer 0426. Mean dissolution time (MDT) for the 20% polox Sample in PBS (g) (g) amer 407/10% poloxamer 188 was measured to be 2.2 hr and 20% P407/2% active agent? 8.03 1.82 for the 20% poloxamer 407/.5% poloxamer 188 showed to be PBS 2.6 hr. Table 7 illustrates the change is gel temperature upon 18% P407/2% active agent? 7.1 2.63 incorporation of a mixture of polymers in a composition PBS 16% P407/2% active agent? 6.45 3.44 PBS TABLE 7 18% P407/2% active agent? 2.63 PBS Viscosity and Tgel of formulations containing 2% active agent PBS 4.9 poloxaner 407/poloxaner 188 Max Viscosity (Pas) 0420. One mL samples are individually placed in 3 mL Sample Tgel (C.) Up to 37° C. MDT (hr) screw cap glass vials (with rubber lining) and closed tightly. 16% P4O7.10% P188 37.0 O.1 The vials are placed in a Market Forge-sterilmatic autoclave 17% P4O7.10% P188 35.4 357 (setting, slow liquids) and sterilized at 250°F. for 25 minutes. 18% P4O7.10% P188 33.5 661 After the autoclaving the samples are left to cool down to US 2012/0277199 A1 Nov. 1, 2012 36
TABLE 7-continued TABLE 9-continued
Viscosity and Tgel of formulations containing Max poloxaner 407/poloxaner 188 Formulation Tgel Viscosity Cmax AUC (Modifier) (° C.) (cP) IgmL Ligh/mL MRT h Max Viscosity (Pas) Sample Tgel ( C.) Up to 37° C. MDT (hr) 007-98 (Neat-no 26.4 348868 8.7 1363 56 modifier) 19% P4O7.10% P188 31.2 678 008-13-OL (sodium 21.7 596765 1.O 497 448 20% P4O7.10% P188 28.9 >712 2.2 Oleate) 20% P4O7.5% P188 27.6 >712 2.6 O08-13-T20 (Tween 26.2 36828S 4.3 686S 59 20) 0427. An equation was fitted to the data obtained and can be utilized to estimate the gelation temperature of F127/F68 Example 13 mixtures (for 17-20% F127 and 0-10% F68). In Vitro Comparison of Release Profile 0433 Dissolution is performed at 37°C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 0428. An equation was fitted to the data obtained and can um), 0.2 mL of a gel formulation described herein is placed be utilized to estimate the Mean Dissolution Time (hr) based into snapwell and left to harden, then 0.5 mL buffer is placed on the gelation temperature of F127/F68 mixtures (for into reservoir and shaken using a Labline orbit shaker at 70 17-25% F127 and 0-10% F68), using results obtained in rpm. Samples are taken every hour (0.1 mL withdrawn and example 6 and 8. replace with warm buffer). Samples are analyzed for active agent concentration by UV at 245 nm against an external calibration standard curve. Pluronic concentration is ana Gelation Temperature Modifiers and the Effect on PK in lyzed at 624 nm using the cobalt thiocyanate method. Relative Guinea Pigs after Intratympanic Administration: rank-order of mean dissolution time (MDT) as a function of % P407 is determined A linear relationship between the for 0429 Table 8 describes the following formulations that mulations mean dissolution time (MDT) and the P407 con were prepared: centration indicates that the active agent is released due to the erosion of the polymer gel (poloxamer) and not via diffusion. TABLE 8 A non-linear relationship indicates release of active agent via % P4O7 in a combination of diffusion and/or polymer gel degradation. % SO MTRIS 0434. The MDT is inversely proportional to the release Formulation (Modifier) Dexamethasone 96 Modifier buffer rate of an active agent from a composition described herein. Experimentally, the released active agent is optionally fitted 007-97 T80 (Tween 80) 1.5 1 16 to the Korsmeyer-Peppas equation: 007-97NMP (NMP) 1.5 1 16 007-98 (Neat-no 1.5 16 modifier) 008-13-OL (Na Oleate) 1.5 1 16 008-13-T20 (Tween 80) 1.5 1 16
0430 Samples were prepared using the following general where Q is the amount of active agent released at time t, QC. method. is the overall released amount of active agent, k is a release 0431. A saline-TR is buffer in dionized water was made, constant of the nth order, n is a dimensionless number related followed by the addition of the modifier (or without). The to the dissolution mechanism and b is the axis intercept, osmolality of this mixture was adjusted if necessary to be in characterizing the initial burst release mechanism wherein the 250-300 mOsm/kg. The solution was then chilled and n=1 characterizes an erosion controlled mechanism. The poloxamer 407 was sprinkled in while mixing until a clear mean dissolution time (MDT) is the sum of different periods solution was obtained. This solution was sterile filtered and of time the drug molecules stay in the matrix before release, was delivered to a sterile dexamethasone containing dexam divided by the total number of molecules and is optionally ethasone enough to reach a concentration of 1.5% w/v dex calculated by: amethasone. Tgel and max viscosity were measured as described herein. nklin 0432 Guinea pigs were administered 50 ul via intratym DT = in + 1 panic delivery and PK in the perilymph was measured as described herein. Table 9 describes certain measured values. 0435 Alternatively, samples are analyzed using the TABLE 9 method described by Li Xin-Yu paper Acta Pharmaceutica Sinica 2008, 43(2):208-203 and Rank-order of mean disso Max lution time (MDT) as a function of% P407 is determined. Formulation Tgel Viscosity Cmax AUC (Modifier) (° C.) (cP) IgmL LightmL MRT h Example 14 007-97 T80 (Tween 25.3 422007 618 9638 55 Effect of Poloxamer Concentration and Active Agent 80) Concentration on Release Kinetics 007-97NMP (NMP) 27.6 3631 O7 7.7 11.95 56 0436 A series of compositions comprising varying con centrations of a gelling agent and micronized dexamethasone US 2012/0277199 A1 Nov. 1, 2012 37 was prepared using procedures described above. The mean undissolved salts. The dichloromethane is removed in vacuo dissolution time (MDT) for each composition in Table 3 was and the residue is dried overnight in an oven. determined using procedures described above. Sample Preparation TABLE 6 0442. The following ciprofloxacin/dexamethasone Preparation of poloxameractive agent compositions samples were prepared as follows: Sample pH MDT 0443 Cold 16% P407 in 50 mM TRIS buffers-saline (pH 15.5% P4O71.5% dexamethasone, PBS 7.4 46h 7.4 and osmolality of 280 mOsm) was placed in a open 16% P4O71.5% dexamethasone, PBS 7.4 40 h. container, then ciprofloxacin free base or ciprofloxacin free 17% P4O71.5% dexamethasone, PBS 7.4 39 15.5% P4O7.4.5% dexamethasone, PBS 7.4 >7 days base hydrate (3.5 moles) was sprinkled in while mixing. 16% P407/4.5% dexamethasone, PBS 7.4 >7 days Ciprofloxacin Suspension was mixed for not less than 10 17% P407/4.5% dexamethasone, PBS 7.4 >7 days minutes, then micronized dexamethasone was added slowly to the mixture while mixing. The homogenous Suspension 0437. The effect of gel strength and active agent concen was then transferred to 3 mL vials and filled at different tration on release kinetics of an active agent from the formu Volumens (v1-4g, V2, 3 g and V3 2 g). The glass vial were lation was determined by measurement of the MDT for sealed with West stoppers (fluorotec coated) and Aluminum poloxamer, and measurement of MDT for active agent. The seals, followed by autoclaving at 250 F. for 30 minutes. halflife of the active agent and mean residence time (MRT) of 0444 The following dexamethasone suspensions were the active agent was also determined for each formulation by prepared by dispersing micronized dexamethasone in either measurement of concentration of the active agent in the peri 2% P407 or 10% P407 at a concentration of 28% dexametha lymph using Korsemeyer-Peppas equation as described Sone. One mL of the homogenous Suspension was then trans above. ferred to 20 mL vials. The glass vial were sealed with West stoppers (fluorotec coated) and Aluminum seals, followed by Example 15 autoclaving at 250 F. for 30 minutes. Purification of Poloxamer Compositions of Samples Manufactured. 0438 Method A: 0439 Poloxamer 407 (BASF Corporation, lot 0445 WPEB612B) is dissolved in of 75/25 water/iso-propanol v/v solution. The solution is equilibrated to 27°C. Sodium chlo ride is added with vigorous mixing and the solution is centri fuged to allow two clear, colorless phases to form. The lower % Cipro- % phase is drained and the solution is again diluted to near its Sample % Ciprofloxacin Hydrate Dexamethasone. In % P407 initial weight/volume by the addition of waterfiso-propanol O17-39B 1.5 O.S 16% P4O7 75/25 V/v solution followed by equilibration to 27° C. and O17-39C 1.5 16% P4O7 O17-41A 6 2 16% P4O7 addition of sodium chloride. The solution is centrifuged to O17-41B 3 1 16% P4O7 allow two clear, colorless phases to form. The lower phase is O17-41C 6 16% P4O7 drained a second time and the solution returned to near its O17-43C 28 290 P4O7 original weight by the addition of water/iso-propanol Solution O17-43D 28 10% P4O7 and sodium chloride as described earlier. The resulting solu tion is centrifuged, the lower phase is drained and discarded. The upper phase from the third extraction is dried then Impurity Profile Before and after Autoclaving extracted with chloroform. The chloroform layer is then evaporated in vacuo. The residue is dried under vacuum. 0440 Method B: %. 17-Ketone Tgel 0441 Poloxamer 407 from BASF Corporation, Mount Sample % impurity C Dex % Dehydro-Dex (C.) Olive, N.J., is dissolved in deionized water. The solution is O17-39B O.O2 BLQ BLQ 24.O maintained close to freezing, then ammonium Sulfate is presterile added. The solution is equilibrated at 2° C. and after two O17-39B v1 O16 1.13 O.63 24.1 sterile distinct phases are formed, the lower phase is discarded, and O17-39B v. O16 1.12 O.65 24.1 the upper phase is collected and weighed. Deionized water is sterile added and the solution is equilibrated to 2° C. followed by O17-39B v3 O.17 1.14 O.64 24.1 addition of ammonium sulfate with stirring. After the salt is sterile O17-39C O.O2 BLQ BLQ 24.2 dissolved, the Solution is maintained at approximately 2°C. presterile until two phases formed. The upper phase is isolated and O17-39C v1 O.09 BLQ BLQ 24.2 diluted with deionized water. The solution is chilled to about sterile 2°C. and ammonium sulfate is added. The phases are allowed O17-39C w O.O7 BLQ BLQ 24.3 to separate as above. The upper phase is isolated and extracted sterile O17-39C v3 O.O7 BLQ BLQ 24.2 with dichloromethane. Two phases are allowed to form over sterile night. The organic (lower) phase is isolated and dried over O17-41A O.O2 BLQ BLQ NA sodium sulfate. The dichloromethane phase is filtered presterile through a PTFE filter (0.45 um pore size) to remove the US 2012/0277199 A1 Nov. 1, 2012
Example 17 -continued Preparation of a Thermosensitive Gel Comprising %. 17-Ketone Tgel Dexamethasone and Moxifloxacin Sample % impurity C Dex % Dehydro-Dex (C.) 0451 O17-41A w. O.09 0.55 O.29 NA sterile O17-41B O.O2 BLQ BLQ NA Quantity (mgg of presterile Ingredient formulation) O17-41B v. O.13 1.09 O.62 NA sterile moxifloxacin 1S.O O17-41C BLQ BLQ NA dexamethasone 1S.O presterile BHT O.OO2 Fractionated Poloxamer 407 12O.O O17-41C w O.14 O.36 NA PBS buffer (0.1M) 9.0 sterile O17-43C BLQ BLQ NA presterile 0452. A formulation comprising micronized dexametha O17-43C w O.O2 BLQ NA Sone and moxifloxacin is prepared according to Example 1 sterile above. Fractionated poloxamer is prepared according to O17-43D BLQ BLQ NA Example 15 described herein. presterile O17-43D v2 O.04 BLQ NA Example 18 sterile Preparation of a Composition Comprising Micron ized Dexamethasone Powder and Ciprofloxacin 0446. An appreciable particle size increase is seen after Powder autoclaving when ciprofloxacin free base is used, primarily 2%. Dexamethasone, 2% Ciprofloxacin HCl in 16% Polox seen as an increase in the size of the ciprofloxacin needles. amer 407. When ciprofloxacin free base hydrate is used above a con 0453 115.5 mg of ciprofloxacin HCl (LKT laboratories)+ centration of 3%, minimal growth or recrystallization is 100.2 mg of micronized dexamethasone (Pfizer) was sus observed after autoclaving. pended to a weight of 5 g with a 16% poloxamer 407 in TRIS 0447. Higher viscosity of suspensions made with 2% buffer, pH was adjusted to 7.5 with 60 uL of 5 N NaOH. Ciprofloxacin/0.7% Dex are seen as compared to the viscosi ties observed with a 6% ciprofloxacin hydrate/2% dexam 2% Dexamethasone, 2% Ciprofloxacin HCL in 50% Polox ethasone. Minimal degradation or change is observed when amer 407/25% Ethanol/25% Water. dexamethasone is autoclaved at high concentrations with up 0454 Weigh 2.5 g of pluronic F127 (Sigma Chemical to 10% P4O7. Co)+1.25 g of ethanol (200 proof. Acros). The mixture was dissolved by applying heat (40-60° C.), then 1.25g of water was added while mixing. Example 16 115.6 mg of ciprofloxacin HCl (LKT laboratories)+111.7 mg of micronized dexamethasone (Pfizer) was suspended in the Dry Heat Sterilization of Dexamethasone poloxamer?ethanol/water solution. 0455 The 50% poloxamer 407/25% ethanol/25% water is 0448 Ten milligrams of micronized dexamethsone pow sterile filtered through a 0.22 Lum PES syringe filter. The der (Spectrum lot XD0385) were filled into 2 mL glass vials P407/EtOH/water mixture which has an initial viscosity of and sealed with a 13 mm butyl str rubber stopper (Kimble) about 3000-8000 cp and thickens upon administration. and placed in the oven at different temperatures for 7-11 0456 Dissolution was performed at 37°C. in Snapwells (6.5 mm diameter polycarbonate membrane with a pore size hours. of 0.4 um), 0.2 mL of formulation was placed into snapwell 0449 HPLC analysis was performed using an Agilent and left to harden, then 0.5 mL of 0.9% saline was placed into 1200 equipped with a Luna C18(2)3 um, 100 A, 250x4.6 mm reservoir and shaken using a Labline orbit shaker at 70 rpm. column) using a 30-95 of solvent B (solvent A35% methanol: Samples were taken every hour (0.1 mL withdrawn and 35% water:30% acetate buffer, solvent B 70% methanol:30% replace with warm buffer). Samples analyzed for dexametha sone and ciprofloxacin concentration by UV at 245 and 270 acetate buffer pH 4) gradient (1-6 min), then isocratic (95% nm, respectively using a Evolution 160 UV/Vis spectropho solvent B) for 11 minutes, for a total run of 22 minutes. tometer (Thermo Scientific). Quantitation performed against Samples were dissolved in ethanol and analyzed. Dry-heat an external calibration standard. sterilization of micronized dexamethasone at a temperature of up to 138°C. did not affect particle size distribution of the MDT (hr) MDT (hr) micronized dexamethasone. HPLC analysis indicated 99% Sample Dexamethasone Ciprofloxacin purity of the dry-heat sterilized micronized dexamethasone. DEX-Cipro in 16% P407 137 2OO 0450. The dry heat sterilized dexamethasone is optionally DEX-Cipro in 50% P407/EtOH 33 23 mixed aseptically with a sterile-filtered poloxamer solution prior to administration. US 2012/0277199 A1 Nov. 1, 2012 39
Examples 19-21 0461) Ciprofloxacin chromatographic purity is shown in 0457 Formulations comprising combinations of amox the table below. icillin+triamcinolone, moxifloxacin-prednisolone, and Zoledronate--dexamethasone are prepared using the above procedure. Area 90 Example 22 RRT Pre autoclaved Autoclaved impurity E O.O2 O.O3 Manufacturing and Properties of a Ciprofloxacin (0.41) Hydrogel Formulations impurity C O.OS O.09 (0.69) 3%. Ciprofloxacin Hydrogel O.87 BLQ O.O2 ciprofloxacin 99.88 99.82 0458 Weigh 1.1399 g of NaCl (fisher lot 080788)+1.5022 impurity D O.O2 O.O3 g of tromethamine (fisher lot 081507)+205g of Millipore DI (1.27) water. Dissolve and adjust pH with ~1.8 mL of a 5 NHCl 2.30 O.O2 O.O2 solution to a pH of 7.75 with a final osmolality of 273 mOsm/ kg. Weigh 58.8 g of the above buffer, chill down, then sprinkle 12% Ciprofloxacin Hydrogel while mixing 11.291 g of poloxamer 407 NF (BASF lot WPNF580C), mix until fully dissolved. 0462 Weigh 126.1 g of the above buffer (3% ciprofloxacin Weigh 64.8g of a the 16% P407 (above solution) into a 100 hydrogel), chill down, then sprinkle while mixing 24.0 g of mL glass bottle containing a 35 mm stir bar then sprinkle poloxamer 407 NF (BASF lot WPNF580C), mix until fully 2.2915g of ciprofloxacin hydrate (Neuland lot CHIO71000). dissolved. Weigh 34.68 g of the 16% P407 (above solution) Mix for not less than 2 hours at a setting of 11 (IKA stirplate) into a 100 mL. glass bottle containing a 35 mm stir bar then minutes while cooling then fill 31 two mL vials with approxi sprinkle 5.38 g of ciprofloxacin hydrate (Neuland lot mately 2 g of Suspension, stopper them with 13 mm West CHIO71000). Mix for not less than 2 hours at a setting of 11 stoppers and seal them with Al seal, autoclave for 30 minutes (IKA stirplate) minutes while cooling then fill 7 two mL vials (a 250° C. with approximately 2 g of suspension, one 3 mL vial with 3 g Release Profile and one 10 mL vial with 8 g of the Suspension, then stopper them with West stoppers and seal them with Al seals, auto 0459 Dissolution was performed at 37°C. in Snapwells clave them for 30 minutes (a 250° C. (6.5 mm diameter polycarbonate membrane with a pore size 0463) To prepare 0.6, 2 and 6% ciprofloxacin hydrogels of 0.4 m), 0.2 mL of gel was placed into snapwell and left to the following procedure was used: 16% P407 was delivered to harden, 0.5 mL of 0.9% saline was placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples were glass vials and autoclaved, then a specific amount of auto taken every hour (All the saline withdrawn and replace with claved 12% ciprofloxacin hydrate was aseptically added and warm 0.9% saline with an osmolality of 290 mOsm). Samples thoroughly mixed, see table below for details. were analyzed for Ciprofloxacin by HPLC.
Rheological Properties % ciprofloxacin 16% 12% ciprofloxacin 0460 Tgel measurements were performed using a Brook in hydrogel P407/vial (g) hydrogel (g) used field viscometer RVDV-II+P with a CP-51 spindle rotated at O6 18.4 1 0.08 rpm (shear rate of 0.31 s) equipped with a temperature 2.0 16.4 3.4 control unit (temperature ramped from 15-37° C. at 1.6° 6.O 10.2 10.6 C./min) Viscosity was measured at 20°C. using a Brookfield viscometer RVDV-II+P with a CP-40 spindle with a shearrate 0464. In vitro release profile of ciprofloxacin hydrogel ramp from 7.5 to 375 s. Data was fitted to the Casson model formulations is shown below. to calculate the plastic viscosity and yield stress of the drug product.
Pre autoclaved Autoclaved Ciprofloxacin MDT
apparent OSmolality 3OO 300 O6 18 (mC)sM) 2 59 pH 7.67 7.66 6 174 Tgel (C.) 26.4 26.6 12 3S4 Max viscosity (Pas) 424 399 slope 29.376 Viscosity (cP) (Casson) 44.6 41.5 R2 O.9999 Yield stress (D/cm) O.S 2.1 MDT ciprofloxacin (h) 83 87 Assay (%) 97 100 Ciprofloxacin 0465. The viscosity of ciprofloxacin suspensions in 16% Appearance White-offwhite White-offwhite poloxamer 407 were measured using a Brookfield viscometer RVDV-II+P with a CP-40 spindle with a ramp speed from 1-50 rpm (shear rate from 7.5 to 375 s) or a CP-50 spindle US 2012/0277199 A1 Nov. 1, 2012 40 with a ramp speed from 1-50 rpm (shear rate from 3.8 to 192 cardiac puncture into heparin coated tubes. To collect the s'), equipped with a temperature control unit (temperature cerebrospinal fluid (CSF), a small skin incision is made just set at 20° C.). posterior to the cranial vertex. The skin is then retracted, and 0466 Ejection forces are directly proportional to the vis the trapezius muscle scraped off the occipital bone. A small cosity of the suspension as expressed by the Poiseuille's hole is then drilled through the bone. The dura is cut with a equation. sharp scalpel and a micropipette inserted to collect blood-free CSF (50 ul). Analytical Method Plastic viscosity Yield Stress Viscosity (a) a shear % API (cP) (D/cm) rate of 38 s' 0469 Determination of active agent concentrations is per 12 130 17.2 238 formed using high pressure liquid chromatography (HPLC) 6 49.1 2.4 92.6 combined with mass spectrometry detection (MS). The limit 3 41 2 79 of detection of the method is 1.0 ng/ml. Samples (perilymph, O 40 O 36 plasma and CSF) are extracted by liquid-liquid extraction using dichloromethane:hexane:MTBE (1:1:1 V/v/v). The organic portion is then dried and the extracts reconstituted Example 23 with a water:methanol solution (1:1, V/v). The samples are analyzed by reversed phase HPLC (1100 series, Agilent) Application of an Enhanced Viscosity Pharmaceuti using an Atlantis dC18 column maintained at 40° C. The cal Formulation onto the Round Window Membrane mobile phase is nebulized using heating nitrogen in a Z-spray 0467 A formulation according to Example 1 is prepared Source/interface and the ionized compounds detected using and loaded into 5 ml Siliconized glass Syringes attached to a MS/MS (Tandem quadrupole mass spectrometer, Quattro 27-gauge luer lock disposable needle. Lidocaine is topically Ultima, Waters). Peak heights of an active agent are deter applied to the tympanic membrane, and a small incision made mined using MassLynx software (Waters). The calibration to allow visualization into the middle ear cavity. The needle curves are obtained by fitting the peak height ratios of analyte/ tip is guided into place over the round window membrane, internal standard and the standard concentrations to a suitable and the formulation applied directly onto the round-window equation using MassLynx. Sample active agent concentra membrane. tions are then interpolated using the equations derived from the calibration curves. Example 24 In Vivo Testing of Intratympanic Injection of Formu Data Analysis lation in a Guinea Pig 0470 Pharmacokinetic parameters are calculated using 0468. Female guinea pigs (Charles River) weighing 200 conventional noncompartmental pharmacokinetic methods. 300 g, of approximately 6-8 weeks of age are used (N=4 per The apparent clearance (CL app) is calculated as the ratio group). Prior to any procedure, animals are anesthetized between the administered intratympanic dose and the expo using a combination of Xylazine (10 mg/kg), ketamine (40 sure (AUC). Thus the injection volume and the concentration mg/kg) and acepromazine (0.75 mg/kg) for up to an hour via of an active agent and poloxamer in a formulation are tested the intramuscular route. If needed, an intraoperative booster to determine optimal parameters for preclinical and clinical is administered intraperitoneally representing one-tenth of studies. the original dose. Intratympanic injection—Each animal is positioned so that the head is tilted at an angle to favor Example 25 injection towards the round window niche. Briefly, under In Vivo Testing of Intratympanic Injection of Formu visualization with an operating microscope, 50 ul of formu lation in Sheep lations comprising 0 to 50% active agent and varying concen trations of P407 are administered to the animals. The formu 0471 Female sheep (Buckham Sheep Farm, Kalamazoo, lations are injected using a 27 G or 30G needle through the Mich.) weighing 50-65kg, of approximately 2-4 years of age tympanic membrane into the Superior posterior quadrant are used (N=1, 2 ears per group). Prior to any procedure, behind which the round window niche is located. During the animals are anesthetized using a combination of Xylazine procedure and until recovery, animals are placed on a tem (0.22 mg/kg), glycopyrrolate (0.01 mg/kg) and ketamine (15 perature controlled (40°C.) heating pad until consciousness mg/kg) administered IM in addition to isoflurane by inhala is regained at which time they are returned to the vivarium. tion. Intratympanic injection—Each intubated animal is Perilymph sampling procedure The skin behind the ear of immobilized and placed laterally in reverse trendelenburg anesthetized guinea pigs is shaved and disinfected with povi position, with the rostrum slightly elevated to ensure access to done-iodine. An incision is then made behind the ear, and the round window. Following ear cleaning (using Otocalm muscles are carefully retracted from over the bulla. A hole is and warm saline), and underotoscopic visualization, 600 ul of drilled though the bulla using a dental burr so that the middle formulations comprising 0 to 50% active agent and P407 are ear is exposed and accessible. The cochlea and the round administered to the animals. The formulation are injected window membrane are visualized under a stereo Surgical using a 25G or 27G needle through the tympanic membrane microscope. A unique microhole is hand drilled through the into the posterior inferior quadrant towards the round window bony shell of the cochlea (active capsule) adjacent to the niche. After dosing, the animal is left on an incline with its round window. Perilymph (5 ul) is then collected using a head up for approximately 30 minto allow the dosing Solution microcapillary inserted into the cochlear Scala tympani. to settle into the tympanic cavity. Procedure is then repeated Plasma and CSF collection methods—Blood is collected by for the opposite ear. Perilymph sampling procedure—The US 2012/0277199 A1 Nov. 1, 2012 animal is intubated and placed in lateral recumbency. A post cells are quantitated with a hemocytometer, and differential auricular skin incision is made and the post-auricular vein cell enumeration performed with Wright's staining. located and ligated. Cautery is performed to expose the bulla and temporal bone. The middle ear is accessed using a nitro Example 28 gen powered drill and a round-tipped bur. The middle ear ossicles are pushed to the side, with care taken to avoid Evaluation of Otic Agent Formulations in an Otitis damaging the round window membrane. Using a 0.5-1 mm Externa Animal Model round-tipped burr, a hole is hand drilled into the basal turn of 0480. Otitis externa is induced in 20 Sprague-Dawley rats the cochlea until the bone is thin enough to pierce with a using a plastic pipette to aggravate the tissue of the ear canal. modified sewing needle. Perilymph (50 ul) is then collected All of the rats develop OE within one day. The formulation of using Hamilton Syringe connected to a 28-32 G needle Example 2 is administered to the ears of half of the rats using inserted into the cochlear scala tympani. Plasma and CSF a needle and Syringe, while the remaining rats receive the collection methods—Blood is collected from the jugular vein same formulation without the otic agent. The ear canal tissue into heparin coated tubes. To collect the cerebrospinal fluid is observed for redness and swelling that characterizes the (CSF), a small skin incision is made over the cisterna magna condition. Light microscopy is used to analyze biopsy and a 22G needle inserted to sample blood-free CSF (500 ul). samples from the rats. 0472. The samples are analysed as described above. The gel elimination time course for each formulation is deter Example 29 mined. A faster gel elimination time course of a formulation indicates lower mean dissolution time (MDT). Thus the injec Clinical Trial of Otic Agent Formulations in Combi tion Volume and the concentration of an active agent and nation with Tympanostomy for Treatment of Otitis poloxamer in a formulation are tested to determine optimal Media with Effusion parameters for preclinical and clinical studies. 0481. The purpose of this study is to determine if a com position comprising a combination of Ciprofloxacin and Dex Example 26 amethasone administered in combination with a tympanos tomy is safe and effective in preventing and/or treating middle In Vivo Extended Release Kinetics in the Ear ear infections in patients with ear tubes. 0473. A cohort of 21 guinea pigs (Charles River, females 0482 Study Type: weighing 200-300g) is intratympanically injected with 50 uL 0483 Interventional 15-17% Pluronic F-127 formulation buffered at 280 mOsm/ 0484 Study Design: kg and containing 1.5% to 35% active agent by weight of the 0485 This will be a non-inferiority open label study to formulation Animals are dosed on day 1. The release profile compare the current standard of care versus the use of for the formulations is determined based on analysis of the extended release intratympanic compositions in combination perilymph and/or middle ear fluids. with tympanostomy. The current standard of care requires the use of otic drops for 5-7 days post-Surgery. The study is Example 27 designed to test whether administration of a Sustained release composition at the time of Surgery obviates the need for Evaluation of Otic agent Formulations in an Otitis out-patient treatment. The test hypothesis is that administra Media Animal Model tion of a single injection of an extended release composition 0474 Induction of Otitis Media at the time of Surgery is not inferior to administration of otic 0475 Healthy adult chinchillas weight 400 to 600 g with drops after Surgery. normal middle ears, ascertained by otoscopy and tympanom 0486 Inclusion Criteria: etry are used for these studies. Eustachian tube obstruction is 0487 6 months to 12 years old, Acute Otitis Media with performed 24 hours before inoculation to prevent the inocu effusion in one or both ears lum from flowing out of the eustachian tube. One milliliter of 0488 Patient may not have had otic surgery other than type 3 S. pneumoniae Strain at 4-h-log phase (containing tube placement in the last year approximately 40 colony forming units (CFU)) is placed 0489 Patient may not have any disease or condition that directly into both middle ear hypotympanic bullae of the would negatively affect the conduct of the study chinhillas. Control mice are inoculated with one milliliter 0490 Patient may not require any other systemic anti Sterile PBS. microbial therapy during the study. 0476 Treatment 0491 Analgesic use (other than acetaminophen) is not 0477. S. pneumoniae inoculated and control mice are allowed Sorted into two groups (n=10 in each group). An otic agent 0492 Patient may not be pre-disposed to neurosensory formulation containing amoxicillin is applied to the walls of hearing loss the tympanic cavity of one group of animals. Control formu 0493 Exclusion Criteria: lation containing no amoxicillin is applied to the second 0494 Age group. The amoxicillin and control formulations are reap 0495 Study Protocol: plied three days after the initial application. The animals are 0496 Twenty patients will be divided into two groups. The sacrificed after the seventh day of treatment. first group of patients will receive an injection of an extended 0478 Analysis of Results release composition comprising micronized ciprofloxacin 0479. Auris media ear fluid (MEF) is sampled at 1, 2, 6, 12, and micronized dexamethasone during the Surgical proce 24, 48 and 72 hours after pneumoccal inocualtion. Quantita dure. Each patient will undergo a tympanostomy for place tive MEF cultures are performed on sheep blood agar, with ment of a tube. During the Surgical procedure, the Surgeon the quantitation threshold set at 50 CFU/ml. Inflammatory will clean the ear of all effusion and while the myngotomoy US 2012/0277199 A1 Nov. 1, 2012 42 incision is open, the Surgeon injects a test composition into rhinoplasty in reducing recurrence of sinusitis in pediatric the middle ear space. The tube is inserted after injection of the patients with a long history of sinusitis and failed medication. extended release composition into the middle ear space. The 0508 Eligibility: test composition is either prepared in the operating room by (0509 2 Years to 17Years, both genders: Planned surgical Suspending dry micronized powder of ciprofloxacin and dex intervention (i.e. endoscopic sinus Surgery, adenoidectomy, amethasone with other excipients, or the test composition is a sinus irrigation for obtaining a culture) recommended by PI, prepared Suspension ready for injection. consented to by patient's legal guardian); Longstanding 0497. The second group of patients will be given ear drops sinusitis: >3 mo symptoms OR 6 episodes/yr AND failed 2 comprising non-micronized water soluble form of ciprof courses antibiotics followed by positive CT scan loxacin and non-micronized water Soluble form of dexam ethasone as immediate release components to be adminis 0510 Exclusion Criteria: tered for 5-7 days after the surgery. 0511 Extensive previous sinonasal Surgery in target ostia; 0498 Patients are monitored with weekly follow up visits cystic fibrosis; extensive sinonasal osteoneogenesis; sinona for one month. Any differences in treatment outcomes sal tumors or obstructive lesions; history of facial trauma that between the two groups are recorded. distorts sinus anatomy and precludes access to the sinus 0499 Primary Outcome Measures: ostium; ciliary dysfunction 0500 Time to cessation of otorrhea as recorded by the 0512 Study Design: parent or guardian via a patient. 0513 Balloon dilation of the sinuses is performed using 0501 Secondary Outcome Measures: commercially available devices which include sinus guiding 0502 Clinical cure rate; Microbiological outcome; Treat catheters, sinus guidewires, sinus exchange and irrigation ment failures: Recurrence of disease. catheters, sinus balloon inflation devices and sinus balloon 0503. The treatment outcome for each group of patients is catheters. Balloon dilation will be performed using endo compared to determine whether administration of the scopic equipment with video documentation capability. A extended release composition comprising ciprofloxacin and single dose of an intrasinusoidal formulation from Example 9 dexamethasone in combination with tympanostomy is more is administered via the catheter into the intrasinusoidal cavity. effective than administration of ear drops comprising cipro Patients are monitored for one year. floxacin and dexamethasone after Surgery for reduction of otorrhea, infections, or inflammation associated with tympa Primary Outcome Measures: nostomy. 0514 Sinus-related Adverse Events during balloon dila Example 30 tion through 12 months; Improvement in sinus symptom SCOS. Treatment of Sinusitis in an Animal Model and Evaluation of InVivo Sustained Release Secondary Outcome Measures: 0504. An animal model described by Chiu et al. in Ameri 0515 Effectiveness of medication through 1 year; effec can Journal of Rhinology, 2007, 21, 5-9, is used in this study. tiveness of Surgery and intrasinusoidal composition as mea 0505. The maxillary sinus ostium of white rabbits is Sured by post-op interventions; days out of school; recurrence obstructed with a pledget through an antrostomy created in rate the anterior face of the maxilla. The sinus is inoculated with Pseudomonas aeruginosa. After 7 days, the antrostomy is Example 32 reopened, the ostial obstruction is removed, and a single lumen catheter is placed. Normal saline is irrigated through Effect of Intrasinusoidal Compositions in Treatment the catheter for 7 days in one group of rabbits (placebo group), of Nasal Polyposis while a control group receives no irrigation. A third test group receives a single dose of a test intrasinusoidal formulation. On 0516. The aim of this study is to determine whether day seven of the study, the rabbits are euthanized, analyzed administration of an intrasinusoidal formulation of Example under light microscopy, and bacterial counts of the nasal 9 reduces the size of nasal polyps, or reduces thickness of lavage are determined Purulence, mucosal and underlying nasal polyps, and relieves symptoms in people with chronic bony inflammation in both the control and the saline irrigation rhinosinusitis (CRS). groups confirms presence of sinusitis. A reduction in bacterial counts in the nasal lavage, purulence and inflammation in the 0517 Eligibility: treatment group indicates an effective therapeutic outcome. 0518. Subjects must meet the criteria for CRS, namely 0506 Sustained release of an active agent is determined in they must have (1) at least two major criteria (facial pain/ the nasal lavage or the sinus lavage using a suitable technique pressure or headache, nasal congestion, anterior or posterior (e.g., UV spectrometry, HPLC, mass spectrometry) for detec nasal drainage, hyposmia/anosmia) for at least 3 consecutive tion of active agent the lavage. Epithelial Scraping from months; (2) an abnormal sinus CT scan in at least two sinus sinonasal passages is used to determine tissue exposure of the areas documented within 3 months of entry or endoscopic active agent. evidence of disease. Subjects must have bilateral polypoid disease demonstrated either by CT or endoscopy with evi Example 31 dence of nasal polyps or polypoid mucosa on examination in at least two of the following areas: right maxillary sinus, left Clinical Trial for Evaluation of an Intrasinusoidal maxillary sinus, right anterior ethmoid sinus, left anterior Formulation in Combination with Surgery ethmoid sinus plus a minimal polyp/polypoid score of 4 on 0507. This is a study to determine safety and efficacy of a the baseline rhinoscopic examination. Nasal polyps are combination of an intrasinusoidal formulation and balloon defined as discreet polyps visible in the middle meatus area. US 2012/0277199 A1 Nov. 1, 2012
0519 Exclusion Criteria: tives to the embodiments described herein are optionally 0520 Subjects who have received antibiotics within 3 employed in practicing the inventions. It is intended that the weeks of the screening visit; Subjects with uncontrolled mod following claims define the scope of the invention and that erate to severe asthma (defined as FEV1<80% with asthma methods and structures within the scope of these claims and control Test <19 for the week prior to entry), recent exacer their equivalents be covered thereby. bation, or use of systemic steroids burst within 6 weeks of 1. A pharmaceutical formulation comprising an active study enrollment. Subjects who are receiving a maintenance agent, a thermosensitive polymer comprising polyoxyethyl dose of corticosteroid. ene and polyoxypropylene copolymers, and 0521. Study Design: a) having a syringable viscosity at time of administration 0522 Patients are administered a single dose of an intrasi Suitable for administration via a 25-31 gauge needle; nusoidal composition of Example 9 via a catheter directly b) having a gelation temperature between about 14°C. and into the nasal polyp, or in the vicinity of the nasal polyp. about 42°C.; Patients are monitored for one year. c) providing in Vivo Sustained release of a therapeutically effective amount of the active agent for a period of at Primary Outcome Measures: least 5 days; and 0523 Quantification of polypoid mucosal thickening in (d) having less than 50 cfu of microbial agents per gram of the anterior ethmoid and maxillary sinuses on sinus CT scan. the formulation; Recurrene of symptoms and/or polyps. provided that (i) the formulation comprises less than 14.5% of the Example 32 thermosensitive polymer by weight of the formula tion and further comprises one or more gelation tem Evaluation of Ion Channel Modulator Administration perature increasing agents; or in Meniere's Patients (ii) the formulation comprises more than 25% of the thermosensitive polymer by weight of the formula 0524) Study Objective tion and further comprises one or more gelation tem 0525. The primary objective of this study will be to assess perature decreasing agents; or the safety and efficacy of dexamethasone in ameliorating (iii) the formulation comprises between about 5% and Meniere's Disease in human subjects. about 20% of the thermosensitive polymer by weight of the formulation, wherein the thermosensitive poly Study Design mer has been purified, and optionally further com 0526. This will be a Prospective, Randomized, Double prises one or more gelation temperature increasing or blind, Placebo-controlled, Multicenter, Phase 1B Study com gelation temperature decreasing agents; or paring dexamethasone administration to placebo in the treat (iv) the formulation comprises between about 14.5% ment of Meniere's disease in patients with unilateral disease. and about 25% of the thermosensitive polymer by Approximately 100 subjects will be enrolled in this study. weight of the formulation and further comprises one Each group will receive either a single dose of a Sustained or more gelation temperature increasing or gelation release an ion channel modulator formulation comprising temperature decreasing agents. dexamethasone or placebo treatment. 2. (canceled) 0527 Subjects who do not complete the study will not be 3. (canceled) replaced. Patients receiving the study drug will be adminis 4. The formulation of claim 1, wherein the formulation is tered a gel formulation of Example 1 directly onto the sub administered at or in the vicinity of the round window mem jects round window membrane and monitored for 3 months. brane of the ear. Each patient will receive a vestibular and hearing evaluation 5. The formulation of claim 1, wherein the in vivo Sustained before the treatment and every two weeks after administration release occurs in the inner ear. of the study drug. 6. (canceled) 0528 Primary Outcome Measures: 7. (canceled) 0529. The primary objective of this study is to evaluate the 8. The formulation of claim 1, wherein the thermosensitive safety and tolerability of two ascending doses of the dexam polymer is P407. ethasone relative to placebo. Safety assessments will be per 9. (canceled) formed for 3 months post single intratympanic injection of 10. (canceled) the dexamethasone or placebo. 11. (canceled) 0530 Secondary Outcome Measures: 12. (canceled) 0531. The secondary objective of this study is to evaluate 13. The formulation of claim 1, wherein the formulation the clinical activity of two doses of dexamethasone relative to comprises a suspension of one or more multiparticulate active placebo. Change in baseline for vertigo frequency will be agents. evaluated. The impact of tinnitus on activities of daily living 14. The formulation of claim 13, wherein the multiparticu will be measured. Hearing loss in the affected ear will be late active agent is a micronized active agent sterilized by measured by audiometric examination. Quality of life will be dry-heat, irradiation or steam sterilization. measured by patient reported questionnaire. Severity of Ver 15. (canceled) tigo episodes will be measured by the patient reported vertigo 16. The formulation of claim 1, wherein the formulation SCO. has total product related impurities of no more than 2% by 0532. While preferred embodiments of the present inven weight of the formulation. tion have been shown and described herein, such embodi 17. The formulation of claim 1, wherein the active agent is ments are provided by way of example only. Various alterna a corticosteroid, or a salt or prodrug or Solvate thereof. US 2012/0277199 A1 Nov. 1, 2012 44
18. The formulation of claim 17, wherein the corticosteroid ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, is 21-acetoxypregnenolone, alclometasone, algestone, amci ceftobirprole, Vancomycin, azithromycin, clarithromycin, nonide, beclomethasone, betamethasone, budesonide, chlo dirithromycin, erythromycin, roXithromycin, troleandomy roprednisone, clobetasol, clobetaSone, clocortolone, clopred cin, tellithromycin, spectinomycin, aztreonam, amoxicillin, nol, corticosterone, cortisone, cortivaZol, deflazacort, ampicillin, azociling, carbenicillin, cloxacillin, dicloxacillin, desonide, desoximetaSone, dexamethasone, diflorasone, flucloxacillin, meZlocillin, meticillin, nafcillin, oxacillin, diflucortolone, difluprednate, enoxolone, fluazacort, fluclo peperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ronide, flumethasone, flunisolide, fluocinolone acetonide, ciprofloxacin, clavulanic acid, enoxacin, gatifloxacin, levof fluocinonide, fluocortin butyl, fluocortolone, fluo loxacin, lomefloxacin, moxifloxacin, nonfloxacin, ofloxacin, rometholone, fluperolone acetate, fluprednidene acetate, flu trovafloxacin, grepafloxacin, sparfloxacin, AL-15469A, prednisolone, flurandrenolide, fluticasone propionate, for AL-38905, OP-145, afenide, prontosil, sulfacetamide, sul mocortal, halcinonide, halobetasol propionate, famethiazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, tri halometaSone, halopredone acetate, hydrocortamate, hydro methoprim, cotrimoxazole, demeclocycline, doxycycline, cortisone, loteprednol etabonate, maZipredone, medrysone, minocycline, Oxytetracycline, tetraycline, lineZolid, arsoge meprednisone, methylprednisolone, mometaSone furoate, banubem chloramphenicol, clindamycin, lincomycin, etham paramethasone, prednicarbate, prednisolone, prednisolone butol, fosfomycin, fusidic acid, furazolidone, isoniazid, lin 25-diethylamino-acetate, prednisolone sodium phosphate, eZolid, metronidazole, mupirocin, nitrofurantoin, prednisone, prednival, prednylidene, rimexolone, tiXocortol, platensimycin, pyrazinamide, quinupristin, dalfopristin, triamcinolone, triamcinolone acetonide, triamcinolone bene rifampicin, thamphenicol, timidazole, amoxicillin+clavu tonide, or triamcinolone hexacetonide, or salt or prodrug lanic acid, Maximin H5, Dermcidin, Cecropins, andropin, thereof. moricin, ceratotoxin, melittin, Magainin, dermaseptin, bom 19. The formulation of claim 17, wherein the corticosteroid binin, brevinin-1, esculentins and buforin II, CAP18, LL37, is dexamethasone, prednisolone, methylprednisolone, triam abaecin, apidaecins, prophenin, indolicidin, brevinins, prote cinolone, or a salt or prodrug or Solvate thereof, or a combi grin, tachyplesins, defensins, drosomycin, alamethicin, pexi nation thereof. ganan or MSI-78, MSI-843, MSI-594, polyphemusin, coli 20. (canceled) cin, pyocin, klebicin, Subtilin, epidermin, herbicolacin, 21. (canceled) brevicin, halocin, agrocin, alveicin, carnocin, curvaticin, 22. The formulation of claim 19, wherein the dexametha divercin, enterocin, enterolysin, erwiniocin, glycinecin, lac Sone, or salt or prodrug or Solvate thereof, is present in an tococin, lacticin, leucoccin, mesentericin, pediocin, plantari amount from about 0.05% to about 40% by weight of the cin, Sakacin, Sulfolobicin, vibriocin, wanerinand, nisin, or a formulation. salt or cocrystal, or prodrug or Solvate thereof, or a combina 23. (canceled) tion thereof. 24. (canceled) 29. (canceled) 25. (canceled) 30. The formulation of claim 27, wherein the antibiotic 26. (canceled) agent is ciprofloxacin or ciprofloxacin hydrate. 27. The formulation of claim 1, wherein the antimicrobial 31. The formulation of claim 30, wherein the ciprofloxacin agent is an antibiotic. or ciprofloxacin hydrate is present in an amount between 28. The formulation of claim 27, wherein the antibiotic is about 0.1 to about 20% by weight of the formulation amikacin, gentamicin, kanamycin, neomycin, netilmicin, 32. (canceled) streptomycin, tobramycin, paromycin, geldanamycin, herbi 33. (canceled) mycin, loracarbef, ertapenem, doripenem, imipenem, mero 34. (canceled) penem, cefaclor, cefamandole, cefotoxin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime,