US 2010 0021416A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0021416 A1 LCHTER et al. (43) Pub. Date: Jan. 28, 2010

(54) CONTROLLED-RELEASE OTIC STRUCTURE (22) Filed: Jul. 20, 2009 MODULATING AND INNATE IMMUNE SYSTEMI MODULATING COMPOSITIONS Related U.S. Application Data AND METHODS FOR THE TREATMENT OF (60) Provisional application No. 61/082,450, filed on Jul. OTC DISORDERS 21, 2008, provisional application No. 61/091,205, filed on Aug. 22, 2008, provisional application No. (75) Inventors: Jay LICHTER, Rancho Santa Fe, 61/094,384, filed on Sep. 4, 2008, provisional applica CA (US); Benedikt VOLLRATH, tion No. 61/101,112, filed on Sep. 29, 2008, provi San Diego, CA (US); Sergio G. sional application No. 61/108,845, filed on Oct. 27. DURON, San Diego, CA (US); 2008, provisional application No. 61/140,033, filed on Carl LEBEL, Malibu, CA (US); Dec. 22, 2008, provisional application No. 61/156. Fabrice PIU, San Diego, CA (US); 771, filed on Mar. 2, 2009, provisional application No. Qiang YE, San Diego, CA (US); 61/091,200, filed on Aug. 22, 2008. Luis A. DELLAMARY, San Publication Classification Marcos, CA (US); Andrew M. TRAMMEL, Olathe, KS (US); (51) Int. C. Michael Christopher SCAIFE, A6II 47/48 (2006.01) Los Altos, CA (US); Jeffrey P. A6II 3/66 (2006.01) HARRIS, La Jolla, CA (US) A638/46 (2006.01) A6II 35/74 (2006.01) A 6LX 3/553 (2006.01) Correspondence Address: A6IP27/16 (2006.01) WILSON, SONSINI, GOODRICH & ROSATI 650 PAGE MILL ROAD (52) U.S. Cl...... 424/78.17: 514/108; 424/94.6; PALO ALTO, CA 94304-1050 (US) 424/93.47: 514/221 (57) ABSTRACT (73) Assignees: OTONOMY, INC., San Diego, CA Disclosed herein are compositions and methods for the treat (US): THE REGENTS OF THE ment of otic disorders with otic structure modulating compo UNIVERSITY OF sitions administered locally to an individual afflicted with an CALIFORNLA, Oakland, CA (US) otic disorder, through direct application of these composi tions and compositions onto or via perfusion into the targeted (21) Appl. No.: 121506,091 auris structure(s). Patent Application Publication Jan. 28, 2010 Sheet 1 of 5 US 2010/0021416 A1

1000

-- Non-Sustained release

100------Cmax

^ -H Sustained release s s as

10 w ss -H BimOdal release

1 s --- Cmin

0.1 H Time (days)

FIG. 1 Patent Application Publication Jan. 28, 2010 Sheet 2 of 5 US 2010/0021416 A1

10000

7 L 1000 % / 100 W

1 O 1/ 2r 3 4 5 6 Percent CMC, by weight->

FIG. 2 Patent Application Publication Jan. 28, 2010 Sheet 3 of 5 US 2010/0021416 A1

100,00075,000 Hill|| || || || 1 || 100,00000:0// / / /

15,000 II////II, / / 7 / o|| IAAA Al-M 4 O 00 III///2 III/// MYf III//// / / / 441/ Y 25 HF/AAI//ZML-1 44 Hit4-H || - lAAA4 4 || J-1 sl//Z 1 1 -5 15 l/A4 44 -14

10 41||241|| 7 % METHOCEL Cellulose Ether FIG. 3 Patent Application Publication Jan. 28, 2010 Sheet 4 of 5 US 2010/0021416 A1

Semi Circular Canals eliptical window pinna Circular window 1-1 Vestibular nerve

malleuS 1- auditory nerve

COChlea

tympanic cavity tympanic membrane auditory (eardrum) Stapes eustachian tube Canal

FIG. 4 Patent Application Publication Jan. 28, 2010 Sheet 5 of 5 US 2010/0021416 A1

1000

Non-micronized otic agent 10 Solution Micronized otic agent Solution Non-micronized otic agent + gelling agent 1 - Cmin Micronized otic agent + gelling agent

0.1 Time (days)

FIG 5 US 2010/0021416 A1 Jan. 28, 2010

CONTROLLED-RELEASE OTC STRUCTURE RefSum's syndrome, Usher's syndrome, or combinations MODULATING AND INNATE IMMUNE thereof. In some embodiments, the otic disorder is otitis SYSTEMI MODULATING COMPOSITIONS externa, otitis media, mastoiditis, AIED, Ramsay Hunts, rep AND METHODS FOR THE TREATMENT OF erfusion injury, labyrinthitis ossificans or combinations OTC DSORDERS thereof. 0005. The auris compositions and therapeutic methods CROSS-REFERENCE described herein have numerous advantages that overcome 0001. This application claims the benefit of U.S. Provi the previously-unrecognized limitations of compositions and sional Application No. 61/082,450, filed 21 Jul. 2008; U.S. therapeutic methods described in prior art. Provisional Application No. 61/091205, filed 22 Aug. 2008: U.S. Provisional Application No. 61/094,384, filed 4 Sep. Sterility 2008; U.S. Provisional Application No. 61/101,112, filed 29 Sep. 2008; U.S. Provisional Application No. 61/108,845, 0006. The environment of the inner ear is an isolated envi filed 27 Oct. 2008; U.S. Provisional Application No. 61/140, ronment. The endolymph and the perilymph are static fluids 033, filed 22 Dec. 2008; U.S. Provisional Application No. and are not in contiguous contact with the circulatory system. 61/156,771, filed 2 Mar. 2009; and U.S. Provisional Applica The blood-labyrinth-barrier (BLEB), which includes a blood tion No. 61/091,200, filed 22 Aug. 2008; all of which are endolymph barrier and a blood-perilymph barrier, consists of incorporated by reference herein in their entirety. tight junctions between specialized epithelial cells in the labyrinth spaces (i.e., the vestibular and cochlear spaces). The BACKGROUND OF THE INVENTION presence of the BLB limits delivery of active agents (e.g., otic 0002 Vertebrates have a pair of ears, placed symmetri structure modulating agent or innate immune system modu cally on opposite sides of the head. The ear serves as both the lating agents) to the isolated microenvironment of the inner sense organ that detects Sound and the organ that maintains ear. Auris hair cells are bathed in endolymphatic or perilym balance and body position. The ear is generally divided into phatic fluids and cochlear recycling of potassium ions is three portions: the outer ear, auris media (or middle ear) and important for hair cell function. When the inner ear is the auris interna (or inner ear). infected, there is an influx of leukocytes and/or immunoglo bulins (e.g. in response to a microbial infection) into the SUMMARY OF THE INVENTION endolymph and/or the perilymph and the ionic composition 0003. Described herein, in certain embodiments, are com of inner ear fluids is upset by the influx of leukocytes and/or positions, compositions, manufacturing methods, therapeutic immunoglobulins. In certain instances, a change in the ionic methods, uses, kits, and delivery devices for the controlled composition of inner ear fluids results in hearing loss, loss of release of an otic structure modulating agent or innate balance and/or ossification of auditory structures. In certain immune system modulating agent to at least one structure or instances, trace amounts of pyrogens and/or microbes trigger region of the ear. Disclosed herein, in certain embodiments, infections and related physiological changes in the isolated are controlled-release compositions for delivering an otic microenvironment of the inner ear. structure modulating agent or innate immune system modu 0007 Due to the susceptibility of the inner ear to infec lating agent to the ear. In some embodiments, the target por tions, auris compositions require a level of sterility that has tion of the ear is the middle ear (or auris media). In some not been recognized hitherto in prior art. Provided herein are embodiments, the target portion of the ear is the inner ear (or auris compositions that are sterilized with Stringent sterility auris interna). In other embodiments, the target portion of the requirements and are suitable for administration to the middle ear is both the auris media and the auris interna. In some and/or inner ear. In some embodiments, the auris compatible embodiments, the controlled-release compositions further compositions described herein are substantially free of pyro comprise a rapid or immediate release component for deliv gens and/or microbes. ering an otic structure modulating agent or innate immune Compatibility with Inner Ear Environment system modulating agent to the targeted auris structure. All 0008. Described herein are otic compositions with an compositions comprise excipients that are auris-acceptable. ionic balance that is compatible with the perilymph and/or the 0004. Also disclosed herein, in certain embodiments, are endolymph and does not cause any change in cochlear poten compositions and devices for the treatment of otic disorders, tial. In specific embodiments, osmolarity/oSmolality of the said compositions and devices comprising an otic structure present compositions is adjusted, for example, by the use of modulating agent or innate immune system modulating appropriate salt concentrations (e.g., concentration of sodium agent. Further disclosed herein, in certain embodiments, are salts) or the use of tonicity agents that render the composi methods for the treatment of otic disorders by administration tions endolymph-compatible and/or perilymph-compatible of a controlled-release composition comprising an otic struc (i.e. isotonic with the endolymph and/or perilymph). In some ture modulating agent or innate immune system modulating instances, the endolymph-compatible and/or perilymph agent to an individual in need thereof. In some embodiments, compatible compositions described herein cause minimal the otic disorder is otitis externa, otitis media, mastoiditis, disturbance to the environment of the inner ear and cause sensorineural hearing loss, ototoxicity, endolymphatic minimum discomfort (e.g., vertigo) to a Subject (e.g., a hydrops, labyrinthitis, Meniere's disease, Meniere's syn human) upon administration. Further, the compositions com drome, microvascular compression syndrome, Vestibular prise polymers that are biodegradable and/or dispersible, and/ neuronitis, acoustic trauma, presbycusis, cholesteatoma, oto or otherwise non-toxic to the inner ear environment. In some sclerosis, Scheibe syndrome, Mondini-Michelle syndrome, embodiments, the compositions described herein are free of Waardenburg's syndrome, Michel syndrome, Alexander's ear preservatives and cause minimal disturbance (e.g., change in deformity, hypertelorism, Jervell-Lange Nielson syndrome, pH or osmolarity, irritation) in auditory structures. In some US 2010/0021416 A1 Jan. 28, 2010 embodiments, the compositions described herein comprise an auris-acceptable polymer, an auris-acceptable viscosity antioxidants that are non-irritating and/or non-toxic to otic enhancing agent, an auris-acceptable gel, an auris-acceptable Structures. paint, an auris-acceptable foam, an auris-acceptable micro sphere or microparticle, an auris-acceptable hydrogel, an Dosing Frequency auris-acceptable in situ forming spongy material, an auris 0009. The current standard of care for auris compositions acceptable actinic radiation curable gel, an auris-acceptable requires multiple administrations of drops or injections (e.g. liposome, an auris-acceptable nanocapsule or nanosphere, an intratympanic injections) over several days (e.g., up to two auris-acceptable thermoreversible gel or combinations weeks), including schedules of receiving multiple injections thereof. In further embodiments, the auris-acceptable viscos per day. In some embodiments, auris compositions described ity enhancing agent is a cellulose, a cellulose ether, alginate, herein are controlled-release compositions and are adminis polyvinylpyrrolidone, a gum, a cellulosic polymer or combi tered at reduced dosing frequency compared to the current nations thereof. In yet another embodiment, the auris-accept standard of care. In certain instances, when an auris compo able viscosity enhancing agent is present in an amount Suffi sition is administered via intratympanic injection, a reduced cient to provide a viscosity of between about 1000 to about frequency of administration alleviates discomfort caused by 1,000,000 centipoise. In still another aspect, the auris-accept multiple intratympanic injections in individuals undergoing able viscosity enhancing agent is present in an amount Suffi treatment for a middle and/or inner ear disease, disorder or cient to provide a viscosity of between about 50,000 to about condition. In certain instances, a reduced frequency of admin istration of intratympanic injections reduces the risk of per 1,000,000 centipoise. manent damage (e.g., perforation) to the tympanic mem 0013. In some embodiments, the compositions disclosed brane. The compositions described herein provide a constant, herein are formulated for a pH that ensures that they are Sustained, extended, delayed or pulsatile rate of release of an compatible with the targeted auris structure. In some embodi active agent into the inner ear environment and thus avoid any ments, the compositions disclosed herein are formulated for a variability in drug exposure in treatment of otic disorders. practical osmolality and/or osmolarity that ensures that homeostasis of the target auris structure is maintained. A Therapeutic Index perilymph-Suitable osmolarity/oSmolality is a practical 0010 Auris compositions described herein are adminis osmolarity/oSmolality that maintains the homeostasis of the tered into the ear canal, or in the vestibule of the ear. In some target auris structure during administration of the pharmaceu embodiments, access to the vestibular and cochlear apparatus tical compositions described herein. occurs through the auris media (e.g., the round window mem 0014 For example, the osmolarity of the perilymph is brane, the oval window? stapes footplate, the annular ligament between about 270-300 mOsm/L and the compositions and through the otic capsule/temporal bone). Otic adminis described herein are optionally formulated to provide a prac tration of the compositions described herein avoids toxicity tical osmolarity of about 150 to about 1000 mOsm/L. In associated with systemic administration (e.g., hepatotoxicity, certain embodiments, the compositions described herein pro cardiotoxicity, gastrointestinal side effects, renal toxicity) of vide a practical osmolarity within about 150 to about 500 the active agents. In some instances, localized administration mOsm/L at the target site of action (e.g., the inner ear and/or in the ear allows an active agent to reach a target (e.g., the the perilymph and/or the endolymph). In certain embodi inner ear) in the absence of systemic accumulation of the ments, the compositions described herein provide a practical active agent. In some instances, local administration to the ear osmolarity within about 200 to about 400 mOsm/L at the provides a higher therapeutic index for an active agent that target site of action (e.g., the inner ear and/or the perilymph would otherwise have dose-limiting systemic toxicity. and/or the endolymph). In certain embodiments, the compo Prevention of Drainage into Eustachian Tube sitions described herein provide a practical osmolarity within 0011. In some instances, a disadvantage of liquid compo about 250 to about 320 mOsm/L at the target site of action sitions is their propensity to drip into the eustachian tube and (e.g., the inner ear and/or the perilymph and/or the cause rapid clearance of the composition from the inner ear. endolymph). In certain embodiments, the compositions Provided herein, in certain embodiments, are auris composi described herein provide a perilymph-suitable osmolarity tions comprising polymers that gel at body temperature and within about 150 to about 500 mOsm/L, about 200 to about remain in contact with the target auditory Surfaces (e.g., the 400 mOsm/L or about 250 to about 320 mOsm/L at the target round window) for extended periods of time. In some site of action (e.g., the inner ear and/or the perilymph and/or embodiments, the compositions further comprise a mucoad the endolymph). In certain embodiments, the compositions hesive that allows the compositions to adhere to otic mucosal described herein provide a perilymph-suitable osmolality Surfaces. In some instances, the auris compositions described within about 150 to about 500 mOsm/kg, about 200 to about hereinavoid attenuation of therapeutic benefit due to drainage 400 mOsm/kg or about 250 to about 320 mOsm/kg at the target site of action (e.g., the inner ear and/or the perilymph or leakage of active agents via the eustachian tube. and/or the endolymph). Similarly, the pH of the perilymph is DESCRIPTION OF CERTAIN EMBODIMENTS about 7.2-7.4, and the pH of the present compositions is formulated (e.g., with the use of buffers) to provide a peri 0012. Described herein, in certain embodiments, are con lymph-suitable pH of about 5.5 to about 9.0, about 6.0 to trolled-release compositions and devices for treating otic dis about 8.0 or about 7.0 to about 7.6. In certain embodiments, orders comprising a therapeutically-effective amount of an the pH of the compositions is within about 6.0 to about 7.6. In otic structure modulating agent or innate immune system certain instances, the pH of the endolymph is about 7.2-7.9, modulating agent, a controlled-release auris-acceptable and the pH of the present compositions is formulated (e.g., excipient and an auris-acceptable vehicle. In one aspect, the with the use of buffers) to be within about 5.5 to about 9.0, controlled-release auris-acceptable excipient is chosen from within about 6.5 to about 8.0 or within about 7.0 to about 7.6. US 2010/0021416 A1 Jan. 28, 2010

0015. In some aspects, the controlled-release auris-ac matases; and strontium-based compounds as disclosed in ceptable excipient is biodegradable and/or bioeliminated WO/2008/027880, which is incorporated by reference herein. (e.g., degraded and/or eliminated through urine, feces or 0020. In some embodiments, the otic structure modulating other routes of elimination). In another aspect, the controlled agent is an otic structure enhancing agent. In some embodi release composition further comprises an auris-acceptable ments, the otic structure enhancing agent rebuilds or Supple mucoadhesive, an auris-acceptable penetration enhancer or ments bone. In some embodiments, the otic structure enhanc an auris-acceptable bioadhesive. ing agent rebuilds or Supplements cartilage. In some 0016. In one aspect, the controlled-release composition is embodiments, the otic structure enhancing agent rebuilds or delivered using a drug delivery device, which is a needle and Supplements a membrane (e.g., a tympanic membrane). In Syringe, a pump, a microinjection device, and in situ forming Some embodiments, the otic structure enhancing agent spongy material or combinations thereof. In some embodi rebuilds or Supplements endolymph. In some embodiments, ments, the otic structure modulating agent or innate immune the otic structure enhancing agent rebuilds or Supplements system modulating agent of the controlled-release composi perilymph. tion has limited or no systemic release, is toxic when admin 0021. In some embodiments, the otic structure modulating istered systemically, has poor pK characteristics, or combi agent is an otic structure enhancing agent. In some embodi nations thereof. ments, the otic structure enhancing agent is actin, aggrecan, 0017. In some embodiments, the otic structure modulating chondroitin, collagen, decorin, dermatan Sulfate, elastin, agent is an otic structure enhancing agent (e.g., a molecular fibrinogen, fibronectin, fimbrin, glial fibrillary acidic protein, component of an otic structure). In some embodiments, the heparan Sulfate, hyaluronic acid, keratin, laminin, nestin, otic structure enhancing agent is actin, aggrecan, chondroitin, NF-L, NF-M, NF H, NF66, peripherin, C-tubulin, B-tubu collagen, decorin, dermatan Sulfate, elastin, fibrinogen, lin, Villin, vimentin, whirlin, or combinations thereof. fibronectin, fimbrin, glial fibrillary acidic protein, heparan 0022. In some embodiments, the innate immune system Sulfate, hyaluronic acid, keratin, laminin, nestin, NF-L, modulating agent is a complement cascade modulating agent NF-M, NF H, NF66, peripherin, C-tubulin, B-tubulin, vil and/or an anaphylatoxin modulator. In some embodiments, lin, vimentin, whirlin, or combinations thereof. the innate immune system modulating agent is a complement 0018. In some embodiments, the otic structure modulating cascade antagonist and/or an anaphylatoxin antagonist. In agent is an otic structure degrading agent. In some embodi Some embodiments, the innate immune system modulating ments, the otic structure degrading agent degrades bone. In agent is a complement cascade agonist and/or an anaphyla Some embodiments, the otic structure degrading agent toxin agonist. degrades cartilage. In some embodiments, the otic structure 0023. In some embodiments, the innate immune system degrading agent degrades a neuron. In some embodiments, modulating agent is CHIPS, PMX53, PMX205, PMX273, the otic structure degrading agent degrades a membrane (e.g., PMX201, PMX218, CO89, L-156,602, C5aRAM, C5aRAD, a tympanic membrane). In some embodiments, the otic struc PR226-MAP, PL37-MAP, SB-290157, GR-2II, AGIIa, ture degrading agent degrades endolymph. In some embodi AGIIb-1, AR-2IIa, AR-2IIb, AR-2IIc, AR-2IId, CVF, CVF, ments, the otic structure degrading agent degrades perilymph. humanized CVF, rC3, HC3-1496, HC3-1496-2, HC3-1496 In some embodiments, the otic structure degrading agent 3, HC3-1496-4, HC3-1496/1617, HC3-1496-8, HC3-1496 degrades liquor puris (i.e., pus). 9, HC3-1496-10, HC3-1496-11, HC3-1496-12, HC3-1496 0019. In some embodiments, the otic structure modulating 13, HC3-1496-14, HC3-1496-15, HC3-1496-16, HC3-1496 agent is an otic structure degrading agent. In some embodi 17, complement component 1 inhibitor, dextran Sulfate, ments, the otic structure degrading agent is an alcohol, an complement component 1 q receptor, C1q inhibitor, decorin, alkanol, an essential oil, a fatty acid, a glycol, laurocapram, a CSPG, CBP2, complement receptor 1, SCR1, APTO70, TP10, pyrrolidone, a Sulfoxide, a Surfactant, an enzyme, or a com TP20, SOR1 desLHR-A), sGR1-SLe, Crry, Crry-Ig, a bination thereof. In some embodiments, the enzyme is a pro flucan, BS8, complestatin, Ecb, Efb, compStatin, roSmarinic tease, a glycosidase, protease, a glycosidase, an actinase, a acid, CRIT, CRIT-H17, glycyrrhetinic acid, an anti-comple caseinase, a chondroitinase, a collagenase, a dermatanase, an ment component 5 (C5) murine monoclonal antibody, pex elastase, a gelatinase, a heparanase, a hyaluronidase, a kera elizumab, an anti-C5 murine single-chain antibody, K76, tinase, a lipase, a metalloproteinase (e.g. matrix metallopro TKIXc, K76 COOH, SCIN, SCIN-B, SCIN-C, CD55, teinase), a staphylokinase, a streptokinase, chymotrypsin, sCD55, CD59, sGD59, a CD59/CD55 fusion protein, a endopeptidase V8, trypsin, thermolysin, pepsin, plasmin, or CD55/MCP fusion protein, BCX-1470, FUT-175, Factor I, combinations thereof. In some embodiments, the otic struc MCP sMCP heparin, LU 51198, clusterin, vitronectin, an ture modulating agent is a modulator of bone remodeling. In anti-properdin antibody, SB 2901 57 (N2-((2,2-diphe Some embodiments, the modulator of bone remodeling is a nylethoxy)acetyl)arginine), anti-MIF antibody, metformin, modulator of osteoblasts or osteoclasts, including but not ISO-1,2-(4-hydroxybenzylidene)amino-3(1H-indol-3-yl) limited to, hormones; bisphosphonates; matrix metallopro propionic acid methyl ester, NAPQI, AVP-28225, or combi teinase inhibitors; an adenylyl cyclase (AC) modulators; pro nations thereof. tease inhibitors; modulators of tartarate resistant acid phos 0024. Also disclosed herein, in certain embodiments, is a phatase (TRACP); estrogen receptor modulators; PPAR Y method for treating anotic disorder comprising administering modulators; HMG-CoA reductase inhibitors; statins; car a composition disclosed herein at least once every 3, 4, 5, 6, 7, bonic anhydrase inhibitors; modulators of the receptor acti 8, 9, 10, 11, 12, 13, 14, or 15 days; at least once a week, once vator of nuclear KB ligand (RANKL): COX-2 inhibitors: every two weeks, once every three weeks, once every four inhibitors of protein prenylation; 5-lipoxygenase inhibitors; weeks, once every five weeks, or once every six weeks; or at inhibitors of TNF: inhibitors of leukotrienes; cytokine modu least once a month, once every two months, once every three lators; inhibitors of TSG-6, modulators of TGF f: nitiric months, once every four months, once every five months, oxide synthase inhibitors; acetylcysteine; modulators of aro once every six months, once every seven months, once every US 2010/0021416 A1 Jan. 28, 2010

eight months, once every nine months, once every ten 0.039 (ii) between about 14% to about 21% by weight months, once every eleven months, or once every twelve of a polyoxyethylene-polyoxypropylene triblock months. In particular embodiments, the controlled-release copolymer of general formula E 106 P70 E106; and compositions described herein provide a Sustained dose of an 0040 (iii) multiparticulate otic structure modulating otic structure modulating agent or innate immune system agent. modulating agent to the inner ear between Subsequent doses 0041. In some embodiments, a pharmaceutical composi of the controlled-release composition. That is, taking one tion or device described herein comprises: example only, if new doses of the otic structure modulating (0.042 (i) between about 0.1% to about 10% by weight of agent or innate immune system modulating agent controlled the otic structure modulating agent, orpharmaceutically release composition are administered via intratympanic acceptable prodrug or salt thereof; injection to the round window membrane every 10 days, then (0.043 (ii) between about 14% to about 21% by weight the controlled-release composition provides an effective dose of a polyoxyethylene-polyoxypropylene triblock of an otic structure modulating agent or innate immune sys copolymer of general formula E106 P70 E106: tem modulating agent to the inner ear (e.g., across the round 0044 (iii) multiparticulate otic structure modulating window membrane) during that 10-day period. agent; and 0025. In one aspect, the composition is administered so that the composition is in contact with the crista fenestrae 0.045 (iv) a gelation temperature between about 19°C. cochleae, the round window membrane or the tympanic cav to about 42°C. Provided herein are pharmaceutical com ity. In one aspect the composition is administered by positions or devices for use in the treatment of an otic intratympanic injection. disease or condition formulated to provide a therapeuti 0026. Provided herein are pharmaceutical compositions cally effective amount of a molecular component of an or devices for use in the treatment of an otic disease or otic structure, the pharmaceutical compositions or condition formulated to provide a therapeutically effective devices comprising Substantially low degradation prod amount of anotic structure modulating agent, the pharmaceu ucts of the otic structure enhancing agent, the pharma tical compositions or devices comprising Substantially low ceutical compositions or devices further comprising two degradation products of the otic structure modulating agent, or more characteristics selected from: the pharmaceutical compositions or devices further compris 0046 (i) between about 0.1% to about 10% by weight of ing two or more characteristics selected from: the otic structure enhancing agent, or pharmaceutically (0027 (i) between about 0.1% to about 10% by weight of acceptable prodrug or salt thereof; the otic structure modulating agent, or pharmaceutically 0047 (ii) between about 14% to about 21% by weight acceptable prodrug or salt thereof; of a polyoxyethylene-polyoxypropylene triblock (0028 (ii) between about 14% to about 21% by weight copolymer of general formula E106 P70 E106: of a polyoxyethylene-polyoxypropylene triblock 0.048 (iii) sterile water, q.s., buffered to provide a pH copolymer of general formula E106 P70 E106: between about 5.5 and about 8.0: 0029 (iii) sterile water, q.s., buffered to provide a pH 0049 (iv) multiparticulate molecular component of an between about 5.5 and about 8.0: 0030 (iv) multiparticulate otic structure modulating otic structure; agent, 0050 (v) a gelation temperature between about 19°C. 0031 (v) a gelation temperature between about 19°C. to about 42°C.; to about 42°C.; 0051 (vi) less than about 50 colony forming units (cfu) 0032 (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of composition; of microbiological agents per gram of composition; 0.052 (vii) less than about 5 endotoxin units (EU) per kg 0033 (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject; of body weight of a subject; 0.053 (viii) a mean dissolution time of about 30 hours 0034 (viii) a mean dissolution time of about 30 hours for the otic structure enhancing agent; and for the otic structure modulating agent; and 0054 (ix) an apparent viscosity of about 100,000 cF to 0035 (ix) an apparent viscosity of about 100,000 cp to about 500,000 cP. about 500,000 cP. 0055. In some embodiments, the pharmaceutical compo 0036. In some embodiments, the pharmaceutical compo sition comprises at least three of the aforementioned charac sition comprises at least three of the aforementioned charac teristics. In some embodiments, the pharmaceutical compo teristics. In some embodiments, the pharmaceutical compo sition comprises at least four of the aforementioned sition comprises at least four of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least five of the aforementioned composition comprises at least five of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least six of the aforementioned composition comprises at least six of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least seven of the aforementioned composition comprises at least seven of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises all of the aforementioned character composition comprises all of the aforementioned character istics. istics. 0037. In some embodiments, a pharmaceutical composi 0056. In some embodiments, a pharmaceutical composi tion or device described herein comprises: tion or device described herein comprises: 0038 (i) between about 0.1% to about 10% by weight of 0057 (i) between about 0.1% to about 10% by weight of the otic structure modulating agent, or pharmaceutically the otic structure enhancing agent, or pharmaceutically acceptable prodrug or salt thereof; acceptable prodrug or salt thereof; US 2010/0021416 A1 Jan. 28, 2010

0058 (ii) between about 14% to about 21% by weight 0.077 (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E 106 P70 E106; and copolymer of general formula E 106 P70 E106; and 0059 (iii) multiparticulate molecular component of an 0078 (iii) multiparticulate otic structure degrading otic structure. agent. 0060. In some embodiments, a pharmaceutical composi 0079. In some embodiments, a pharmaceutical composi tion or device described herein comprises: tion or device described herein comprises: 0061 (i) between about 0.1% to about 10% by weight of 0080 (i) between about 0.1% to about 10% by weight of the otic structure enhancing agent, or pharmaceutically the otic structure degrading agent, or pharmaceutically acceptable prodrug or salt thereof; acceptable prodrug or salt thereof; 0062 (ii) between about 14% to about 21% by weight I0081 (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106: copolymer of general formula E106 P70 E106: 0063 (iii) multiparticulate molecular component of an 0082 (iii) multiparticulate otic structure degrading otic structure; and agent; and 0064 (iv) a gelation temperature between about 19°C. 0.083 (iv) a gelation temperature between about 19°C. to about 42°C. Provided herein are pharmaceutical com to about 42°C. positions or devices for use in the treatment of an otic I0084 Provided herein are pharmaceutical compositions disease or condition formulated to provide a therapeuti or devices for use in the treatment of an otic disease or cally effective amount of an otic structure degrading condition formulated to provide a therapeutically effective agent, the pharmaceutical compositions or devices com amount of an innate immune system modulating agent, the prising Substantially low degradation products of the pharmaceutical compositions or devices comprising Substan otic structure degrading agent, the pharmaceutical com tially low degradation products of the innate immune system positions or devices further comprising two or more modulating agent, the pharmaceutical compositions or characteristics selected from: devices further comprising two or more characteristics selected from: 0065 (i) between about 0.1% to about 10% by weight of I0085 (i) between about 0.1% to about 10% by weight of the otic structure degrading agent, or pharmaceutically the innate immune system modulating agent, orpharma acceptable prodrug or salt thereof; ceutically acceptable prodrug or salt thereof; 0066 (ii) between about 14% to about 21% by weight I0086 (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106: copolymer of general formula E106 P70 E106: 0067 (iii) sterile water, q.s., buffered to provide a pH 0.087 (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0: between about 5.5 and about 8.0: 0068 (iv) multiparticulate otic structure degrading 0088 (iv) multiparticulate innate immune system agent, modulating agent; 0069 (v) a gelation temperature between about 19°C. 0089 (v) a gelation temperature between about 19°C. to about 42°C.; to about 42°C.; 0070 (vi) less than about 50 colony forming units (cfu) 0090 (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of composition; of microbiological agents per gram of composition; 0071 (vii) less than about 5 endotoxin units (EU) per kg 0.091 (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject; of body weight of a subject; 0072 (viii) a mean dissolution time of about 30 hours 0092 (viii) a mean dissolution time of about 30 hours for the otic structure degrading agent; and for the innate immune system modulating agent; and (0073 (ix) an apparent viscosity of about 100,000 cp to (0.093 (ix) an apparent viscosity of about 100,000 cF to about 500,000 cP. about 500,000 cP. 0074. In some embodiments, the pharmaceutical compo 0094. In some embodiments, the pharmaceutical compo sition comprises at least three of the aforementioned charac sition comprises at least three of the aforementioned charac teristics. In some embodiments, the pharmaceutical compo teristics. In some embodiments, the pharmaceutical compo sition comprises at least four of the aforementioned sition comprises at least four of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least five of the aforementioned composition comprises at least five of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least six of the aforementioned composition comprises at least six of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises at least seven of the aforementioned composition comprises at least seven of the aforementioned characteristics. In some embodiments, the pharmaceutical characteristics. In some embodiments, the pharmaceutical composition comprises all of the aforementioned character composition comprises all of the aforementioned character istics. istics. 0075. In some embodiments, a pharmaceutical composi 0095. In some embodiments, a pharmaceutical composi tion or device described herein comprises: tion or device described herein comprises: (0076 (i) between about 0.1% to about 10% by weight of (0.096 (i) between about 0.1% to about 10% by weight of the otic structure degrading agent, or pharmaceutically the innate immune system modulating agent, orpharma acceptable prodrug or salt thereof; ceutically acceptable prodrug or salt thereof. US 2010/0021416 A1 Jan. 28, 2010

(0097 (ii) between about 14% to about 21% by weight degrading agent degrades a neuron. In some embodiments, of a polyoxyethylene-polyoxypropylene triblock the otic structure degrading agent degrades a membrane. In copolymer of general formula E 106 P70 E106; and Some embodiments, the otic structure degrading agent 0.098 (iii) multiparticulate innate immune system degrades liquor puris. In some embodiments, the otic struc modulating agent. ture degrading agent degrades endolymph or perilymph. 0099. In some embodiments, a pharmaceutical composi 0116. In some embodiments, a pharmaceutical composi tion or device described herein comprises: tion or device described above provides a practical osmolarity 0100 (i) between about 0.1% to about 10% by weight of between about 150 and 500 mOsm/L. In some embodiments, the innate immune system modulating agent, orpharma a pharmaceutical composition or device described above pro ceutically acceptable prodrug or salt thereof. vides a practical osmolarity between about 200 and 400 0101 (ii) between about 14% to about 21% by weight mOsm/L. In some embodiments, a pharmaceutical composi of a polyoxyethylene-polyoxypropylene triblock tion or device described above provides a practical osmolarity copolymer of general formula E106 P70 E106: between about 250 and 320 mOsm/L. 0102 (iii) multiparticulate innate immune system 0117. In some embodiments, the otic structure modulating modulating agent; and agent or innate immune system modulating agent is released 0103 (iv) a gelation temperature between about 19°C. from the pharmaceutical composition or device described to about 42° C. above for a period of at least 3 days. In some embodiments, 0104 Provided herein are methods of treating an otic dis the otic structure modulating agent or innate immune system ease or condition characterized by excess otic structures com modulating agent is released from the pharmaceutical com prising administering to an individual in need thereof an position or device described above for a period of at least 5 intratympanic composition or device comprising: atherapeu days. In some embodiments, the otic structure modulating tically effective amount of an otic structure degrading agent agent or innate immune system modulating agent is released having Substantially low degradation products; and wherein from the pharmaceutical composition or device described the composition or device comprises two or more character above for a period of at least 10 days. In some embodiments, istics selected from: the otic structure modulating agent or innate immune system 0105 (i) between about 0.1% to about 10% by weight of modulating agent is released from the pharmaceutical com the otic structure degrading agent, or pharmaceutically position or device described above for a period of at least 14 acceptable prodrug or salt thereof; days. In some embodiments, the otic structure modulating 0106 (ii) between about 14% to about 21% by weight agent or innate immune system modulating agent is released of a polyoxyethylene-polyoxypropylene triblock from the pharmaceutical composition or device described copolymer of general formula E106 P70 E106: above for a period of at least one month. 0107 (iii) sterile water, q.s., buffered to provide a pH 0118. In some embodiments, a pharmaceutical composi between about 5.5 and about 8.0: tion or device described above comprises an otic structure 0.108 (iv) multiparticulate otic structure degrading modulating agent or innate immune system modulating agent agent, as a neutral molecule, a free acid, a free base, a salt or a 0109 (v) a gelation temperature between about 19°C. prodrug. In some embodiments, a pharmaceutical composi to about 42°C.; tion or device described above comprises an otic structure 0110 (vi) less than about 50 colony forming units (cfu) modulating agent or innate immune system modulating agent of microbiological agents per gram of composition, and as a neutral molecule, a free acid, a free base, a salt or a 0111 (vii) less than about 5 endotoxin units (EU) per kg prodrug, or a combination thereof. of body weight of a subject; 0119. In some embodiments, a pharmaceutical composi 0112 (viii) a mean dissolution time of about 30 hours tion or device described above comprises an otic structure for the otic structure degrading agent; and modulating agent or innate immune system modulating agent 0113 (ix) an apparent viscosity of about 100,000 cp to as multiparticulates. In some embodiments, a pharmaceutical about 500,000 cP. composition or device described above comprises an otic 0114. In some embodiments, the pharmaceutical compo structure modulating agent or innate immune system modu sition comprises at least three of the aforementioned charac lating agent in the form of micronized particles. In some teristics. In some embodiments, the pharmaceutical compo embodiments, a pharmaceutical composition or device sition comprises at least four of the aforementioned described above comprises anotic structure modulating agent characteristics. In some embodiments, the pharmaceutical or innate immune system modulating agent as micronized composition comprises at least five of the aforementioned powders. characteristics. In some embodiments, the pharmaceutical 0120 In some embodiments, a pharmaceutical composi composition comprises at least six of the aforementioned tion or device described above comprises about 10% of a characteristics. In some embodiments, the pharmaceutical polyoxyethylene-polyoxypropylene triblock copolymer of composition comprises at least seven of the aforementioned general formula E106 P70 E106 by weight of the composi characteristics. In some embodiments, the pharmaceutical tion. In some embodiments, a pharmaceutical composition or composition comprises all of the aforementioned character device described above comprises about 15% of a polyoxy istics. ethylene-polyoxypropylene triblock copolymer of general 0115. In some embodiments, the otic structure degrading formula E106 P70 E106 by weight of the composition. In agent is released from the composition for a period of at least Some embodiments, a pharmaceutical composition or device 3 days. In some embodiments, the otic structure degrading described above comprises about 20% of a polyoxyethylene agent is essentially in the form of micronized particles. In polyoxypropylene triblock copolymer of general formula Some embodiments, the otic structure degrading agent E106 P70 E106 by weight of the composition. In some degrades bone. In some embodiments, the otic structure embodiments, a pharmaceutical composition or device US 2010/0021416 A1 Jan. 28, 2010 described above comprises about 25% of a polyoxyethylene about 70% of an otic structure modulating agent or innate polyoxypropylene triblock copolymer of general formula immune system modulating agent, or pharmaceutically E106 P70 E106 by weight of the composition. acceptable prodrug or salt thereof, by weight of the compo 0121. In some embodiments, a pharmaceutical composi sition. In some embodiments, a pharmaceutical composition or device described above comprises about 80% of an otic tion or device described herein comprises about 1% of anotic structure modulating agent or innate immune system modu structure modulating agent or innate immune system modu lating agent, or pharmaceutically acceptable prodrug or salt lating agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the composition. In some embodiments, thereof, by weight of the composition. In some embodiments, a pharmaceutical composition or device described above a pharmaceutical composition or device described above comprises about 90% of anotic structure modulating agent or comprises about 2% of an otic structure modulating agent or innate immune system modulating agent, or pharmaceuti innate immune system modulating agent, or pharmaceuti cally acceptable prodrug or salt thereof, by weight of the cally acceptable prodrug or salt thereof, by weight of the composition. composition. In some embodiments, a pharmaceutical com position or device described herein comprises about 3% of an 0122. In some embodiments, a pharmaceutical composi otic structure modulating agent or innate immune system tion or device described above has a pH between about 5.5 modulating agent, or pharmaceutically acceptable prodrug or and about 8.0. In some embodiments, a pharmaceutical com salt thereof, by weight of the composition. In some embodi position or device described above has a pH between about ments, a pharmaceutical composition or device described 6.0 and about 8.0. In some embodiments, a pharmaceutical herein comprises about 4% of an otic structure modulating composition or device described above has a pH between agent or innate immune system modulating agent, or phar about 6.0 and about 7.6. maceutically acceptable prodrug or salt thereof, by weight of 0123. In some embodiments, a pharmaceutical composi the composition. In some embodiments, a pharmaceutical tion or device described above contains less than 100 colony composition or device described above comprises about 5% forming units (cfu) of microbiological agents per gram of of an otic structure modulating agent or innate immune sys composition. In some embodiments, a pharmaceutical com tem modulating agent, or pharmaceutically acceptable pro position or device described above contains less than 50 drug or salt thereof, by weight of the composition. In some colony forming units (cfu) of microbiological agents per embodiments, a pharmaceutical composition or device gram of composition. In some embodiments, a pharmaceuti described above comprises about 10% of an otic structure cal composition or device described above contains less than modulating agent or innate immune system modulating 10 colony forming units (cfu) of microbiological agents per agent, orpharmaceutically acceptable prodrug or salt thereof, gram of composition. by weight of the composition. In some embodiments, a phar 0.124. In some embodiments, a pharmaceutical composi maceutical composition or device described above comprises tion or device described above contains less than 5 endotoxin about 15% of an otic structure modulating agent or innate units (EU) per kg of body weight of a subject. In some immune system modulating agent, or pharmaceutically embodiments, a pharmaceutical composition or device acceptable prodrug or salt thereof, by weight of the compo described above contains less than 4 endotoxin units (EU) per sition. In some embodiments, a pharmaceutical composition kg of body weight of a subject. or device described above comprises about 20% of an otic 0.125. In some embodiments, a pharmaceutical composi structure modulating agent or innate immune system modu tion or device described above provides a gelation tempera lating agent, or pharmaceutically acceptable prodrug or salt ture between about between about 19°C. to about 42°C. In thereof, by weight of the composition. In some embodiments, Some embodiments, a pharmaceutical composition or device a pharmaceutical composition or device described above described above provides a gelation temperature between comprises about 25% of anotic structure modulating agent or about between about 19°C. to about 37°C. In some embodi innate immune system modulating agent, or pharmaceuti ments, a pharmaceutical composition or device described cally acceptable prodrug or salt thereof, by weight of the above provides a gelation temperature between about composition. In some embodiments, a pharmaceutical com between about 19° C. to about 30° C. position or device described above comprises about 30% of 0.126 In some embodiments, the pharmaceutical compo an otic structure modulating agent or innate immune system sition or device is an auris-acceptable thermoreversible gel. In modulating agent, or pharmaceutically acceptable prodrug or Some embodiments, the polyoxyethylene-polyoxypropylene salt thereof, by weight of the composition. In some embodi triblock copolymer is biodegradable and/or bioeliminated ments, a pharmaceutical composition or device described (e.g., the copolymer is eliminated from the body by a biodeg above comprises about 40% of an otic structure modulating radation process, e.g., elimination in the urine, the feces or the agent or innate immune system modulating agent, or phar like). In some embodiments, a pharmaceutical composition maceutically acceptable prodrug or salt thereof, by weight of or device described hereinfurther comprises a mucoadhesive. the composition. In some embodiments, a pharmaceutical In some embodiments, a pharmaceutical composition or composition or device described above comprises about 50% device described herein further comprises a penetration of an otic structure modulating agent or innate immune sys enhancer. In some embodiments, a pharmaceutical composi tem modulating agent, or pharmaceutically acceptable pro tion or device described hereinfurther comprises a thickening drug or salt thereof, by weight of the composition. In some agent. In some embodiments, a pharmaceutical composition embodiments, a pharmaceutical composition or device or device described herein further comprises a dye. described above comprises about 60% of an otic structure 0127. In some embodiments, a pharmaceutical composi modulating agent or innate immune system modulating tion or device described herein further comprises a drug agent, orpharmaceutically acceptable prodrug or salt thereof, delivery device selected from a needle and Syringe, a pump, a by weight of the composition. In some embodiments, a phar microinjection device, a wick, an in situ forming spongy maceutical composition or device described above comprises material or combinations thereof. US 2010/0021416 A1 Jan. 28, 2010

0128. In some embodiments, a pharmaceutical composi 0.136 (iii) sterile water, q.s., buffered to provide a pH tion or device described herein is a pharmaceutical composi between about 5.5 and about 8.0: tion or device wherein the otic structure modulating agent or 0.137 (iv) multiparticulate otic structure modulating innate immune system modulating agent, or pharmaceuti agent, cally acceptable salt thereof, has limited or no systemic 0.138 (v) a gelation temperature between about 19°C. release, systemic toxicity, poor PK characteristics, or combi to about 42°C.; nations thereof. In some embodiments, of the pharmaceutical 0.139 (vi) less than about 50 colony forming units (cfu) compositions or devices described herein, the otic structure of microbiological agents per gram of composition, and modulating agent or innate immune system modulating agent 0140 (vii) less than about 5 endotoxin units (EU) per kg is in the form of a neutral molecule, a free base, a free acid, a of body weight of a subject. Also provided herein is a salt, a prodrug, or a combination thereof. In some embodi method of treating anotic disease or condition compris ments, of the pharmaceutical compositions or devices ing administering to an individual in need thereof an described herein, the otic structure modulating agentorinnate intratympanic composition or device comprising a immune system modulating agent is administered in the form therapeutically effective amount of an otic structure of a phosphate or ester prodrug. In some embodiments, phar degrading agent, the composition or device comprising maceutical compositions or devices described herein com Substantially low degradation products of an otic struc prise an otic structure modulating agent or innate immune ture degrading agent, the composition or device further system modulating agent, orpharmaceutically acceptable salt comprising two or more characteristics selected from: thereof, prodrug or combination thereof as an immediate 0141 (i) between about 0.1% to about 10% by weight of release agent. the otic structure degrading agent, or pharmaceutically 0129. In some embodiments, pharmaceutical composi acceptable prodrug or salt thereof; tions or devices described herein further comprise an addi 0.142 (ii) between about 14% to about 21% by weight tional therapeutic agent. In some embodiments, the additional of a polyoxyethylene-polyoxypropylene triblock therapeutic agent is a an acidifying agent, an anesthetic, an copolymer of general formula E106 P70 E106: analgesic, an antibiotic, antiemetic, an antifungal, an anti 0.143 (iii) sterile water, q.s., buffered to provide a pH microbial agent, an antipsychotic (especially those in the between about 5.5 and about 8.0: phenothiazine class), an antiseptic, an antiviral, an astringent, 0144 (iv) multiparticulate otic structure degrading a chemotherapeutic agent, a collagen, a corticosteroid, a agent, diuretic, a keratolytic agent, a nitric oxide synthase inhibitor, (0145 (v) a gelation temperature between about 19°C. combinations thereof. to about 42°C.; 0146 (vi) less than about 50 colony forming units (cfu) 0130. In some embodiments, pharmaceutical composi of microbiological agents per gram of composition, and tions or devices described herein are pharmaceutical compo 0147 (vii) less than about 5 endotoxin units (EU) per kg sitions or devices wherein the pH of the pharmaceutical com of body weight of a subject. position or device is between about 6.0 to about 7.6. 0148 Also provided herein is a method of treating an otic 0131. In some embodiments, of the pharmaceutical com disease or condition comprising administering to an indi positions or devices described herein, the ratio of a polyoxy vidual in need thereof an intratympanic composition or ethylene-polyoxypropylene triblock copolymer of general device comprising a therapeutically effective amount of otic formula E106 P70 E106 to a thickening agent is from about structure enhancing agent, the composition or device com 40:1 to about 5:1. In some embodiments, the thickening agent prising Substantially low degradation products of otic struc is carboxymethyl cellulose, hydroxypropyl cellulose or ture enhancing agent, the composition or device further com hydroxypropyl methylcellulose. prising two or more characteristics selected from: 0132. In some embodiments, the otic disease or condition 0149 (i) between about 0.1% to about 10% by weight of is endolymphatic hydrops, kinetosis, labyrinthitis, mal de the otic structure enhancing agent, or pharmaceutically debarquement, Meniere's disease, Meniere's syndrome, acceptable prodrug or salt thereof; Ramsay Hunt's syndrome (Herpes Zoster infection), recur 0150 (ii) between about 14% to about 21% by weight rent vestibulopathy, tinnitus, Vertigo, microvascular compres of a polyoxyethylene-polyoxypropylene triblock sion syndrome, utricular dysfunction, Vestibular neuronitis, copolymer of general formula E106 P70 E106: benign paroxysmal positional vertigo, or combinations 0151 (iii) sterile water, q.s., buffered to provide a pH thereof. between about 5.5 and about 8.0: 0.133 Also provided herein is a method of treating an otic 0152 (iv) multiparticulate molecular component of an disease or condition comprising administering to an indi otic structure; vidual in need thereof an intratympanic composition or 0.153 (v) a gelation temperature between about 19°C. device comprising a therapeutically effective amount of an to about 42°C.; otic structure modulating agent, the composition or device 0154 (vi) less than about 50 colony forming units (cfu) comprising Substantially low degradation products of an otic of microbiological agents per gram of composition, and structure modulating agent, the composition or device further 0.155 (vii) less than about 5 endotoxin units (EU) per kg comprising two or more characteristics selected from: of body weight of a subject. I0134 (i) between about 0.1% to about 10% by weight of 0156 Also provided herein is a method of treating an otic the otic structure modulating agent, or pharmaceutically disease or condition comprising administering to an indi acceptable prodrug or salt thereof; vidual in need thereof an intratympanic composition or I0135 (ii) between about 14% to about 21% by weight device comprising a therapeutically effective amount of an of a polyoxyethylene-polyoxypropylene triblock innate immune system modulating agent, the composition or copolymer of general formula E106 P70 E106: device comprising Substantially low degradation products of US 2010/0021416 A1 Jan. 28, 2010 an innate immune system modulating agent, the composition deformity, hypertelorism, Jervell-Lange Nielson syndrome, or device further comprising two or more characteristics RefSum's syndrome, Usher's syndrome, or combinations selected from: thereof. (O157 (i) between about 0.1% to about 10% by weight of the innate immune system modulating agent, orpharma BRIEF DESCRIPTION OF FIGURES ceutically acceptable prodrug or salt thereof. 0166 FIG. 1 illustrates a comparison of non-sustained 0158 (ii) between about 14% to about 21% by weight release and Sustained release compositions. of a polyoxyethylene-polyoxypropylene triblock 0.167 FIG. 2 illustrates the effect of concentration on the copolymer of general formula E106 P70 E106: viscosity of aqueous solutions of Blanose refined CMC. 0159 (iii) sterile water, q.s., buffered to provide a pH (0168 FIG. 3 illustrates the effect of concentration on the between about 5.5 and about 8.0: viscosity of aqueous solutions of Methocel. FIG. 4 provides 0160 (iv) multiparticulate innate immune system an illustrative representation of the anatomy of the ear. modulating agent; 0169 FIG. 5 illustrates tunable release of an active agent 0.161 (v) a gelation temperature between about 19°C. from four compositions. to about 42°C.; 0162 (vi) less than about 50 colony forming units (cfu) DETAILED DESCRIPTION OF THE INVENTION of microbiological agents per gram of composition, and (0170 Provided herein are controlled-release otic structure 0163 (vii) less than about 5 endotoxin units (EU) per kg modulating compositions and compositions to treat (e.g., of body weight of a subject. ameliorate or reduce the effects of) an otic disease, disorder, 0164. In some embodiments of the methods described or condition characterized by an excess or deficiency in an herein, the otic structure modulating agent or innate immune otic structure. In some embodiments, the controlled-release system modulating agent is released from the composition or otic structure modulating compositions and compositions treat (e.g., ameliorate or reduce the effects of) an otic disease, devices for a period of at least 3 days. In some embodiments disorder, or condition characterized by an excess of otic struc of the methods described herein, the otic structure modulating tures. In some embodiments, the controlled-release otic struc agent or innate immune system modulating agent is released ture modulating compositions and compositions treat (e.g., from the composition or device for a period of at least 4 days. ameliorate or reduce the effects of) an otic disease, disorder, In some embodiments of the methods described herein, the or condition characterized by a deficiency of otic structures. otic structure modulating agent or innate immune system In some embodiments, the otic disease, disorder, or condition modulating agent is released from the composition or device is otitis externa, otitis media, mastoiditis, sensorineural hear for a period of at least 5 days. In some embodiments of the ing loss, ototoxicity, endolymphatic hydrops, labyrinthitis, methods described herein, the otic structure modulating agent Meniere's disease, Meniere's syndrome, microvascular com or innate immune system modulating agent is released from pression syndrome, vestibular neuronitis, acoustic trauma, the composition or device for a period of at least 6 days. In presbycusis, cholesteatoma, otosclerosis, Scheibe syndrome, some embodiments of the methods described herein, the otic Mondini-Michelle syndrome, Waardenburg's syndrome, structure modulating agent or innate immune system modu Michel syndrome, Alexander's ear deformity, hypertelorism, lating agent is released from the composition or device for a Jervell-Lange Nielson syndrome, Refsum's syndrome, Ush period of at least 7 days. In some embodiments of the methods er's syndrome, or combinations thereof. described herein, the otic structure modulating agentorinnate 0171 Further provided herein are controlled-release immune system modulating agent is released from the com complement modulating compositions and compositions to position or device for a period of at least 8 days. In some treat (e.g., ameliorate or reduce the effects of) an otic disease, embodiments of the methods described herein, the otic struc disorder, or condition characterized by dysfunction of the ture modulating agent or innate immune system modulating innate immune system. In some embodiments, the controlled agent is released from the composition or device for a period release complement modulating compositions and devices treat (e.g., ameliorate or reduce the effects of) an otic disease, of at least 9 days. In some embodiments of the methods disorder, or condition characterized by the over-activity of the described herein, the otic structure modulating agentorinnate innate immune system. In some embodiments, the otic dis immune system modulating agent is released from the com ease, disorder, or condition is otitis externa, otitis media, position or device for a period of at least 10 days. In some mastoiditis, AIED, Ramsay Hunts, reperfusion injury, laby embodiments of the method described above, the otic struc rinthitis ossificans or combinations thereof. ture modulating agent or innate immune system modulating 0172. In some embodiments, the otic structure modulating agent is essentially in the form of micronized particles. agent is an otic structure degrading agent. In some embodi 0165. In some embodiments of the methods described ments, the otic structure modulating agent is otic structure herein, the composition is administered across the round win enhancing agent. dow. In some embodiments of the methods described herein, 0173. In some embodiments, the innate immune system the otic disease or condition is otitis externa, otitis media, modulating agent is a complement cascade modulating agent mastoiditis, sensorineural hearing loss, ototoxicity, endolym and/or an anaphylatoxin modulator. In some embodiments, phatic hydrops, labyrinthitis, Meniere's disease, Meniere's the innate immune system modulating agent is a complement syndrome, microvascular compression syndrome, Vestibular cascade antagonist and/or an anaphylatoxin antagonist. In neuronitis, acoustic trauma, presbycusis, cholesteatoma, oto Some embodiments, the innate immune system modulating sclerosis, Scheibe syndrome, Mondini-Michelle syndrome, agent is a complement cascade agonist and/or an anaphyla Waardenburg's syndrome, Michel syndrome, Alexander's ear toxin agonist. US 2010/0021416 A1 Jan. 28, 2010

0.174. A few therapeutic products are available for the result of systemic administration of the otic structure modu treatment of otic disorders; however, systemic routes via oral, lating compositions. The locally applied otic structure modu intravenous or intramuscular routes are currently used to lating compositions and devices are compatible with the tar deliver these therapeutic agents. In some instances, systemic geted auris structures, and administered either directly to the drug administration creates a potential inequality in drug desired targeted auris structure (e.g., the cochlear region, the concentration with higher circulating levels in the serum, and tympanic cavity or the external ear), or administered to a lower levels in the target auris media and auris interna organ structure in direct communication with areas of the auris structures. As a result, fairly large amounts of drug are interna (e.g., the round window membrane, the crista fenes required to overcome this inequality in order to deliver suffi trae cochleae or the oval window membrane). By specifically cient, therapeutically effective quantities to the inner ear. In targeting an auris structure, adverse side effects as a result of addition, systemic drug administration may increase the like systemic treatment are avoided. Moreover, clinical studies lihood of systemic toxicities and adverse side effects as a have shown the benefit of having long term exposure of drug result of the high serum amounts required to effectuate Suf to the perilymph of the cochlea, for example with improved ficient local delivery to the target site. Systemic toxicities may clinical efficacy of Sudden hearing loss when the therapeutic also occur as a result of liver breakdown and processing of the agent is given on multiple occasions. Thus, by providing a therapeutic agents, forming toxic metabolites that effectively controlled-release otic structure modulating composition to erase any benefit attained from the administered therapeutic. treat otic disorders, a constant, variable and/or extended 0175 To overcome the toxic and attendant side effects of Source of an otic structure modulating agent or innate systemic delivery, disclosed herein are methods and compo immune system modulating agent is provided to the Subject sitions and devices for local delivery of therapeutic agents to Suffering from an otic disorder, reducing or eliminating targeted auris structures. Access to, for example, the vestibu uncertainty in treatment. Accordingly, one embodiment dis lar and cochlear apparatus will occur through the auris media closed herein is to provide a composition that enables an otic including round window membrane, the oval window? stapes structure modulating agent or innate immune system modu footplate, the annular ligament and through the otic capsule/ lating agent to be released in therapeutically effective doses temporal bone. either at variable or constant rates such as to ensure a con 0176 Intratympanic injection of therapeutic agents is the tinuous release of anotic structure modulating agentorinnate technique of injecting a therapeutic agent behind the tym immune system modulating agent. In some embodiments, an panic membrane into the auris media and/or auris interna. otic structure modulating agent or innate immune system This technique presents several challenges; for example, modulating agent disclosed herein is administered as an access to the round window membrane, the site of drug immediate release composition. In other embodiments, an absorption into the auris interna, is challenging. otic structure modulating agent or innate immune system 0177. Further, intra-tympanic injections create several modulating agent is administered as a Sustained release com unrecognized problems not addressed by currently available position, released either continuously, variably or in a pulsa treatment regimens, such as changing the osmolarity and pH tile manner, or variants thereof. In still other embodiments, an of the perilymph and endolymph, and introducing pathogens otic structure modulating agent or innate immune system and endotoxins that directly or indirectly damage inner ear modulating agent composition is administered as both an structures. One of the reasons the art may not have recognized immediate release and Sustained release composition, these problems is that there are no approved intra-tympanic released either continuously, variably or in a pulsatile man compositions: the inner ear provides Sui generis composition ner, or variants thereof. The release is optionally dependent challenges. Thus, compositions developed for other parts of on environmental or physiological conditions, for example, the body have little to no relevance for an intra-tympanic the external ionic environment (see, e.g. OroSR) release sys composition. tem, Johnson & Johnson). 0.178 There is no guidance in the prior art regarding 0181. In addition, localized treatment of the targeted auris requirements (e.g., level of Sterility, pH, osmolarity) for otic structure also affords the use of previously undesired thera compositions that are Suitable for administration to humans. peutic agents, including agents with poor pK profiles, poor There is wide anatomical disparity between the ears of ani uptake, low systemic release and/or toxicity issues. Because mals across species. A consequence of the inter-species dif of the localized targeting of the otic structure modulating ferences in auditory structures is that animal models of inner compositions and devices, as well as the biological blood ear disease are often unreliable as a tool for testing therapeu barrier present in the auris interna, the risk of adverse effects tics that are being developed for clinical approval. will be reduced as a result of treatment with previously char 0179 Provided herein are otic compositions that meet acterized toxic or ineffective otic structure modulating agent stringent criteria for pH, osmolarity, ionic balance, Sterility, or innate immune system modulating agents. Accordingly, endotoxin and/or pyrogen levels. The auris compositions also contemplated within the scope of the embodiments described herein are compatible with the microenvironment herein is the use of an otic structure modulating agent or of the inner ear (e.g., the perilymph) and are Suitable for innate immune system modulating agents in the treatment of administration to humans. In some embodiments, the com disorders that have been previously rejected by practitioners positions described herein comprise dyes and aid visualiza because of adverse effects or ineffectiveness of the otic struc tion of the administered compositions obviating the need for ture modulating agent or innate immune system modulating invasive procedures (e.g., removal of perilymph) during pre agent. clinical and/or clinical development of intratympanic thera 0182 Also included within the embodiments disclosed peutics. herein is the use of additional auris-compatible agents in 0180 Provided herein are controlled-release otic structure combination with the otic structure modulating compositions modulating compositions and compositions to locally treat and devices disclosed herein. When used, such agents assist targeted auris structures, thereby avoiding side effects as a in the treatment of hearing or equilibrium loss or dysfunction US 2010/0021416 A1 Jan. 28, 2010

as a result of otitis externa, otitis media, mastoiditis, senso tive treatment of the otic disorders contemplated herein with rineural hearing loss, ototoxicity, endolymphatic hydrops, minimal side effects in the targeted regions or areas. labyrinthitis, Meniere's disease, Meniere's syndrome, 0185. Intratympanic injection of delivery devices creates microvascular compression syndrome, Vestibular neuronitis, several additional problems that must also be addressed acoustic trauma, presbycusis, cholesteatoma, otosclerosis, before the composition or device can be administered. For Scheibe syndrome, Mondini-Michelle syndrome, Waarden example, there are many excipients that are ototoxic. While burg's syndrome, Michel syndrome, Alexander's ear defor these excipients can be used when formulating an active agent mity, hypertelorism, Jervell-Lange Nielson syndrome, Ref for delivery by another method (e.g., topical), their use should Sum's syndrome, Usher's syndrome, or combinations thereof. be limited, reduced or eliminated when formulating a com Accordingly, additional agents that ameliorate or reduce the position or device to be administered to the ear due to their effects of otitis externa, otitis media, mastoiditis, sensorineu ototoxic effects. ral hearing loss, ototoxicity, endolymphatic hydrops, labyrin 0186 By way of non-limiting example, the use of the thitis, Meniere's disease, Meniere's syndrome, microvascular following commonly used solvents should be limited, compression syndrome, vestibular neuronitis, acoustic reduced or eliminated when formulating agents for adminis trauma, presbycusis, cholesteatoma, otosclerosis, Scheibe tration to the ear: alcohols, propylene glycol, and cyclohex ane. Thus, in Some embodiments, a device disclosed herein is syndrome, Mondini-Michelle syndrome, Waardenburg's syn free or Substantially free of alcohols, propylene glycol, and drome, Michel syndrome, Alexander's ear deformity, hyper cyclohexane. In some embodiments, a device disclosed telorism, JerVell-Lange Nielson syndrome, Refsum’s Syn herein comprises less than about 50 ppm of each of alcohols, drome, Usher's syndrome, otitis externa, otitis media, propylene glycol, and cyclohexane. In some embodiments, a mastoiditis, AIED, Ramsay Hunts, reperfusion injury, laby device disclosed herein comprises less than about 25 ppm of rinthitis ossificans, or combinations thereof are also contem each of alcohols, propylene glycol, and cyclohexane. In some plated to be used in combination with anotic structure modu embodiments, a device disclosed herein comprises less than lating agent or innate immune system modulating agent. In about 20 ppm of each of alcohols, propylene glycol, and Some embodiments, the additional agent is an acidifying cyclohexane. In some embodiments, a device disclosed agent, an anesthetic, an analgesic, an antibiotic, antiemetic, herein comprises less than about 10 ppm of each of alcohols, an antifungal, an anti-microbial agent, an antipsychotic (es propylene glycol, and cyclohexane. In some embodiments, a pecially those in the phenothiazine class), an antiseptic, an device disclosed herein comprises less than about 5 ppm of antiviral, an astringent, a chemotherapeutic agent, a collagen, each of alcohols, propylene glycol, and cyclohexane. In some a corticosteroid, a diuretic, a keratolytic agent, a nitric oxide embodiments, a device disclosed herein comprises less than synthase inhibitor, or combinations thereof. about 1 ppm of each of alcohols, propylene glycol, and cyclo 0183 In some embodiments, an auris-acceptable con hexane. trolled-release otic structure modulating composition 0187 Further, by way of non-limiting example, the use of described herein is administered to the target ear region and the following commonly utilized preservatives should be lim an oral dose of an otic structure modulating agent or innate ited, reduced or eliminated when formulating agents for immune system modulating agent is additionally adminis administration to the ear: Benzethonium chloride, Benzalko tered. In some embodiments, an oral dose of an otic structure nium chloride, and Thiomersal. Thus, in Some embodiments, modulating agent or innate immune system modulating agent a device disclosed herein is free or substantially free of ben is administered before administration of the auris-acceptable Zethonium chloride, benzalkonium chloride, and thiomersal. controlled-release otic structure modulating composition, In some embodiments, a device disclosed herein comprises and then the oral dose is tapered off over the period of time less than about 50 ppm of each of benzethonium chloride, that the controlled-release otic structure modulating compo benzalkonium chloride, and thiomersal. In some embodi sition is provided. Alternatively, an oral dose of an otic struc ments, a device disclosed herein comprises less than about 25 ture modulating agent or innate immune system modulating ppm of each of benzethonium chloride, benzalkonium chlo agent is administered during administration of the controlled ride, and thiomersal. In some embodiments, a device dis release otic structure modulating composition, and then the closed herein comprises less than about 20 ppm of each of oral dose is tapered off over the period of time that the con benzethonium chloride, benzalkonium chloride, and thiomer trolled-release otic structure modulating composition is pro sal. In some embodiments, a device disclosed herein com vided. Alternatively, an oral dose of an otic structure modu prises less than about 10 ppm of each of benzethonium chlo lating agent or innate immune system modulating agent is ride, benzalkonium chloride, and thiomersal. In some administered after administration of the controlled-release embodiments, a device disclosed herein comprises less than otic structure modulating composition, and then the oral dose about 5 ppm of each of benzethonium chloride, benzalko is tapered off over the period of time that the controlled nium chloride, and thiomersal. In some embodiments, a release otic structure modulating composition is provided. device disclosed herein comprises less than about 1 ppm of 0184. In addition, the otic structure modulating agent or each of benzethonium chloride, benzalkonium chloride, and innate immune system modulating agent pharmaceutical thiomersal. compositions or compositions or devices included herein also 0188 Certain antiseptics used to disinfect components of include carriers, adjuvants (e.g., preserving, stabilizing, wet therapeutic preparations (or the devices utilized to administer ting or emulsifying agents), Solution promoters, salts for the preparations) should be limited, reduced, or eliminated in regulating the osmotic pressure, and/or buffers. Such carriers, otic preparations. For example, acetic acid, iodine, and mer adjuvants, and other excipients will be compatible with the bromin are all known to be ototoxic. Additionally, chlorhex environment in the targeted auris structure(s). Specifically idene, a commonly used antiseptic, should be limited, contemplated are carriers, adjuvants and excipients that lack reduced or eliminated to disinfect any component of an otic ototoxicity or are minimally ototoxic in order to allow effec preparation (including devices used to administer the prepa US 2010/0021416 A1 Jan. 28, 2010

ration) as it is highly ototoxic in minute concentrations (e.g., or interacting in a deleterious manner with any of the com 0.05%). Thus, in some embodiments, a device disclosed ponents of the composition in that it is contained. herein is free or substantially free of acetic acid, iodine, 0.192 As used herein, amelioration or lessening of the merbromin, and chlorhexidene. In some embodiments, a symptoms of a particular otic disease, disorder or condition device disclosed herein comprises less than about 50 ppm of by administration of a particular compound or pharmaceuti each of acetic acid, iodine, merbromin, and chlorhexidene. In cal composition refers to any decrease of severity, delay in Some embodiments, a device disclosed herein comprises less onset, slowing of progression, or shortening of duration, than about 25 ppm of each of acetic acid, iodine, merbromin, whether permanent or temporary, lasting or transient that is and chlorhexidene. In some embodiments, a device disclosed attributed to or associated with administration of the com herein comprises less than about 20 ppm of each of acetic pound or composition. acid, iodine, merbromin, and chlorhexidene. In some 0193 “Antioxidants' are auris-pharmaceutically accept embodiments, a device disclosed herein comprises less than able antioxidants, and include, for example, butylated about 10 ppm of each of acetic acid, iodine, merbromin, and hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, chlorhexidene. In some embodiments, a device disclosed sodium metabisulfite and tocopherol. In certain embodi herein comprises less than about 5 ppm of each of acetic acid, ments, antioxidants enhance chemical stability where iodine, merbromin, and chlorhexidene. In some embodi required. Antioxidants are also used to counteract the ototoxic ments, a device disclosed herein comprises less than about 1 effects of certain therapeutic agents, including agents that are ppm of each of acetic acid, iodine, merbromin, and chlorhex used in combination with the otic structure modulating agent idene. orinnate immune system modulating agents disclosed herein. 0189 Further, otic preparations require particularly low 0194 Auris interna’ refers to the inner ear, including the concentrations of several potentially-common contaminants cochlea and the vestibular labyrinth, and the round window that are known to be ototoxic. Other dosage forms, while that connects the cochlea with the middle ear. seeking to limit the contamination attributable to these com pounds, do not require the stringent precautions that otic (0195 “Auris-bioavailability” or “Auris-interna bioavail preparations require. For example, the following contami ability” or “Auris-media bioavailability” or “Auris-externa nants should be absent or nearly absent from otic prepara bioavailability” refers to the percentage of the administered tions: arsenic, lead, mercury, and tin. Thus, in some embodi dose of compounds disclosed herein that becomes available ments, a device disclosed herein is free or substantially free of in the targeted auris structure of the animal or human being arsenic, lead, mercury, and tin. In some embodiments, a studied. device disclosed herein comprises less than about 50 ppm of (0196) “Auris media' refers to the middle ear, including the each of arsenic, lead, mercury, and tin. In some embodiments, tympanic cavity, auditory ossicles and oval window, which a device disclosed herein comprises less than about 25 ppm of connects the middle ear with the inner ear. each of arsenic, lead, mercury, and tin. In some embodiments, 0197) 'Auris externa” refers to the outer ear, including the a device disclosed herein comprises less than about 20 ppm of pinna, the auditory canal, and the tympanic membrane, which each of arsenic, lead, mercury, and tin. In some embodiments, connects the outer ear with the middle ear. a device disclosed herein comprises less than about 10 ppm of 0198 “Blood plasma concentration” refers to the concen each of arsenic, lead, mercury, and tin. In some embodiments, tration of compounds provided herein in the plasma compo a device disclosed herein comprises less than about 5 ppm of nent of blood of a subject. each of arsenic, lead, mercury, and tin. In some embodiments, 0199. “Carrier materials” are excipients that are compat a device disclosed herein comprises less than about 1 ppm of ible with otic structure modulating agent or innate immune each of arsenic, lead, mercury, and tin. system modulating agent(s), the targeted auris structure(s) 0190. To prevent ototoxicity, otic structure modulating and the release profile properties of the auris-acceptable phar agentorinnate immune system modulating agent pharmaceu maceutical compositions. Such carrier materials include, e.g., tical compositions or compositions or devices disclosed binders, Suspending agents, disintegration agents, filling herein are optionally targeted to distinct regions of the tar agents, Surfactants, solubilizers, stabilizers, lubricants, wet geted auris structures, including but not limited to the tym ting agents, diluents, and the like. "Auris-pharmaceutically panic cavity, Vestibular bony and membranous labyrinths, compatible carrier materials” include, but are not limited to, cochlear bony and membranous labyrinths and other ana acacia, gelatin, colloidal silicon dioxide, calcium glycero tomical or physiological structures located within the auris phosphate, calcium lactate, maltodextrin, glycerine, magne interna. sium silicate, polyvinylpyrrolidone (PVP), cholesterol, cho lesterol esters, sodium caseinate, Soy lecithin, taurocholic CERTAIN DEFINITIONS acid, phosphatidylcholine, Sodium chloride, tricalcium phos 0191 The term “auris-acceptable' with respect to a com phate, dipotassium phosphate, cellulose and cellulose conju position, composition or ingredient, as used herein, includes gates, Sugars sodium Stearoyl lactylate, carrageenan, having no persistent detrimental effect on the auris media (or monoglyceride, diglyceride, pregelatinized Starch, and the middle ear) and the auris interna (or inner ear) of the subject like. being treated. By “auris-pharmaceutically acceptable as 0200. The term “complement modulating agent', as used used herein, refers to a material. Such as a carrier or diluent, herein, means an agent that increases or inhibits the activity of which does not abrogate the biological activity or properties a component of the complement system. In some embodi of the compound in reference to the auris media (or middle ments, the complement modulating agent increases the activ ear) and the auris interna (or inner ear), and is relatively or is ity of a component of the complement system. In some reduced in toxicity to the auris media (or middle ear) and the embodiments, the complement modulating agent inhibits auris interna (or inner ear), i.e., the material is administered to (partially or fully) the activity of a component of the comple an individual without causing undesirable biological effects ment system. US 2010/0021416 A1 Jan. 28, 2010

0201 The term "diluent” refers to chemical compounds ture modulating agent or innate immune system modulating that are used to dilute the otic structure modulating agent or agents are administered by the same or different route of innate immune system modulating agent prior to delivery and administration or at the same or different time. that are compatible with the targeted auris structure(s). 0204 The terms “effective amount’ or “therapeutically 0202 “Dispersing agents, and/or "viscosity modulating effective amount, as used herein, refer to a sufficient amount agents' are materials that control the diffusion and homoge of the otic structure modulating agent or innate immune sys neity of the otic structure modulating agent or innate immune tem modulating agents being administered that would be system modulating agent through liquid media. Examples of expected to relieve to some extent one or more of the Symp diffusion facilitators/dispersing agents include but are not toms of the disease or condition being treated. For example, limited to hydrophilic polymers, electrolytes, Tween R. 60 or the result of administration of the otic structure modulating 80, PEG, polyvinylpyrrolidone (PVP; commercially known agent or innate immune system modulating agents disclosed as Plasdone(R), and the carbohydrate-based dispersing agents herein is reduction and/or alleviation of the signs, symptoms, Such as, for example, hydroxypropyl celluloses (e.g., HPC. or causes of Meniere's disease. For example, an “effective HPC-SL, and HPC-L), hydroxypropyl methylcelluloses amount for therapeutic uses is the amount of the otic struc (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC ture modulating agent or innate immune system modulating K10OM), carboxymethylcellulose sodium, methylcellulose, agent, including a composition as disclosed herein required to hydroxyethylcellulose, hydroxypropylcellulose, hydrox provide a decrease oramelioration in disease symptoms with ypropylmethylcellulose phthalate, hydroxypropylmethylcel out undue adverse side effects. The term “therapeutically lulose acetate stearate (HPMCAS), noncrystalline cellulose, effective amount includes, for example, a prophylactically magnesium aluminum silicate, triethanolamine, polyvinyl effective amount. An "effective amount of an otic structure alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer modulating agent or innate immune system modulating agent (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with composition disclosed herein is an amount effective to ethylene oxide and formaldehyde (also known as tyloxapol), achieve a desired pharmacologic effect or therapeutic poloxamers (e.g., Pluronic F127, Pluronics F68(R), F88(R), and improvement without undue adverse side effects. It is under F108(R), which are block copolymers of ethylene oxide and stood that “an effective amount’ or “a therapeutically effec propylene oxide); and poloxamines (e.g., Tetronic 908R, also tive amount varies, in some embodiments, from Subject to known as Poloxamine 908R, which is a tetrafunctional block Subject, due to variation in metabolism of the compound copolymer derived from sequential addition of propylene administered, age, weight, general condition of the Subject, oxide and ethylene oxide to ethylenediamine (BASF Corpo the condition being treated, the severity of the condition being ration, Parsippany, N.J.)), polyvinylpyrrolidone K12, polyvi treated, and the judgment of the prescribing physician. It is nylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvi also understood that “an effective amount” in an extended nylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate release dosing format may differ from “an effective amount copolymer (S-630), polyethylene glycol, e.g., the polyethyl in an immediate-release dosing format based upon pharma ene glycol has a molecular weight of about 300 to about 6000, cokinetic and pharmacodynamic considerations. or about 3350 to about 4000, or about 7000 to about 5400, 0205 The terms "enhance' or "enhancing refers to an Sodium carboxymethylcellulose, methylcellulose, polysor increase or prolongation of either the potency or duration of a bate-80, Sodium alginate, gums, such as, e.g., gum tragacanth desired effect of the otic structure modulating agent or innate and gum acacia, guar gum, Xanthans, including Xanthan gum, immune system modulating agent, or a diminution of any Sugars, cellulosics, such as, e.g., sodium carboxymethylcel adverse symptoms such as localized pain that is consequent lulose, methylcellulose, sodium carboxymethylcellulose, upon administration of the therapeutic agent. Thus, in regard polysorbate-80, Sodium alginate, polyethoxylated Sorbitan to enhancing the effect of the otic structure modulating agent monolaurate, polyethoxylated Sorbitan monolaurate, povi orinnate immune system modulating agents disclosed herein, done, carbomers, polyvinyl alcohol (PVA), alginates, chito the term "enhancing refers to the ability to increase or pro sans and combinations thereof. Plasticizers such as cellulose long, either in potency or duration, the effect of other thera or triethyl cellulose are also be used as dispersing agents. peutic agents that are used in combination with the otic struc Optional dispersing agents useful in liposomal dispersions ture modulating agent or innate immune system modulating and self-emulsifying dispersions of the otic structure modu agents disclosed herein. An "enhancing-effective amount, as lating agent or innate immune system modulating agents used herein, refers to an amount of an otic structure modulat disclosed herein are dimyristoyl phosphatidylcholine, phos ing agent or innate immune system modulating agents, or phatidylcholines (c8-c18), phosphatidylethanolamines (c8 other therapeutic agent, which is adequate to enhance the c18), phosphatidylglycerols (c8-c18), natural phosphatidyl effect of another therapeutic agent or otic structure modulat choline from eggs or Soy, natural phosphatidylglycerol from ing agent or innate immune system modulating agents in a eggs or soy, cholesterol and isopropyl myristate. desired system. When used in a patient, amounts effective for 0203 “Drug absorption” or “absorption” refers to the pro this use will depend on the severity and course of the disease, cess of movement of the otic structure modulating agent or disorder or condition, previous therapy, the patient's health innate immune system modulating agent(s) from the local status and response to the drugs, and the judgment of the ized site of administration, by way of example only, the round treating physician. window membrane of the inner ear, and across a barrier (the 0206. The term “inhibiting includes preventing, slowing, round window membranes, as described below) into the auris or reversing the development of a condition, for example, interna or inner ear structures. The terms “co-administration' otitis externa, or advancement of a condition in a patient or the like, as used herein, are meant to encompass adminis necessitating treatment. tration of the otic structure modulating agent or innate 0207. The term “innate immune system modulating immune system modulating agents to a single patient, and are agent, as used herein, means an agent that increases or inhib intended to include treatment regimens in that the otic struc its the activity of a component of the innate immune system. US 2010/0021416 A1 Jan. 28, 2010

In some embodiments, the innate immune system modulating tically active form of the compound. To produce a prodrug, a agent increases the activity of a component of the innate pharmaceutically active compound is modified Such that the immune system. In some embodiments, the innate immune active compound will be regenerated upon in vivo adminis system modulating agent inhibits (partially or fully) the activ tration. In one embodiment, the prodrug is designed to alter ity of a component of the innate immune system. the metabolic stability or the transport characteristics of a 0208 “Balance disorder” refers to a disorder, illness, or drug, to mask side effects or toxicity, or to alter other charac condition which causes a Subject to feel unsteady, or to have teristics or properties of a drug. Compounds provided herein, a sensation of movement. Included in this definition are diz in some embodiments, are derivatized into Suitable prodrugs. Ziness, vertigo, disequilibrium, and pre-syncope. Diseases 0216 “Round window membrane' is the membrane in which are classified as balance disorders include, but are not humans that covers the fenestrae cochlea (also known as the limited to, mal de debarquement, benign paroxysmal posi circular window, fenestrae rotunda, or round window). In tional vertigo, and labyrinthitis. humans, the thickness of round window membrane is about 0209. The terms “kit' and “article of manufacture are 70 micron. used as synonyms. 0217 “Solubilizers’ refers to auris-acceptable com 0210. As used herein, the term “otic intervention” means pounds such as triacetin, triethylcitrate, ethyl oleate, ethyl an external insult or trauma to one or more auris structures caprylate, sodium lauryl Sulfate, sodium caprate. Sucrose and includes implants, otic Surgery, injections, cannulations, esters, alkylglucosides, sodium doccusate, vitamin ETPGS, or the like. Implants include auris-interna or auris-media dimethylacetamide, N-methylpyrrolidone, N-hydroxyeth medical devices, examples of which include cochlear ylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl implants, hearing sparing devices, hearing-improvement cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, devices, short electrodes, micro-prostheses or piston-like isopropyl alcohol, cholesterol, bile salts, polyethylene glycol prostheses; needles; stem cell transplants; drug delivery 200-600, glycofurol, transcutol, propylene glycol, and dim devices; any cell-based therapeutic; or the like. Otic Surgery ethyl isosorbide and the like. includes middle ear Surgery, inner ear Surgery, typanostomy, 0218 "Stabilizers’ refers to compounds such as any anti cochleostomy, labyrinthotomy, mastoidectomy, stapedec oxidation agents, buffers, acids, preservatives and the like that tomy, stapedotomy, tympanostomy, endolymphatic sacculo are compatible with the environment of the targeted auris tomy or the like. Injections include intratympanic injections, structure. Stabilizers include but are not limited to agents that intracochlear injections, injections across the round window will do any of (1) improve the compatibility of excipients with membrane or the like. Cannulations include intratympanic, a container, or a delivery system, including a syringe or a intracochlear, endolymphatic, perilymphatic or vestibular glass bottle, (2) improve the stability of a component of the cannulations or the like. composition, or (3) improve composition stability. 0211 "Otic structure modulating agent', as used herein, 0219. As used herein, the term “substantially low degra means otic structure enhancing agent, or an agent that dation products’ means less than 5% by weight of the active degrades the molecular components of an otic structure. agent are degradation products of the active agent. In further 0212 “Pharmacokinetics' refers to the factors that deter embodiments, the term means less than 3% by weight of the mine the attainment and maintenance of the appropriate con active agent are degradation products of the active agent. In centration of drug at the desired site within the targeted auris yet further embodiments, the term means less than 2% by Structure. weight of the active agent are degradation products of the 0213. In prophylactic applications, compositions contain active agent. In further embodiments, the term means less ing the agents described herein are administered to a patient than 1% by weight of the active agent are degradation prod Susceptible to or otherwise at risk of a particular disease, ucts of the active agent. disorder or condition, for otitis externa, otitis media, mas 0220. As used herein, “excess otic structures” include, by toiditis, sensorineural hearing loss, ototoxicity, endolym way of example, excess bone growth (e.g. in the stapes), phatic hydrops, labyrinthitis, Meniere's disease, Meniere's blockage of otic structures (e.g., due to excessive secretion of syndrome, microvascular compression syndrome, Vestibular mucous, pus or effusion), excess effusion in the inner ear neuronitis, acoustic trauma, presbycusis, cholesteatoma, oto (e.g., due to inflammation) or any other abnormality in any sclerosis, Scheibe syndrome, Mondini-Michelle syndrome, otic structure that can cause an otic disease or condition Waardenburg's syndrome, Michel syndrome, Alexander's ear described herein. deformity, hypertelorism, Jervell-Lange Nielson syndrome, 0221. As used herein “essentially in the form of micron RefSum's syndrome, and Usher's syndrome. Such an amount ized powder” includes, by way of example only, greater than is defined to be a “prophylactically effective amount or dose.” 70% by weight of the active agent is in the form of micronized In this use, the precise amounts also depend on the patient's particles of the active agent. In further embodiments, the term state of health, weight, and the like. As used herein, a “phar means greater than 80% by weight of the active agent is in the maceutical device' includes any composition described form of micronized particles of the active agent. In yet further herein that, upon administration to an ear, provides a reservoir embodiments, the term means greater than 90% by weight of for extended release of an active agent described herein. the active agent is in the form of micronized particles of the 0214. The mean residence time (MRT) is the average time active agent. that molecules of an active agent reside in an otic structure 0222 "Steady state.” as used herein, is when the amount of after a dose. drug administered to the targeted auris structure is equal to the 0215. A "prodrug” refers to the otic structure modulating amount of drug eliminated within one dosing interval result agent or innate immune system modulating agent that is con ing in a plateau or constant levels of drug exposure within the Verted into the parent drug in vivo. In certain embodiments, a targeted structure. prodrug is enzymatically metabolized by one or more steps or 0223) As used herein, the term “subject' is used to mean processes to the biologically, pharmaceutically or therapeu any animal, preferably a mammal, including a human or US 2010/0021416 A1 Jan. 28, 2010

non-human. The terms patient and Subject may be used inter transformed and transduced to the auris interna for further changeably. Neither term is to be interpreted as requiring the processing. Stiffness, rigidity or loss of movement of the Supervision of a medical professional (e.g., a doctor, nurse, auditory ossicles, tympanic membrane or oval window leads physician's assistant, orderly, hospice worker). to hearing loss, e.g. otosclerosis, or rigidity of the stapes bone. 0224 “Surfactants’ refers to compounds that are auris 0229. The tympanic cavity also connects to the throat via acceptable, such as sodium lauryl Sulfate, sodium docusate, the eustachian tube. The eustachian tube provides the ability Tween(R) 60 or 80, triacetin, vitamin E TPGS, Sorbitan to equalize the pressure between the outside air and the monooleate, polyoxyethylene Sorbitan monooleate, polysor middle ear cavity. The round window, a component of the bates, polaxomers, bile salts, glyceryl monostearate, copoly auris interna but that is also accessible within the tympanic mers of ethylene oxide and propylene oxide, e.g., Pluronic(R) cavity, opens into the cochlea of the auris interna. The round (BASF), and the like. Some other surfactants include poly window is covered by round window membrane, which con oxyethylene fatty acid glycerides and vegetable oils, e.g., sists of three layers: an external or mucous layer, an interme polyoxyethylene (60) hydrogenated castor oil; and polyoxy diate or fibrous layer, and an internal membrane, which com ethylene alkylethers and alkylphenyl ethers, e.g., Octoxynol municates directly with the cochlear fluid. The round 10, octoxynol 40. In some embodiments, Surfactants are window, therefore, has direct communication with the auris included to enhance physical stability or for other purposes. interna via the internal membrane. 0225. The terms “treat,” “treating” or “treatment,” as used 0230 Movements in the oval and round window are inter herein, include alleviating, abating or ameliorating a disease connected, i.e. as the stapes bone transmits movement from or condition symptoms, preventing additional symptoms, the tympanic membrane to the oval window to move inward ameliorating or preventing the underlying metabolic causes against the auris interna fluid, the round window (round win of symptoms, inhibiting the disease or condition, e.g., arrest dow membrane) is correspondingly pushed out and away ing the development of the disease or condition, relieving the from the cochlear fluid. This movement of the round window disease or condition, causing regression of the disease or allows movement of fluid within the cochlea, which leads in condition, relieving a condition caused by the disease or turn to movement of the cochlear inner hair cells, allowing condition, or stopping the symptoms of the disease or condi hearing signals to be transduced. Stiffness and rigidity in tion either prophylactically and/or therapeutically. round window membrane leads to hearing loss because of the 0226. Other objects, features, and advantages of the meth lack of ability of movement in the cochlear fluid. Recent ods and compositions described herein will become apparent studies have focused on implanting mechanical transducers from the following detailed description. It should be under onto the round window, which bypasses the normal conduc stood, however, which the detailed description and the spe tive pathway through the oval window and provides amplified cific examples, while indicating specific embodiments, are input into the cochlear chamber. given by way of illustration only. 0231 Auditory signal transduction takes place in the auris interna. The fluid-filled auris interna, or inner ear, consists of Anatomy of the Ear two major components: the cochlear and the vestibular appa 0227. As shown in FIG. 4, the outer ear is the external ratus. The auris interna is located in part within the osseous or portion of the organ and is composed of the pinna (auricle), bony labyrinth, an intricate series of passages in the temporal the auditory canal (external auditory meatus) and the outward bone of the skull. The vestibular apparatus is the organ of facing portion of the tympanic membrane, also known as the balance and consists of the three semi-circular canals and the ear drum. The pinna, which is the fleshy part of the external vestibule. The three semi-circular canals are arranged relative ear that is visible on the side of the head, collects sound waves to each other such that movement of the head along the three and directs them toward the auditory canal. Thus, the function orthogonal planes in space can be detected by the movement of the outer ear, in part, is to collect and direct sound waves of the fluid and Subsequent signal processing by the sensory towards the tympanic membrane and the middle ear. organs of the semi-circular canals, called the crista amp 0228. The middle ear is an air-filled cavity, called the ullaris. The crista ampullaris contains hair cells and Support tympanic cavity, behind the tympanic membrane. The tym ing cells, and is covered by a dome-shaped gelatinous mass panic membrane, also known as the ear drum, is a thin mem called the cupula. The hairs of the hair cells are embedded in brane that separates the external ear from the middle ear. The the cupula. The semi-circular canals detect dynamic equilib middle earlies within the temporal bone, and includes within rium, the equilibrium of rotational or angular movements. this space the three earbones (auditory ossicles): the malleus, 0232. When the head turns rapidly, the semicircular canals the incus and the stapes. The auditory ossicles are linked move with the head, but endolymph fluid located in the mem together via tiny ligaments, which form a bridge across the branous semi-circular canals tends to remain stationary. The space of the tympanic cavity. The malleus, which is attached endolymph fluid pushes against the cupula, which tilts to one to the tympanic membrane at one end, is linked to the incus at side. As the cupulatilts, it bends some of the hairs on the hair its anterior end, which in turn is linked to the stapes. The cells of the crista ampullaris, which triggers a sensory stapes is attached to the oval window, one of two windows impulse. Because each semicircular canal is located in a located within the tympanic cavity. A fibrous tissue layer, different plane, the corresponding crista ampullaris of each known as the annular ligament connects the stapes to the oval semi-circular canal responds differently to the same move window. Sound waves from the outer ear first cause the tym ment of the head. This creates a mosaic of impulses that are panic membrane to vibrate. The vibration is transmitted transmitted to the central nervous system on the vestibular across to the cochlea through the auditory ossicles and oval branch of the vestibulocochlear nerve. The central nervous window, which transfers the motion to the fluids in the auris system interprets this information and initiates the appropri interna. Thus, the auditory ossicles are arranged to provide a ate responses to maintain balance. Of importance in the cen mechanical linkage between the tympanic membrane and the tral nervous system is the cerebellum, which mediates the oval window of the fluid-filled auris interna, where sound is sense of balance and equilibrium. US 2010/0021416 A1 Jan. 28, 2010

0233. The vestibule is the central portion of the auris cell receptors in the Organ of Corti then move against the interna and contains mechanoreceptors bearing hair cells that tectorial membrane, causing a mechanical deformation in the ascertain static equilibrium, or the position of the head rela tectorial membrane. This mechanical deformation initiates tive to gravity. Static equilibrium plays a role when the head the nerve impulse that travels via the vestibulocochlear nerve is motionless or moving in a straight line. The membranous to the central nervous system, mechanically transmitting the labyrinth in the vestibule is divided into two sac-like struc Sound wave received into signals that are Subsequently pro tures, the utricle and the saccule. Each structure in turn con cessed by the central nervous system. tains a small structure called a macula, which is responsible for maintenance of static equilibrium. The macula consists of Diseases sensory hair cells, which are embedded in a gelatinous mass 0238 Autoimmune Inner Ear Disease (similar to the cupula) that covers the macula. Grains of 0239 Autoimmune inner ear disease (AIED) is one of the calcium carbonate, called otoliths, are embedded on the Sur few reversible causes of sensorineural hearing loss. It is a rare face of the gelatinous layer. disorder appearing in both adults and children that often 0234. When the head is in an upright position, the hairs are involves a bilateral disturbance of the audio and vestibular straight along the macula. When the head tilts, the gelatinous functions of the auris interna. In many cases, AIED occurs mass and otoliths tilts correspondingly, bending some of the without systemic autoimmune symptoms, but up to one-third hairs on the hair cells of the macula. This bending action of patients also suffer from a systemic autoimmune illness, initiates a signal impulse to the central nervous system, which Such as inflammatory bowel disease, rheumatoid arthritis travels via the vestibular branch of the vestibulocochlear (Murdin, L. et al (2007) Hearing difficulties are common in nerve, which in turn relays motor impulses to the appropriate patients with rheumatoid arthritis, in Clin Rheumatol, 27(5): muscles to maintain balance. 637-640), Ankylosing spondylitis, Systemic Lupus Erythe 0235. The cochlea is the portion of the auris interna related matosus (SLE), Sjögren's Syndrome, Cogan's disease, ulcer to hearing. The cochlea is a tapered tube-like structure that is ative colitis, Wegener's granulomatosis and Scleroderma. coiled into a shape resembling a snail. The inside of the Behget's disease, a multisystem disease, also commonly has cochlea is divided into three regions, which is further defined audiovestibular problems. There is some evidence for food by the position of the vestibular membrane and the basilar related allergies as a cause for cochlear and vestibular autoim membrane. The portion above the vestibular membrane is the munity, but there is presently no agreement as to its impor scala vestibuli, which extends from the oval window to the tance in the aetiology of the disease. A classification scheme apex of the cochlea and contains perilymph fluid, an aqueous for AIED has been developed (Harris and Keithley, (2002) liquid low in potassium and high in Sodium content. The Autoimmune inner ear disease, in Otorhinolaryngology basilar membrane defines the scala tympani region, which Head and Neck Surgery. 91, 18-32). extends from the apex of the cochlea to the round window and 0240. The immune system normally performs a crucial also contains perilymph. The basilar membrane contains role in protecting the inner ear from invasive pathogens Such thousands of stiff fibers, which gradually increase in length as bacteria and viruses. However, in AIED the immune sys from the round window to the apex of the cochlea. The fibers tem itself begins to damage the delicate inner ear tissues. The of the basement membrane vibrate when activated by sound. inner ear is fully capable of mounting a localized immune In between the scala vestibuli and the scala tympani is the response to foreign antigens. When a foreign antigen enters cochlear duct, which ends as a closed sac at the apex of the the inner ear, it is first processed by immunocompetent cells cochlea. The cochlear duct contains endolymph fluid, which which reside in and around the endolymphatic sac. Once the is similar to cerebrospinal fluid and is high in potassium. foreign antigen has been processed by these immunocompe 0236. The organ of Corti, the sensory organ for hearing, is tent cells, these cells Secrete various cytokines which modu located on the basilar membrane and extends upward into the late the immune response of the inner ear. One result of this cochlear duct. The organ of Corti contains hair cells, which cytokine release is to facilitate the influx of inflammatory have hairlike projections that extend from their free surface, cells which are recruited from the systemic circulation. These and contacts a gelatinous Surface called the tectorial mem systemic inflammatory cells enter the cochlea via diapedesis brane. Although hair cells have no axons, they are surrounded through the spiral modiolar vein and its tributaries, and begin by sensory nerve fibers that form the cochlear branch of the to participate in antigen uptake and deregulation just as it vestibulocochlear nerve (cranial nerve VIII). occurs in other parts of the body. Interleukin 1 (IL-1) plays an 0237 As discussed, the oval window, also known as the important role in modulating the innate (nonspecific) immune elliptical window communicates with the stapes to relay response and is a known activator of resting Thelper cells and Sound waves that vibrate from the tympanic membrane. B-cells. Thelper cells, once activated by IL-1, produce IL-2. Vibrations transferred to the oval window increases pressure IL-2 secretion results in differentiation of pluripotent T-cells inside the fluid-filled cochlea via the perilymph and scala into helper, cytotoxic and Suppressor T-cell Subtypes. IL-2 vestibuli/scala tympani, which in turn causes the round win also assists T helper cells in the activation of B lymphocytes dow membrane to expand in response. The concerted inward and probably plays a pivotal role in the immunoregulation of pressing of the oval window/outward expansion of the round the immune response of the vestibular and cochlear regions. window allows for the movement of fluid within the cochlea IL-2 is within the perilymph of the auris interna as early as 6 without a change of intra-cochlear pressure. However, as hafter antigen challenge with peak levels at 18h after antigen vibrations travel through the perilymph in the scala vestibuli, challenge. The perilymphatic levels of IL-2 then dissipate, they create corresponding oscillations in the vestibular mem and it is no longer present within the perilymph at 120 hours brane. These corresponding oscillations travel through the post antigen challenge. endolymph of the cochlear duct, and transfer to the basilar 0241. Both IL-1B and tumor necrosis factor-O. (TNF-C.) membrane. When the basilar membrane oscillates, or moves may play a key role in the initiation and amplification of the up and down, the organ of Corti moves along with it. The hair immune response. IL-1B is expressed by the fibrocytes of the US 2010/0021416 A1 Jan. 28, 2010

spiral ligament in the presence of trauma Such as Surgical membranes which contain multiple nerves. Fluctuation in the trauma or acoustic trauma in a nonspecific response. TNF-C. pressure stresses the membranes and the nerves they house. If is expressed either by infiltrating systemic cells or by resident the pressure is great enough, disruptions may form in the cells contained within the endolymphatic sac in the presence membranes. This results in a mixing of the fluids which can of antigen. TNF-C. is released as part of the adaptive (specific) lead to a depolarization blockade and transient loss of func immune response in animal models. When antigen is injected tion. Changes in the rate of vestibular nerve firing often lead into the auris interna of mice, IL-1B and TNF-C. are both to vertigo. Further, the organ of Corti may also be affected. expressed and a vigorous immune response occurs. However, Distortions of the basilar membrane and the inner and outer when antigen is introduced to the auris interna via the cerebral hair cells can lead to hearing loss and/or tinnitus. spinal fluid in the absence of trauma, only TNF-C. is expressed 0247 Causes include metabolic disturbances, hormonal and the immune response in minimal. Importantly, cochlear imbalances, autoimmune disease, and viral, bacterial, or fun trauma in isolation also results in a minimal immune gal infections. Symptoms include hearing loss, Vertigo, tin response. These results suggest that both the nonspecific and nitus, and aural fullness. Nystagmus may also be present. specific components of the immune response act in concert in Treatment includes systemic administration of benzodiaz the auris interna to achieve a maximal response. epine, diuretics (to decrease the fluid pressure), corticoster 0242. Accordingly, if the cochlea is traumatized and an oids, and/or anti-bacterial, anti-viral, or anti-fungal agents. antigen is injected (or in the case of autoimmune disease, the 0248 Recurrent Vestibulopathy patient has immune cells directed against inner ear antigens), 0249 Recurrent vestibulopathy is a condition wherein the both the nonspecific and the specific immune responses can Subject experiences multiple episodes of severe vertigo. The be activated simultaneously. This results in the concurrent episodes of Vertigo may last for minutes or hours. Unlike production of IL-1B as well as TNF-C. which causes a greatly Meniere's Disease, it is not accompanied by hearing loss. In amplified level of inflammation leading to Substantial dam Some cases it may develop into Meniere's Disease or Benign age to the auris interna. Subsequent experiments in animal Paroxysmal Positional Vertigo. Treatment is similar to that of models confirm that an important step in immune-mediated Meniere's Disease. damage requires that the auris interna be conditioned by the (0250 Tinnitus non-specific innate immune response before the specific 0251 Tinnitus is defined as the perception of sound in the adaptive immune response can lead to enough inflammation absence of any external stimuli. It may occur in one or both to result in damage (Hashimoto, Audiol. Neurootol. (2005), ears, continuously or sporadically, and is most often 10, 35-43). As a result, agents which downregulate or block described as a ringing Sound. It is most often used as a diag the specific immune response, and in particular the effect of nostic symptom for other diseases. There are two types of TNF-C., prevent the excessive immune response seen when tinnitus: objective and subjective. The former is a sound cre both the specific and nonspecific immune responses are ated in the body which is audible to anyone. The latter is simultaneously activated. audible only to the affected individual. Studies estimate that 0243 As such, some embodiments include the treatment over 50 million Americans experience some form of tinnitus. of autoimmune ear disease by administering anti-TNF Of those 50 million, about 12 million experience severe tin agents. Etanercept (ENBREL(R), an anti-TNF drug, is emerg nitus. ing as a promising agent for treatment of autoimmune inner 0252. There are several treatments for tinnitus. Lidocaine, ear disease. Additionally, the anti-TNF agents infliximab administered by IV, reduces or eliminates the noise associated (REMICADE(R), adalimumab (HUMIRAR) and golimumab with tinnitus in about 60-80% of sufferers. Selective neu are also useful in treatment of autoimmune inner ear disor rotransmitter reuptake inhibitors, such as nortriptyline, Ser ders. Clinical trial protocols of systemic treatment of indi traline, and paroxetine, have also demonstrated efficacy viduals with AIED include injections of anti-TNF agents as against tinnitus. BenZodiazepines are also prescribed to treat an injection on a twice-weekly basis. Additional embodi tinnitus. ments include the treatment of autoimmune ear disease by (0253) Vertigo administering an immunomodulating agent selected from a 0254 Vertigo is described as a feeling of spinning or sway TACE inhibitor, an IKK inhibitor, a calcineurin inhibitor, a ing while the body is stationary. There are two types of ver flavone derivative, a toll-like inhibitor, an interleukin-inhibi tigo. Subjective vertigo is the false sensation of movement of tor, or combinations thereof. the body. Objective vertigo is the perception that one's sur 0244. In other embodiments, included is the treatment of rounding are in motion. It is often accompanied by nausea, autoimmune otic disorders with a combination of an immu Vomiting, and difficulty maintaining balance. nomodulating agent with another pharmaceutical agent 0255 While not wishing to be bound by any one theory, it including steroids, chemotherapeutic agents, collagen, is hypothesized that vertigo is caused by an over-accumula gamma globulin infusion or other immune modulating drugs. tion of endolymph. This fluid imbalance results in increased Steroids include, e.g. prednisone or decadron. Chemothera pressure on the cells of the inner ear which leads to the peutic agents, include, e.g. cytoxan, azathiaprine or methotr sensation of movement. The most common cause of vertigo is exate. Plasmapheresis procedures are optionally used. Treat benign paroxysmal positional vertigo, or BPPV. It can also be ment with oral collagen, gamma globulin infusions or other brought on by a head injury, or a Sudden change of blood immune modulating drugs (e.g. beta-interferon, alpha inter pressure. It is a diagnostic symptom of several diseases feron or copaxone) are also optionally used in combination including Superior canal dehiscence syndrome and Meniere's with an anti-TNF drug. disease. 0245 Endolymphatic Hydrops 0256 Benign Paroxysmal Positional Vertigo 0246 Endolymphatic hydrops refers to an increase in the 0257 Benign paroxysmal positional vertigo is caused by hydraulic pressure within the endolymphatic system of the the movement of free floating calcium carbonate crystals inner ear. The endolymph and perilymph are separated by thin (otoliths) from the utricle to one of the semicircular canals, US 2010/0021416 A1 Jan. 28, 2010

most often the posterior semicircular canal. Movement of the toms include, but are not limited to, congestion of the ears, head results in the movement of the otoliths causing abnormal discomfort, pus, and pressure imbalances. OME is a condi endolymph displacement and a resultant sensation of vertigo. tion characterized by the accumulation of in the middle ear The episodes of vertigo usually last for about a minute and are space. It often results from negative pressure produced by rarely accompanied by other auditory symptoms. altered Eustachian tube function. The accumulation of fluid 0258 Mal de Debarquement Sometimes leads to conductive hearing impairment (e.g. 0259 Mal de debarquement is a condition which usually when it interferes with the ability of the eardrum to vibrate). occurs Subsequent to a Sustained motion event, for example, a If the condition persists, the fluid can increase in Viscosity cruise, car trip, or airplane ride. It is characterized by a per increasing the likelihood of hearing loss. sistent sense of motion, difficulty maintaining balance, 0266 Because OM can be caused by a virus, bacteria or fatigue, and cognitive impairment. Symptoms may also both, it is often difficult to identify the exact cause and thus the include diZZiness, headaches, hyperacusis, and/or tinnitus. most appropriate treatment. Treatment options for OM Symptoms often last in excess of a month. Treatment includes include antibiotics, such as penicillins (e.g., amoxicillin and benzodiazepines, diuretics, Sodium channel blockers, and tri amoxicillin-clavulanate), clavulanate acid, trimethoprim cyclic antidepressants. Sulfamethoxazole, cephalosporins (e.g., cefuroxime, cefla 0260 Otitis Externa cor, cefprozil, loracarbef, cefindir, cefixime, cefpodoxime 0261. Otitis externa (OE), also referred to as swimmer's proxetil, cefibuten, and ceftriaxone), macrollides and azalides ear, is an inflammation and/or infection of the external ear. OE (e.g., erythromycin, clarithromycin, and azithromycin), Sul is often caused by bacteria in the outer ear, which establish fonamides, and combinations thereof. Surgical intervention infection following damage to the skin of the ear canal. Pri is also available, including myringotomy, an operation to mary bacterial pathogens that cause OE are Pseudomonas insert a tympanostomy tube through the tympanic membrane aeruginosa and Staphylococcus aureus, but the condition is and into the patient’s middle ear to drain the fluid and balance associated with the presence of many other Strains of gram the pressure between the outer and middle ear. Antipyretics positive and negative bacteria. OE is also sometimes caused and analgesics, including benzocaine, ibuprofen and acetami by fungal infection in the outer ear, including Candida albi nophen, may also be prescribed to treat accompanying fever cans and Aspergillus. Symptoms of OE include otalgia, or pain effects. Swelling, and otorrhea. If the condition progresses signifi 0267 Mastoiditis cantly, OE may cause temporary conductive hearing loss as a 0268 Mastoiditis is an infection of the mastoid process, result of the Swelling and discharge. which is the portion of the temporal bone behind the ear. It is 0262 Treatment of OE involves eliminating the aggravat typically caused by untreated acute otitis media. Madtoiditis ing pathogen from the ear canal and reducing inflammation, may be acute or chronic. Symptoms include pain, Swelling, which is usually accomplished by administering combina and tenderness in the mastoid region, as well as otalgia, tions of antimicrobial agents, e.g., antibacterial and antifun erythematosus, and otorrhea. gal agents, with anti-inflammatory agents, e.g., Steroids. 0269 Mastoiditis typically occurs as bacteria spread from Typical antibacterial agents for the treatment of OE include the middle ear to the mastoid air cells, where the inflamma aminoglycosides (e.g., neomycin, gentamycin, and tobramy tion causes damage to the bony structures. The most common cin), polymyxins (e.g., polymyxin B), fluoroquinolone (e.g., bacterial pathogens are Streptococcus pneumoniae, Strepto ofloxacin and ciprofloxacin), cephalosporins (e.g., COccus pyogenes, Staphylococcus aureus, and gram-negative cefuroxime, ceflacor, cefprozil, loracarbef, cefindir, cefixime, bacilli. Accordingly, antimicrobial agent formulations dis cefpodoxime proxetil, cefibuten, and ceftriaxone), penicillins closed herein comprising antibacterial agents effective (e.g., amoxicillin, amoxicillin-clavulanate, and penicillinase against the bacteria are useful for the treatment of mastoiditis, resistant penicillins), and combinations thereof. Typical anti including acute mastoiditis and chronic mastoiditis. fungal agents for the treatment of OE include clotrimazole, 0270 Bullous myringitis is an infection of the tympanic thimerasol, M-cresyl acetate, tolnaftate, itraconazole, and membrane, caused by a variety of bacteria and viruses, combinations thereof. Acetic acid is also administered to the including Mycoplasma bacteria. The infection leads to ear, alone and in combination with other agents, to treat inflammation of the tympanic membrane and nearby canal, bacterial and fungal infections. When the pain of OE is and causes the formation of blisters on the ear drum. The extremely severe such that it interferes with normal activity, primary symptom of Bullous myringitis is pain, which may e.g., sleeping, pain relievers such as topical analgesics or oral be relieved through the administration of analgesics. Antimi narcotics may be given until the underlying inflammation and crobial formulations disclosed herein comprising antibacte infection are alleviated. rial and antiviral agents are useful for the treatment of Bullous 0263. Otitis Media myringitis. 0264. Otitis media (OM), which includes acute otitis 0271 Sensorineural Hearing Loss media (AOM), chronic otitis media, otitis media with effu 0272. Sensorineural hearing loss is a type of hearing loss sion (OME), secretory otitis media, and chronic secretory which results from defects (congenital and acquired) in the otitis media as examples, is a condition that presents in the vestibulocochlear nerve (also known as cranial nerve VIII), or area between the ear drum and the inner ear. Bacterial infec sensory cells of the inner ear. The majority of defects of the tion accounts for a large percentage of OM cases, with more inner ear are defects of otic hair cells. than 40% of cases attributed to Streptococcus pneumoniae 0273 Aplasia of the cochlea, chromosomal defects, and infection. However, viruses, as well as other microbes, may congenital cholesteatoma are examples of congenital defects also account for OM conditions. which can result in sensorineural hearing loss. By way of 0265 AOM is a condition that is most often purely viral non-limiting example, inflammatory diseases (e.g. Suppura and self-limited. Viral AOM can lead to bacterial otitis media tive labyrinthitis, meningitis, mumps, measles, viral syphilis, in a very short period of time, especially in children. Symp and autoimmune disorders), Meniere's Disease, exposure to US 2010/0021416 A1 Jan. 28, 2010

ototoxic drugs (e.g. aminoglycosides, loop diuretics, antime located in the plasma membrane of the neuron. When the tabolites, salicylates, and cisplatin), physical trauma, pres channels open, Na" and Cations flow into the neuron and K" byacusis, and acoustic trauma (prolonged exposure to Sound ions flow out of the neuron. in excess of 90 dB) can all result in acquired sensorineural 0284. The NMDA receptor is activated by the binding of hearing loss. both glutamate and NMDA. Activation of the NMDA recep 0274. If the defect resulting in sensorineural hearing loss tor, results in the opening of ion channels located in the is a defect in the auditory pathways, the sensorineural hearing plasma membrane of the neuron. However, these channels are loss is called central hearing loss. If the defect resulting in blocked by Mg" ions. Activation of the AMPA receptor sensorineural hearing loss is a defect in the auditory path results in the expulsion of Mg ions from the ion channels ways, the sensorineural hearing loss is called cortical deaf into the synapse. When the ion channels open, and the Mg" CSS. ions evacuate the ion channels, Na" and Ca" ions flow into 0275 Ototoxicity the neuron, and K" ions flow out of the neuron. 0276 Ototoxicity refers to hearing loss caused by a toxin. 0285) Excitotoxicity occurs when the NMDA receptor and The hearing loss may be due to trauma to otic hair cells, the AMPA receptors are over-activated by the binding of exces cochlea, and/or the cranial nerve VII. Multiple drugs are sive amounts of ligands, for example, abnormal amounts of known to be ototoxic. Often ototoxicity is dose-dependent. It glutamate. The over-activation of these receptors causes excessive opening of the ion channels under their control. may be permanent or reversible upon withdrawal of the drug. This allows abnormally high levels of Ca" and Na" to enter 0277 Known ototoxic drugs include, but are not limited the neuron. The influx of these levels of Ca" and Na" into the to, the aminoglycoside class of antibiotics (e.g. gentamicin, neuron causes the neuron to fire more often, resulting in a and amikacin), Some members of the macrollide class of anti rapid buildup of free radicals and inflammatory compounds biotics (e.g. erythromycin), some members of the glycopep within the cell. The free radicals eventually damage the mito tide class of antibiotics (e.g. Vancomycin), Salicylic acid, chondria, depleting the cell's energy stores. Furthermore, nicotine, some chemotherapeutic agents (e.g. actinomycin, excess levels of Ca" and Nations activate excess levels of bleomycin, cisplatin, carboplatin and Vincristine), and some enzymes including, but not limited to, phospholipases, endo members of the loop diuretic family of drugs (e.g. furo nucleases, and proteases. The over-activation of these semide). enzymes results in damage to the cytoskeleton, plasma mem 0278 Cisplatin and the aminoglycoside class of antibiot brane, mitochondria, and DNA of the sensory neuron. ics induce the production of reactive oxygen species (ROS). 0286 Ramsay Hunt's Syndrome (Herpes Zoster Infec ROS can damage cells directly by damaging DNA, polypep tion) tides, and/or lipids. Antioxidants prevent damage of ROS by 0287 Ramsay Hunt's Syndrome is caused by a herpes preventing their formation or Scavenging free radicals before Zoster infection of the auditory nerve. The infection may they can damage the cell. Both cisplatin and the aminoglyco cause severe earpain, hearing loss, Vertigo, as well as blisters side class of antibiotics are also thought to damage the earby on the outer ear, in the ear canal, as well as on the skin of the binding melanin in the stria vascularis of the inner ear. face or neck Supplied by the nerves. Facial muscles may also 0279 Salicylic acid is classified as ototoxic as it inhibits become paralyzed if the facial nerves are compressed by the the function of the polypeptideprestin. Prestin mediates outer Swelling. Hearing loss may be temporary or permanent, with otic hair cell motility by controlling the exchange of chloride Vertigo Symptoms usually lasting from several days to weeks. and carbonate across the plasma membrane of outerotic hair 0288 Treatment of Ramsay Hunt's syndrome includes cells. It is only found in the outerotic hair cells, not the inner administration of antiviral agents, including acyclovir. Other otic hair cells. Accordingly, disclosed herein is the use of antiviral agents include famciclovir and Valacyclovir. Com controlled release auris-compositions comprising antioxi bination of antiviral and corticosteroid therapy may also be dants to prevent, ameliorate or lessen ototoxic effects of che employed to ameliorate herpes Zoster infection. Analgesics or motherapy, including but not limited to cisplatin treatment, narcotics may also be administered to relieve the pain, and aminoglycoside or salicylic acid administration, or otheroto diazepam or other central nervous system agents to suppress toxic agents. Vertigo. Capsaicin, lidocaine patches and nerve blocks are 0280 Excitotoxicity optionally used. Surgery may also be performed on com 0281 Excitotoxicity refers to the death or damaging of pressed facial nerves to relieve facial paralysis. neurons and/or otic hair cells by glutamate and/or similar (0289 Labyrinthitis Substances. 0290 Labyrinthitis is an inflammation of the labyrinths of 0282 Glutamate is the most abundant excitatory neu the ear which contain the vestibular system of the inner ear. rotransmitter in the central nervous system. Pre-synaptic neu Causes include bacterial, viral, and fungal infections. It may rons release glutamate upon stimulation. It flows across the also be caused by a head injury or allergies. Symptoms of synapse, binds to receptors located on post-synaptic neurons, labyrinthitis include difficulty maintaining balance, dizzi and activates these neurons. The glutamate receptors include ness, vertigo, tinnitus, and hearing loss. Recovery may take the NMDA, AMPA, and kainate receptors. Glutamate trans one to six weeks; however, chronic symptoms may be present porters are tasked with removing extracellular glutamate for years. from the synapse. Certain events (e.g. ischemia or stroke) can 0291. There are several treatments for labyrinthitis. damage the transporters. This results in excess glutamate Prochlorperazine is often prescribed as an antiemetic. Sero accumulating in the synapse. Excess glutamate in Synapses tonin-reuptake inhibitors have been shown to stimulate new results in the over-activation of the glutamate receptors. neural growth within the inner ear. Additionally, treatment (0283. The AMPA receptor is activated by the binding of with antibiotics is prescribed if the cause is a bacterial infec both glutamate and AMPA. Activation of certain isoforms of tion, and treatment with corticosteroids and antivirals is rec the AMPA receptor results in the opening of ion channels ommended if the condition is caused by a viral infection. US 2010/0021416 A1 Jan. 28, 2010 20

0292 Kinetosis dysfunction. Other treatments include gentamicin applica 0293 Kinetosis, also known as motion sickness, is a con tion, which when injected into the eardrum destroys sensory dition in which there is a disconnection between visually hair cell function, thereby eradicating inner ear balance func perceived movement and the vestibular system's sense of tion. Severing of the vestibular nerve may also be employed, movement. DiZZiness, fatigue, and nausea are the most com which while preserving hearing, may control vertigo. mon symptoms of kinetosis. Dimenhydrinate, cinnarizine, (0300 Meniere's Syndrome and meclizine are all systemic treatments for kinetosis. Addi 0301 Meniere's Syndrome, which displays similar symp tionally, benzodiazepines and antihistamines have demon toms as Meniere's disease, is attributed as a secondary afflic strated efficacy in treating kinetosis. tion to another disease process, e.g. thyroid disease or inner 0294 Meniere's Disease ear inflammation due to syphilis infection. Meniere's Syn 0295 Meniere's Disease is an idiopathic condition char drome, thus, are secondary effects to various process that acterized by Sudden attacks of Vertigo, nausea and Vomiting interfere with normal production or resorption of endolymph, that may last for 3 to 24 hours, and may subside gradually. including endocrine abnormalities, electrolyte imbalance, Progressive hearing loss, tinnitus and a sensation of pressure autoimmune dysfunction, medications, infections (e.g. para in the ears accompanies the disease through time. The cause sitic infections) or hyperlipidemia. Treatment of patients of Meniere's disease is likely related to an imbalance of inner afflicted with Meniere's Syndrome is similar to Meniere's ear fluid homeostasis, including an increase in production or Disease. a decrease in reabsorption of inner ear fluid. 0302 Microvascular Compression Syndrome 0296 Studies of the vasopressin (VP)-mediated aquaporin 0303 Microvascular compression syndrome (MCS), also 2 (AQP2) system in the inner ear suggest a role for VP in called “vascular compression' or “neurovascular compres inducing endolymph production, thereby increasing pressure sion', is a disorder characterized by Vertigo and tinnitus. It is in the vestibular and cochlear structures. VP levels were caused by the irritation of Cranial Nerve VII by a blood found to be upregulated in endolymphatic hydrops (Me vessel. Other symptoms found in subjects with MCS include, niere's Disease) cases, and chronic administration of VP in but are not limited to, severe motion intolerance, and neural guinea pigs was found to induce endolymphatic hydrops. gic like “quick spins. MCS is treated with carbamazepine, Treatment with VPantagonists, including infusion of OPC TRILEPTAL(R), and baclofen. It can also be surgically 31260 (a competitive antagonist of V-R) into the scalatym treated. pani resulted in a marked reduction of Meniere's disease 0304 Vestibular Neuronitis symptoms. Other VP antagonists include WAY-140288, 0305 Vestibular neuronitis, or vestibular neuropathy, is an CL-385004, tolvaptan, conivaptan, SR 121463A and VPA acute, Sustained dysfunction of the peripheral vestibular sys 985. (Sanghi et al. Eur: Heart J. (2005) 26:538-543; Palmet tem. It is theorized that vestibular neuronitis is caused by a al. Nephrol. Dial Transplant (1999) 14:2559-2562). disruption of afferent neuronal input from one or both of the 0297 Other studies suggest a role for estrogen-related vestibular apparatuses. Sources of this disruption include receptor B/NR3B2 (ERR/Nr3b2) in regulating endolymph viral infection and acute localized ischemia of the vestibular production, and therefore pressure in the vestibular/cochlear nerve and/or labyrinth. apparatus. Knock-out studies in mice demonstrate the role of 0306 The most significant finding when diagnosing ves the polypeptide product of the Nr3b2 gene in regulating tibular neuronitis is spontaneous, unidirectional, horizontal endolymph fluid production. Nr3b2 expression has been nystagmus. It is often accompanied by nausea, vomiting, and localized in the endolymph-secreting strial marginal cells and Vertigo. It is, however, generally not accompanied by hearing vestibular dark cells of the cochlea and vestibular apparatus, loss or other auditory symptoms. respectively. Moreover, conditional knockout of the Nr3b2 0307 There are several treatments for vestibular neuroni gene results in deafness and diminished endolymphatic fluid tis. H1-receptor antagonists, such as dimenhydrinate, diphen volume. Treatment with antagonists to ERR/Nr3b2 may hydramine, meclizine, and promethazine, diminish vestibular assist in reducing endolymphatic Volume, and thus alter pres stimulation and depress labyrinthine function through anti Sure in the auris interna structures. cholinergic effects. BenZodiazepines, such as diazepam and 0298. Other treatments may be aimed at dealing with the lorazepam, are also used to inhibit vestibular responses due to immediate symptoms and prevention of recurrence. Low their effects on the GABA receptor. Anticholinergics, for Sodium diets, avoidance of caffeine, alcohol, and tobacco example scopolamine, are also prescribed. They function by have been advocated. Medications that may temporarily Suppressing conduction in the vestibular cerebellarpathways. relieve vertigo attacks include antihistamines (including Finally, corticosteroids (i.e. prednisone) are prescribed to meclizine and other antihistamines), and central nervous sys ameliorate the inflammation of the vestibular nerve and asso tem agents, including barbiturates and/or benzodiazepines, ciated apparatus. including lorazepam or diazepam. Other examples of drugs 0308 Acoustic Trauma that may be useful in relieving symptoms include muscarinic 0309 Hearing loss may also occur from prolonged expo antagonists, including scopolamine. Nausea and Vomiting Sure to loud noises, such as loud music, heavy equipment or may be relieved by Suppositories containing antipsychotic machinery, airplanes or gunfire. The hearing loss occurs as agents, including the phenothiazine agent prochlorperazine. result of destruction of hair cell receptors in the inner ear. This 0299 Surgical procedures that have been used to relieve hearing loss is often accompanied by tinnitus. Permanent symptoms include the destruction of vestibular and/or damage to hearing loss is often diagnosed. cochlear function to relieve vertigo Symptoms. These proce 0310 Although there is currently no treatment for noise dures aim to either reduce fluid pressure in the inner ear induced hearing loss, several treatment regimens have been and/or to destroy inner ear balance function. An endolym experimentally developed, including treatment with insulin phatic shunt procedure, which relieves fluid pressure, may be like growth factor 1 (IGF-1). (Lee et al. Otol. Neurotol. (2007) placed in the inner ear to relieve symptoms of vestibular 28:976-981). US 2010/0021416 A1 Jan. 28, 2010

0311 Presbycusis ear. Otospongiosis can produce symptoms of progressive sen 0312 Presbycusis, or age-related hearing loss, occurs as a Sorineural hearing loss, tinnitus, dizziness, and Meniere's part of normal aging, and occurs as a result of degeneration of syndrome. The sclerotic phase may still have elements of the receptor cells in the spiral organ of Corti in the inner ear. active demineralization of the bone around the inner ear, but Other causes may also be attributed to a decrease in a number also with a harder or Sclerotic element to it. A visual exam can of nerve fibers in the vestibulocochlear nerve, as well as a loss not determine whether the bone is spongiotic or sclerotic. To of flexibility of the basilar membrane in the cochlea. There is the naked eye it appears to be hard bone and is therefore called currently no known cure for permanent hearing damage as a otosclerosis, although it may be in its active phase and more result of presbycusis or excessive noise. aptly calledotospongiosis. By common usage, both phases of 0313. Hereditary Disorders this disorder are referred to as otosclerosis. 0314. Hereditary disorders, including Scheibe, Mondini 0320 Conductive hearing loss in otosclerosis is caused by Michelle, Waardenburg's, Michel, Alexander's ear deformity, two main sites of involvement of the sclerotic (or scar-like) hypertelorism, Jervel-Lange Nielson, Refsum’s and Usher's lesions. The abnormal bone growth fixates the stapes foot syndromes, are found in approximately 20% of patients with plate to the oval window of the cochlea. This impairs move sensorineural hearing loss. Congenital ear malformations ment of the stapes and therefore transmission of Sound into may result from defects in the development of the membra the inner ear ("ossicular coupling). Additionally the nous labyrinthine, the osseous labyrinthine, or both. Along cochlear round window can also become Sclerotic, and impair with profound hearing loss and vestibular function abnor movement of Sound pressure waves through the inner ear malities, hereditary deformities may also be associated with ("acoustic coupling'). Otosclerosis may also cause a senso other dysfunctions, including development of recurring men rineural hearing loss, i.e. nerve fibers or hearing hair cells of ingitis, cerebral spinal fluid (CSF) leaks, as well as perilym the cochlea may be damaged in patients with otosclerosis. phatic fistulas. Treatment of chronic infections may be neces The release of hydrolytic enzymes into the inner ear struc sitated in hereditary disorder patients. tures by the Spongiotic lesions may play a role in the loss of 0315 Otosclerosis cochlear hearing cells. 0316 Bone remodeling is a life long process where old 0321 Genetic factors play a role in the aetiology of the bone is removed from the skeleton (bone resorption) and new disease but measles virus infection and autoimmunity may bone is added (bone formation). These processes also control also play contributing roles. Treatment of otosclerosis the reshaping or replacement of bone during growth and includes Surgery to remove the fixated Stapes bone, called a following injuries. An imbalance in the regulation of bone stapedectomy. Disclosed herein are non-surgical methods for resorption and bone formation results in many bone diseases treatment of otosclerosis. Such as otosclerosis. 0322 Cholesteatoma 0317 Bone remodeling involves erosion of bone by osteo 0323. A cholesteatoma is a hyperproliferative cyst often clasts, which is followed by osteoblasts refilling the resorp found in the middle ear. Cholesteatoma are classified as con tion sites. Osteoclasts adhere to bone and remove it by acidi genital or acquired. Acquired cholesteatomas result from fication and proteolytic digestion. Tunnels are then formed in retraction of the ear drum (primary) and/or a tear in the ear the bone, and the tunnels function as pathways for osteoblasts drum (secondary). and small blood vessels. Fresh layers of osteoid, a cement 0324. The most common primary cholesteatoma results like Substance, are deposited in the tunnels by osteoblasts and from the pars flaccida retracting into the epitympanum. As the this eventually becomes new bone matrix. pars flaccida continues to retract, the lateral wall of the epi 0318 Osteoclasts secrete various enzymes that act in dis tympanum slowly erodes. This produces a defect in the lateral Solution of bone material. For example, tartrate resistant acid wall of the epitympanum that slowly expands. A less common phosphatase (TRACP) decalcifies the bone, while cathepsin type of primary acquired cholesteatoma results from the K digests the bone matrix proteins. The modulation of bone retraction of the posterior quadrant of the tympanic mem homeostasis is controlled by several factors. These factors brane retracts into the posterior middle ear. As the tympanic can be divided into three groups: 1) those influencing the membrane retracts, squamous epithelium envelops the stapes activity of osteoblasts, e.g., parathyroid hormone (PTH) or 1, and retracts into the sinus tympani. Secondary cholesteato 25-dihydroxyvitamin D, 2) those affecting osteoclast pre mas result from injury to the tympanic membrane (e.g. a cursors or osteoclasts, e.g., osteoblasts produce osteoprote perforation resulting from otitis media; trauma; or a Surgi gerin (OPG) and RANKL which play a role in osteoclast cally-induced injury). differentiation; and 3) those with bipotential effects (e.g., 0325 Complications associated with a growing choleste TGF-B can either inhibitor promote osteoclast differentiation atoma include injury to the osteoclasts and, in Some cases, by acting on osteoblasts or osteoclasts, respectively). deterioration of the thin bone layer separating the top of the 0319 “Otosclerosis” is localized bone remodeling within ear from the brain. Damage to the osteoclasts results from the the otic capsule of the human temporal bone. Three ossicles, persistent application of pressure to the bones resulting from the malleus, incus and stapes conduct sound in the middle ear the expansion of the cholesteatoma. Additionally, the pres from the tympanic membrane to the oval window of the inner ence of multiple cytokines (e.g. TNF-C. TGF-B1, TGF-32, ear. The lesions in the bony structures of the ear begin by Il-1, and IL-6) in the epithelium of the cholesteatoma can softening/resorption of stable otic capsule bone (“active result in further degradation of the Surrounding bones. phase'), followed by a reparative phase with bone deposition. 0326 Patients with a cholesteatoma often present with There is an abundance of osteoclasts in the bone in the active earache, hearing loss, mucopurulent discharge, and/or dizzi phase of otosclerosis. Lamellarbone is removed by the osteo ness. Physical examination can confirm the presence of a clasts and replaced by woven spongiotic bone of greater cholesteatoma. Symptoms which can be identified upon thickness and vascularity. This spongiotic phase (“otospon physical examination include damage to the ossicles, and a giosis) produces its most significant effect upon the inner canal filled with mucopus and granulation tissue. US 2010/0021416 A1 Jan. 28, 2010 22

0327. There is currently no effective medical therapy for 0336 Pharmaceutical Agents cholesteatomas. As a cholesteatoma has no blood Supply, it 0337 Provided herein are otic structure modulating agent cannot be treated with systemic antibiotics. Topical adminis compositions or formulations that modulate destroyed, tration of antibiotics often fails to treat a cholesteatoma. stunted, malfunctioning, damaged, fragile or missing otic Reperfusion Injury structures. In some embodiments, the otic structure modulat 0328 ing agent compositions or formulations participate in the 0329 Ischemia is a condition characterized by a lack of, or degradation of destroyed, stunted, malfunctioning, damaged, an inadequate amount of blood Supply to an organ. Ischemia fragile, or missing otic structures. In some embodiments, the often results in irreversible damage to tissue (e.g. from necro otic structure modulating agent compositions or formulations sis) due to the resultant lack of, or insufficiency of oxygen. participate in the construction of destroyed, stunted, malfunc Irreversible damage to an organ can arise from as little as 20 tioning, damaged, fragile, or missing otic structures. In some minutes of complete oxygen deprivation. embodiments, the otic structure modulating agent is an ago 0330 Ischemia is a sequelae of disorders such as, but not nist of anotic structure modulating target, a partial agonist of limited to, heart diseases, transient ischemic attacks, cere an otic structure modulating target, an antagonist of an otic brovascular accidents, ruptured arteriovenous malforma structure modulating target, a partial antagonist of an otic tions, peripheral artery occlusive disease, stroke, and head structure modulating target, an inverse agonist of an otic injury. Cochlear ischemia results from, among other causes, structure modulating target, a competitive antagonist of an otic structure modulating target, a neutral antagonist of an occlusion the vertebral arteries and/or cerebral arteries, otic structure modulating target, an orthostericantagonist of stroke, cardiovascular disease, and acoustic trauma. anotic structure modulating target, an allostericantagonist of 0331 Reperfusion is the restoration of normal blood sup an otic structure modulating target, a positive allosteric ply to an organ following ischemia. In certain instances, rep modulator of an otic structure modulating target or combina erfusion results in additional damage to tissues already dam tions thereof. aged due to an ischemic episode and Surrounding tissues 0338 Provided herein are innate immune system modu (reperfusion injury). In certain instances, reperfusion injury lating compositions or formulations that modulate a compo results from the white blood cells in the restored blood supply nent of the innate immune system. In some embodiments, the reacting to the tissue damaged by ischemia. Additionally, in innate immune system modulating agent increases the activ certain instances, the complement system (which is carried in ity of a component of the innate immune system. In some the restored blood Supply) damages tissue injured by embodiments, the innate immune system modulating agent ischemia, and the surrounding tissues (e.g. by the MAC, inhibits (partially or fully) the activity of a component of the facilitation of opsonization, and the presence of multiple ana innate immune system. In some embodiments, the innate phylatoxins). In certain instances, depletion or inactivation of immune system is the complement system. the complement system ameliorates reperfusion injury. 0339) Otic and vestibular disorders have causes and symp 0332 Labyrinthitis Ossificans toms that are responsive to the pharmaceutical agents dis 0333 Labyrinthitis ossificans (aka labyrinthine ossifica closed herein, or other pharmaceutical agents. Otic structure tion, cochlear ossification, or vestibular ossification) is a con modulating agent or innate immune system modulating dition characterized by the development or growth of bone agents which are not disclosed or exemplified herein but (e.g. the deposition of osteoid followed by mineralization and which ameliorate or eradicate otic disorders are expressly reorganization) into the spaces within the lumen of the boney included and intended within the scope of the embodiments labyrinth. This ossification of the lumen of the labyrinth leads presented. to the destruction of the endolymphatic and perilymphatic 0340 Moreover, pharmaceutical agents which have been spaces, deafness, and dysfunction of the vestibular system. In previously shown to be toxic, harmful or non-effective during the cochlear area of the labyrinth, the Scala tympani is most systemic or localized application in other organ systems, for often the site of ossification. example through toxic metabolites formed after hepatic pro 0334. It is most often an inflammatory response resulting cessing, toxicity of the drug in particular organs, tissues or from AIED or the presence of a pathogen (e.g. S. pneumoniae systems, through high levels needed to achieve efficacy, and H. influenzae) that leads to the ossification of the laby through the inability to be released through systemic path rinth. With regards to pathogenic infections, complete ossifi ways or through poor pK characteristics, are useful in some cation will occur within a few months of infection. In certain embodiments herein. Accordingly, pharmaceutical agents instances, depletion or inactivation of the complement system which have limited or no systemic release, systemic toxicity, ameliorates the development of labyrinthitis ossificans. Addi poor pK characteristics or combinations thereof are contem tionally, disorders such as vascular obstruction of the laby plated within the scope of the embodiments disclosed herein. rinthine artery, temporal bone trauma, leukemia, and tumors 0341 The otic structure modulating agent or innate of the temporal bone can also result in the development of immune system modulating agent formulations disclosed labyrinthitis ossificans. herein are optionally targeted directly to otic structures where 0335 Treatment of an underlying pathogenic infection treatment is needed; for example, one embodiment contem (e.g. meningitis, otitis media, and labyrinthitis) fully or par plated is the direct application of the otic structure modulat tially prevents the development of labyrinthitis ossificans. ing agent or innate immune system modulating agent formu Further, deactivation of the complement system also fully or lations disclosed herein onto the round window membrane or partially prevents the development of labyrinthitis ossificans. the crista fenestrae cochlea of the auris interna, allowing However, if the disease is allowed to progress Surgical direct access and treatment of the auris interna, or inner ear removal of the excess bone is a current remedy. Additionally, components. In other embodiments, the otic structure modu in severe cases of labyrinthitis ossificans, cochlear implants lating agent or innate immune system modulating agent for are required to restore hearing. mulation disclosed herein is applied directly to the oval win US 2010/0021416 A1 Jan. 28, 2010

dow. In yet other embodiments, direct access is obtained tilage. In certain instances, chondroitin is a molecular com through microinjection directly into the auris interna, for ponent of cartilage. In certain instances, collagen is a molecu example, through cochlear microperfusion. Such embodi lar component of a major component of the extracellular ments also optionally comprise a drug delivery device, matrix, cartilage, ligaments, tendons, bone, and/or blood ves wherein the drug delivery device delivers the otic structure sels. In certain instances, decorin is a molecular component of modulating agent or innate immune system modulating agent the extracellular matrix, and/or connective tissue. In certain formulations through use of a needle and Syringe, a pump, a instances, dermatan Sulfate is a molecular component of epi microinjection device, an in situ forming spongy material or thelial tissue. In certain instances, elastin is a molecular com any combination thereof. ponent of connective tissue. In certain instances, fibrinogenis 0342 Some pharmaceutical agents, either alone or in a molecular component of blood. In certain instances, combination, are ototoxic. For example, some chemothera fibronectin is a molecular component of cytoskeleton and/or peutic agents, including actinomycin, bleomycin, cisplatin, the extracellular matrix. In certain instances, fimbrin is a carboplatin and Vincristine; and antibiotics, including eryth molecular component of a cytoskeleton, stereocilia, and/oran romycin, gentamicin, Streptomycin, dihydrostreptomycin, actoclampin motor. In certain instances, glial fibrillary acidic tobramycin, netilmicin, amikacin, neomycin, kanamycin, protein is a molecular component of glial cells. In certain etiomycin, Vancomycin, metronidizole, capreomycin, are instances, heparan Sulfate is a molecular component of epi mildly to very toxic, and affect the vestibular and cochlear thelial tissue and/or cytoskeleton. In certain instances, hyalu structures differentially. However, in some instances, the ronic acid is a molecular component of connective, epithelial, combination of an ototoxic drug, for example cisplatin, in and neural tissues, and/or the extracellular matrix. In certain combination with an otoprotectant is protective by lessening instances, keratin is a molecular component of epithelium the ototoxic effects of the drug. Moreover, the localized appli tissue. In certain instances, laminin is a molecular component cation of the potentially ototoxic drug also lessens the toxic of the extracellular matrix. In certain instances, C-tubulin is a effects that would otherwise occur through systemic applica molecular component of cytoskeletons. In certain instances, tion through the use of lower amounts with maintained effi nestin is a molecular component of neurons. In certain cacy, or the use of targeted amounts for a shorter period of instances, NF-L is a molecular component of neurons. In time. certain instances, NF-M is a molecular component of neu 0343 Moreover, some pharmaceutical excipients, dilu rons. In certain instances, NF-H is a molecular component ents or carriers are potentially ototoxic. For example, benza of neurons. In certain instances, NF66 is a molecular compo lkonium chloride, a common preservative, is ototoxic and nent of neurons. In certain instances, peripherin is a molecu therefore potentially harmful if introduced into the vestibular lar component of neurons. In certain instances, vimentin is a or cochlear structures. Informulating a controlled release otic molecular component of neurons. In certain instances, B-tu structure modulating agent or innate immune system modu bulin is a molecular component of cytoskeletons. In certain lating agent formulation, it is advised to avoid or combine the instances, Villin is a molecular component of cytoskeleton, appropriate excipients, diluents or carriers to lessen or elimi Stereocilia, and/oran actoclampin motor. In certain instances, nate potential ototoxic components from the formulation, or whirlin is a molecular component of stereocilia. to decrease the amount of such excipients, diluents or carriers. 0347 In certain instances, an otic structure enhancing Optionally, a controlled release otic structure modulating agent is hyaluronic acid (e.g. Restylane(R), Perlane(R), (Q-Med agentorinnate immune system modulating agent formulation AB, Sweden and Medicis Aesthetics)). Juvederm R). In some includes otoprotective agents, such as antioxidants, alpha instances hyaluronic acid is obtained from pathogens (e.g., lipoic acid, calcium, fosfomycin or iron chelators, to coun streptococcus bacteria). In some instances, hyaluronic acid is teract potential ototoxic effects that may arise from the use of obtained from avian sources (e.g. HyalofommR), (Genzyme specific therapeutic agents or excipients, diluents or carriers. Corporation)). In some instances, an otic structure enhancing 0344 Otic Structure Enhancing Agents agent is collagen (e.g., Zyplast(R), Zyderm R), Cosmoderm R), 0345 Contemplated for use with the formulations dis Cosmoplast R. (Inamed Corporation)). In some instances col closed herein are agents for treating or ameliorating hearing lagen is obtained from humans. In some instances collagen is loss or reduction resulting from destroyed, stunted, malfunc obtained from animal sources. tioning, damaged, fragile or missing otic structures (e.g. tis 0348 Otic Bone Remodeling Agents Sues, membranes, cells, cartilage, bone). Accordingly, some 0349 Contemplated for use with the formulations dis embodiments incorporate the use of molecular components closed herein are agents for treating or ameliorating hearing of otic structures. In certain instances, the molecular compo loss, and/or a balance disorder resulting from destroyed, nents of otic structures are utilized by a body to replace or stunted, malfunctioning, damaged, fragile or missing otic repair destroyed, stunted, malfunctioning, damaged, fragile bone structures (e.g. otosclerosis). Further contemplated for or missing otic structures. In some embodiments, the compo use with the formulations disclosed herein are agents for nents of otic structures are polypeptides or polyglycans. In modulating otic bone remodeling. In some embodiments, the Some embodiments, the components of otic structures are modulator of bone remodeling is a modulator of osteoblasts actin, aggrecan, chondroitin, collagen, decorin, dermatan Sul or osteoclasts. In some instances, the modulator of bone fate, elastin, fibrinogen, fibronectin, fimbrin, glial fibrillary remodeling is a hormone. In certain instances, the modular of acidic protein, heparan Sulfate, hyaluronic acid, keratin, lami bone remodeling is a bisphosphonate. In some embodiments, nin, nestin, NF-L, NF-M, NF H, NF66, peripherin, C.-tubu the modulator of bone remodeling is a matrix metalloprotein lin, B-tubulin, villin, vimentin, whirlin, or combinations ase inhibitor. In some instances, the modulator of bone thereof. remodeling is an adenylyl cyclase (AC) modulator. In certain 0346. In certain instances, actin is a molecular component instances, the modulator of bone remodeling is a protease of a cytoskeleton, Stereocilia, and/oran actoclampin motor. In inhibitor. In some embodiments, the modulator of bone certain instances, aggrecan is a molecular component of car remodeling is a modulator of tartarate resistant acid phos US 2010/0021416 A1 Jan. 28, 2010 24 phatase (TRACP). In some instance, the modulator of bone 0353. In some embodiments, the agent that participates in remodeling is an estrogen receptor modulator. In some the degradation of an otic structure is an alcohol or alkanol embodiments, the modulator of bone remodeling is a PPARY (e.g. decanol, and ethanol), an essential oil (e.g. basil oil, modulator. In certain instances, the modulator of bone remod palmarosa oil, petitgrain oil, and thyme oil), a fatty acid eling is an HMG-CoA reductase inhibitor. In some embodi (capric acid, lauric acid, linoleic acid, myristic acid, and oleic ments, the modulator of bone remodeling is a statin. In some acid), a glycol (e.g. polyethylene glycol, and proplyene gly col), laurocapram, a pyrrolidone (e.g. 2-pyrrolidone, N-me instances, the modulator of bone remodeling is a carbonic thylpyrrolidone, and N-(2-hydroxyethyl)-2-pyrrolidone), a anhydrase inhibitor. In some embodiments, the modulator of sulfoxide (e.g. DMSO, n-Decylmethyl Sulfoxide), a surfac bone remodeling is a modulator of the receptor activator of tant (e.g. Span 80, sodium lauryl sulfate. Tween 20, and nuclear KB ligand (RANKL). In certain instances, the modu Tween 80), a bile salt (e.g. sodium glycocholate, Sodium lator of bone remodeling is a COX-2 inhibitor. In some deoxycholate, sodium taurocholate, sodium taurodihydro embodiments, the modulator of bone remodeling is an inhibi fusidate, sodium glycodihydrofusidate and the like), a chelat tor of protein prenylation. In certain instances, the modulator ing agent (e.g. EDTA, citric acid, Salicylates and the like), an of bone remodeling is a 5-lipoxygenase inhibitor. In some enzyme, or combinations thereof. In some embodiments, the instances, the modulator of bone remodeling is an inhibitor of enzyme is a protease, a glycosidase, an actinase, a chondroiti TNF. In some embodiments, the modulator of bone remodel nase, a collagenase, a dermatanase, an elastase, a gelatinase, ing is an inhibitor of leukotrienes. In some embodiments, the a heparanase, a hyaluronidase, a keratinase, a lipase, a met modulator of bone remodeling is a cytokine modulator. In allproteinase (e.g. matrix metallproteinase), a staphyloki Some instances, the modulator of bone remodeling is an nase, a streptokinase, chymotrypsin, endopeptidase V8, inhibitor of TSG-6. In some embodiments, the modulator of trypsin, thermolysin, pepsin, plasmin, or combinations bone remodeling is a modulator of TGF B. In some instances, thereof. the modulator of bone remodeling is a nitiric oxide synthase 0354. In some embodiments, the enzyme is an actinase inhibitors. In some embodiments, the modulator of bone (e.g. fragilysin). In certain instances, administration or appli remodeling is an acetylcysteine. In certain embodiments, the cation of an actinase degrades an actin. modulator of bone remodeling is a modulator of aromatases. 0355. In some embodiments, the enzyme degrades chon In some instances, the modulator of bone remodeling is a droitin, dermatan, and/or hyaluronic acid. In certain strontium-based compound as disclosed in WO/2008/ instances, administration or application of a chondroitinase 027880, which is incorporated by reference herein for the (e.g. N-acetylgalactosamine-6-sulfatase; N-acetylgalac Subject matter disclosed. tosamine-4-sulfatase; Chondroitin AC lyase; Chondroitin B 0350 Otic Structure Degrading Agents lyase; Chondroitin-sulfate-ABC endolyase; and Chon 0351 Contemplated for use with the formulations dis droitin-sulfate-ABC exolyase) degrades a chondroitin, der closed herein are agents for treating or ameliorating hearing matan, and/or a hyaluronic acid. In certain instances, admin loss, and/or a balance disorder resulting from destroyed, istration or application of a dermatanase degrades a dermatan stunted, malfunctioning, damaged, fragile or missing otic Sulfate. In certain instances, administration or application of structures (e.g. Meniere's disease, endolymphatic hydrops, a hyaluronidase (hyaluronoglucosaminidase; hyaluronoglu vestibular neuronitis). Further contemplated for use with the curonidase; hyaluronate lyase) degrades a hyaluronic acid, formulations disclosed herein are agents which facilitate the condroitin, and/or dermatan. In certain instances, hyalu penetration of anotic active agent into the middle and/or inner ronidase degrades fluids that accumulate in tympanostomy earby degrading barriers (e.g. cells, lipid matrix, extracellular tubes and/or mucus that is present in the middle ear. matrix, desmosome). Further contemplated for use with the 0356. In certain instances, a glycosidase degrades mucus formulations disclosed herein are agents that act as anti that is present in the middle ear. microbial agents (e.g. agents that inhibit the adhesion of 0357. In some embodiments, the enzyme is a heparanase microbes to otic structures). Additionally, contemplated for (e.g. heparan-alpha-glucosaminide N-acetyltransferase; use with the formulations disclosed herein are agents for N-acetylglucosamine-6-sulfatase; and iduronate-2-sulfa treating or ameliorating hearing loss or reduction resulting tase). In certain instances, administration or application of a from the accumulation of fluid (e.g. mucus and pus) and/or heparanase degrades a heparan Sulfate. In certain instances, a cerumen within the ear (e.g. the outer ear, middle ear, and heparinase degrades heparin Sulfate moieties from nasopha inner ear). Accordingly, some embodiments incorporate the ryngeal epithelia cells resulting in the detachment of pneu use of an agent that participates in the degradation an otic mococci from nasopharyngeal epithelia cells. structure (e.g. a neuron, a membrane, cartilage, bone, 0358. In some embodiments, the enzyme is a keratinase endolymph, perilymph). (e.g. peptidase K; and candidapepsin). In certain instances, 0352. In some embodiments, the otic structure modulating administration or application of a keratinase degrades a kera agent is an otic structure degrading agent. In some embodi tin. ments, the otic structure degrading agent degrades bone. In 0359. In some embodiments, the enzyme is a lipase (e.g. Some embodiments, the otic structure degrading agent triacylglycerollipase; acylglycerol lipase, lipoprotein lipase; degrades cartilage. In some embodiments, the otic structure and hormone-sensitive lipase). In certain instances, adminis degrading agent degrades a neuron. In some embodiments, tration or application of a lipase degrades a lipid. In certain the otic structure degrading agent degrades a membrane (e.g., instances, administration or application of a lipase degrades a tympanic membrane). In some embodiments, the otic struc CUC. ture degrading agent degrades endolymph. In some embodi 0360. In some embodiments, the enzyme is a metallpro ments, the otic structure degrading agent degrades perilymph. teinase. In certain instances, administration or application of In some embodiments, the otic structure degrading agent a metallproteinase degrades a polypeptide. In some embodi degrades liquor puris (i.e., pus). ments, the metallproteinase is a matrix metalloproteinase or US 2010/0021416 A1 Jan. 28, 2010

thermolysin. In some embodiments, the matrix metallopro hyaluronidase, Vitrase(R) (ISTA Pharmaceuticals). In certain teinase is a collagenase, a gelatinase, a stromelysin, an MT1 instances, a hyaluronidase described herein is a recombinant MMP, an MT2-MMP, an MT3-MMP, an MT4-MMP, an hyaluronidase. In some instances, a hyaluronidase described MT5-MMP, and an MT6-MMP. In certain instances, admin herein is a humanized recombinant hyaluronidase. In some istration or application of a collagenase degrades a collagen. instances, a hyaluronidase described herein is a pegylated In certain instances, administration or application of a colla hyaluronidase (e.g., PEGPH20 (Halozyme)). In certain genase degrades cerumen. In certain instances, administra instances, the enzyme is obtained from a pathogen. In certain tion or application of a gelatinase degrades a gelatin and/or a instances, the pathogen is Streptococcus and the enzyme is a type IV collagen. In certain instances, administration or hyaluronidase, and/or a streptokinase. In certain instances, application of a stromelysin degrades an extracellular matrix the pathogenis Staphylococcus and the enzyme is a lipase, V8 protein. In certain instances, administration or application of protease, elastase, hyaluronidase, and/or a staphlokinase. In thermolysin degrades a polypeptide by cleaving the peptide certain instances, the pathogen is Bacillus anthracis, or a chain at a hydrophobic amino acid. Clostridium and the enzyme is a metalloproteinase. In certain 0361. In some embodiments, the enzyme is plasmin, a instances, the pathogen is Bacillus thermoproteolyticus and plasminogen activator, and/or combinations thereof. In cer the enzyme is thermolysin. In certain instances, the pathogen tain instances, administration or application of a plasmin is Candida albicans and the enzyme is candidapepsin. degrades a fibrin, a fibronectin, a thrombospondin, a laminin, 0365 Anaphylatoxin Modulators and a von Willebrand factor. In some embodiments, the plas 0366. In some embodiments, an anaphylatoxin modulator minogen activator is staphylokinase, streptokinase, and/or is administered to a subject in need thereof. In some embodi combinations thereof. In certain instances, administration or ments, the anaphylatoxin modulator is an antagonist of C5a. application of a staphylokinase activates a plasminogen to In some embodiments, the C5a antagonist is chemotaxis form a plasmin. In certain instances, administration or appli inhibitory protein of S. aureus (CHIPS), PMX53 (AcFIOP cation of a streptokinase activates a plasminogen to form a DCha-WR), PMX205 (HC OPdChaWRI), PMX273 plasmin. In certain instances, plasmin degrades basement (AcFIOP-DPhe-WRI), PMX201 (AcFIOP-DCha-WCit), membranes. PMX218 (HC OPdPheWRI), C089 (NMePhe-Lys-Pro 0362. In some embodiments, the enzyme is a serine pro dCha-X-dArg), L-156,602 (D-Alanine.(RS,2R,5R,6R)-tet tease. In certain instances, administration or application of a rahydro-R,2-dihydroxy-R,6-dimethyl-5-[(2S)-2-methylbu serine protease degrades a polypeptide. In certain instances, tyl-2H-pyran-2-acetyl-(3S)-3-hydroxy-L-leucyl-(3R)- administration or application of a serine protease degrades hexahydro-3-pyridazinecarbonyl-N-hydroxy-L- cerumen. In some embodiments, the serine protease is chy alanylglycyl-(3S)-hexahydro-3-pyridazinecarbonyl-N- motrypsin, elastase, trypsin, and/or V8 protease. In certain hydroxy-(7f2)-lactone, CAS #: 125228-51-5), C5aRAM, instances, administration or application of chymotrypsin C5aRAD, or combinations thereof. In certain instances, a C5a degrades a polypeptide by cleaving the peptide chain at the antagonist binds to a C5aR and thereby antagonizes the bind carboxyl side of a tyrosine, a tryptophan, and a phenylalanine. ing of C5a. In certain instances, CHIPS binds to the C5a In certain instances, administration or application of an receptor (C5aR) on a macrophage thereby inhibiting the C5a elastase degrades an elastin. In certain instances, administra induced chemotaxis of a macrophage. In certain instances, tion or application of trypsin degrades a polypeptide by cleav C5aRAM and C5aRAD are derived from the modification of ing the peptide chain at the carboxyl side of a lysine or an the C terminus of C5a. arginine. In certain instances, administration or application of 0367. In some embodiments, the antagonist of C5aRacti V8 protease degrades a polypeptide by cleaving the peptide Vation is an antisense peptide. In some embodiments, the chain at the carboxyl side of an aspartic acid and/or glutamic antisense peptide of C5a is PR226-MAP (LRTWSRRA acid. TRSTKTLKVV), PL37-MAP (RAARISLGPRCIKAFTE), 0363. In some embodiments, the enzyme is an aspartic or combinations thereof. In certain instances, a C5a antago protease. In certain instances, administration or application of nist binds to a C5aR and thereby antagonizes the binding of an aspartic protease degrades a polypeptide. In certain C5a. instances, administration or application of an aspartic pro 0368. In some embodiments, an anaphylatoxin modulator tease degrades cerumen. In some embodiments, the aspartic is administered to a subject in need thereof. In some embodi protease is pepsin, plasmepsin, or combinations thereof. In ments, the anaphylatoxin modulator is an antagonist of C3a. certain instances, administration or application of a pepsin In some embodiments, the C3a antagonist is SB-2901 57 degrades a polypeptide by cleaving the peptide chain at car (N(2)-(2,2-diphenylethoxy)acetyl-L-arginine). In certain boxyl side of an aromatic amino acid such as phenylalanine instances, SB-290157 binds to the C3a receptor (C3aR) and tyrosine. In certain instances, administration or applica thereby blocking the binding of C3a. tion of a plasmepsin degrades a polypeptide (e.g. hemoglo 0369 Complement Activators bin) by cleaving the peptide chain at two aspartic acid resi 0370. In some embodiments, a complement activator is dues. administered to a subject in need thereof. In some embodi 0364. In certain instances, the otic structure degrading ments, the complement activator is GR-2II, a pectic ara agent is a hyaluronidase. In certain instances, a hyaluronidase binogalactan (e.g. AGIIa, and AGIIb-1), a pectin (e.g. is a human or bovine hyaluronidase. In some instances, a AR-2IIa, AR-2IIb, AR-2IIc, and AR-2IId), CVF, or combi hyaluronidase is a human hyaluronidase (e.g., hyaluronidase nations thereof. In certain instances, AR-2IIa, AR-2IIb, and found in human sperm, PH20 (Halozyme), Hyelenex R (Bax AR-2IIc activate the complement system via the classical ter International, Inc.)). In some instances, a hyaluronidase is pathway and not the alternative pathway. a bovine hyaluronidase (e.g., bovine testicular hyaluronidase, 0371 Cobra Venom Factor (CVF) is a three-chain Amphadase R (Amphastar Pharmaceuticals), Hydase R (Pri (C-chain, 3-chain, and Y-chain) glycoprotein extracted from maPharm, Inc). In some instances, a hyluronidase is an ovine the reptile Naja sp. CVF is a human complement system US 2010/0021416 A1 Jan. 28, 2010 26 activating protein. It is structurally homologous to C3b. In In certain instances, C1q regulates the presentation of adhe certain instances, CVF binds to Factor B which is then sion molecules on endothelial cells. In certain instances, a cleaved by Factor D. The resulting complex, CVFBb, func C1q receptor (e.g. cc 1qR, C1qRp, and gC1qR) prevents tions as a C3 convertase and a C5 convertase. At 7.5 hours complement-mediated lysis of C1q sensitized erythrocytes. CVFBb exhibits a longer half-life than C3bBb (1.5 minutes). In certain instances, administration of C1 inhibitor prevents Further, CVFBb is resistant to disassembly by Factor H and reperfusion injury. CVF is resistant to inactivation by Factor I. As a result, 0377. In some embodiments, an antagonist of C1q binding CVFBb will continuously hydrolyze C3 and C5. The continu is administered to a subject in need thereof. In some embodi ous hydrolyzation of C3 and C5 results in the depletion (or ments, the antagonist of C1q binding is C1q inhibitor, deco exhaustion) of the complement system within several hours. rin, CSPG (chondroitin sulfate proteoglycan), CBP2 However, resynthesis of the components of the complement (complement binding peptide 2), or combinations thereof. In system begins quickly and the entire system is reconstituted certain instances, CSPG partially or fully inhibits the binding with 5-10 days. of C1q to C1s and C1r, thereby interfering with the formation 0372. In certain instances, CVF is highly antigenic in vivo. of the enzyme C. In certain instances, CBP2 interferes with As a result, several humanized analogs and/or derivatives of the binding of C1q to an antigen or antigen-bound antibody. CVF have been engineered. In certain instances, these deriva 0378 Complement Receptor 1 tives exhibit similar activity to natural CVF (e.g. 50-97% of 0379. In some embodiments, a complement receptor 1 the activity of natural CVF); however, they do not or have a (CR1) is administered to a subject in need thereof. By binding reduced capability of activating an immune response in vivo. to C3b and C4b CR1 promotes phagocytosis and clearance of In certain analogs and/or derivatives, several amino acids antigen-antibody complexes. Further, it inhibits both the clas from the B-chain of the CVF polypeptide are removed. In sic and alternative pathways. In certain instances, CR1 acts as further analogs and/or derivatives, the CVF polypeptide is a decay-accelerator for both C3 and C5. Additionally, in conjugated to a human antibody (e.g. monoclonal antibodies certain instances, CR1 acts as a Factor I cofactor. against antigen on human leukemia cells, human neuroblas 0380. In some embodiments, a soluble CR1 (SCR1) is toma cells, and human melanoma cells). In some analogs administered to a subject in need thereof. Soluble CR1 lacks and/or derivatives, a human C3 derivative and/or analog (e.g. the transmembrane and cytoplasmic domains of CR1. In cer recombinant C3, rC3, humanized CVF) is engineered such tain instances, SCR1 decrease the amount of MAC produced that the human C3 derivative and/or analog comprises a por by the complement system. In certain instances, SCR1 ame tion of a CVF polypeptide sequence. In other analogs and/or liorates ischemic/reperfusion injuries. In certain instances, derivatives, portions of a human C3 polypeptide (e.g. the SCR1 reduces cellular and tissue injuries in animal models C-chain; or portions of the carboxy terminal) are replaced with acute or chronic inflammatory disorders. In some with the corresponding portion of the CVF polypeptide. In embodiments, the sOR1 is APTO70 (Mirococept), TP10 certain derivatives and/or analogs, the C-chain of the human (Avant Immunotherapeutics), TP20 (Avant Immunothera C3 is replaced by the corresponding carboxy terminal amino peutics), or combinations thereof. acids of the CVF polypeptide. In some embodiments, the 0381. In some embodiments, a soluble CR1 (SCR1) lack CVF analog and/or derivative is HC3-1496, HC3-1496-2, ing the long homologous repeat A (LHR-A) domain (SCR1 HC3-1496-3, HC3-1496-4, HC3-1496/1617, HC3-1496-8, des|HR-A) is administered to a subject in need thereof. HC3-1496-9, HC3-1496-10, HC3-1496-11, HC3-1496-12, SCR1 des. HR-A) lacks the transmembrane and cytoplasmic HC3-1496-13, HC3-1496-14, HC3-1496-15, HC3-1496-16, domains of CR1 and the C4b binding domain. In certain HC3-1496-17, or combinations thereof. For disclosures instances, SCR1 desLHR-A inhibits the alternative pathway regarding the aforementioned CVF analogs and/or deriva but exhibits a diminished ability to inhibit the classical path tives see PCT Pub. No. WO 2005/003159; and PCT Pub. No. way as compared to SCR1. WO 2008/060634, which are herein incorporated by refer 0382. In some embodiments, a soluble CR1 (SCR1) bound ence for Such disclosures. For additional disclosures regard by SLe moieties is administered to a subject in need thereof. ing CVF derivatives and/or analogs see U.S. Pat. No. 5,714, SLe' is a carbohydrate ligand for selectins that, in certain 344, which is hereby incorporated by reference for such instances, inhibits E-selectin and P-selectin mediated neutro disclosures. phil adhesion. In certain instances, SCR1-SLe’ inhibits 0373. In some embodiments, CVF is administered to a complement activation and inhibits the recruitment of neu subject in need thereof (e.g. a subject who will benefit from trophils to the site of inflammation. complement depletion). In some embodiments, a CVF (0383 Complement Receptor 1-Related Gene/Protein derivative is administered to a subject in need thereof. 0384. In some embodiments, a complement receptor 1-re 0374 Complement Component 1 Modulators lated gene/proteiny (Crry) is administered to a subject in need 0375. In some embodiments, a complement component 1 thereof. In some embodiments, a recombinant Crry (Crry-Ig) (C1) modulator is administered to a subject in need thereof. In is administered to a subject in need thereof. Crry inhibits both Some embodiments, the complement C1 modulator is a C1 the classic and alternative pathways. In certain instances, inhibitor. In certain instances, the C1 inhibitor prevents fluid Crry acts as a decay-accelerator for both C3 and C5. Addi phase C1 activation. In certain instances, administration of tionally, in certain instances, Crry acts as a Factor I cofactor. C1 inhibitor prevents reperfusion injury. In some embodi 0385 Complement Component 3 Convertase Modulators ments, dextran Sulfate is administered to a subject in need 0386. In some embodiments, a modulator of C3 conver thereof. In some embodiments, C1 inhibitor is administered tase is administered to a Subject in need thereof. In some before, after, or simultaneous with dextran sulfate. In certain embodiments, the C3 convertase modulator is a fucan. In instances, dextran Sulfate potentiates C1 inhibitor. Some embodiments, a fucan is extracted from brown seaweed 0376. In some embodiments, a complement component 1 q (e.g. Phaeophyceae, Ascophyllum nodosum, and Ecklonia receptor (C1 qR) is administered to a subject in need thereof. kurome). In certain instances, a fucan partially or fully Sup US 2010/0021416 A1 Jan. 28, 2010 27 presses the classical pathway. In certain instances, a fucan 0394 Complement Component 5 Convertase Modulators partially or fully suppresses the alternative pathway. In some 0395. In some embodiments, a modulator of C5 conver embodiments, the fucan is BS8. In certain instances, BS8 tase is administered to a Subject in need thereof. In some partially or fully inhibited formation of C4bC2a by interfer embodiments, the C5 convertase modulator is an anti complement component 5 (C5) murine monoclonal. In cer ing with C1 activation. In certain instances, BS8 partially or tain instances, an anti-C5 mAb partially or fully inhibits the fully inhibited formation of C4bC2a by interfering C4 cleav cleavage of C5 by C5 convertase. In certain instances, an age. In certain instances, BS8, partially or fully inhibits C3Bb anti-C5 mAB inhibits the formation of C5a. In certain by interfering with the binding of Factor B to C3b and by instances, an anti-C5 mAb partially or fully inhibits the for interfering with the binding of properdin. mation of C5b and thus the formation of a MAC. In certain 0387. In some embodiments, a modulator of C3 conver instances, an anti-C5 mAB does not inhibit the cleavage of a tase is administered to a Subject in need thereof. In some C3. In some embodiments, an anti-C5 mAB is derived from embodiments, the C3 convertase modulator is complestatin. the variable region of the N1978 mAb. In certain instances, In certain instances, complestatin interferes with the binding administration of an anti-C5 mAB ameliorates an autoim of C4b and C2b, and thus antagonizes the formation of the mune disease. In certain instances, an anti-C5 mAB partially classical C3 convertase (C4bC2b). or fully inhibits CD11b up-regulation. In certain instances, decreases the number of P-selectin presenting platelets. In 0388. In some embodiments, a modulator of C3 conver certain instances, an anti-C5 mAB reduces the formation of tase is administered to a Subject in need thereof. In some leukocyte-platelet aggregates. In some embodiments, the C5 embodiments, the C3 convertase modulator is extracellular antibody is pexelizumab. complement-binding protein (Ecb). In certain instances, Ecb 0396. In some embodiments, an anti-C5 murine single is isolated from S. aureus. In certain instances, it modulates chain antibody is administered to a subject in need thereof. In C3b containing molecules (e.g. the alternative C3 convertase Some embodiments, an anti-C5 murine single-chain antibody C3bB3, and the C5 convertases C4bC2aC3b and C3bBbC3b) is derived from the variable region of the N1978 mAb. In by blocking the ability of C3b containing molecules to cleave certain instances, an anti-C5 murine single-chain antibody is their substrates (e.g. C3 and C5). inhibits the cleavage of C5 and the production of C5a. In 0389. In some embodiments, a modulator of C3 conver certain instances, an anti-C5 murine single-chain antibody is tase is administered to a Subject in need thereof. In some partially or fully inhibits C5b-9-mediated hemolysis of eryth embodiments, the C3 convertase modulator is extracellular rocytes. In some embodiments, an anti-C5 humanized single fibrinogen-binding protein (Efb). In certain instances, Efb is chain antibody (e.g. 5G1.1-SC) is administered to a subject in isolated from S. aureus. In certain instances, Efb modulates need thereof. C3b containing molecules (e.g. the alternative C3 convertase 0397. In some embodiments, a modulator of C5 conver C3bB3) by blocking the ability of C3bBb to cleave C3. tase is administered to a Subject in need thereof. In some 0390. In some embodiments, a modulator of C3 conver embodiments, the C5 convertase modulator is K76 (6,7-di tase is administered to a Subject in need thereof. In some formyl-3',4',4a',5'6",7,8,8a'-octahydro-4,6,7-trihydroxy-2", embodiments, the C3 convertase modulator is compStatin. In 5',5'.8a'-tetramethyl spiro1'(2H)-naphthalene-2(3M)-ben certain instances, compStatin antagonizes C3 convertases by Zofuran), or a derivative thereof (e.g. TKIXc, and K76 binding to C3 and partially or fully inhibiting the ability for a COOH). In certain instances, K76 antagonizes C5 convertase C3 convertase to bind to and cleave C3. by interfering with the ability of C5 convertase to bind to and/or cleave C5. 0391. In some embodiments, a modulator of C3 conver 0398. In some embodiments, a modulator of C5 conver tase is administered to a Subject in need thereof. In some tase is administered to a Subject in need thereof. In some embodiments, the C3 convertase modulator is roSmarinic embodiments, the C5 convertase modulator is a staphylococ acid. In certain instances, rosmarinic acid reacts with the cal complement inhibitor (e.g. SCIN, SCIN-B, and SCIN-C). activated thioester of metastable C3b. In certain instances, the In certain instances, a staphylococcal complement inhibitoris reaction of rosmarinic acid and the activated thioester of isolated from S. aureus. In certain instances, an SCIN binds to metastable C3b results in covalent attachment of rosmarinic and stabilizes a C3 convertase (e.g. C4bC2a and C3bBb). In acid to a C3 convertase. In certain instances, the covalent certain instances, the binding of an SCIN prevents the binding attachment of roSmarinic acid to a C3 convertase prevents the of a C3b subunit to the complex; thus, preventing the forma binding of a C3 convertase to a host cell or pathogen. tion of a C5 convertase from a C3 convertase. 0392. In some embodiments, a modulator of C3 conver 0399 CD55 tase is administered to a Subject in need thereof. In some 0400. In some embodiments, a CD55 is administered to a embodiments, the C3 convertase modulator is CRIT. In some subject in need thereof. CD55, also known as Decay Accel embodiments, the C3 convertase modulator is a peptide erating Factor (DAF), binds both C4b and C3b. In certain sequence comprising the C-terminal 11-amino-acid of the instances, the binding of CD55 to C4b disassociates the C3 first CRIT-extracellular domain (CRIT-H17). In certain convertase of the classical pathway and thus also inhibits the instances, CRIT inhibits the formation of C3 convertase. In formation of the classical C5 convertase. In certain instances, certain instances, CRIT binds to C2, thus inhibiting C4b from the binding of CD55 to C3b disassociates the C3 and C5 binding to C2 and forming C3 convertase. convertases of the alternative pathway. In some embodi 0393. In some embodiments, a modulator of C3 conver ments, a CD55 protein is a soluble protein (SCD55). In some tase is administered to a Subject in need thereof. In some embodiments, SCD55 is administered to a subject in need embodiments, the C3 convertase modulator is glycyrrhetinic thereof. acid. In certain instances, glycyrrhetinic acid modulates C2 04.01 CD59 and thus modulates the formation of the classical pathway C3 0402. In some embodiments, a CD59 protein is adminis COnVertase. tered to a subject in need thereof. In certain instances, CD59 US 2010/0021416 A1 Jan. 28, 2010 28 inhibits the formation of a MAC by binding to C8 and C9 and some embodiments, sMCP and/or MCP is administered with thereby preventing their binding to the C5bC6C7 complex. In CD55. In certain instances, administration of sMCP inhibits some embodiments, a soluble CD59 (sCD59) protein is complement-mediated inflammation. In certain instances, administered to a subject in need thereof. administration of MCP activates Factor I leading to the inac 0403 CD55/CD59 Fusion Proteins tivation of a C3 convertase of the classical pathway and/or a 04.04. In some embodiments, a CD59/CD55 fusion protein C3 convertase of the alternative pathway. In certain instances, is administered to a subject in need thereof. In certain administration of MCP activates Factor I leading to a decrease instances, the CD59 subunit inhibits the formation of a MAC in the production of C5 convertase the classical pathway by binding to C8 and C9 and thereby preventing their binding and/or inactivation of a C5 convertase of the alternative path to the C5bC6C7 complex. In certain instances, a CD59/CD55 way. fusion protein prevents the formation of a MAC, and prevents 0412 Heparin the formation of or inhibits the activity of a C5 convertase. In 0413. In some embodiments, heparin or a derivative certain instances, the CD55 subunit binds to C4b thereby thereof (e.g. LU 51198) is administered to a subject in need disassociating the C3 convertase of the classical pathway and thereof. In certain instances, heparin interacts with C, C2, inhibiting the formation of the classical C5 convertase. In C3, C4, C5, C6, C7, C8, C9, C11 NH, factor I, factor H, factor certain instances, the CD55 subunit binds to C3b thereby B and factor P. In certain instances, heparin partially or fully disassociating the C5 convertase of the alternative pathway. inhibits the formation of the alternative pathway C3 conver 04.05 CD55/MCP Fusion Proteins tase (C3 Bb) and the classical pathway C3 convertase 0406. In some embodiments, a CD55/MCP fusion protein (C4bC2a). is administered to a subject in need thereof. In certain 0414 MAC Modulators instances, the CD55 subunit binds to C4b thereby disassoci 0415. In some embodiments, an MAC modulator is ating the C3 convertase of the classical pathway and inhibit administered to a subject in need thereof. In some embodi ing the formation of the classical C5 convertase. In certain ments, the MAC modulator is clusterin, vitronectin. In certain instances, the CD55 subunit binds to C3b thereby disassoci instances, clusterin partially or fully inhibits the formation of ating the C5 convertase of the alternative pathway. In certain fluid-phase MAC. In certain instances, vitronectin partially or instances, the MCP (Membrane Cofactor Protein, or CD46) fully inhibits the formation of fluid-phase MAC. Subunit is a co-factor of Factor I. In certain instances, the 0416 MIF Modulators MCP subunit activates Factor I leading to the inactivation of 0417. In some embodiments, an MIF modulator is admin a C3 convertase of the classical pathway and/or a C3 conver istered to a subject in need thereof. In some embodiments, the tase of the alternative pathway. In some embodiments, the MIF modulator is an inhibitor and/oran antagonist of MIF. In CD55/MCP fusion protein is a soluble protein sGD55/MCP Some embodiments, an MIF modulator decreases inflamma (Complement Activation Blocker-2, CAB-2). In certain tion. In some embodiments, an MIF modulator downregu instances, CAB-2 exhibits greater antagonism of convertases lates the production of a cytokine (e.g. TNF-C. and IL-8). In (e.g. C3 and C5) as compared to either CD55 administered Some embodiments, an MIF modulator ameliorates the Symp alone, MCP administer alone, or CD55 and MCP adminis toms of OME. In some embodiments, the inhibitor and/or tered in combination. In certain instances, CAB-2 inhibits antagonist of MIF is an anti-MIF antibody. In certain complement activation in vivo. instances, the administration of an anti-MIF antibody 0407 Factor D Modulators decreases the production of TNF-C. and IL-8. In some 0408. In some embodiments, a Factor D modulator is embodiments, the inhibitor and/or antagonist of MIF is met administered to a subject in need thereof. In some embodi formin. In certain instances, the administration of metformin ments, the Factor D modulator is a Factor Dantagonist. In decreases plasma MIF concentrations. In some embodiments, some embodiments, the Factor Dantagonist is BCX-1470 the inhibitor and/or antagonist of MIF is ISO-1 ((S,R)-3 (4- (2-amidino-6-(2-thiophene carboxy)benzothiophene meth hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl anesulfonate); FUT-175 (6-amidino-2-naphthyl p-guanidi ester). In certain instances, the administration of an ISO-1 nobenzoate dimethane-Sulphonate); or combinations thereof. decreases the production of TNF-C. and IL-8. In some In certain instances, Factor Dantagonists inhibit the forma embodiments, the inhibitor and/or antagonist of MIF is 2-(4- tion of the alternative pathway fluid phase C3 convertase by hydroxybenzylidene)amino-3(1H-indol-3-yl)propionic antagonizing Factor D's ability to bind to and cleave Factor B. acid methyl ester. In some embodiments, the inhibitor and/or 04.09 Factor I and Factor I Co-Factors antagonist of MIF is NAPQI (N-acetyl-p-benzoquinone 0410. In some embodiments, a Factor I protease and a imine). In some embodiments, the inhibitor and/orantagonist co-factor thereofare administered to a subject in need thereof. of MIF is AVP-28225 (Avanir Pharmaceuticals). In certain instances, Factor I when bound to a co-factor, 0418 Properdin Antibodies cleaves C3b and/or C4b; thus, inactivating them. The inacti 0419. In some embodiments, an anti-properdinantibody is vation of C4b (iC4b) inhibits the activity of a C3 convertase of administered to a subject in need thereof. In some embodi the classical pathway and thus also inhibits the formation of ments, the anti-properdinantibody is a monoclonal antibody. the classical C5 convertase. Further, the inactivation of C3b In certain instances, an anti-properdin inhibits the stabiliza (iC3b) inhibits the activity of a C3 and C5 convertases of the tion of the alternative pathway unstable C3 convertase alternative pathway. (C3 Bb). In certain instances, an anti-properdin antibody 0411. In some embodiments, a Membrane Cofactor Pro inhibits the formation of the alternative pathway C5 conver tein (MCP OR CD46) is administered to a subject in need tase (C3BbC3). In certain instances, an anti-properdin anti thereof. MCP is a co-factor of Factor I. In some embodiments, body inhibits the formation of MAC. MCP is administered to a subject in need thereof in soluble 0420 Miscellaneous Complement Modulators form (sMCP). In some embodiments, sMCP and/or MCP is 0421. In some embodiments, the complement modulator administered before, after, or simultaneously with Factor I. In is glycyrrhizin, glycyrrhetinic acid, or combinations thereof. US 2010/0021416 A1 Jan. 28, 2010 29

In certain instances, glycyrrhetinic acid modulates C2 and immune system modulating agent in a pharmaceutical com thus modulates the formation of the classical pathway C3 position or device described herein is about 90% by weight of COnVertase. the composition. 0423. In some embodiments, the compositions described Concentration of Active Agent herein have a concentration of active pharmaceutical ingre dient, or pharmaceutically acceptable prodrug or salt thereof, 0422. In some embodiments, the concentration of an otic between about 0.1 to about 70 mg/mL, between about 0.5 structure modulating agent or innate immune system modu mg/mL to about 70 mg/mL, between about 0.5 mg/mL to lating agent in a pharmaceutical composition or device about 50 mg/mL, between about 0.5 mg/mL to about 20 described herein is about 1% by weight of the composition. In mg/mL, between about 1 mg to about 70 mg/mL, between Some embodiments, the concentration of an otic structure about 1 mg to about 50 mg/mL, between about 1 mg/mL and modulating agent or innate immune system modulating agent about 20 mg/mL, between about 1 mg/mL to about 10 in a pharmaceutical composition or device described herein is mg/mL, or between about 1 mg/mL to about 5 mg/mL, of the about 2% by weight of the composition. In some embodi active agent, or pharmaceutically acceptable prodrug or salt ments, the concentration of anotic structure modulating agent thereof, by volume of the composition. or innate immune system modulating agent in a pharmaceu Combination Therapy tical composition or device described herein is about 3% by weight of the composition. In some embodiments, the con 0424. In some embodiments, the formulations disclosed centration of an otic structure modulating agent or innate herein are administered in combination with an additional immune system modulating agent in a pharmaceutical com otic active agent. In some embodiments, the formulations position or device described herein is about 4% by weight of disclosed herein are administered before, during, or after the composition. In some embodiments, the concentration of administration of an additional active agent. In some embodi an otic structure modulating agent or innate immune system ments, the additional otic active agent is an antihistamine, modulating agent in a pharmaceutical composition or device GABA receptor modulator, a neurotransmitter reuptake described herein is about 5% by weight of the composition. In inhibitor, an anticholinergic, a local anesthetic, an inhibitor of Some embodiments, the concentration of an otic structure the MAPK/JNK cascade, a calcium channel blocker, a modulating agent or innate immune system modulating agent Sodium channel blocker, an agonist of HO, an antagonist of a in a pharmaceutical composition or device described herein is caspase, an antagonist of a calpain, a sirtuin agonist, an Src about 10% by weight of the composition. In some embodi antagonist, a carbamate, a gamma-secretase inhibitor, a ments, the concentration of anotic structure modulating agent glutamate receptor modulator, a growth factor, an ototoxic or innate immune system modulating agent in a pharmaceu agent, a thyroid hormone receptor modulator, a TRPV modu tical composition or device described herein is about 15% by lator, an antiemetic agent, an antimicrobial agent, an antisep weight of the composition. In some embodiments, the con tic agent, an antioxidant, a TNF antagonist, a TNF-C. convert centration of an otic structure modulating agent or innate ing enzyme inhibitor, an IKK inhibitor, a calcineurin immune system modulating agent in a pharmaceutical com inhibitor, a toll-like receptor inhibitor, an interleukin inhibi position or device described herein is about 20% by weight of tor, a NOS inhibitor, a platelet activating factor antagonist, or the composition. In some embodiments, the concentration of combinations thereof. an otic structure modulating agent or innate immune system 0425. In certain instances, the otic structure degrading modulating agent in a pharmaceutical composition or device agents and compositions disclosed herein facilitate the pen described herein is about 25% by weight of the composition. etration of anotic active agent into the middle and/or inner ear In some embodiments, the concentration of an otic structure by degrading otic structures (e.g. cells, lipid matrix, extracel modulating agent or innate immune system modulating agent lular matrix, desmosome). In certain instances, a smaller dose in a pharmaceutical composition or device described herein is of the additional active agent is administered to a Subject in about 30% by weight of the composition. In some embodi need thereof when the otic active agent is administered with ments, the concentration of anotic structure modulating agent the otic structure degrading agents and compositions dis or innate immune system modulating agent in a pharmaceu closed herein. In certain instances, an improved pharmacoki tical composition or device described herein is about 40% by netic profile for the otic active agent is obtained when the otic weight of the composition. In some embodiments, the con active agent is administered with the otic structure degrading centration of an otic structure modulating agent or innate agents and compositions disclosed herein. immune system modulating agent in a pharmaceutical com 0426 Anticholinergics position or device described herein is about 50% by weight of 0427 Anticholinergics are optionally used with the for the composition. In some embodiments, the concentration of mulations disclosed herein. Anticholinergics include glyco an otic structure modulating agent or innate immune system pyrrolate, homatropine, Scopolamine or atropine. modulating agent in a pharmaceutical composition or device 0428 Anti-Emetic Agents described herein is about 60% by weight of the composition. 0429 Anti-Emetic agents are optionally used in the for In some embodiments, the concentration of an otic structure mulations disclosed herein. Exemplary anti-emetic agents modulating agent or innate immune system modulating agent include promethazine, prochlorperazine, trimethobenza in a pharmaceutical composition or device described herein is mide, and triethylperazine. Other anti-emetic agents include about 70% by weight of the composition. In some embodi 5HT3 antagonists such as dolasetron, granisetron, ments, the concentration of anotic structure modulating agent ondansetron, tropisetron, and palonosetron; and neuroleptics or innate immune system modulating agent in a pharmaceu Such as droperidol. Further anti-emetic agents include anti tical composition or device described herein is about 80% by histamines, such as meclizine; phenothiazines such as per weight of the composition. In some embodiments, the con phenazine, and thiethyl perazine; dopamine antagonists, centration of an otic structure modulating agent or innate including domperidone, properidol, haloperidol, chlorprom US 2010/0021416 A1 Jan. 28, 2010 30 azine, promethazine, prochlorperazine, metoclopramide and Vir, peramivir, pleconaril, podophyllotoxin, protease inhibi combinations thereof, cannabinoids, including dronabinol, tors, reverse transcriptase inhibitors, ribavirin, rimantadine, nabilone, sativeX, and combinations thereof, anticholin ritonavir, saquinavir, stavudine, tenofovir, tenofovir diso ergics, including Scopolamine; and steroids, including dex proxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, amethasone; trimethobenzamine, emetrol, propofol, musci Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitab mol, and combinations thereof. ine, Zanamivir, Zidovudine, and combinations thereof. 0430 Antihistamines 0436 Antifungal agents may include ammolfine, uten 0431 Antihistamines are optionally used in the formula afine, naftifine, terbinafine, flucytosine, fluconazole, itra tions disclosed herein. Antihistamines include, and are not conazole, ketoconazole, posaconazole, ravuconazole, Vori limited to, meclizine, diphenhydramine, dimenhydrinate, conazole, clotrimazole, econazole, miconazole, oxiconazole, loratadine, quetiapine, mepyramine, piperoxan, antazoline, Sulconazole, terconazole, tioconazole, nikkomycin Z, caspo carbinoxamine, doxylamine, clemastine, pheniramine, chlo fungin, micafungin, anidulafungin, amphotericin B, liposo rphenamine, chlorpheniramine, dexchlorpheniramine, bro mal nystastin, pimaricin, griseofulvin, ciclopiroX olamine, mpheniramine, triprolidine, cyclizine, chlorcyclizine, haloprogin, tolnaftate, undecylenate, and combinations hydroxy Zine, promethazine, alimemazine, trimeprazine, thereof. Antiparasitic agents may include amitraz, amoscan cyproheptadine, azatadine, ketotifen, Oxatomide, betahistine ate, avermectin, carbadox, diethylcarbamizine, dimetrida dihydrochloride. Zole, diminaZene, ivermectin, macrofilaricide, malathion, 0432 Antimicrobial Agents mitaban, oxamniquine, permethrin, praziquantel, prantel 0433 Antimicrobial agents are also contemplated as use pamoate, Selamectin, sodium Stibogluconate, thiabendazole, ful with the formulations disclosed herein. Some examples of and combinations thereof. antimicrobial agents include agents that act to inhibit or eradi 0437. Antioxidants cate microbes, including bacteria, fungi or parasites. Specific 0438 Antioxidants are also contemplated as being useful antimicrobial agents may be used to combat specific with the formulations disclosed herein are agents that modu microbes. Accordingly, a skilled practitioner would know late the degeneration of neurons and/or hair cells of the auris. which antimicrobial agent would be relevant or useful Accordingly, some embodiments incorporate the use of anti depending on the microbe identified, or the symptoms dis oxidants. In some embodiments, the antioxidant is vitamin C, played. Antimicrobial agents include antibiotics, antiviral N-acetylcysteine, vitamin E. Ebselen (2-phenyl-1,2-benzi agents, antifungal agents, and antiparasitic agents. soselenazol-3(2H)-one (also called PZ51 or DR3305), L-me 0434 Antibiotics may also include amikacin, gentamicin, thionine, Idebenone (2-(10-hydroxydecyl)-5,6-dimethoxy-3- kanamycin, neomycin, netilmicin, streptomycin, tobramy methyl-cyclohexa-2,5-diene-1,4-dione). cin, paromomycin, geldanmycin, herbimycin, loracarbef, 0439 Anti-Septic Agents ertapenem, doripenem, imipenem, cilastatin, meropenem, 0440 Anti-septic agents are also contemplated as useful cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefaman with the formulations disclosed herein. Anti-septic agents dole, cefoxitin, defprozil, cefuroxime, cefixime, cefdinir, include, but are not limited to, acetic acid, boric acid, gentian cefditoren, cefoperaZone, cefotaxime, cefpodoxime, ceftazi violet, hydrogen peroxide, carbamide peroxide, chlorhexi dime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefto dine, Saline, mercurochrome, povidone iodine, polyhyroxine biprole, teicoplanin, Vancomycin, azithromycin, clarithro iodine, cresylate and aluminum acetate, and mixtures thereof. mycin, dirithromycin, erythromycin, roXithromycin, 0441 Calcium Channel Blockers troleandomycin, tellithromycin, spectinomycin, aztreonam, 0442 Calcium channel blockers are optionally used with amoxicillin, amplicillin, azlocillin, carbenicillin, cloxacillin, the formulations disclosed herein. Exemplary calcium chan dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, nel blockers include Verapamil, nimodipine, diltiazem, oxacillin, penicillin, piperacillin, ticarcillan, bacitracin, colis omega-conotoxin, GVIA, amlodipine, felodipine, lacidipine, tin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levo mibefradil, NPPB (5-Nitro-2-(3-phenylpropylamino)ben floxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, Zoic Acid), flunarizine, or combinations thereof. trovfloxacin, mafenide, prontosil, Sulfacetamide, Sulfame 0443 Caspase Antagonists thizole, Sulfanimilimde. Sulfsalazine, Sulfsioxazole, trime 0444 Caspase antagonists are optionally used in the for thoprim, demeclocycline, doxycycline, minocycline, oxtetra mulations disclosed herein. Caspase antagonists include, but cycline, tetracycline, arsphenamine, chloramphenicol, are not limited to, Z-VAD-FMK (Benzyloxycarbonyl-Val clindamycin, lincomycin, ethambutol, fosfomycin, fusidic Ala-Asp(OMe)-fluoromethylketone); Z-LEHD-FMK (ben acid, furazolidone, isoniazid, lineZolid, metronidazole, mupi Zyloxycarbonyl-Leu-GlucCMe)-His-Asp(OMe)-fluorom rocin, nitrofurantoin, platensimycin, pyrazinamide, quinus ethylketone); B-D-FMK (boc-aspartyl (Ome)- pristin?dalfopristin, rifampin, tinidazole, and combinations fluoromethylketone); Ac-LEHD-CHO(N-acetyl-Leu-Glu thereof. His-Asp-CHO): Ac-IETD-CHO(N-acetyl-Ile-Glu-Thr-Asp 0435 Antiviral agents may include acyclovir, famciclovir CHO): Z-IETD-FMK (benzyloxycarbonyl-Ile-Glu(OMe)- and Valacyclovir. Other antiviral agents include abacavir, aci Thr-Asp(OMe)-fluoromethylketone); FAM-LEHD-FMK clovir, adfovir, amantadine, amprenavir, arbidol, atazanavir, (benzyloxycarbonyl Leu-Glu-His-Asp-fluoromethyl artipla, brivudine, cidofovir, combivir, edoxudine, efavirenz, ketone); FAM-LETD-FMK (benzyloxycarbonyl Leu-Glu emitricitabine, enfuVirtide, entecavir, fomvirsen, foSam Thr-Asp-fluoromethyl ketone); Q-VD-OPH (Quinoline-Val prenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitab Asp-CH O Ph); or combinations thereof. ine, immunovir, idoxuridine, imiquimod, indinavir, inosine, 0445 Calcineurin Inhibitors integrase inhibitors, interferons, including interferon type III, 0446 Calcineurin inhibitors are optionally used in the for interferon type II, interferon type I, lamivudine, lopinavir, mulations disclosed herein. Some examples of calcineurin loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevi inhibitors include cyclosporine, tacrolimus and pimecroli rapine, nexavir, nucleoside analogues, oseltamivir, penciclo S. US 2010/0021416 A1 Jan. 28, 2010

0447 Calpain Antagonists (2R,4R-4-aminopyrrolidine-2,4-dicarboxylate), (S)- 0448 Calpain antagonists are optionally used with the 3C4HPG ((S)-3-carboxy-4-hydroxyphenylglycine): (S)- formulations disclosed herein. Calpain antagonists include, 4C3HPG ((S)-4-carboxy-3-hydroxyphenylglycine); but are not limited to, leupeptine; PD-150606 (3-(4-Iodophe L-CCG-1 ((2S,1'S,2S)-2-(carboxycyclopropyl)glycine); nyl)-2-mercapto-(Z)-2-propenoic acid); MDL-28170 (Z-Val ACPT-1 ((1S,3R,4S)-1-aminocyclopentane-1,3,4-tricar Phe-CHO); calpeptin; acetyl-calpastatin: MG 132 (N-(phe boxylic acid); L-AP4 (L-(+)-2-Amino-4-phosphonobutyric nylmethoxy)carbonyl-L-leucyl-N-(1S)-1-formyl-3- acid): (S)-3,4-DCPG ((S)-3,4-dicarboxyphenylglycine); methylbutyl-L-leucinamide); MYODUR; BN 82270 (RS)-3,4-DCPG ((RS)-3,4-dicarboxyphenylglycine); (RS)- (Ipsen); BN 2204 (Ipsen); or combinations thereof. 4-phosphonophenylglycine ((RS)PPG); AMN082 (N'-bis 0449 Carbamates (diphenylmethyl)-1,2-ethanediamine dihydrochloride); 0450 Carbamates are optionally used in the formulations DCG-IV ((2S,2R,3R)-2-(2',3'-dicarboxycyclopropyl)gly disclosed herein. Examples of carbamates include 2-phenyl cine); 3,5-Dimethylpyrrole-2,4-dicarboxylic acid 2-propyl 1.2-ethanediol monocarbomates and dicarbamates, deriva ester 4-(12.2-trimethyl-propyl) ester (3,5-dimethyl PPP); tives thereof, and/or combinations thereof. 3,3'-difluorobenzaldazine (DFB), 3,3'-dimlethoxyben 0451) GABA Receptor Modulators Zaldazine (DMeOB), 3,3'-dichlorobenzaldazine (DCB) and 0452 GABA Receptor Modulators are optionally used other allosteric modulators of mGluRs disclosed in Mol. with the formulations disclosed herein. By way of example, Pharmacol. 2003, 64, 731-740; (E)-6-methyl-2-(phenyldiaz GABA Receptor Modulators include alprazolam, bro enyl)pyridin-3-ol (SIB 1757); (E)-2-methyl-6-styrylpyridine mazepam, brotizolam, chlordiazepoxide, clonazepam, clo (SIB 1893): 2-methyl-6-(phenylethynyl)pyridine (MPEP), razepate, diazepam, estazolam, flunitrazepam, flurazepam, 2-methyl-4-((6-methylpyridin-2-yl)ethynyl)thiazole loprazolam, lorazepam, lormetazepam, idazolam, (MTEP): 7-(Hydroxyimino)cyclopropabchromen-1-car nimetazepam, nitrazepam, oxazepam, prazepam, boxylate ethyl ester (CPCCOEt), N-cyclohexyl-3-methyl temazepam, triazolam, furosemide, bumetanide, ethacrynic benzodthiazolo 3.2-aimidazole-2-carboxamide (YM acid, gabapentin, pregabalin, muscimol, or baclofen. 2.98198), tricyclo[3.3.3.1 nonanyl quinoxaline-2- 0453 Gamma-Secretase Inhibitors carboxamide (NPS2390); 6-methoxy-N-(4-methoxyphenyl) 0454 Gamma-Secretase Inhibitors are optionally used in quinazolin-4-amine (LY 456239); mGluR1 antagonists the formulations disclosed herein. Gamma-Secretase Inhibi disclosed in WO2004/058754 and WO2005/009987: 2-(4-(2, tors include, but are not limited to, LY450139 (hydroxy 3-dihydro-1H-inden-2-ylamino)-5,6,7,8-tetrahydroquinazo lvaleryl monobenzocaprolactam), L685458 (1S-benzyl-4R lin-2-ylthio)ethanol: 3-(5-(pyridin-2-yl)-2H-tetrazol-2-yl) 1-1-S-carbamoyl-2-phenethylcarbamoyl)-1S-3- benzonitrile, 2-(2-methoxy-4-(4-(pyridin-2-yl)oxazol-2-yl) methylbutylcarbamoyl-2R-hydroxy-5- phenyl)acetonitrile; 2-(4-(benzodoxazol-2-yl)-2- phenylpentyl)carbamic acid tert-butylester); LY411575 (N- methoxyphenyl)acetonitrile; 6-(3-methoxy-4-(pyridin-2-yl) (2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N'-(7S)- phenyl)imidazo[2.1-bithiazole: (S)-(4-fluorophenyl)(3-(3- 5-methyl-6-oxo-6,7-dihydro-5H-dibenzobidazepin-7yl (4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl) L-alaninamide), MK-0752 (Merck), tarenflurbil, and/or methanone (ADX47273) and/or combinations thereof. BMS-299897 (2-(1R)-1-(4-chlorophenyl)sulfonyl(2,5-di 0457 Growth Factors fluorophenyl)aminoethyl-5-fluorobenzenepropanoic acid). 0458 Growth factors are optionally used in the formula 0455 Glutamate-Receptor Modulators tions disclosed herein. Exemplary growth factors include 0456 Glutamate receptor modulating agents are option brain-derived neurotrophic factor (BDNF), ciliary neu ally used with the formulations disclosed herein. In some rotrophic factor (CNTF), glial cell-line derived neurotrophic embodiments, glutamate receptor modulating agents include factor (GDNF), neurotrophin-3, neurotrophin-4, and/or com CNQX (6-cyano-7-nitroquinoxaline-2,3-dione); NBQX binations thereof. In some embodiments, the growth factor is (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzof duinoxaline-2, a fibroblast growth factor (FGF), an insulin-like growth factor 3-dione); DNQX (6,7-dinitroquinoxaline-2,3-dione); (IGF), an epidermal growth factor (EGF), a platlet-derived kynurenic acid; 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-f growth factor (PGF) and/or agonists thereof. quinoxaline: 1-aminoadamantane, dextromethorphan, dex 0459 HO-1 Agonists trorphan, ibogaine, ketamine, nitrous oxide, phencyclidine, 0460 Agoniosts of HO-1 are optionally used with the riluzole, tiletamine, memantine, dizocilpine, aptiganel, rem formulations disclosed herein. Agonists of HO-1 include, but acimide, 7-chlorokynurenate, DCKA (5,7-dichlorokynurenic are not limited to, piperine, hemin, and/or brazilin. acid), kynurenic acid, 1-aminocyclopropanecarboxylic acid 0461 IKK Inhibitors (ACPC), AP7 (2-amino-7-phosphonoheptanoic acid), APV 0462 IKK inhibitors are optionally used in the formula (R-2-amino-5-phosphonopentanoate), CPPene (3-(R)-2- tions disclosed herein. Examples of IKK inhibitors include carboxypiperazin-4-yl-prop-2-enyl-1-phosphonic acid); SPC-839, PS-1145, BMS-345541, and SC-514. (+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phe 0463 Interleukin Inhibitors nylpiperidino)-1-pro-panol: (1S,2S)-1-(4-hydroxy-3-meth 0464 Interleukins inhibitors are optionally used with the oxyphenyl)-2-(4-hydroxy-4-phenylpiperi-dino)-1-propanol; formulations disclosed herein. In some embodiments, inter (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-)- leukin inhibitors include WS-4 (an antibody against IL-8); chroman-4,7-diol: (1R,2R)-1-(4-hydroxy-3-methylphe Ser IL-8); or Ala IL-8), (See U.S. Pat. No. 5,451.399 nyl)-2-(4-(4-fluoro-phenyl)-4-hydroxypiperidin-1-yl)-pro which is hereby incorporated by reference for disclosures pan-1-ol-mesylate; LY389795 ((-)-2-thia-4-aminobicyclo relating to these peptides); IL-IRA; SB 265610 (N-(2-Bro hexane-4,6-dicarboxylate); LY379268 ((-)-2-oxa-4- mophenyl)-N'-(7-cyano-1H-benzotriazol-4-yl)urea); SB aminobicyclo-hexane-4,6-dicarboxylate); LY354740 ((+)-2- 225002 (N-(2-Bromophenyl)-N'-(2-hydroxy-4-nitrophenyl) aminobicyclo-hexane-2,6dicarboxylate); DCG-IV ((2S,2R, urea); SB203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinyl 3R)-2-(2',3'-dicarboxycyclopropyl)glycine); 2R,4R-APDC phenyl)-5-(4-pyridyl) 1H-imidazole); SB272844 (Glaxo

US 2010/0021416 A1 Jan. 28, 2010 yribose; B-D-1'-5-methyl-nico-tinamide-2'- amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)- deoxyribofuranoside: B-1'-4,5-dimethyl-nicotinamide-2'-de 3-quinolinecarbonitrile); CPG-77675; or combinations oxyribose; O B-D-1'-4,5-dimethyl-nicotinamide-2'- thereof. For disclosure of additional antagonists of the Src deoxyribofuranoside; dipyridamole, ZM 336372 (3- family of kinases, see U.S. Pub. No. 2006/0172971, which is (dimethylamino)-N-3-(4-hydroxybenzoyl)-amino-4-met hereby incorporated by reference for those disclosures. hylphenylbenzamide), camptothecin, coumestrol, nordihy 0483 TACE Inhibitors droguaiaretic acid, esculetin, SRT1720 (Sirtris), SRT-1460 0484 TACE inhibitors are optionally used in the formula (Sirtris), SRT2183 (Sirtris), analogs thereof, or combinations tions disclosed herein. Examples of TACE inhibitors include thereof. Nitroarginine analog A, GW3333, TMI-1, BMS-561392, 0479. Sodium Channel Blockers DPC-3333, TMI-2, BMS-566394, TMI-005, apratastat, 0480 Sodium channel blocking agents are optionally used GW4459, W-3646, IK-682, GI-5402, GI-245402, BB-2983, in the formulations disclosed herein. Sodium channel block DPC-A38088, DPH-067517, R-618, and CH-138. ing agents include, but are not limited to, Vinpocetine ((3a, 0485 Thyroid Hormone Receptor Modulation 16a)-Eburnamenine-14-carboxylic acid ethyl ester); 0486 Thyroid Hormone Receptor modulating agents are sipatrigine (2-(4-Methylpiperazin-1-yl)-5-(2,3,5-trichlo optionally used with the formulations disclosed herein. In rophenyl)-pyrimidin-4-amine); amiloride (3,5-diamino-N- Some instances, Thyroid Hormone Receptor modulating (aminoiminomethyl)-6-chloropyrazinecarbox amide hydro agents include Ts (3.5.3'-triiodo-L-thyronine); KB-141 (3.5- chloride); carbamazepine (5H-dibenzob.fazepine-5- dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic carboxamide); TTX (octahydro-12-(hydroxymethyl)-2- acid); GC-1 (3,5-dimethyl-4-(4-hydroxy-3-isopropylben imino-5,9:7.10a-dimethano-10aH-1.3dioxocino 6.5-d Zyl)-phenoxy acetic acid); GC-24 (3,5-dimethyl-4-(4-hy pyrimidine-4,7,10,11,12-pen tol); RS100642 (1-(2,6- droxy-3'-benzyl)benzylphenoxyacetic acid); sobetirome dimethyl-phenoxy)-2-ethylaminopropane hydrochloride); (QRX-431): 4-OH-PCB106 (4-OH-2',3,3',4',5'-pentachlo mexiletine ((1-(2,6-dimethylphenoxy)-2-aminopropane robiphenyl); MB07811 ((2R,4S)-4-(3-chlorophenyl)-2-(3. hydrochloride)); QX-314 (N-(2,6-Dimethylphenylcarbam 5-dimethyl-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)ime oylmethyl)triethylammonium bromide); phenyloin (5.5- thyl)-2-oxido-1,3,2-dioxaphosphonane); MB07344 (3.5- diphenylimidazolidine-2,4-dione); lamotrigine (6-(2,3- dimethyl-4-(4-hydroxy-3-isopropylbenzyl)phenoxy) dichlorophenyl)-1,2,4-triazine-3,5-diamine); 4030W92 (2,4- methylphosphonic acid); and combinations thereof. In diamino-5-(2,3-dichlorophenyl)-6- certain instances, KB-141; GC-1; sobetirome; and GC-24 are fluoromethylpyrimidine); BW10O3C87 (5-(2,3,5- selective for TRB. trichlorophenyl) pyrimidine-2.4-1.1 ethanesulphonate); 0487. Toll-Like Receptor Inhibitors QX-222 (2-(2,6-dimethylphenyl)amino-N.N.N-trimethyl 0488 Toll-like receptor (TLR) inhibitors are optionally 2-oxoetha niminium chloride); ambroXol (trans-4-(2- used in the formulations disclosed herein. By way of Amino-3,5-dibromophenyl)methylaminocyclo hexanol example, TLR inhibitors include ST2 antibody; sST2-Fc hydrochloride); R56865 (N-1-(4-(4-fluorophenoxy)butyl (functional murine soluble ST2-human IgG1 Fc fusion pro 4-piperidinyl-N-methyl-2-benzo-thiazolamine); lubeluzole; tein; see Biochemical and Biophysical Research Communi ajmaline ((17R.21 alpha)-ajmalan-17,21-diol); procainamide cations, 29 Dec. 2006, vol. 351, no. 4, 940-946 which is (4-amino-N-(2-diethylaminoethyl)benzamide hydrochlo herein incorporated by reference for disclosures related to ride); flecainide; riluzoleor; or combinations thereof. sST2-Fc); CRX-526 (Corixa); lipid IV: RSLA (Rhodo 0481 Src Antagonists bacter sphaeroides lipidA); E5531 (6-O-2-deoxy-6-O-me 0482 SRC antagonists are optionally used with the for thyl-4-O-phosphono-3-O-(R)-3-Z-dodec-5-endoyloxy mulations disclosed herein. Src antagonists are also contem decl-2-3-oxo-tetradecanoylamino-B-O-phosphono-C-D- plated as modulators of bone remodeling in the otic capsule. glucopyranose tetrasodium salt); E5564 (O-D- SRC antagonists include, and are not limited to, 1-Naphthyl Glucopyranose.3-O-decyl-2-deoxy-6-O-2-deoxy-3-O- PP1 (1-(1,1-Dimethylethyl)-3-(1-naphthalenyl)-1H-pyra (3R)-3-methoxydecyl-6-O-methyl-2-(11Z)-1-oxo-11 Zolo 3,4-dipyrimidin-4-amine); Lavendustin A (5-(2,5-Di octadecenylamino-4-O-phosphono-B-D-glucopyranosyl hydroxyphenyl)methyl(2-hydroxyphenyl)methylamino 2-(1,3-dioxotetradecyl)amino-1-(dihydrogen phosphate), 2-hydroxybenzoic acid); MNS (3.4-Methylenedioxy-b- tetrasodium salt); compound 4a (hydrocinnamoyl-L-Valyl nitrostyrene); PP1(1-(1,1-Dimethylethyl)-1-(4- pyrrolidine; see PNAS, Jun. 24, 2003, vol. 100, no. 13, 7971 methylphenyl)-1H-pyrazolo 3,4-dpyrimidin-4-amine); PP2 7976 which is herein incorporated by reference for disclo (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo 3,4- sures related to compound 4a); CPG 52364 (Coley Pharma dpyrimidin-4-amine); KX1-004 (Kinex); KX1-005 (Kinex): ceutical Group); LY294.002 (2-(4-Morpholinyl)-8-phenyl KX1-136 (Kinex); KX1-174 (Kinex); KX1-141 (Kinex): 4H-1-benzopyran-4-one); PD98059 (2-(2-amino-3- KX2-328 (Kinex); KX1-306 (Kinex); KX1-329 (Kinex): methoxyphenyl)-4H-1-Benzopyran-4-one); chloroquine; KX2-391 (Kinex); KX2-377 (Kinex); ZD4190 (Astra Zen and an immune regulatory oligonucleotide (for disclosures eca; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-(1H-1.2. relating to IROs see U.S. Patent Application Publication No. 3-triazol-1-yl)ethoxy)guinazolin-4-amine); AP22408 (Ariad 2008/0089883). Pharmaceuticals); AP23236 (Ariad Pharmaceuticals); 0489 TNF Antagonists AP23451 (Ariad Pharmaceuticals); AP23464 (Ariad Phar 0490 Anti-TNF agents are also contemplated as useful maceuticals); AZD0530 (Astra Zeneca); AZM475271 with the formulations disclosed herein. Anti-TNF agents are (M475271; Astra Zeneca); Dasatinib (N-(2-chloro-6-meth also contemplated as useful in modulation of bone remodel ylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-meth ing in the otic capsule. Anti-TNF agents include, by way of ylpyrimidin-4-ylamino) thiazole-5-carboxamide); GN963 example, etanercept (ENBREL(R), infliximab (REMI (trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)cyclohexanol CADE(R), adalimumab (HUMIRAR), and golimumab sulfate); Bosutinib (4-((2,4-dichloro-5-methoxyphenyl) (CNTO 148), TNF receptors (pegylated soluble TNF receptor US 2010/0021416 A1 Jan. 28, 2010 34 type 1; Amgen); TNF binding factors (Onercept: Serono); 0501 Leukotriene Inhibitors TNF antibodies (US Patent App. No. 2005/0123541; US 0502 Leukotriene inhibitors are optionally used in the Patent App. No. 2004/0185047); single domain antibodies formulations disclosed herein. Leukotriene inhibitors are also against the p55 TNF receptor (US Patent App. No. 2008/ contemplated as modulators of bone remodeling in the otic 0008.8713); solubleTNF receptors (US Patent App. No. 2007/ capsule and include, by way of example, BAYX 1005, mon 0249538): fusion polypeptides binding to TNF (US Patent telukast, Zafirlukast, LY-171,883 (tomelukast), and zileuton. App. No. 2007/0128.177); TNF-converting enzyme inhibitors 0503 Lipoxygenase Inhibitors and Protein Prenylation (Skotnicki et al., Annual Reports in Medicinal Chemistry Inhibitors 0504 Lipoxygenase inhibitors are optionally used in the (2003), 38, 153-162): IKK inhibitors (Karin et al., Nature formulations disclosed herein and are also contemplated as Reviews Drug Discovery (2004), 3, 17-26) and flavone modulators of bone remodeling in the otic capsule. Lipoxy derivatives (US Patent App. No. 2006/0105967), all of which genase inhibitors include, and are not limited to, azelastine; are incorporated by reference for such disclosure. diethylcarbamazine; nordihydroguaiaretic acid; Zileuton; 0491 Estrogen Receptor Modulators A63162; and A-64077. Other protein prenylation inhibitors 0492 Estrogen Receptor Modulators are optionally used are also contemplated as modulators of bone remodeling in in the formulations disclosed herein and are also contem the otic capsule including farnesyl transferase inhibitors plated as modulators of bone remodeling in the otic capsule. R115777 (tipifarnib), BMS-214662, CP-609,754, and Estrogen receptor modulators include, and are not limited to, SCH66336 (lonafarnib). afimoxifene (4-hydroxytamoxifen); arZoxifene; baZedox 0505 RANKL Modulators ifene; clomifene; femarelle (DT56a); lasofoxifene; ormelox 0506 RANKL inhibitors are optionally used in the formu ifene; ospemifine; raloxifene; tamoxifen; GW5638; lations disclosed herein and are contemplated as modulators LY353381; ICI 182,780 (fulvestrant, FASLODEX(R): isofla of bone remodeling in the otic capsule. Exemplary RANKL vones, and SR16234. modulators include denosumab (AMG-162), and SCIO-469. 0493 Bisphosphonates 0507 Aromatase Inhibitors 0494 Bisphosphonates are optionally used in the formu 0508 Aromatase inhibitors are optionally used in the for lations disclosed herein. Bisphosphonates are contemplated mulations disclosed herein and are contemplated as modula as modulators of bone remodeling in the otic capsule. tors of bone remodeling in the otic capsule. Aromatase inhibi Examples of Bisphosphonates include Etidronate tors include, by way of example, 40H androstenedione: (DIDRONELR): Clodronate (BONEFOS(R); Tiluldronate AROMASINR) (exemestane); FEMARAR) (letrozole); and (SKELID(R); Pamidronate (APD, AREDIAR); Neridronate: ARIMIDEX(R) (anastrozole). Olpadronate; Alendronate (FOSFAMAX(R); Ibandronate 0509 COX-2 Inhibitors (BONIVAR); Risedronate (ACTONELR); Zoledronate 0510 COX-2 inhibitors are optionally used in the formu (ZOMETAR). lations disclosed herein and are contemplated as modulators 0495 Carbonic Anhydrase Inhibitors of bone remodeling in the otic capsule. Examples of COX-2 inhibitors include, and are not limited to, celecoxib (CELE 0496 Carbonic anhydrase inhibitors are optionally used in BREX(R), rofecoxib (VIOXX(R), valdecoxib (BEXTRAR): the formulations disclosed herein. Carbonic anhydrase aspirin; ibuprofen, meloxicam and naproxen. inhibitors are also contemplated as modulators of bone 0511) Adenylyl Cyclase (AC) Modulators remodeling in the otic capsule. Exemplary carbonic anhy 0512 AC inhibitors are optionally used in the formula drase inhibitors include Acetazolamide, Brinzolamide, Met tions disclosed herein and are contemplated as modulators of haZolamide, Dorzolamide, Sezolamide, Topiramate, bone remodeling in the otic capsule. AC modulators include MK-927, MK-417, and MK-507. hormones such as parathyroid hormone and analogues 0497 Matrix MetalloProteinase Modulators thereof including the analogues disclosed in U.S. Pat. No. 0498. Matrix metalloproteinase inhibitors are optionally 6,541,450, which is herein incorporated by reference. used in the formulations disclosed herein. Matrix metallopro 0513 Hormones teinase inhibitors are also contemplated as modulators of 0514 Hormones are optionally used in the formulations bone remodeling in the otic capsule. Matrix metalloprotein disclosed herein and are contemplated as modulators of bone ase inhibitors include, and are not limited to, Ro 28-2653; remodeling in the otic capsule. Exemplary hormones include MMI-166; MMI270 (CGS27023A), COL-3 (NSC-683551), parathyroid hormone (PTH) and analogues thereof, vitamin PG-530742, S-3304, and ACZ885. Dandanalogues thereof, calcitonin; growth factors including 0499 Cathepsin K Inhibitors and Protease Inhibitors IL-6, CSF; and estrogen. 0500 Cathepsin K inhibitors are optionally used in the 0515 PPARY Modulators formulations disclosed herein. Cathepsin K inhibitors and 0516 PPAR Y modulators are optionally used in the for other protease inhibitors are also contemplated as modulators mulations disclosed herein and are contemplated as modula of bone remodeling in the otic capsule. Examples of Cathe tors of bone remodeling in the otic capsule. Non-limiting psin K inhibitors include ballicatib, odanacatib (MK-0822), examples of PPARY modulators include rosiglitazone, piogli CRA-013783/L-006235, AAE581, and MK886. Other pro taZone, GW9662, SR-202, ciglitazone, troglitazone, tease inhibitors include, by way of example, Saquinavir GW1929, GW7647 (FORTOVASE(R), INVIRASE(R); Ritonavir (NORVIRR): 0517 RNAi Indinavir (CRIXIVANR); Nelfinavir (VIRACEPTR): 0518. In some embodiments, where inhibition or down Amprenavir (AGENERASE(R); Lopinavir (KALETRAR): regulation of a target is desired (e.g. genes in the MAPK/JNK Atazanavir (REYATAZR); Fosamprenavir (LEXIVAR): cascade, caspase genes, Src genes, calpain genes, Ca" chan Tipranavir (APTIVUSR); Darunavir (PREZISTAR) and cys nel genes), RNA interference may be utilized. In some tatin B. embodiments, the agent that inhibits or down-regulates the US 2010/0021416 A1 Jan. 28, 2010

target is an siRNA molecule. In certain instances, the siRNA molecule. In some embodiments, the vector is a plasmid (e.g., molecule inhibits the transcription of a target by RNA inter pSUPER: pSUPER.neo; pSUPER.neo-gfp). ference (RNAi). In some embodiments, a double stranded 0523. In some embodiments, the vector is incorporated RNA (dsRNA) molecule with sequences complementary to a into a controlled-release auris-acceptable microsphere or target is generated (e.g. by PCR). In some embodiments, a microparticle, hydrogel, liposome, or thermoreversible gel. 20-25bp siRNA molecule with sequences complementary to In Some embodiments, the auris-acceptable microsphere, a target is generated. In some embodiments, the 20-25 bp hydrogel, liposome, paint, foam, in situ forming spongy siRNA molecule has 2-5bp overhangs on the 3' end of each material, nanocapsule or nanosphere or thermoreversible gel strand, and a 5" phosphate terminus and a 3' hydroxyl termi is injected into the inner ear. In some embodiments, the auris nus. In some embodiments, the 20-25bp siRNA molecule has acceptable microsphere or microparticle, hydrogel, lipo bluntends. For techniques for generating RNA sequences see Some, or thermoreversible gel. In some embodiments, the Molecular Cloning: A Laboratory Manual, second edition auris-acceptable microsphere, hydrogel, liposome, paint, (Sambrook et al., 1989) and Molecular Cloning: A Labora foam, in situ forming spongy material, nanocapsule or nano tory Manual, third edition (Sambrook and Russel, 2001), sphere or thermoreversible gel is injected into the cochlea, the jointly referred to herein as “Sambrook”); Current Protocols organ of Corti, the vestibular labyrinth, or a combination in Molecular Biology (F. M. Ausubel et al., eds., 1987, includ thereof. ing supplements through 2001); Current Protocols in Nucleic 0524 Statins Acid Chemistry John Wiley & Sons, Inc., New York, 2000) 0525 Statins (or HMG-CoA reductase inhibitors) are which are hereby incorporated by reference for such disclo optionally used in the formulations disclosed herein and are SU contemplated as modulators of bone remodeling in the otic 0519. In some embodiments, the dsRNA or siRNA mol capsule. Statins include, by way of example, Atorvastatin ecule is incorporated into a controlled-release auris-accept (LIPITORR, TORVASTR): Cerivastatin (LIPOBAYR, BAY able microsphere or microparticle, hydrogel, liposome, or COL(R); Fluvastatin (LESCOLR); Lovastatin (MEVA thermoreversible gel. In some embodiments, the auris-ac CORR), ALTOCORR), ALTOPREVR); Mevastatin; Pitavas ceptable microsphere, hydrogel, liposome, paint, foam, in tatin (LIVALOR), PITAVAR); Pravastatin (PRAVACHOL(R), situ forming spongy material, nanocapsule or nanosphere or SELEKTINER, LIPOSTATR); Rosuvastatin (CRE thermoreversible gel is injected into the inner ear. In some STORR); Simvastatin (ZOCORR); Simvastatin-i-Ezetimibe embodiments, the auris-acceptable microsphere or micropar (VYTORINR); Lovastatin-i-Niacin (ADVICORR) Combina ticle, hydrogel, liposome, or thermoreversible gel. In some tion therapy); Atorvastatin-Amlodipine Besylate (CA embodiments, the auris-acceptable microsphere, hydrogel, DUETR) Combination therapy); Simvastatin-i-Niacin (SIM liposome, paint, foam, in situ forming spongy material, nano COR(R) Combination therapy). capsule or nanosphere orthermoreversible gel is injected into the cochlea, the organ of Corti, the vestibular labyrinth, or a 0526 TRACP Modulators combination thereof. 0527 TRACP modulators are optionally used in the for mulations disclosed herein and are contemplated as modula 0520. In certain instances, after administration of the tors of bone remodeling in the otic capsule. TRACP modula dsRNA or siRNA molecule, cells at the site of administration tors include, by way of example only, cystatin B. (e.g. the cells of cochlea, organ of Corti, and/or the vestibular labyrinth) are transformed with the dsRNA or siRNA mol 0528 TGF B Modulators ecule. In certain instances following transformation, the 0529. TGF B inhibitors are optionally used in the formu dsRNA molecule is cleaved into multiple fragments of about lations disclosed herein and are contemplated as modulators 20-25bp to yield siRNA molecules. In certain instances, the of bone remodeling in the otic capsule. TGF B inhibitors fragments have about 2 bp overhangs on the 3' end of each include, and are not limited to, CAT-192 (Human Anti-TGF Strand. Beta1 Monoclonal Antibody); GC1008 (human anti-trans 0521. In certain instances, an siRNA molecule is divided forming growth factor-beta (TGFB) monoclonal antibody); into two strands (the guide Strand and the anti-guide Strand) and other small molecule modulators of TGF f disclosed in by an RNA-induced Silencing Complex (RISC). In certain Yingling et al., Nature Reviews, 2004, 3, 1011-1022, which is instances, the guide Strand is incorporated into the catalytic incorporated by reference herein. component of the RISC (i.e. argonaute). In certain instances, 0530 TRPV Modulation the guide strand binds to a complementary target mRNA 0531) TRPV modulating agents are optionally used with sequence. In certain instances, the RISC cleaves the target the formulations disclosed herein. Examples of TRPV modu mRNA. In certain instances, the expression of the target gene lating agents include capsaicin, resiniferatoxin, the TRPV is down-regulated. modulators disclosed in US application publications 2005/ 0522. In some embodiments, a sequence complementary 0277643, 2005/0215572, 2006/0194801, 2006/0205773, to a target is ligated into a vector. In some embodiments, the 2006/0194801, 2008/0175794, 2008/0153857, 2008/ sequence is placed between two promoters. In some embodi 0085901, 20080015183, 2006/0030618, 2005/0277646, ments, the promoters are orientated in opposite directions. In 2005/0277631, 2005/0272931, 2005/0227986, 2005/ Some embodiments, the vector is contacted with a cell. In 0153984, 2006/0270682, 2006/0211741, 2006/0205980, and certain instances, a cell is transformed with the vector. In 2006/0100490, and/or combinations thereof. certain instances following transformation, sense and anti 0532. Presented below (Table 1) are examples of active sense Strands of the sequence are generated. In certain agents contemplated for use with the compositions and instances, the sense and anti-sense Strands hybridize to form devices disclosed herein. In some embodiments, one or more a dsRNA molecule which is cleaved into siRNA molecules. In active agents disclosed in Table 1 are used in a composition or certain instances, the strands hybridize to form an siRNA device described herein. US 2010/0021416 A1 Jan. 28, 2010 36

General Methods of Sterilization TABLE 1. 0534 Provided herein are otic compositions that amelio Auris Condition Therapeutic Agent rate or lessen otic disorders described herein. Further pro Benign Paroxysmal Diphenhydramine vided herein, in some embodiments, are methods comprising Positional Vertigo the administration of saidotic compositions. In some embodi Benign Paroxysmal Lorazepam ments, the compositions or devices are sterilized. Included Positional Vertigo within the embodiments disclosed herein are means and pro Benign Paroxysmal Meclizine cesses for sterilization of a pharmaceutical composition or Positional Vertigo Benign Paroxysmal Oldansetron device disclosed herein for use in humans. The goal is to Positional Vertigo provide a safe pharmaceutical product, relatively free of Hearing Loss Estrogen infection causing micro-organisms. The U.S. Food and Drug AIED Etanercept (Enbrel) Administration has provided regulatory guidance in the pub AIED GW3333 AIED Copaxone lication “Guidance for Industry: Sterile Drug Products Pro Hearing Loss Estrogen and duced by Aseptic Processing available at: http://www.fda. progesterone (E+ P) gov/cder/guidance/5882fn1.htm, which is incorporated Hearing Loss Folic acid herein by reference in its entirety. Hearing Loss Lactated Ringer's with 0.03% Ofloxacin 0535. As used herein, “sterilization” means a process used Hearing Loss Methotrexate to destroy or remove microorganisms that are present in a Hearing Loss N-acetyl cysteine product or packaging. Any Suitable method available for ster Meniere's Disease Betahistine ilization of objects and compositions is contemplated for use Meniere's Disease Sildenafil Meniere's Disease Tacrolimus with the compositions and devices disclosed herein. Avail iddle Ear Effusion Pneumonococcal vaccine able methods for the inactivation of microorganisms include, itis Externa Diclofenac sodium; but are not limited to, the application of extreme heat, lethal dexotic chemicals, or gamma radiation. Disclosed herein, in some itis Externa, AL-15469AAL-38905 embodiments, are processes for the preparation of an otic i is Media Amoxicillin clavulanate therapeutic composition comprising Subjecting the composi i is Media Dornase alfa tion to a sterilization method selected from heat sterilization, i is Media Echinacea purpurea chemical sterilization, radiation sterilization or filtration ster i is Media Faropenem medoxomil i is Media Levofloxacin ilization. The method used depends largely upon the nature of i is Media PNCRM9 the device or composition to be sterilized. Detailed descrip i is Media Pneumococcal vaccine tions of many methods of sterilization are given in Chapter 40 i is Media Telithromycin of Remington: The Science and Practice of Pharmacy pub i is Media Zmax i is Media with Lansoprazole lished by Lippincott, Williams & Wilkins, and is incorporated usion by reference with respect to this subject matter. i is Media, Acute AL-15469A; AL-38905 0536 Sterilization by Heat i is Media, Acute Amoxicillin 0537 Many methods are available for sterilization by the i is Media, Acute Amoxicillin-clavulanate i is Media, Acute Azithromycin application of extreme heat. One method is through the use of i is Media, Acute Azithromycin SR a saturated Steam autoclave. In this method, Saturated Steam at i is Media, Acute Cefinir a temperature of at least 121° C. is allowed to contact the i is Media, Acute Hyland's earache drops object to be sterilized. The transfer of heat is either directly to i is Media, Acute Montelukast i is Media, Acute Pneumonococcal vaccine the microorganism, in the case of an object to be sterilized, or i is Media, Acute AL-15469AAL38905 indirectly to the microorganism by heating the bulk of an ith Typanostomy aqueous solution to be sterilized. This method is widely prac bes ticed as it allows flexibility, safety and economy in the ster itis Media, Sulfamethoxazole hronic trimethoprim ilization process. itis Media, Azithromycin 0538. Dry heat sterilization is a method that is used to kill S uppurative microorganisms and perform depyrogenation at elevated O itis Media, Telithromycin temperatures. This process takes place in an apparatus Suit Suppurative able for heating HEPA-filtered microorganism-free air to Otosclerosis Acetylcysteine Ototoxicity Aspirin temperatures of at least 130-180°C. for the sterilization pro Tinnitus Acamprosate cess and to temperatures of at least 230-250° C. for the depy Tinnitus Gabapentin rogenation process. Water to reconstitute concentrated or Tinnitus Modafinil powdered compositions is also sterilized by autoclave. In Tinnitus Neramexane Some embodiments, the compositions described herein com Tinnitus Neramexane meSylate prise micronized pharmaceutical that are sterilized by dry Tinnitus Piribedli heating, e.g., heating for about 7-11 hours at internal powder Tinnitus Vardenafil Tinnitus Vestipitant + Paroxetine temperatures of 130-140° C., or for 1-2 hours at internal Tinnitus Vestiplitant temperatures of 150-180° C. Tinnitus Zinc sulfate 0539 Chemical Sterilization 0540 Chemical sterilization methods are an alternative for products that do not withstand the extremes of heat ster 0533. In some embodiments, the additional therapeutic ilization. In this method, a variety of gases and vapors with agent is an immediate release agent. In some embodiments, germicidal properties, such as ethylene oxide, chlorine diox the additional therapeutic agent is a controlled-release agent. ide, formaldehyde or OZone are used as the anti-apoptotic US 2010/0021416 A1 Jan. 28, 2010 37 agents. The germicidal activity of ethylene oxide, for the sterility of the particle composition is ensured by low example, arises from its ability to serve as a reactive alkylat temperature sterile filtration. In a further embodiment, low ing agent. Thus, the sterilization process requires the ethylene temperature sterile filtration is carried out at a temperature oxide vapors to make direct contact with the product to be between 0 and 30° C., between 0 and 20° C., between 0 and sterilized. 10° C., between 10 and 20° C., or between 20 and 30° C. 0541. Radiation Sterilization 0547. In another embodiment is a process for the prepara 0542. One advantage of radiation sterilization is the ability tion of an auris-acceptable particle composition comprising: to sterilize many types of products without heat degradation filtering the aqueous Solution containing the particle compo or other damage. The radiation commonly employed is beta sition at low temperature through a sterilization filter, lyo radiation or alternatively, gamma radiation from a "Co philizing the sterile solution; and reconstituting the particle Source. The penetrating ability of gamma radiation allows its composition with sterile water prior to administration. In use in the sterilization of many product types, including solu Some embodiments, a composition described herein is manu tions, compositions and heterogeneous mixtures. The germi factured as a Suspension in a single vial composition contain cidal effects of irradiation arise from the interaction of ing the micronized active pharmaceutical ingredient. A single gamma radiation with biological macromolecules. This inter vial composition is prepared by aseptically mixing a sterile action generates charged species and free radicals. Subse poloxamer Solution with sterile micronized active ingredient quent chemical reactions, such as rearrangements and cross (e.g., PD98059) and transferring the composition to sterile linking processes, result in the loss of normal function for pharmaceutical containers. In some embodiments, a single these biological macromolecules. The compositions vial containing a composition described herein as a Suspen described herein are also optionally sterilized using beta irra sion is resuspended before dispensing and/or administration. diation. 0548. In specific embodiments, filtration and/or filling 0543 Filtration procedures are carried out at about 5° C. below the gel tem 0544 Filtration sterilization is a method used to remove perature (T) of a composition described herein and with but not destroy microorganisms from solutions. Membrane viscosity below a theoretical value of 100 cp to allow for filters are used to filter heat-sensitive solutions. Such filters filtration in a reasonable time using a peristaltic pump. are thin, strong, homogenous polymers of mixed cellulosic 0549. In another embodiment the auris-acceptable otic esters (MCE), polyvinylidene fluoride (PVF; also known as therapeutic agent composition comprises a nanoparticle com PVDF), or polytetrafluoroethylene (PTFE) and have pore position wherein the nanoparticle composition is suitable for sizes ranging from 0.1 to 0.22 Lum. Solutions of various char filtration sterilization. In a further embodiment the nanopar acteristics are optionally filtered using different filter mem ticle composition comprises nanoparticles of less than 300 branes. For example, PVF and PTFE membranes are well nm in size, of less than 200 nm in size, or of less than 100 nm. Suited to filtering organic solvents while aqueous solutions in size. In another embodiment the auris-acceptable compo are filtered through PVF or MCE membranes. Filter appara sition comprises a microsphere composition wherein the Ste tus are available for use on many scales ranging from the rility of the microsphere is ensured by sterile filtration of the single point-of-use disposable filter attached to a syringe up precursor organic Solution and aqueous solutions. In another to commercial scale filters for use in manufacturing plants. embodiment the auris-acceptable composition comprises a The membrane filters are sterilized by autoclave or chemical thermoreversible gel composition wherein the sterility of the sterilization. Validation of membrane filtration systems is gel composition is ensured by low temperature sterile filtra performed following standardized protocols (Microbiologi tion. In a further embodiment, the low temperature sterile cal Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3. filtration occurs at a temperature between 0 and 30° C., or Washington, D.C: Health Industry Manufacturers Associa between 0 and 20°C., or between 0 and 10°C., or between 10 tion, 1981) and involve challenging the membrane filter with and 20°C., or between 20 and 30°C. In another embodiment a known quantity (ca. 107 cm) of unusually small microor is a process for the preparation of an auris-acceptable ther ganisms, such as Brevundimonas diminuta (ATCC 19146). moreversible gel composition comprising: filtering the aque 0545 Pharmaceutical compositions are optionally steril ous solution containing the thermoreversible gel components ized by passing through membrane filters. Compositions at low temperature through a sterilization filter, lyophilizing comprising nanoparticles (U.S. Pat. No. 6,139,870) or mul the sterile solution; and reconstituting the thermoreversible tilamellar vesicles (Richard et al., International Journal of gel composition with sterile water prior to administration. Pharmaceutics (2006), 312(1-2): 144-50) are amenable to 0550. In certain embodiments, the active ingredients are sterilization by filtration through 0.22 m filters without dissolved in a suitable vehicle (e.g. a buffer) and sterilized destroying their organized structure. separately (e.g. by heat treatment, filtration, gamma radia 0546. In some embodiments, the methods disclosed herein tion). In some instances, the active ingredients are sterilized comprise sterilizing the composition (or components thereof) separately in a dry state. In some instances, the active ingre by means of filtration sterilization. In another embodiment dients are sterilized as a Suspension or as a colloidal Suspen the auris-acceptable otic therapeutic agent composition com Sion. The remaining excipients (e.g., fluid gel components prises a particle wherein the particle composition is suitable present in auris compositions) are sterilized in a separate step for filtration sterilization. In a further embodiment said par by a suitable method (e.g. filtration and/or irradiation of a ticle composition comprises particles of less than 300 nm in cooled mixture of excipients); the two solutions that are sepa size, of less than 200 nm in size, of less than 100 nm in size. rately sterilized are then mixed aseptically to provide a final In another embodiment the auris-acceptable composition auris composition. In some instances, the final aseptic mixing comprises a particle composition wherein the sterility of the is performed just prior to administration of a composition particle is ensured by sterile filtration of the precursor com described herein. ponent Solutions. In another embodiment the auris-accept 0551. In some instances, conventionally used methods of able composition comprises a particle composition wherein sterilization (e.g., heat treatment (e.g., in an autoclave), US 2010/0021416 A1 Jan. 28, 2010

gamma irradiation, filtration) lead to irreversible degradation growth medium indicates contamination. Drawbacks to this of polymeric components (e.g., thermosetting, gelling or method include the Small sampling size of bulk materials that mucoadhesive polymer components) and/or the active agent reduces sensitivity, and detection of microorganism growth in the composition. In some instances, sterilization of an auris based on a visual observation. An alternative method is mem composition by filtration through membranes (e.g., 0.2 LM brane filtration sterility testing. In this method, a volume of membranes) is not possible if the composition comprises product is passed through a small membrane filter paper. The thixotropic polymers that gel during the process of filtration. filter paper is then placed into media to promote the growth of 0552. Accordingly, provided herein are methods for ster microorganisms. This method has the advantage of greater ilization of auris compositions that prevent degradation of sensitivity as the entire bulk product is sampled. The com polymeric components (e.g., thermosetting and/or gelling mercially available Millipore Steritest sterility testing system and/or mucoadhesive polymer components) and/or the active is optionally used for determinations by membrane filtration agent during the process of sterilization. In some embodi sterility testing. For the filtration testing of creams or oint ments, degradation of the active agent (e.g., any therapeutic ments Steritest filter system No. TLHVSL210 are used. For otic agent described herein) is reduced or eliminated through the filtration testing of emulsions or viscous products Steritest the use of specific pH ranges for buffer components and filter system No. TLAREM210 or TDAREM210 are used. specific proportions of gelling agents in the compositions. In For the filtration testing of pre-filled syringes Steritest filter Some embodiments, the choice of an appropriate gelling system No. TTHASY210 are used. For the filtration testing of agent and/or thermosetting polymer allows for Sterilization of material dispensed as an aerosol or foam Steritest filter sys compositions described herein by filtration. In some embodi tem No. TTHVA210 are used. For the filtration testing of ments, the use of an appropriate thermosetting polymer and soluble powders in ampoules or vials Steritest filter system an appropriate copolymer (e.g., a gelling agent) in combina No. TTHADA210 or TTHADV210 are used. tion with a specific pH range for the composition allows for 0556 Testing for E. coli and Salmonella includes the use high temperature sterilization of compositions described with of lactose broths incubated at 30-35° C. for 24-72 hours, Substantially no degradation of the therapeutic agent or the incubation in MacConkey and/or EMBagars for 18-24 hours, polymeric excipients. An advantage of the methods of steril and/or the use of Rappaport medium. Testing for the detection ization provided herein is that, in certain instances, the com of Paeruginosa includes the use of NAC agar. United States positions are subjected to terminal sterilization via autoclav Pharmacopeia Chapter <62> further enumerates testing pro ing without any loss of the active agent and/or excipients cedures for specified objectionable microorganisms. and/or polymeric components during the sterilization step 0557. In certain embodiments, any controlled-release and are rendered substantially free of microbes and/or pyro composition described herein has less than about 60 colony genS. forming units (CFU), less than about 50 colony forming units, 0553 Microorganisms less than about 40 colony forming units, or less than about 30 0554 Provided herein are auris-acceptable compositions colony forming units of microbial agents per gram of com or devices that ameliorate or lessen otic disorders described position. In certain embodiments, the otic compositions herein. Further provided herein are methods comprising the described herein are formulated to be isotonic with the administration of said otic compositions. In some embodi endolymph and/or the perilymph. ments, the compositions or devices are substantially free of 0558 Endotoxins microorganisms. Acceptable sterility levels are based on 0559 Provided herein are otic compositions that amelio applicable standards that define therapeutically acceptable rate or lessen otic disorders described herein. Further pro otic compositions, including but not limited to United States vided herein are methods comprising the administration of Pharmacopeia Chapters <1111 > et seq. For example, accept said otic compositions. In some embodiments, the composi able sterility levels include about 10 colony forming units tions or devices are substantially free of endotoxins. An addi (cfu) per gram of composition, about 50 cfu per gram of tional aspect of the sterilization process is the removal of composition, about 100 cfu per gram of composition, about by-products from the killing of microorganisms (hereinafter, 500 cfu per gram of composition or about 1000 cfu per gram “Product). The process of depyrogenation removes pyro of composition. In some embodiments, acceptable sterility gens from the sample. Pyrogens are endotoxins or exotoxins levels for compositions include less than 10 cfu/mL, less that that induce an immune response. An example of an endotoxin 50 cfu/mL, less than 500 cfu/mL or less than 1000 cfu/mL is the lipopolysaccharide (LPS) molecule found in the cell microbial agents. In addition, acceptable sterility levels wall of gram-negative bacteria. While sterilization proce include the exclusion of specified objectionable microbio dures such as autoclaving or treatment with ethylene oxide logical agents. By way of example, specified objectionable kill the bacteria, the LPS residue induces a proinflammatory microbiological agents include but are not limited to Escheri immune response, Such as septic shock. Because the molecu chia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa lar size of endotoxins can vary widely, the presence of endot (P. aeruginosa) and/or other specific microbial agents. oxins is expressed in “endotoxin units’ (EU). One EU is 0555 Sterility of the auris-acceptable otic therapeutic equivalent to 100 picograms of E. coli LPS. Humans can agent composition is confirmed through a sterility assurance develop a response to as little as 5 EU/kg of body weight. The program in accordance with United States Pharmacopeia sterility is expressed in any units as recognized in the art. In Chapters <61>, <62> and <71>. A key component of the certain embodiments, otic compositions described herein sterility assurance quality control, quality assurance and Vali contain lower endotoxin levels (e.g. <4 EU/kg of body weight dation process is the method of sterility testing. Sterility of a Subject) when compared to conventionally acceptable testing, by way of example only, is performed by two meth endotoxin levels (e.g., 5 EU/kg of body weight of a subject). ods. The first is direct inoculation wherein a sample of the In some embodiments, the auris-acceptable otic therapeutic composition to be tested is added to growth medium and agent composition has less than about 5 EU/kg of body incubated for a period of time up to 21 days. Turbidity of the weight of a Subject. In other embodiments, the auris-accept US 2010/0021416 A1 Jan. 28, 2010 39 able otic therapeutic agent composition has less than about 4 (1990), 43:578-82). In an additional embodiment, the auris EU/kg of body weight of a subject. In additional embodi acceptable otic therapeutic agent composition is subject to ments, the auris-acceptable otic therapeutic agent composi depyrogenation. In a further embodiment, the process for the tion has less than about 3 EU/kg of body weight of a subject. manufacture of the auris-acceptable otic therapeutic agent In additional embodiments, the auris-acceptable otic thera composition comprises testing the composition for pyroge peutic agent composition has less than about 2 EU/kg of body nicity. In certain embodiments, the compositions described weight of a Subject. herein are Substantially free of pyrogens. 0560. In some embodiments, the auris-acceptable otic therapeutic agent composition or device has less than about 5 pH and Practical Osmolarity EU/kg of composition. In other embodiments, the auris-ac 0563. In some embodiments, an otic composition or ceptable otic therapeutic agent composition has less than device disclosed herein is formulated to provide an ionic about 4 EU/kg of composition. In additional embodiments, balance that is compatible with inner ear fluids (e.g., the auris-acceptable otic therapeutic agent composition has endolymph and/or perilymph). less than about 3 EU/kg of composition. In some embodi 0564. In certain instances, the ionic composition of the ments, the auris-acceptable otic therapeutic agent composi endolymph and perilymph regulate the electrochemical tion has less than about 5 EU/kg Product. In other embodi impulses of hair cells and thus hearing. In certain instances, ments, the auris-acceptable otic therapeutic agent changes in the conduction of electrochemical impulses along composition has less than about 1 EU/kg Product. In addi otic hair cells results in hearing loss. In certain instances, tional embodiments, the auris-acceptable otic therapeutic changes in the ionic balance of the endolymph or perilymph agent composition has less than about 0.2 EU/kg Product. In results in complete hearing loss. In certain instances, changes Some embodiments, the auris-acceptable otic therapeutic in the ionic balance of the endolymph or perilymph results in agent composition has less than about 5 EU/g of unit or partial hearing loss. In certain instances, changes in the ionic Product. In other embodiments, the auris-acceptable otic balance of the endolymph or perilymph results in permanent therapeutic agent composition has less than about 4 EU/g of hearing loss. In certain instances, changes in the ionic balance unit or Product. In additional embodiments, the auris-accept of the endolymph or perilymph results in temporary hearing able otic therapeutic agent composition has less than about 3 loss. EU/g of unit or Product. In some embodiments, the auris 0565. In some embodiments, a composition or device dis acceptable otic therapeutic agent composition has less than closed herein is formulated in order to not disrupt the ionic about 5 EU/mg of unit or Product. In other embodiments, the balance of the endolymph. In some embodiments, a compo auris-acceptable otic therapeutic agent composition has less sition or device disclosed herein has an ionic balance that is than about 4 EU/mg of unit or Product. In additional embodi the same as or Substantially the same as the endolymph. In ments, the auris-acceptable otic therapeutic agent composi Some embodiments, a composition or device disclosed herein tion has less than about 3 EU/mg of unit or Product. In certain does not does not disrupt the ionic balance of the endolymph embodiments, otic compositions described herein contain So as to result in partial or complete hearing loss. In some from about 1 to about 5 EU/mL of composition. In certain embodiments, a composition or device disclosed herein does embodiments, otic compositions described herein contain not does not disrupt the ionic balance of the endolymph so as from about 2 to about 5 EU/mL of composition, from about 3 to result in temporary or permanent hearing loss. to about 5 EU/mL of composition, or from about 4 to about 5 0566 In some embodiments, a composition or device dis EU/mL of composition. closed herein does not substantially disrupt the ionic balance 0561. In certain embodiments, otic compositions or of the perilymph. In some embodiments, a composition or devices described herein contain lower endotoxin levels (e.g. device disclosed herein has an ionic balance that is the same <0.5 EU/mL of composition) when compared to convention as or Substantially the same as the perilymph. In some ally acceptable endotoxin levels (e.g., 0.5 EU/mL of compo embodiments, a composition or device disclosed herein does sition). In some embodiments, the auris-acceptable otic thera not result in partial or complete hearing loss as the composi peutic agent composition or device has less than about 0.5 tion or device does not disrupt the ionic balance of the peri EU/mL of composition. In other embodiments, the auris lymph. In some embodiments, a composition or device dis acceptable otic therapeutic agent composition has less than closed herein does not result in temporary or permanent about 0.4 EU/mL of composition. In additional embodi hearing loss as the composition or device does not disrupt the ments, the auris-acceptable otic therapeutic agent composi ionic balance of the perilymph. tion has less than about 0.2 EU/mL of composition. 0567 As used herein, “practical osmolarity/osmolality” 0562 Pyrogen detection, by way of example only, is per or “deliverable osmolarity/osmolality” means the osmolarity/ formed by several methods. Suitable tests for sterility include osmolality of a composition or device as determined by mea tests described in United States Pharmacopoeia (USP) <71> Suring the osmolarity/oSmolality of the active agent and all Sterility Tests (23rd edition, 1995). The rabbit pyrogen test excipients except the gelling and/or the thickening agent and the Limulus amebocyte lysate test are both specified in the (e.g., polyoxyethylene-polyooxypropylene copolymers, car United States Pharmacopeia Chapters <85> and <151> boxymethylcellulose or the like). The practical osmolarity of (USP23/NF 18, Biological Tests, The United States Pharma a composition or device disclosed herein is measured by a copeial Convention, Rockville, Md., 1995). Alternative pyro Suitable method, e.g., a freezing point depression method as gen assays have been developed based upon the monocyte described in Viegas et al., Int. J. Pharm., 1998, 160, 157-162. activation-cytokine assay. Uniform cell lines suitable for In some instances, the practical osmolarity of a composition quality control applications have been developed and have or device disclosed herein is measured by vapor pressure demonstrated the ability to detect pyrogenicity in Samples oSmometry (e.g., vapor pressure depression method) that that have passed the rabbit pyrogen test and the Limulus allows for determination of the osmolarity of a composition amebocyte lysate test (Taktak et al., J. Pharm. Pharmacol. or device at higher temperatures. In some instances, vapor US 2010/0021416 A1 Jan. 28, 2010 40 pressure depression method allows for determination of the about 8.0. In some embodiments, the pH of a composition osmolarity of a composition or device comprising a gelling described herein is adjusted to a perilymph-Suitable pH range agent (e.g., a thermoreversible polymer) at a higher tempera of about 7.0-7.6. ture wherein the gelling agent is in the form of a gel. 0574. In some embodiments, useful compositions also 0568. In some embodiments, the osmolarity at a target site include one or more pH adjusting agents or buffering agents. of action (e.g., the perilymph) is about the same as the deliv Suitable pH adjusting agents or buffers include, but are not ered osmolarity (i.e., osmolarity of materials that cross or limited to acetate, bicarbonate, ammonium chloride, citrate, penetrate the round window membrane) of a composition or phosphate, pharmaceutically acceptable salts thereof and device described herein. In some embodiments, a composi combinations or mixtures thereof. 0575. In one embodiment, when one or more buffers are tion or device described herein has a deliverable osmolarity of utilized in the compositions of the present disclosure, they are about 150 mOsm/L to about 500 mOsm/L, about 250 combined (e.g., with a pharmaceutically acceptable vehicle) mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about and are present in the final composition (e.g., in an amount 350 mOsm/L, about 280 mOsm/L to about 370 mOsm/L or ranging from about 0.1% to about 20%, from about 0.5% to about 250 mOsm/L to about 320 mOsm/L. about 10%). In certain embodiments of the present disclo 0569. The practical osmolality of an otic composition or Sure, the amount of buffer included in the gel compositions device disclosed herein is from about 100 mOsm/kg to about are an amount Such that the pH of the gel composition does 1000 mOsm/kg, from about 200 mOsm/kg to about 800 not interfere with the body's natural buffering system. mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, 0576. In one embodiment, diluents are also used to stabi or from about 250 mOsm/kg to about 320 mOsm/kg, or from lize compounds because they can provide a more stable envi about 250 mCSm/kg to about 350 mOsm/kg or from about ronment. Salts dissolved in buffered solutions (that also can 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, provide pH control or maintenance) are utilized as diluents in a composition or device described herein has a practical the art, including, but not limited to a phosphate buffered osmolarity of about 100 mOsm/L to about 1000 mOsm/L. saline Solution. about 200 mOsm/L to about 800 mOsm/L, about 250 0577. In some embodiments, any gel composition mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about described herein has a pH that allows for sterilization (e.g., by 350 mOsm/L, about 250 mOsm/L to about 320 mOsm/L, or filtration or aseptic mixing or heat treatment and/or autoclav about 280 mOsm/L to about 320 mOsm/L. ing (e.g., terminal sterilization)) of a gel composition without degradation of the pharmaceutical agent or the polymers 0570. The main cation present in the endolymph is potas comprising the gel. In order to reduce hydrolysis and/or deg sium. In addition the endolymph has a high concentration of radation of the otic agent and/or the gel polymer during ster positively charged amino acids. The main cation present in ilization, the buffer pH is designed to maintain pH of the the perilymph is sodium. In certain instances, the ionic com composition in the 7-8 range during the process of steriliza position of the endolymph and perilymph regulate the elec tion (e.g., high temperature autoclaving). trochemical impulses of hair cells. In certain instances, any 0578. In specific embodiments, any gel composition change in the ionic balance of the endolymph or perilymph described herein has a pH that allows for terminal sterilization results in a loss of hearing due to changes in the conduction of (e.g., by heat treatment and/or autoclaving) of a gel compo electrochemical impulses along otic hair cells. In some sition without degradation of the pharmaceutical agent or the embodiments, a composition disclosed herein does not dis polymers comprising the gel. For example, in order to reduce rupt the ionic balance of the perilymph. In some embodi hydrolysis and/or degradation of the otic agent and/or the gel ments, a composition disclosed herein has an ionic balance polymer during autoclaving, the buffer pH is designed to that is the same as or Substantially the same as the perilymph. maintain pH of the composition in the 7-8 range at elevated In some embodiments, a composition disclosed herein does temperatures. Any appropriate buffer is used depending on not disrupt the ionic balance of the endolymph. In some the otic agent used in the composition. In some instances, embodiments, a composition disclosed herein has an ionic since pKa of TRIS decreases as temperature increases at balance that is the same as or Substantially the same as the approximately -0.03/C. and pKa of PBS increases as tem endolymph. In some embodiments, an otic composition perature increases at approximately 0.003/C., autoclaving at described herein is formulated to provide an ionic balance 250° F (121°C.) results in a significant downward pH shift that is compatible with inner ear fluids (e.g., endolymph (i.e. more acidic) in the TRIS buffer whereas a relatively and/or perilymph). much less upward pH shift in the PBS buffer and therefore 0571. The endolymph and the perilymph have a pH that is much increased hydrolysis and/or degradation of an otic close to the physiological pH of blood. The endolymph has a agent in TRIS than in PBS. Degradation of an otic agent is pH range of about 7.2-7.9; the perilymph has a pH range of reduced by the use of an appropriate combination of a buffer about 7.2-7.4. The in situ pH of the proximal endolymph is and polymeric additives (e.g. P407, CMC) as described about 7.4 while the pH of distal endolymph is about 7.9. herein. 0572. In some embodiments, the pH of a composition 0579. In some embodiments, a composition pH of described herein is adjusted (e.g., by use of a buffer) to an between about 5.0 and about 9.0, between about 5.5 and about endolymph-compatible pH range of about 5.5 to 9.0. In spe 8.5, between about 6.0 and about 7.6, between about 7 and cific embodiments, the pH of a composition described herein about 7.8, between about 7.0 and about 7.6, between about 7.2 is adjusted to a perilymph-suitable pH range of about 5.5 to and 7.6, or between about 7.2 and about 7.4 is suitable for about 9.0. sterilization (e.g., by filtration or aseptic mixing or heat treat 0573. In some embodiments, the pH of a composition ment and/or autoclaving (e.g., terminal sterilization)) of auris described herein is adjusted to a perilymph-Suitable range of compositions described herein. In specific embodiments a about 5.5 to about 8.0, about 6 to about 8.0 or about 6.6 to composition pH of about 6.0, about 6.5, about 7.0, about 7.1, US 2010/0021416 A1 Jan. 28, 2010

about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6 is eversible polymer (e.g., pluronic F127) in any composition Suitable for sterilization (e.g., by filtration or aseptic mixing described herein is about 19% of the total weight of the or heat treatment and/or autoclaving (e.g., terminal steriliza composition. In some embodiments, the amount of thermor tion)) of any composition described herein. eversible polymer (e.g., pluronic F127) in any composition 0580. In some embodiments, the compositions have a pH described herein is about 20% of the total weight of the as described herein, and include a thickening agent (e.g., a composition. In some embodiments, the amount of thermor Viscosity enhancing agent) Such as, by way of non-limiting eversible polymer (e.g., pluronic F127) in any composition example, a cellulose based thickening agent described herein. described herein is about 21% of the total weight of the In some instances, the addition of a secondary polymer (e.g., composition. In some embodiments, the amount of thermor a thickening agent) and a pH of composition as described eversible polymer (e.g., pluronic F127) in any composition herein, allows for sterilization of a composition described described herein is about 23% of the total weight of the herein without any Substantial degradation of the otic agent composition. In some embodiments, the amount of thermor and/or the polymer components in the otic composition. In eversible polymer (e.g., pluronic F127) in any composition some embodiments, the ratio of a thermoreversible polox described herein is about 25% of the total weight of the amer to a thickening agent in a composition that has a pH as composition. described herein, is about 40:1, about 35:1, about 30:1, about 0583. In some embodiments, the amount of thickening 25:1, about 20:1, about 15:1 about 10:1, or about 5:1. For agent (e.g., a gelling agent) in any composition described example, in certain embodiments, a Sustained and/or herein is about 1%, about 5%, about 10%, or about 15% of the extended release composition described herein comprises a total weight of the composition. In some embodiments, the combination of poloxamer 407 (pluronic F127) and car amount of thickening agent (e.g., a gelling agent) in any boxymethylcellulose (CMC) in a ratio of about 40:1, about composition described herein is about 0.5%, about 1%, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 10:1 or about 5:1. 4%, about 4.5%, or about 5% of the total weight of the 0581. In some embodiments, the amount of thermorevers composition. ible polymer in any composition described herein is about 0584. In some embodiments, the pharmaceutical compo 10%, about 15%, about 20%, about 25%, about 30%, about sitions described herein are stable with respect to pH over a 35% or about 40% of the total weight of the composition. In period of any of at least about 1 day, at least about 2 days, at some embodiments, the amount of thermoreversible polymer least about 3 days, at least about 4 days, at least about 5 days, in any composition described herein is about 10%, about at least about 6 days, at least about 1 week, at least about 2 11%, about 12%, about 13%, about 14%, about 15%, about weeks, at least about 3 weeks, at least about 4 weeks, at least 16%, about 17%, about 18%, about 19%, about 20%, about about 5 weeks, at least about 6 weeks, at least about 7 weeks, 21%, about 22%, about 23%, about 24% or about 25% of the at least about 8 weeks, at least about 1 month, at least about 2 total weight of the composition. In some embodiments, the months, at least about 3 months, at least about 4 months, at amount of thermoreversible polymer (e.g., pluronic F127) in least about 5 months, or at least about 6 months. In other any composition described herein is about 7.5% of the total embodiments, the compositions described herein are stable weight of the composition. In some embodiments, the amount with respect to pH over a period of at least about 1 week. Also of thermoreversible polymer (e.g., pluronic F127) in any described herein are compositions that are stable with respect composition described herein is about 10% of the total weight to pH over a period of at least about 1 month. of the composition. 0585 Tonicity Agents 0582. In some embodiments, the amount of thermorevers 0586. In general, the endolymph has a higher osmolality ible polymer (e.g., pluronic F127) in any composition than the perilymph. For example, the endolymph has an described herein is about 11% of the total weight of the osmolality of about 304 mCsm/kg HO while the perilymph composition. In some embodiments, the amount of thermor has an osmolality of about 294 mOsm/kg HO. In certain eversible polymer (e.g., pluronic F127) in any composition embodiments, tonicity agents are added to the compositions described herein is about 12% of the total weight of the described herein in an amount as to provide a practical osmo composition. In some embodiments, the amount of thermor lality of anotic composition of about 100 mOsm/kg to about eversible polymer (e.g., pluronic F127) in any composition 1000 mOsm/kg, from about 200 mOsm/kg to about 800 described herein is about 13% of the total weight of the mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, composition. In some embodiments, the amount of thermor or from about 250 mOsm/kg to about 350 mOsm/kg or from eversible polymer (e.g., pluronic F127) in any composition about 280 mOsm/kg to about 320 mOsm/kg. In some embodi described herein is about 14% of the total weight of the ments, the compositions described herein have a practical composition. In some embodiments, the amount of thermor osmolarity of about 100 mOsm/L to about 1000 mOsm/L. eversible polymer (e.g., pluronic F127) in any composition about 200 mOsm/L to about 800 mOsm/L, about 250 described herein is about 15% of the total weight of the mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about composition. In some embodiments, the amount of thermor 350 mOsm/L, about 280 mOsm/L to about 320 mOsm/L or eversible polymer (e.g., pluronic F127) in any composition about 250 mOsm/L to about 320 mOsm/L. described herein is about 16% of the total weight of the 0587. In some embodiments, the deliverable osmolarity of composition. In some embodiments, the amount of thermor any composition described herein is designed to be isotonic eversible polymer (e.g., pluronic F127) in any composition with the targeted otic structure (e.g., endolymph, perilymph described herein is about 17% of the total weight of the or the like). In specific embodiments, auris compositions composition. In some embodiments, the amount of thermor described herein are formulated to provide a delivered peri eversible polymer (e.g., pluronic F127) in any composition lymph-Suitable osmolarity at the target site of action of about described herein is about 18% of the total weight of the 250 to about 320 mOsm/L (osmolality of about 250 to about composition. In some embodiments, the amount of thermor 320 mOsm/kg HO); and preferably about 270 to about 320 US 2010/0021416 A1 Jan. 28, 2010 42 mOsm/L (osmolality of about 270 to about 320 mOsm/kg ug/mL, between about 1 g/mL and about 250 ug/mL, HO). In specific embodiments, the deliverable osmolarity/ between about 1 lug and about 100 ug/mL, between about 1 osmolality of the compositions (i.e., the osmolarity/oSmola ug/mL and about 50 g/mL, or between about 1 lug/mL and lity of the composition in the absence of gelling or thickening about 20 ug/mL of the active agent by Volume of the compo agents (e.g., thermoreversible gel polymers)) is adjusted, for sition. example, by the use of appropriate salt concentrations (e.g., concentration of potassium or sodium salts) or the use of tonicity agents that renders the compositions endolymph Particle Size compatible and/or perilymph-compatible (i.e. isotonic with 0591 Size reduction is used to increase surface area and/ the endolymph and/or perilymph) upon delivery at the target or modulate composition dissolution properties. It is also site. The osmolarity of a composition comprising a thermor used to maintain a consistent average particle size distribution eversible gel polymer is an unreliable measure due to the (PSD) (e.g., micrometer-sized particles, nanometer-sized association of varying amounts of water with the monomeric particles or the like) for any composition described herein. In units of the polymer. The practical osmolarity of a composi Some embodiments, any composition described herein is tion is a reliable measure and is measured by any Suitable multiparticulate (i.e., comprises a plurality of particle sizes method (e.g., freezing point depression method, vapor (e.g., micronized particles, nano-sized particles, non-sized depression method). In some instances, the compositions particles, colloidal particles)). described herein provide a deliverable osmolarity (e.g., at a 0592. In some embodiments, any composition described target site (e.g., perilymph)) that causes minimal disturbance herein comprises one or more multiparticulate (e.g., micron to the environment of the inner ear and causes minimum ized) therapeutic agents. Micronization is a process of reduc discomfort (e.g., vertigo and/or nausea) to a mammal upon ing the average diameter of particles of a solid material. administration. Micronized particles are from about micrometer-sized in 0588. In some embodiments, any composition described diameter to about nanometer-sized in diameter. In some herein is isotonic with the perilymph and/or endolymph. Iso embodiments, the average diameter of particles in a micron tonic compositions are provided by the addition of a tonicity ized solid is from about 0.5 um to about 500 um. In some agent. Suitable tonicity agents include, but are not limited to embodiments, the average diameter of particles in a micron any pharmaceutically acceptable Sugar, salt or any combina ized solid is from about 1 um to about 200 um. In some tions or mixtures thereof. Such as, but not limited to dextrose, embodiments, the average diameter of particles in a micron glycerin, mannitol, sorbitol, sodium chloride, and other elec ized solid is from about 2 um to about 100 um. In some trolytes. embodiments, the average diameter of particles in a micron 0589 Useful auris compositions include one or more salts ized solid is from about 3 um to about 50 um. In some in an amount required to bring osmolality of the composition embodiments, a particulate micronized solid comprises par into an acceptable range. Such salts include those having ticle sizes of less than about 5 microns, less than about 20 Sodium, potassium or ammonium cations and chloride, cit microns and/or less than about 100 microns. In some embodi rate, ascorbate, borate, phosphate, bicarbonate, Sulfate, thio ments, the use of particulates (e.g., micronized particles) of sulfate orbisulfite anions; suitable salts include sodium chlo an otic structure modulating agent or innate immune system ride, potassium chloride, Sodium thiosulfate, sodium bisulfite modulating agent allows for extended and/or Sustained and ammonium sulfate. release of the otic structure modulating agent or innate 0590. In some embodiments, the compositions described immune system modulating agent from any composition herein have a pH and/or practical osmolarity as described described herein compared to a composition comprising non herein, and have a concentration of active pharmaceutical multiparticulate (e.g., non-micronized) otic structure modu ingredient between about 1 uM and about 10 uM, between lating agent or innate immune system modulating agent. In about 1 mM and about 100 mM, between about 0.1 mM and Some instances, compositions containing multiparticulate about 100 mM, between about 0.1 mM and about 100 nM. In (e.g. micronized) otic structure modulating agent or innate Some embodiments, the compositions described herein have a immune system modulating agent are ejected from a 1 mL pH and/or practical osmolarity as described herein, and have Syringe adapted with a 27G needle without any plugging or a concentration of active pharmaceutical ingredient between clogging. about 0.01%-about 20%, between about 0.01%-about 10%, 0593. In some instances, any particle in any composition between about 0.01%-about 7.5%, between about 0.01%-6%, described herein is a coated particle (e.g., a coated micronized between about 0.01-5%, between about 0.1-about 10%, or particle, nano-particle) and/or a microsphere and/or a liposo between about 0.1-about 6% of the active ingredient by mal particle. Particle size reduction techniques include, by weight of the composition. In some embodiments, the com way of example, grinding, milling (e.g., air-attrition milling positions described herein have a pH and/or practical osmo (jet milling), ball milling), coacervation, complex coacerva larity as described herein, and have a concentration of active tion, high pressure homogenization, spray drying and/or pharmaceutical ingredient between about 0.1 and about 70 Supercritical fluid crystallization. In some instances, particles mg, between about 1 mg and about 70 mg/mL, between about are sized by mechanical impact (e.g., by hammer mills, ball 1 mg and about 50 mg/mL, between about 1 mg/mL and about mill and/or pin mills). In some instances, particles are sized 20 mg/mL, between about 1 mg/mL to about 10 mg/mL, via fluid energy (e.g., by spiral jet mills, loop jet mills, and/or between about 1 mg/mL to about 5 mg/mL, or between about fluidized bedjet mills). In some embodiments, compositions 0.5 mg/mL to about 5 mg/mL of the active agent by volume of described herein comprise crystalline particles and/or isotro the composition. In some embodiments, the compositions pic particles. In some embodiments, compositions described described herein have a pH and/or practical osmolarity as herein comprise amorphous particles and/or anisotropic par described herein, and have a concentration of active pharma ticles. In some embodiments, compositions described herein ceutical ingredient between about 1 g/mL and about 500 comprise therapeutic agent particles wherein the therapeutic US 2010/0021416 A1 Jan. 28, 2010

agent is a neutral molecule, a free acid, a free base, or a salt, Solid, liquid or gel matrices. In some embodiments, the mul or a prodrug of a therapeutic agent, or any combination tiparticulates and/or micronized otic structure modulating thereof. agent or innate immune system modulating agents described 0594. In some embodiments, a composition described herein are delivered to an auris structure (e.g., inner ear) by herein comprises an otic structure modulating agent or innate means of any type of matrix including Solid, liquid or gel immune system modulating agents wherein the otic structure matrices via intratympanic injection. modulating agent or innate immune system modulating agent comprises nanoparticulates. In some embodiments, a compo Pharmaceutical Compositions sition described herein comprises otic structure modulating 0598. Provided herein are pharmaceutical compositions agent or innate immune system modulating agent beads (e.g., or devices that include an otic structure modulating agent or tacrolimus beads) that are optionally coated with controlled innate immune system modulating agent and a pharmaceuti release excipients. In some embodiments, a composition cally acceptable diluent(s), excipient(s), or carrier(s). In some described herein comprises an otic structure modulating embodiments, the pharmaceutical compositions include agent or innate immune system modulating agent that is other medicinal orpharmaceutical agents, carriers, adjuvants, granulated and/or reduced in size and coated with controlled Such as preserving, stabilizing, wetting or emulsifying release excipients; the granulated coated otic structure modu agents, solution promoters, salts for regulating the osmotic lating agent or innate immune system modulating agent par pressure, and/or buffers. In other embodiments, the pharma ticulates are then optionally micronized and/or formulated in ceutical compositions also contain other therapeutic Sub any of the compositions described herein. StanceS. 0595. In some instances, a combination of anotic structure 0599. Some pharmaceutical excipients, diluents or carri modulating agent or innate immune system modulating agent ers are potentially ototoxic. For example, benzalkonium chlo as a neutral molecule, a free acid, a free base and a salt of the ride, a common preservative, is ototoxic and therefore poten otic structure modulating agent or innate immune system tially harmful if introduced into the vestibular or cochlear modulating agent is used to prepare pulsed release otic agent structures. In formulating a controlled-release otic structure compositions using the procedures described herein. In some modulating composition, it is advised to avoid or combine the compositions, a combination of a micronized otic structure appropriate excipients, diluents or carriers to lessen or elimi modulating agent or innate immune system modulating agent nate potential ototoxic components from the composition, or (and/or salt or prodrug thereof) and coated particles (e.g., to decrease the amount of such excipients, diluents or carriers. nanoparticles, liposomes, microspheres) is used to prepare Optionally, a controlled-release otic structure modulating pulsed release otic agent compositions using any procedure composition includes otoprotective agents, such as antioxi described herein. Alternatively, a pulsed release profile is dants, alpha lipoic acid, calcium, fosfomycin or iron chela achieved by solubilizing up to 20% of the delivered dose of tors, to counteract potential ototoxic effects that may arise the otic structure modulating agent or innate immune system from the use of specific therapeutic agents or excipients, modulating agent (e.g., micronized otic structure modulating diluents or carriers. agent or innate immune system modulating agent, a neutral 0600. In some embodiments, the compositions or devices molecule, free base, free acid or salt or prodrug thereof, described herein include a dye to help enhance the visualiza multiparticulate otic structure modulating agent or innate tion of the gel when applied. In some embodiments, dyes that immune system modulating agent, a neutral molecule, a free are compatible with the auris-acceptable compositions or base, free acid or salt or prodrug thereof) with the aid of devices described herein include Evans blue (e.g., 0.5% of the cyclodextrins, surfactants (e.g., poloxamers (407, 338, 188), total weight of an otic composition), Methylene blue (e.g., tween (80, 60, 20, 81), PEG-hydrogenated castor oil, cosol 1% of the total weight of anotic composition), Isosulfan blue vents like N-methyl-2-Pyrrolidone or the like and preparing (e.g., 1% of the total weight of an otic composition), Trypan pulsed release compositions using any procedure described blue (e.g., 0.15% of the total weight of an otic composition), herein. and/or indocyanine green (e.g., 25 mg/vial). Other common 0596. In specific embodiments, any auris-compatible dyes, e.g., FD&C red 40, FD&C red 3, FD&C yellow 5, composition described herein comprises one or more micron FD&C yellow 6, FD&C blue 1, FD&C blue2, FD&C green 3, ized pharmaceutical agents (e.g., otic structure modulating fluorescence dyes (e.g., Fluorescein isothiocyanate, agent or innate immune system modulating agents). In some rhodamine, Alexa Fluors, DyLight Fluors) and/or dyes that of Such embodiments, a micronized pharmaceutical agent are visualizable in conjunction with non-invasive imaging comprises micronized particles, coated (e.g., with an techniques such as MRI, CAT scans, PET scans or the like. extended release coat) micronized particles, or a combination Gadolinium-based MRI dyes, iodine-base dyes, barium thereof. In some of such embodiments, a micronized pharma based dyes or the like are also contemplated for use with any ceutical agent comprising micronized particles, coated otic composition described herein. Other dyes that are com micronized particles, or a combination thereof, comprises an patible with any composition described herein are listed in the otic structure modulating agent or innate immune system Sigma-Aldrich catalog under dyes (that is included herein by modulating agent as a neutral molecule, a free acid, a free reference for such disclosure). base, a salt, a prodrug or any combination thereof. In certain 0601 Any pharmaceutical composition or device embodiments, a pharmaceutical composition described described herein is administered by locating the composition herein comprises an otic structure modulating agent or innate or device in contact with the crista fenestrae cochlea, the immune system modulating agent as a micronized powder. round window, the tympanic cavity, the tympanic membrane, 0597. The multiparticulates and/or micronized otic struc the auris media or the auris externa. ture modulating agent or innate immune system modulating 0602. In one specific embodiment of the auris-acceptable agents described herein are delivered to an auris structure controlled-release otic structure modulating agent or innate (e.g., inner ear) by means of any type of matrix including immune system modulating agent pharmaceutical composi US 2010/0021416 A1 Jan. 28, 2010 44 tions described herein, the otic structure modulating agent or round window membrane via intratympanic injection. In innate immune system modulating agent is provided in a gel other embodiments, the auris gel compositions are adminis matrix, also referred to herein as 'auris acceptable gel com tered on or near the round window or the crista fenestrae positions.” “auris interna-acceptable gel compositions.” cochleae through entry via a post-auricular incision and Sur “auris media-acceptable gel compositions.” “auris externa gical manipulation into or near the round window or the crista acceptable gel compositions', 'auris gel compositions' or fenestrae cochleae area. Alternatively, the auris gel composi variations thereof. All of the components of the gel compo tion is applied via Syringe and needle, wherein the needle is sition must be compatible with the targeted auris structure. inserted through the tympanic membrane and guided to the Further, the gel compositions provide controlled-release of area of the round window or crista fenestrae cochleae. The the otic structure modulating agent or innate immune system auris gel compositions are then deposited on or near the round modulating agent to the desired site within the targeted auris window or crista fenestrae cochleae for localized treatment. structure; in some embodiments, the gel composition also has In other embodiments, the auris gel compositions are applied an immediate or rapid release component for delivery of the via microcatheters implanted into the patient, and in yet fur otic structure modulating agent or innate immune system ther embodiments the compositions are administered via a modulating agent to the desired target site. In other embodi pump device onto or near the round window membrane. In ments, the gel composition has a Sustained release component still further embodiments, the auris gel compositions are for delivery of the otic structure modulating agent or innate applied at or near the round window membrane via a micro immune system modulating agent. In some embodiments, the injection device. In yet other embodiments, the auris gel gel composition comprises a multiparticulate (e.g., micron compositions are applied in the tympanic cavity. In some ized) otic structure modulating agent or innate immune sys embodiments, the auris gel compositions are applied on the tem modulating agent. In some embodiments, the auris gel tympanic membrane. In still other embodiments, the auris gel compositions are biodegradable. In other embodiments, the compositions are applied onto or in the auditory canal. auris gel compositions include a mucoadhesive excipient to 0605. In further specific embodiments, any pharmaceuti allow adhesion to the external mucous layer of the round cal composition or device described herein comprises a mul window membrane. In yet other embodiments, the auris gel tiparticulate otic structure modulating agent or innate compositions include a penetration enhancer excipient; in immune system modulating agent in a liquid matrix (e.g., a further embodiments, the auris gel composition contains a liquid composition for intratympanic injection, orotic drops). Viscosity enhancing agent Sufficient to provide a viscosity of In certain embodiments, any pharmaceutical composition between about 500 and 1,000,000 centipoise, between about described herein comprises a multiparticulate otic structure 750 and 1,000,000 centipoise; between about 1000 and 1,000, modulating agent or innate immune system modulating agent 000 centipoise; between about 1000 and 400,000 centipoise: in a solid matrix. between about 2000 and 100,000 centipoise; between about 3000 and 50,000 centipoise; between about 4000 and 25,000 Controlled-Release Compositions centipoise; between about 5000 and 20,000 centipoise; or 0606. In general, controlled-release drug compositions between about 6000 and 15,000 centipoise. In some embodi impart control over the release of drug with respect to site of ments, the auris gel composition contains a viscosity enhanc release and time of release within the body. As discussed ing agent Sufficient to provide a viscosity of between about herein, controlled-release refers to immediate release, 50,0000 and 1,000,000 centipoise. delayed release, Sustained release, extended release, variable 0603. In other embodiments, the auris interna pharmaceu release, pulsatile release and bi-modal release. Many advan tical compositions described herein further provide an auris tages are offered by controlled-release. First, controlled-re acceptable hydrogel; in yet other embodiments, the auris lease of a pharmaceutical agent allows less frequent dosing pharmaceutical compositions provide an auris-acceptable and thus minimizes repeated treatment. Second, controlled microsphere or microparticle; in still other embodiments, the release treatment results in more efficient drug utilization and auris pharmaceutical compositions provide an auris-accept less of the compound remains as a residue. Third, controlled able liposome. In some embodiments, the auris pharmaceu release offers the possibility of localized drug delivery by tical compositions provide an auris-acceptable foam; in yet placement of a delivery device or composition at the site of other embodiments, the auris pharmaceutical compositions disease. Still further, controlled-release offers the opportunity provide an auris-acceptable paint; in still further embodi to administer and release two or more different drugs, each ments, the auris pharmaceutical compositions provide an having a unique release profile, or to release the same drug at auris-acceptable in situ forming spongy material. In some different rates or for different durations, by means of a single embodiments, the auris pharmaceutical compositions pro dosage unit. vide an auris-acceptable solvent release gel. In some embodi 0607 Accordingly, one aspect of the embodiments dis ments, the auris pharmaceutical compositions provide an closed herein is to provide a controlled-release otic structure actinic radiation curable gel. Further embodiments include a modulating auris-acceptable composition or. The controlled thermoreversible gel in the auris pharmaceutical composi release aspect of the compositions and/or compositions and/ tion, Such that upon preparation of the gel at room tempera or devices disclosed herein is imparted through a variety of ture or below, the composition is a fluid, but upon application agents, including but not limited to excipients, agents or of the gel into or near the auris interna and/or auris media materials that are acceptable for use in the auris interna or target site, including the tympanic cavity, round window otherotic structure. By way of example only, such excipients, membrane or the crista fenestrae cochleae, the auris-pharma agents or materials include an auris-acceptable polymer, an ceutical composition stiffens or hardens into a gel-like Sub auris-acceptable viscosity enhancing agent, an auris-accept Stance. able gel, an auris-acceptable paint, an auris-acceptable foam, 0604. In further or alternative embodiments, the auris gel an auris-acceptable Xerogel, an auris-acceptable microsphere compositions are capable of being administered on or near the or microparticle, an auris-acceptable hydrogel, an auris-ac US 2010/0021416 A1 Jan. 28, 2010 ceptable in situ forming spongy material, an auris-acceptable into aqueous solutions. These polymers have the ability to actinic radiation curable gel, an auris-acceptable solvent change from the liquid state to the gel State attemperatures release gel, an auris-acceptable liposome, an auris-acceptable close to body temperature, therefore allowing useful compo nanocapsule or nanosphere, an auris-acceptable thermor sitions that are applied to the targeted auris structure(s). The eversible gel, or combinations thereof. liquid state-to-gel State phase transition is dependent on the polymer concentration and the ingredients in the Solution. Auris-Acceptable Gels 0612 Poloxamer 407 (PF-127) is a nonionic surfactant 0608 Gels, sometimes referred to as jellies, have been composed of polyoxyethylene-polyoxypropylene copoly defined in various ways. For example, the United States Phar mers. Other poloxamers include 188 (F-68 grade), 237 (F-87 macopoeia defines gels as semisolid systems consisting of grade), 338 (F-108 grade). Aqueous solutions of poloxamers either Suspensions made up of Small inorganic particles or are stable in the presence of acids, alkalis, and metal ions. large organic molecules interpenetrated by a liquid. Gels PF-127 is a commercially available polyoxyethylene-polyox include a single-phase or a two-phase system. A single-phase ypropylene triblock copolymer of general formula E106 P70 gel consists of organic macromolecules distributed uniformly E106, with an average molar mass of 13,000. The polymer throughout a liquid in Such a manner that no apparent bound can be further purified by suitable methods that will enhance aries exist between the dispersed macromolecules and the gelation properties of the polymer. It contains approximately liquid. Some single-phase gels are prepared from Synthetic 70% ethylene oxide, which accounts for its hydrophilicity. It macromolecules (e.g., carbomer) or from natural gums, (e.g., is one of the series of poloxamer ABA block copolymers, tragacanth). In some embodiments, single-phase gels are gen whose members share the chemical formula shown below. erally aqueous, but will also be made using alcohols and oils. Two-phase gels consist of a network of Small discrete par ticles. hydrophilic hydrophilic 0609 Gels can also be classified as being hydrophobic or -N- -- hydrophilic. In certain embodiments, the base of a hydropho bic gel consists of a liquid paraffin with polyethylene or fatty i-to-cis-cis-to-n-cis-to-ch-cis-on oils gelled with colloidal silica, or aluminum or Zinc Soaps. In CH3 contrast, the base of hydrophobic gels usually consists of N-- water, glycerol, or propylene glycol gelled with a suitable hydrophobic gelling agent (e.g., tragacanth, Starch, cellulose derivatives, carboxyvinylpolymers, and magnesium-aluminum silicates). In certain embodiments, the rheology of the compositions or 0613 PF-127 is of particular interest since concentrated devices disclosed herein is pseudo plastic, plastic, thixotro solutions (>20% w/w) of the copolymer are transformed from pic, or dilatant. low viscosity transparent Solutions to solid gels on heating to 0610. In one embodiment the enhanced viscosity auris body temperature. This phenomenon, therefore, Suggests that acceptable composition described herein is not a liquid at when placed in contact with the body, the gel preparation will room temperature. In certain embodiments, the enhanced form a semi-solid structure and a Sustained release depot. Viscosity composition is characterized by a phase transition Furthermore, PF-127 has good solubilizing capacity, low tox between room temperature and body temperature (including icity and is, therefore, considered a good medium for drug an individual with a serious fever, e.g., up to about 42°C.). In delivery systems. some embodiments, the phase transition occurs at 1° C. below 0.614. In an alternative embodiment, the thermogel is a body temperature, at 2°C. below body temperature, at 3° C. PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature below body temperature, at 4°C. below body temperature, at (1997), 388:860-2: Jeong et al. J. Control. Release (2000), 6°C. below body temperature, at 8° C. below body tempera 63:155-63; Jeong et al. Adv. Drug Delivery Rev. (2002), ture, or at 10° C. below body temperature. In some embodi 54:37-51). The polymer exhibits sol-gel behavior over a con ments, the phase transition occurs at about 15° C. below body centration of about 5% w/w to about 40% w/w. Depending on temperature, at about 20° C. below body temperature or at the properties desired, the lactide/glycolide molar ratio in the about 25° C. below body temperature. In specific embodi PLGA copolymer ranges from about 1:1 to about 20:1. The ments, the gelation temperature (Tgel) of a composition resulting copolymers are soluble in water and form a free described herein is about 20°C., about 25°C., or about 30°C. flowing liquid at room temperature, but form a hydrogel at In certain embodiments, the gelation temperature (Tgel) of a body temperature. A commercially available PEG-PLGA composition described herein is about 35°C., or about 40°C. PEG triblock copolymer is RESOMER RGP tiš0106 manu In one embodiment, administration of any composition factured by Boehringer Ingelheim. This material is composed described herein at about body temperature reduces or inhib of a PGLA copolymer of 50:50 poly(DL-lactide-co-gly its vertigo associated with intratympanic administration of collide) and is 10% w/w of PEG and has a molecular weight of otic compositions. Included within the definition of body about 6000. temperature is the body temperature of a healthy individual, 0615 ReGel(R) is a tradename of MacroMed Incorporated or an unhealthy individual, including an individual with a for a class of low molecular weight, biodegradable block fever (up to ~42°C.). In some embodiments, the pharmaceu copolymers having reverse thermal gelation properties as tical compositions or devices described herein are liquids at described in U.S. Pat. Nos. 6,004,573, 6,117,949, 6,201,072, about room temperature and are administered at or about and 6,287,588. It also includes biodegradable polymeric drug room temperature, reducing or ameliorating side effects Such carriers disclosed in pending U.S. patent application Ser. Nos. as, for example, Vertigo. 09/906,041, 09/559,799 and 10/919,603. The biodegradable 0611 Polymers composed of polyoxypropylene and poly drug carrier comprises ABA-type or BAB-type triblock oxyethylene form thermoreversible gels when incorporated copolymers or mixtures thereof, wherein the A-blocks are US 2010/0021416 A1 Jan. 28, 2010 46 relatively hydrophobic and comprise biodegradable polyes thermostatic container at about 0-10°C. in order to dissolve ters or poly(orthoester)s, and the B-blocks are relatively the polymer. The mixture is stirred or shaken to bring about a hydrophilic and comprise polyethylene glycol (PEG), said more rapid dissolution of the thermoreversible gel polymer. copolymers having a hydrophobic content of between 50.1 to The otic structure modulating agent or innate immune system 83% by weight and a hydrophilic content of between 17 to modulating agent and various additives such as buffers, salts, 49.9% by weight, and an overall block copolymer molecular and preservatives are Subsequently added and dissolved. In weight of between 2000 and 8000 Daltons. The drug carriers Some instances the otic structure modulating agent or innate exhibit water solubility at temperatures below normal mam immune system modulating agent and/or other pharmaceuti malian body temperatures and undergo reversible thermal cally active agent is suspended if it is insoluble in water. The gelation to then exist as a gel attemperatures equal to physi pH is modulated by the addition of appropriate buffering ological mammalian body temperatures. The biodegradable, agents. round window membrane mucoadhesive characteris hydrophobic A polymer block comprises a polyester or poly tics are optionally imparted to a thermoreversible gel by (ortho ester), in that the polyester is synthesized from mono incorporation of round window membrane mucoadhesive mers selected from the group consisting of D.L-lactide, carbomers, such as Carbopol R 934P to the composition (Ma D-lactide, L-lactide, D.L-lactic acid, D-lactic acid, L-lactic jithiya et al, AAPS PharmSciTech (2006), 7(3), p. E1; acid, glycolide, glycolic acid, e-caprolactone, e-hydroxyhex EP0551626, both of that is incorporated herein by reference anoic acid, Y-butyrolactone, Y-hydroxybutyric acid, B-Valero for such disclosure). lactone, B-hydroxyvaleric acid, hydroxybutyric acids, malic 0618. In one embodiment are auris-acceptable pharma acid, and copolymers thereof and having an average molecu ceutical gel compositions that do not require the use of an lar weight of between about 600 and 3000 Daltons. The added viscosity enhancing agent. Such gel compositions hydrophilic B-block segment is preferably polyethylene gly incorporate at least one pharmaceutically acceptable buffer. col (PEG) having an average molecular weight of between In one aspect is a gel composition comprising anotic structure about 500 and 2200 Daltons. modulating agent or innate immune system modulating agent 0616. Additional biodegradable thermoplastic polyesters and a pharmaceutically acceptable buffer. In another embodi include AtriGel R (provided by Atrix Laboratories, Inc.) and/ ment, the pharmaceutically acceptable excipient or carrier is or those disclosed, e.g., in U.S. Pat. Nos. 5,324,519; 4.938, a gelling agent. 763; 5,702,716; 5,744, 153; and 5,990, 194; wherein the suit 0619. In other embodiments, useful otic structure modu able biodegradable thermoplastic polyester is disclosed as a lating agent or innate immune system modulating agentauris thermoplastic polymer. Examples of suitable biodegradable acceptable pharmaceutical compositions also include one or thermoplastic polyesters include polylactides, polygly more pH adjusting agents or buffering agents to provide an collides, polycaprolactones, copolymers thereof, terpolymers endolymph or perilymph suitable pH. Suitable pH adjusting thereof, and any combinations thereof. In some such embodi agents or buffers include, but are not limited to acetate, bicar ments, the Suitable biodegradable thermoplastic polyester is a bonate, ammonium chloride, citrate, phosphate, pharmaceu polylactide, a polyglycolide, a copolymer thereof, a terpoly tically acceptable salts thereof and combinations or mixtures mer thereof, or a combination thereof. In one embodiment, thereof. Such pH adjusting agents and buffers are included in the biodegradable thermoplastic polyester is 50/50 poly(DL an amount required to maintain pH of the composition lactide-co-glycolide) having a carboxy terminal group; is between a pH of about 5 and about 9, in one embodiment a pH present in about 30 wt.% to about 40 wt.% of the composi between about 6.5 to about 7.5, and in yet another embodi tion; and has an average molecular weight of about 23,000 to ment at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, about 45,000. Alternatively, in another embodiment, the bio 7.4, 7.5. In one embodiment, when one or more buffers are degradable thermoplastic polyester is 75/25 poly (DL-lac utilized in the compositions of the present disclosure, they are tide-co-glycolide) without a carboxy terminal group; is combined, e.g., with a pharmaceutically acceptable vehicle present in about 40 wt.% to about 50 wt.% of the composi and are present in the final composition, e.g., in an amount tion; and has an average molecular weight of about 15,000 to ranging from about 0.1% to about 20%, from about 0.5% to about 24,000. In further or alternative embodiments, the ter about 10%. In certain embodiments of the present disclosure, minal groups of the poly(DL-lactide-co-glycolide) are either the amount of buffer included in the gel compositions is an hydroxyl, carboxyl, or ester depending upon the method of amount Such that the pH of the gel composition does not polymerization. Polycondensation of lactic or glycolic acid interfere with the natural buffering system of the auris media provides a polymer with terminal hydroxyl and carboxyl or auris interna, or does not interfere with the natural pH of the groups. Ring-opening polymerization of the cyclic lactide or endolymph or perilymph: depending on where in the cochlea glycolide monomers with water, lactic acid, or glycolic acid the otic structure modulating agent or innate immune system provides polymers with the same terminal groups. However, modulating agent composition is targeted. In some embodi ring-opening of the cyclic monomers with a monofunctional ments, from about 10 uM to about 200 mM concentration of alcohol Such as methanol, ethanol, or 1-dodecanol provides a a buffer is present in the gel composition. In certain embodi polymer with one hydroxyl group and one ester terminal ments, from about a 5 mM to about a 200 mM concentration groups. Ring-opening polymerization of the cyclic mono ofa buffer is present. In certain embodiments, from about a 20 mers with a diol Such as 1.6-hexanediol or polyethylene gly mM to about a 100 mM concentration of a buffer is present. In col provides a polymer with only hydroxyl terminal groups. one embodiment is a buffer Such as acetate or citrate at 0617. Since the polymer systems of thermoreversible gels slightly acidic pH. In one embodiment the buffer is a sodium dissolve more completely at reduced temperatures, methods acetate buffer having a pH of about 4.5 to about 6.5. In one of solubilization include adding the required amount of poly embodiment the buffer is a sodium citrate buffer having a pH mer to the amount of water to be used at reduced tempera of about 5.0 to about 8.0, or about 5.5 to about 7.0. tures. Generally after wetting the polymer by shaking, the 0620. In an alternative embodiment, the buffer used is mixture is capped and placed in a cold chamber or in a tris(hydroxymethyl)aminomethane, bicarbonate, carbonate US 2010/0021416 A1 Jan. 28, 2010 47 or phosphate at slightly basic pH. In one embodiment, the 50,000 cP, about 100 cP to about 1,000 cP. about 500 cP to buffer is a sodium bicarbonate buffer having a pH of about 6.5 about 1500 cB, about 1000 cp to about 3000 cP, about 2000 cP to about 8.5, or about 7.0 to about 8.0. In another embodiment to about 8,000 cP, about 4,000 cP to about 50,000 cP. about the buffer is a sodium phosphate dibasic buffer having a pH of 10,000 cP to about 500,000 cP, about 15,000 cp to about about 6.0 to about 9.0. 1,000,000 cp. In other embodiments, when an even more 0621. Also described herein are controlled-release com Viscous medium is desired, the biocompatible gel comprises positions or devices comprising an otic structure modulating at least about 35%, at least about 45%, at least about 55%, at agent or innate immune system modulating agent and a vis least about 65%, at least about 70%, at least about 75%, or cosity enhancing agent. Suitable viscosity-enhancing agents even at least about 80% or so by weight of the otic structure include by way of example only, gelling agents and Suspend modulating agent or innate immune system modulating ing agents. In one embodiment, the enhanced viscosity com agent. In highly concentrated samples, the biocompatible position does not include a buffer. In other embodiments, the enhanced viscosity composition comprises at least about enhanced viscosity composition includes a pharmaceutically 25%, at least about 35%, at least about 45%, at least about acceptable buffer. Sodium chloride or other tonicity agents 55%, at least about 65%, at least about 75%, at least about are optionally used to adjust tonicity, if necessary. 85%, at least about 90% or at least about 95% or more by 0622. By way of example only, the auris-acceptable vis weight of the otic structure modulating agent or innate cosity agent include hydroxypropyl methylcellulose, immune system modulating agent. hydroxyethyl cellulose, polyvinylpyrrolidone, carboxym 0624. In some embodiments, the viscosity of the gelcom ethyl cellulose, polyvinyl alcohol, Sodium chondroitin Sul positions presented herein are measured by any means fate, Sodium hyaluronate. Other viscosity enhancing agents described. For example, in some embodiments, an LVDV-II+ compatible with the targeted auris structure include, but are CP Cone Plate Viscometer and a Cone Spindle CPE-40 is not limited to, acacia (gum arabic), agar, aluminum magne used to calculate the Viscosity of the gel composition sium silicate, sodium alginate, sodium Stearate, bladder described herein. In other embodiments, a Brookfield wrack, bentonite, carbomer, carrageenan, Carbopol. Xanthan, (spindle and cup) viscometer is used to calculate the viscosity cellulose, microcrystalline cellulose (MCC), ceratonia, of the gel composition described herein. In some embodi chitin, carboxymethylated chitosan, chondrus, dextrose, fur ments, the Viscosity ranges referred to herein are measured at cellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose, room temperature. In other embodiments, the Viscosity Sucrose, maltodextrin, mannitol, Sorbitol, honey, maize ranges referred to herein are measured at body temperature Starch, wheat starch, rice starch, potato starch, gelatin, Ster (e.g., at the average body temperature of a healthy human). culia gum, Xanthum gum, gum tragacanth, ethyl cellulose, 0625. In one embodiment, the pharmaceutically accept ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl able enhanced viscosity auris-acceptable composition com cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellu prises an otic structure modulating agent or innate immune lose, hydroxypropyl cellulose, poly(hydroxyethyl methacry system modulating agent and at least one gelling agent. Suit late), oxypolygelatin, pectin, polygeline, povidone, propy able gelling agents for use in preparation of the gel composi lene carbonate, methyl vinyl ether/maleic anhydride tion include, but are not limited to, celluloses, cellulose copolymer (PVM/MA), poly(methoxyethyl methacrylate), derivatives, cellulose ethers (e.g., carboxymethylcellulose, poly(methoxyethoxyethyl methacrylate), hydroxypropyl cel ethylcellulose, hydroxyethylcellulose, hydroxymethylcellu lulose, hydroxypropylmethyl-cellulose (HPMC), sodium lose, hydroxypropylmethylcellulose, hydroxypropylcellu carboxymethyl-cellulose (CMC), silicon dioxide, polyvi lose, methylcellulose), guar gum, Xanthan gum, locust bean nylpyrrolidone (PVP: povidone), Splenda(R) (dextrose, mal gum, alginates (e.g., alginic acid), silicates, starch, traga todextrin and Sucralose) or combinations thereof. In specific canth, carboxyvinyl polymers, carrageenan, paraffin, petro embodiments, the viscosity-enhancing excipient is a combi latum and any combinations or mixtures thereof. In some nation of MCC and CMC. In another embodiment, the vis other embodiments, hydroxypropylmethylcellulose (Metho cosity-enhancing agent is a combination of carboxymethy cel(R) is utilized as the gelling agent. In certain embodiments, lated chitosan, or chitin, and alginate. The combination of the Viscosity enhancing agents described herein are also uti chitin and alginate with the otic structure modulating agent or lized as the gelling agent for the gel compositions presented innate immune system modulating agents disclosed herein herein. acts as a controlled-release composition, restricting the dif 0626. In some embodiments, the otic therapeutic agents fusion of the otic structure modulating agent or innate disclosed herein are dispensed as an auris-acceptable paint. immune system modulating agents from the composition. As used herein, paints (also known as film formers) are solu Moreover, the combination of carboxymethylated chitosan tions comprised of a solvent, a monomer or polymer, an active and alginate is optionally used to assist in increasing the agent, and optionally one or more pharmaceutically-accept permeability of the otic structure modulating agent or innate able excipients. After application to a tissue, the solvent immune system modulating agents through the round win evaporates leaving behind a thin coating comprised of the dow membrane. monomers or polymers, and the active agent. The coating 0623. In some embodiments, is an enhanced viscosity protects active agents and maintains them in an immobilized composition, comprising from about 0.1 mM and about 100 state at the site of application. This decreases the amount of mM of an otic structure modulating agent or innate immune active agent that may be lost and correspondingly increases system modulating agent, a pharmaceutically acceptable vis the amount delivered to the subject. By way of non-limiting cosity agent, and water for injection, the concentration of the example, paints include collodions (e.g. Flexible Collodion, Viscosity agent in the water being sufficient to provide a USP), and solutions comprising saccharide siloxane copoly enhanced Viscosity composition with a final viscosity from mers and a cross-linking agent. Collodions are ethyl ether/ about 100 to about 100,000 cP. In certain embodiments, the ethanol solutions containing pyroxylin (a nitrocellulose). viscosity of the gel is in the range from about 100 to about After application, the ethyl ether?ethanol solution evaporates US 2010/0021416 A1 Jan. 28, 2010 48 leaving behind a thin film of pyroxylin. In solutions compris slightly less viscous, or slightly more fluid auris-acceptable ing saccharide siloxane copolymers, the saccharide siloxane pharmaceutical gel compositions are desired, the biocompat copolymers form the coating after evaporation of the solvent ible gel portion of the composition comprises at least about initiates the cross-linking of the Saccharide siloxane copoly 50% by weight, at least about 60% by weight, at least about mers. For additional disclosures regarding paints, see Rem 70% by weight, or even at least about 80% or 90% by weight ington. The Science and Practice of Pharmacy that is hereby of the compound. All intermediate integers within these incorporated with respect to this Subject matter. The paints ranges are contemplated to fall within the scope of this dis contemplated for use herein, are flexible such that they do not closure, and in Some alternative embodiments, even more interfere with the propagation of pressure waves through the fluid (and consequently less viscous) auris-acceptable gel ear. Further, the paints may be applied as a liquid (i.e. solu compositions are formulated, such as for example, those in tion, Suspension, or emulsion), a semisolid (i.e., a gel, foam, that the gel or matrix component of the mixture comprises not paste, or jelly) or an aerosol. more than about 50% by weight, not more than about 40% by 0627. In some embodiments, the otic therapeutic agents weight, not more than about 30% by weight, or even those disclosed herein are dispensed as a controlled-release foam. than comprise not more than about 15% or about 20% by Examples of suitable foamable carriers for use in the compo weight of the composition. sitions disclosed herein include, but are not limited to, algi nate and derivatives thereof, carboxymethylcellulose and Auris-Acceptable Suspending Agents derivatives thereof, collagen, polysaccharides, including, for example, dextran, dextran derivatives, pectin, starch, modi 0630. In one embodiment, an otic structure modulating fied Starches Such as Starches having additional carboxyl and/ agent or innate immune system modulating agent is included or carboxamide groups and/or having hydrophilic side in a pharmaceutically acceptable enhanced viscosity compo chains, cellulose and derivatives thereof, agar and derivatives sition wherein the composition further comprises at least one thereof. Such as agar Stabilized with polyacrylamide, poly Suspending agent, wherein the Suspending agent assists in ethylene oxides, glycol methacrylates, gelatin, gums such as imparting controlled-release characteristics to the composi Xanthum, guar, karaya, gellan, arabic, tragacanth and locust tion. In some embodiments, Suspending agents also serve to bean gum, or combinations thereof. Also Suitable are the salts increase the Viscosity of the auris-acceptable otic structure of the aforementioned carriers, for example, Sodium alginate. modulating compositions and compositions. The composition optionally further comprises a foaming 0631 Suspending agents include, by way of example only, agent, which promotes the formation of the foam, including a compounds such as polyvinylpyrrolidone, e.g., polyvinylpyr Surfactant or external propellant. Examples of suitable foam rolidone K12, polyvinylpyrrolidone K17, polyvinylpyrroli ing agents include cetrimide, lecithin, Soaps, silicones and the done K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/ like. Commercially available surfactants such as Tween(R) are vinyl acetate copolymer (S630), Sodium also suitable. carboxymethylcellulose, methylcellulose, hydroxypropylm 0628. In some embodiments, other gel compositions are ethylcellulose (hypromellose), hydroxymethylcellulose useful depending upon the particular otic structure modulat acetate stearate, polysorbate-80, hydroxyethylcellulose, ing agent or innate immune system modulating agent, other Sodium alginate, gums, such as, e.g., gum tragacanthandgum pharmaceutical agent or excipients/additives used, and as acacia, guar gum, Xanthans, including Xanthan gum, Sugars, such are considered to fall within the scope of the present cellulosics, such as, e.g., sodium carboxymethylcellulose, disclosure. For example, other commercially-available glyc methylcellulose, sodium carboxymethylcellulose, hydrox erin-based gels, glycerin-derived compounds, conjugated, or ypropylmethylcellulose, hydroxyethylcellulose, polysor crosslinked gels, matrices, hydrogels, and polymers, as well bate-80, Sodium alginate, polyethoxylated Sorbitan monolau as gelatins and their derivatives, alginates, and alginate-based rate, polyethoxylated Sorbitan monolaurate, povidone and the gels, and even various native and synthetic hydrogel and like. In some embodiments, useful aqueous Suspensions also hydrogel-derived compounds are all expected to be useful in contain one or more polymers as Suspending agents. Useful the otic structure modulating compositions described herein. polymers include water-soluble polymers such as cellulosic In some embodiments, auris-acceptable gels include, but are polymers, e.g., hydroxypropyl methylcellulose, and water not limited to, alginate hydrogels SAF(R)-Gel (ConvaTec, insoluble polymers such as cross-linked carboxyl-containing Princeton, N.J.), Duoderm R. Hydroactive Gel (ConvaTec), polymers. Nu-gel(R) (Johnson & Johnson Medical, Arlington,Tex.); Car 0632. In one embodiment, the present disclosure provides rasynR (V) Acemannan Hydrogel (Carrington Laboratories, auris-acceptable gel compositions comprising a therapeuti Inc., Irving, Tex.); glycerin gels Elta R. Hydrogel (Swiss cally effective amount of an otic structure modulating agent American Products, Inc., Dallas, Tex.) and K-YR) Sterile or innate immune system modulating agent in a hydroxyethyl (Johnson & Johnson). In further embodiments, biodegradable cellulose gel. Hydroxyethyl cellulose (HEC) is obtained as a biocompatible gels also represent compounds present in dry powder that is reconstituted in water or an aqueous buffer auris-acceptable compositions disclosed and described solution to give the desired viscosity (generally about 200 cps herein. to about 30,000 cps, corresponding to about 0.2 to about 10% 0629. In some compositions developed for administration HEC). In one embodiment the concentration of HEC is to a mammal, and for compositions formulated for human between about 1% and about 15%, about 1% and about 2%, or administration, the auris-acceptable gel comprises Substan about 1.5% to about 2%. tially all of the weight of the composition. In other embodi 0633. In other embodiments, the auris-acceptable compo ments, the auris-acceptable gel comprises as much as about sitions, including gel compositions and Viscosity-enhanced 98% or about 99% of the composition by weight. This is compositions, further include excipients, other medicinal or desirous when a Substantially non-fluid, or substantially vis pharmaceutical agents, carriers, adjuvants, such as preserv cous composition is needed. In a further embodiment, when ing, stabilizing, wetting or emulsifying agents, Solution pro US 2010/0021416 A1 Jan. 28, 2010 49 moters, salts, solubilizers, an antifoaming agent, an antioxi ing groups, Suitable Surface property for wetting mucus/mu dant, a dispersing agent, a wetting agent, a Surfactant, and cosal tissue surfaces or sufficient flexibility to penetrate the combinations thereof. mucus network. 0638 Round window membrane mucoadhesive agents Auris-Acceptable Actinic Radiation Curable Gel that are used with the auris-acceptable compositions include, 0634. In other embodiments, the gel is an actinic radiation but are not limited to, at least one soluble polyvinylpyrroli curable gel. Such that following administration to or near the done polymer (PVP); a water-swellable, but water-insoluble, targeted auris structure, use of actinic radiation (or light, fibrous, cross-linked carboxy-functional polymer; a including UV light, visible light, or infrared light) the desired crosslinked poly(acrylic acid) (e.g. Carbopol R 947P); a car gel properties are formed. By way of example only, fiber bomer homopolymer, a carbomer copolymer, a hydrophilic optics are used to provide the actinic radiation so as to form polysaccharide gum, maltodextrin, a cross-linked alignate the desired gel properties. In some embodiments, the fiber gum gel, a water-dispersible polycarboxylated vinyl polymer, optics and the gel administration device form a single unit. In at least two particulate components selected from the group other embodiments, the fiber optics and the gel administration consisting of titanium dioxide, silicon dioxide, and clay, or a device are provided separately. mixture thereof. The round window membrane mucoadhe sive agent is optionally used in combination with an auris Auris-Acceptable Solvent Release Gel acceptable viscosity increasing excipient, or used alone to increase the interaction of the composition with the mucosal 0635. In some embodiments, the gel is a solvent release layer targetotic component. In one non-limiting example, the gel Such that the desired gel properties are formed after mucoadhesive agent is maltodextrin and/or an alginate gum. administration to or near the targeted auris structure, which is, When used, the round window membrane mucoadhesive as the solvent in the injected gel composition diffuses out the character imparted to the composition is at a level that is gel, a gel having the desired gel properties is formed. For sufficient to deliver an effective amount of the otic structure example, a composition that comprises Sucrose acetate isobu modulating agent or innate immune system modulating agent tyrate, a pharmaceutically acceptable solvent, one or more composition to, for example, the mucosal layer of round additives, and the otic structure modulating agent or innate window membrane or the crista fenestrae cochleae in an immune system modulating agent is administered at or near amount that coats the mucosal membrane, and thereafter the round window membrane: diffusion of the solvent out of deliver the composition to the affected areas, including by the injected composition provides a depot having the desired way of example only, the vestibular and/or cochlear structures gel properties. For example, use of a water soluble solvent of the auris interna. When used, the mucoadhesive character provides a high viscosity depot when the solvent diffuses istics of the compositions provided herein are determined, rapidly out of the injected composition. On the other hand, and using this information (along with the other teachings use of a hydrophobic solvent (e.g., benzylbenzoate) provides provided herein), the appropriate amounts are determined. a less viscous depot. One example of an auris-acceptable One method for determining Sufficient mucoadhesiveness solvent release gel composition is the SABERTM Delivery includes monitoring changes in the interaction of the compo System marketed by DURECT Corporation. sition with a mucosal layer, including but not limited to mea Suring changes in residence or retention time of the compo Auris-Acceptable In Situ Forming Spongy Material sition in the absence and presence of the mucoadhesive 0636. Also contemplated within the scope of the embodi excipient. ments is the use of a spongy material, formed in situ in the 0639. Mucoadhesive agents have been described, for auris interna or auris media. In some embodiments, the example, in U.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028, spongy material is formed from hyaluronic acid or its deriva 6,348,502, 6,319,513, 6,306,789, 5,814,330, and 4,900,552, tives. The spongy material is impregnated with a desired otic each of that is hereby incorporated by reference for such structure modulating agent or innate immune system modu disclosure. lating agent and placed within the auris media So as to provide 0640. In another non-limiting example, a mucoadhesive controlled-release of the otic structure modulating agent or agent is, for example, at least two particulate components innate immune system modulating agent within the auris selected from titanium dioxide, silicon dioxide, and clay, media, or in contact with the round window membrane so as wherein the composition is not further diluted with any liquid to provide controlled-release of the otic structure modulating prior to administration and the level of silicon dioxide, if agent or innate immune system modulating agent into the present, is from about 3% to about 15%, by weight of the auris interna. In some embodiments, the spongy material is composition. Silicon dioxide, if present, includes fumed sili biodegradable. con dioxide, precipitated silicon dioxide, coacervated silicon dioxide, gel silicon dioxide, and mixtures thereof. Clay, if Round Window Membrane Mucoadhesives present, includes kaolin minerals, serpentine minerals, Smec 0637 Also contemplated within the scope of the embodi tites, illite or a mixture thereof. For example, clay includes ments is the addition of a round window membrane mucoad laponite, bentonite, hectorite, Saponite, montmorillonites or a hesive with the otic structure modulating compositions and mixture thereof. devices disclosed herein. The term mucoadhesion is used 0641. In one non-limiting example, the round window for materials that bind to the mucin layer of a biological membrane mucoadhesive agent is maltodextrin. Maltodex membrane, such as the external membrane of the 3-layered trin is a carbohydrate produced by the hydrolysis of starch round window membrane. To serve as round window mem that is optionally derived from corn, potato, wheat or other brane mucoadhesive polymers, the polymers possess some plant products. Maltodextrin is optionally used either alone or general physiochemical features Such as predominantly in combination with other round window membrane mucoad anionic hydrophilicity with numerous hydrogen bond form hesive agents to impart mucoadhesive characteristics on the US 2010/0021416 A1 Jan. 28, 2010 50 compositions disclosed herein. In one embodiment, a combi glycoside wherein the alkylglycoside comprises 90%, 91%, nation of maltodextrin and a carbopol polymer are used to 92%, 93%, 94%, 95%, 96%,97%.98%, 99%, 99.1%, 99.5%, increase the round window membrane mucoadhesive charac or 99.9% of the Banomer. teristics of the compositions or devices disclosed herein. 0642. In another embodiment, the round window mem Auris-Acceptable Controlled-Release Particles brane mucoadhesive agent is an alkyl-glycoside and/or a sac 0644 Otic structure modulating agent or innate immune charide alkyl ester. As used herein, an “alkyl-glycoside' system modulating agents and/or other pharmaceutical means a compound comprising any hydrophilic saccharide agents disclosed herein are optionally incorporated within (e.g. Sucrose, maltose, or glucose) linked to a hydrophobic controlled-release particles, lipid complexes, liposomes, alkyl. In some embodiments, the round window membrane nanoparticles, microparticles, microspheres, coacervates, mucoadhesive agent is an alkyl-glycoside wherein the alkyl nanocapsules or other agents that enhance or facilitate the glycoside comprises a Sugar linked to a hydrophobic alkyl localized delivery of the otic structure modulating agent or (e.g., an alkyl comprising about 6 to about 25 carbon atoms) innate immune system modulating agent. In some embodi by an amide linkage, an amine linkage, a carbamate linkage, ments, a single enhanced viscosity composition is used, in that an otic structure modulating agent or innate immune an ether linkage, a thioether linkage, an ester linkage, a system modulating agent is present, while in other embodi thioester linkage, a glycosidic linkage, a thioglycosidic link ments, a pharmaceutical composition that comprises a mix age, and/or aureidelinkage. In some embodiments, the round ture of two or more distinct enhanced Viscosity compositions window membrane mucoadhesive agent is a hexyl-, heptyl-, is used, in that an otic structure modulating agent or innate octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetrade immune system modulating agent is present. In some cyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl C- or embodiments, combinations of Sols, gels and/or biocompat B-D-maltoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, unde ible matrices is also employed to provide desirable character cyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, istics of the controlled-release otic structure modulating com heptadecyl-, and octadecyl C- or B-D-glucoside; hexyl-, hep positions or compositions. In certain embodiments, the tyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tet controlled-release otic structure modulating compositions or radecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl compositions are cross-linked by one or more agents to alter C- or B-D-Sucroside; hexyl-, heptyl-, octyl-, dodecyl-, tride or improve the properties of the composition. cyl-, and tetradecyl-3-D-thiomaltoside; heptyl- or octyl-1- 0645 Examples of microspheres relevant to the pharma thio-Cl- or B-D-glucopyranoside; alkyl thiosucroses; alkyl ceutical compositions disclosed herein include: Luzzi, L.A., maltotriosides; long chain aliphatic carbonic acid amides of J. Pharm. Psy. 59:1367 (1970); U.S. Pat. No. 4,530,840: Sucrose B-amino-alkyl ethers; derivatives of palatinose or Lewis, D. H., “Controlled-release of Bioactive Agents from isomaltamine linked by an amide linkage to an alkyl chain Lactides/Glycolide Polymers' in Biodegradable Polymers as and derivatives of isomaltamine linked by urea to an alkyl Drug Delivery Systems, Chasin, M. and Langer, R., eds., chain; long chain aliphatic carbonic acid ureides of Sucrose Marcel Decker (1990); U.S. Pat. No. 4,675, 189; Becket al., B-amino-alkyl ethers and long chain aliphatic carbonic acid “Poly(lactic acid) and Poly(lactic acid-co-glycolic acid) Con amides of Sucrose B-amino-alkyl ethers. In some embodi traceptive Delivery Systems.” in Long Acting Steroid Con ments, the round window membrane mucoadhesive agent is traception, Mishell, D. R., ed., Raven Press (1983); U.S. Pat. an alkyl-glycoside wherein the alkyl glycoside is maltose, No. 4,758,435; U.S. Pat. No. 3,773,919; U.S. Pat. No. 4,474, Sucrose, glucose, or a combination thereoflinked by a glyco 572. Examples of protein therapeutics formulated as micro sidic linkage to an alkyl chain of 9-16 carbon atoms (e.g., spheres include: U.S. Pat. No. 6,458.387: U.S. Pat. No. 6,268, nonyl-, decyl-, dodecyl- and tetradecyl Sucroside; nonyl-, 053: U.S. Pat. No. 6,090,925: U.S. Pat. No. 5,981,719; and decyl-, dodecyl- and tetradecylglucoside; and nonyl-, decyl-, U.S. Pat. No. 5,578,709, and are herein incorporated by ref dodecyl- and tetradecyl maltoside). In some embodiments, erence for Such disclosure. the round window membrane mucoadhesive agent is an alkyl 0646 Microspheres usually have a spherical shape, glycoside wherein the alkyl glycoside is dodecylmaltoside, although irregularly-shaped microparticles are possible. tridecylmaltoside, and tetradecylmaltoside. Microspheres may vary in size, ranging from Submicron to 0643. In some embodiments, the round window mem 1000 micron diameters. Microspheres suitable for use with brane mucoadhesive agent is an alkyl-glycoside wherein the the auris-acceptable compositions disclosed herein are Sub alkyl-glycoside is a disaccharide with at least one glucose. In micron to 250 micron diameter microspheres, allowing Some embodiments, the auris acceptable penetration administration by injection with a standard gauge needle. The enhancer is a Surfactant comprising C-D-glucopyranosyl-B- auris-acceptable microspheres are prepared by any method glycopyranoside, n-Dodecyl-4-O-O-D-glucopyranosyl-B- that produces microspheres in a size range acceptable for use glycopyranoside, and/or n-tetradecyl-4-O-O-D-glucopyra in an injectable composition. Injection is optionally accom nosyl-3-glycopyranoside. In some embodiments, the round plished with standard gauge needles used for administering window membrane mucoadhesive agent is an alkyl-glycoside liquid compositions. wherein the alkyl-glycoside has a critical miscelle concentra 0647 Suitable examples of polymeric matrix materials for tion (CMC) of less than about 1 mM in pure water or in use in the auris-acceptable controlled-release particles herein aqueous Solutions. In some embodiments, the round window include poly(glycolic acid), poly-d. 1-lactic acid, poly-1-lac membrane mucoadhesive agent is an alkyl-glycoside wherein tic acid, copolymers of the foregoing, poly(aliphatic carboxy an oxygenatom within the alkyl-glycoside is Substituted with lic acids), copolyoxalates, polycaprolactone, polydioxonene, a Sulfur atom. In some embodiments, the round window poly(orthocarbonates), poly(acetals), poly(lactic acid-capro membrane mucoadhesive agent is an alkyl-glycoside wherein lactone), polyorthoesters, poly(glycolic acid-caprolactone), the alkylglycoside is the Banomer. In some embodiments, the polydioxonene, polyanhydrides, polyphosphazines, and round window membrane mucoadhesive agent is an alkyl natural polymers including albumin, casein, and some waxes, US 2010/0021416 A1 Jan. 28, 2010

Such as, glycerol mono- and distearate, and the like. Various particles have also been used in protein therapeutic compo commercially available poly (lactide-co-glycolide) materials sitions (Naha et al. Journal of Microencapsulation 4 Feb., (PLGA) are optionally used in the method disclosed herein. 2008 (online publication)). In one embodiment, the enhanced For example, poly (d.1-lactic-co-glycolic acid) is commer Viscosity auris-acceptable compositions described herein cially available from Boehringer-Ingelheim as RESOMER comprises otic structure modulating microspheres wherein RG 503H. This product has a mole percent composition of the microspheres are formed from a methacrylate polymer or 50% lactide and 50% glycolide. These copolymers are avail copolymer. In an additional embodiment, the enhanced vis able in a wide range of molecular weights and ratios of lactic cosity composition described herein comprises otic structure acid to glycolic acid. One embodiment includes the use of the modulating microspheres wherein the microspheres are polymer poly(d.1-lactide-co-glycolide). The molar ratio of mucoadhesive. Other controlled-release systems, including lactide to glycolide in Such a copolymer includes the range of incorporation or deposit of polymeric materials or matrices from about 95.5 to about 50:50. onto Solid or hollow spheres containing otic structure modu 0648. The molecular weight of the polymeric matrix mate lating agent or innate immune system modulating agents, are rial is of some importance. The molecular weight should be also explicitly contemplated within the embodiments dis high enough so that it forms satisfactory polymer coatings, closed herein. The types of controlled-release systems avail i.e., the polymer should be a good film former. Usually, a able without significantly losing activity of the otic structure satisfactory molecular weight is in the range of 5,000 to modulating agent or innate immune system modulating agent 500,000 Daltons. The molecular weight of a polymer is also are determined using the teachings, examples, and principles important from the point of view that molecular weight influ disclosed herein ences the biodegradation rate of the polymer. For a diffusional 0651. An example of a conventional microencapsulation mechanism of drug release, the polymer should remain intact process for pharmaceutical preparations is shown in U.S. Pat. until all of the drug is released from the microparticles and No. 3,737,337, incorporated herein by reference for such then degrade. The drug is also released from the micropar disclosure. The otic structure modulating Substances to be ticles as the polymeric excipient bioerodes. By an appropriate encapsulated or embedded are dissolved or dispersed in the selection of polymeric materials a microsphere composition organic solution of the polymer (phase A), using conventional is made such that the resulting microspheres exhibit both mixers, including (in the preparation of dispersion) vibrators diffusional release and biodegradation release properties. and high-speed stirrers, etc. The dispersion of phase (A), This is useful in affording multiphasic release patterns. containing the core material in Solution or in Suspension, is 0649. A variety of methods are known by that compounds carried out in the aqueous phase (B), again using conventional are encapsulated in microspheres. In these methods, the otic mixers, such as high-speed mixers, vibration mixers, or even structure modulating agent or innate immune system modu spray noZZles, in that case the particle size of the micro lating agent is generally dispersed or emulsified, using stir spheres will be determined not only by the concentration of rers, agitators, or other dynamic mixing techniques, in a sol phase (A), but also by the emulsate or microsphere size. With vent containing a wall-forming material. Solvent is then conventional techniques for the microencapsulation of anotic removed from the microspheres, and thereafter the micro structure modulating agent or innate immune system modu sphere product is obtained. lating agents, the microspheres form when the solvent con 0650. In one embodiment, controlled-release otic struc taining an active agent and a polymer is emulsified or dis ture modulating compositions are made through the incorpo persed in an immiscible solution by stirring, agitating, ration of the otic structure modulating agent or innate vibrating, or some other dynamic mixing technique, often for immune system modulating agents and/or other pharmaceu a relatively long period of time. tical agents into ethylene-vinyl acetate copolymer matrices. 0652 Methods for the construction of microspheres are (See U.S. Pat. No. 6,083,534, incorporated herein for such also described in U.S. Pat. No. 4,389,330, and U.S. Pat. No. disclosure). In another embodiment, otic structure modulat 4,530,840, incorporated herein by reference for such disclo ing agent or innate immune system modulating agents are Sure. The desired otic structure modulating agent or innate incorporated into poly (lactic-glycolic acid) or poly-L-lactic immune system modulating agent is dissolved or dispersed in acid microspheres. Id. In yet another embodiment, the otic an appropriate solvent. To the agent-containing medium is structure modulating agent or innate immune system modu added the polymeric matrix material in an amount relative to lating agents are encapsulated into alginate microspheres. the active ingredient that gives a product of the desired load (See U.S. Pat. No. 6,036.978, incorporated herein for such ing of active agent. Optionally, all of the ingredients of the disclosure). Biocompatible methacrylate-based polymers to otic structure modulating microsphere product can be encapsulate the otic structure modulating compounds or com blended in the solvent medium together. Suitable solvents for positions are optionally used in the compositions and meth the agent and the polymeric matrix material include organic ods disclosed herein. A wide range of methacrylate-based Solvents such as acetone, halogenated hydrocarbons such as polymer Systems are commercially available. Such as the chloroform, methylene chloride and the like, aromatic hydro EUDRAGIT polymers marketed by Evonik. One useful carbon compounds, halogenated aromatic hydrocarbon com aspect of methacrylate polymers is that the properties of the pounds, cyclic ethers, alcohols, ethyl acetate and the like. composition are varied by incorporating various co-poly 0653. The mixture of ingredients in the solvent is emulsi mers. For example, poly(acrylic acid-co-methylmethacry fied in a continuous-phase processing medium; the continu late) microparticles exhibit enhanced mucoadhesion proper ous-phase medium being such that a dispersion of microdrop ties as the carboxylic acid groups in the poly(acrylic acid) lets containing the indicated ingredients is formed in the form hydrogen bonds with mucin (Park et al., Pharm. Res. continuous-phase medium. Naturally, the continuous-phase (1987) 4(6):457-464). Variation of the ratio between acrylic processing medium and the organic solvent must be immis acid and methylmethacrylate monomers serves to modulate cible, and includes water although nonaqueous media Such as the properties of the co-polymer. Methacrylate-based micro Xylene and toluene and synthetic oils and natural oils are US 2010/0021416 A1 Jan. 28, 2010 52 optionally used. Optionally, a Surfactant is added to the con efficient in encapsulating the otic structure modulating agent tinuous-phase processing medium to prevent the micropar or innate immune system modulating agent since core load ticles from agglomerating and to control the size of the Sol ings of up to 80 wt.%, preferably up to 60 wt.% are obtained. vent microdroplets in the emulsion. A preferred surfactant 0657 Alternatively, controlled-release microspheres con dispersing medium combination is a 1 to 10 wt.% poly (vinyl taining an otic structure modulating agent or innate immune alcohol) in water mixture. The dispersion is formed by system modulating agent is prepared through the use of static mechanical agitation of the mixed materials. An emulsion is mixers. Static or motionless mixers consist of a conduit or optionally formed by adding Small drops of the active agent tube in that is received a number of static mixing agents. wall forming material Solution to the continuous phase pro Static mixers provide homogeneous mixing in a relatively cessing medium. The temperature during the formation of the short length of conduit, and in a relatively short period of emulsion is not especially critical but influences the size and time. With static mixers, the fluid moves through the mixer, quality of the microspheres and the solubility of the drug in rather than some part of the mixer, such as a blade, moving the continuous phase. It is desirable to have as little of the through the fluid. agent in the continuous phase as possible. Moreover, depend 0658. A static mixer is optionally used to create an emul ing on the solvent and continuous-phase processing medium Sion. When using a static mixer to form an emulsion, several employed, the temperature must not be too low or the solvent factors determine emulsion particle size, including the den and processing medium will Solidify or the processing sity and Viscosity of the various solutions or phases to be medium will become too viscous for practical purposes, or mixed, Volume ratio of the phases, interfacial tension between too high that the processing medium will evaporate, or that the phases, static mixer parameters (conduit diameter; length the liquid processing medium will not be maintained. More of mixing element; number of mixing elements), and linear over, the temperature of the medium cannot be so high that the velocity through the static mixer. Temperature is a variable stability of the particular agent being incorporated in the because it affects density, Viscosity, and interfacial tension. microspheres is adversely affected. Accordingly, the disper The controlling variables are linear velocity, sheer rate, and sion process is conducted at any temperature that maintains pressure drop per unit length of Static mixer. stable operating conditions, which preferred temperature 0659. In order to create microspheres containing an otic being about 15° C. to 60° C., depending upon the drug and structure modulating agent or innate immune system modu excipient selected. lating agent using a static mixer process, an organic phase and 0654 The dispersion that is formed is a stable emulsion an aqueous phase are combined. The organic and aqueous and from this dispersion the organic solvent immiscible fluid phases are largely or substantially immiscible, with the aque is optionally partially removed in the first step of the solvent ous phase constituting the continuous phase of the emulsion. removal process. The solvent is removed by techniques such The organic phase includes anotic structure modulating agent as heating, the application of a reduced pressure or a combi or innate immune system modulating agent as well as a wall nation of both. The temperature employed to evaporate sol forming polymer or polymeric matrix material. The organic vent from the microdroplets is not critical, but should not be phase is prepared by dissolving an otic structure modulating that high that it degrades the otic structure modulating agent agent or innate immune system modulating agent in an or innate immune system modulating agent employed in the organic or other Suitable solvent, or by forming a dispersion preparation of a given microparticle, nor should it be so high or an emulsion containing the otic structure modulating agent as to evaporate solvent at Such a rapid rate to cause defects in or innate immune system modulating agent. The organic the wall forming material. Generally, from 5 to 75%, of the phase and the aqueous phase are pumped so that the two solvent is removed in the first solvent removal step. phases flow simultaneously through a static mixer, thereby 0655. After the first stage, the dispersed microparticles in forming an emulsion that comprises microspheres containing the solvent immiscible fluid medium are isolated from the the otic structure modulating agent or innate immune system fluid medium by any convenient means of separation. Thus, modulating agent encapsulated in the polymeric matrix mate for example, the fluid is decanted from the microsphere or the rial. The organic and aqueous phases are pumped through the microsphere Suspension is filtered. Still other, various com static mixer into a large Volume of quench liquid to extract or binations of separation techniques are used if desired. remove the organic solvent. Organic solvent is optionally 0656. Following the isolation of the microspheres from removed from the microspheres while they are washing or the continuous-phase processing medium, the remainder of being stirred in the quench liquid. After the microspheres are the solvent in the microspheres is removed by extraction. In washed in a quench liquid, they are isolated, as through a this step, the microspheres are Suspended in the same con sieve, and dried. tinuous-phase processing medium used in step one, with or 0660. In one embodiment, microspheres are prepared without Surfactant, or in another liquid. The extraction using a static mixer. The process is not limited to the Solvent medium removes the solvent from the microspheres and yet extraction technique discussed above, but is used with other does not dissolve the microspheres. During the extraction, the encapsulation techniques. For example, the process is option extraction medium with dissolved solvent is optionally ally used with a phase separation encapsulation technique. To removed and replaced with fresh extraction medium. This is do so, an organic phase is prepared that comprises an otic best done on a continual basis. The rate of extraction medium structure modulating agent or innate immune system modu replenishment of a given process is a variable that is deter lating agent Suspended or dispersed in a polymer Solution. mined at the time the process is performed and, therefore, no The non-solvent second phase is free from solvents for the precise limits for the rate must be predetermined. After the polymer and active agent. A preferred non-solvent second majority of the solvent has been removed from the micro phase is silicone oil. The organic phase and the non-solvent spheres, the microspheres are dried by exposure to air or by phase are pumped through a static mixer into a non-solvent other conventional drying techniques such as vacuum drying, quench liquid, such as heptane. The semi-solid particles are drying over a desiccant, or the like. This process is very quenched for complete hardening and washing. The process US 2010/0021416 A1 Jan. 28, 2010 of microencapsulation includes spray drying, Solvent evapo 0664 Otic structure modulating agent or innate immune ration, a combination of evaporation and extraction, and melt system modulating agents are also inserted into the lipid extrusion. nanocapsules by incubation for 90 minutes with an aqueous 0661. In another embodiment, the microencapsulation micellar Solution of the auris active agent. The Suspension is process involves the use of a static mixer with a single solvent. then Vortexed every 15 minutes, and then quenched in an ice This process is described in detail in U.S. application Ser. No. bath for 1 minute. 08/338,805, herein incorporated by reference for such disclo 0665 Suitable auris-acceptable surfactants are, by way of example, cholic acid or taurocholic acid salts. Taurocholic Sure. An alternative process involves the use of a static mixer acid, the conjugate formed from cholic acid and taurine, is a with co-solvents. In this process, biodegradable microspheres fully metabolizable Sulfonic acid Surfactant. An analog of comprising a biodegradable polymeric binder and an otic taurocholic acid, tauroursodeoxycholic acid (TUDCA), is a structure modulating agent or innate immune system modu naturally occurring bile acid and is a conjugate of taurine and lating agent are prepared, which comprises a blend of at least ursodeoxycholic acid (UDCA). Other naturally occurring two Substantially non-toxic solvents, free of halogenated anionic (e.g., galactocerebroside Sulfate), neutral (e.g., lacto hydrocarbons to dissolve both the agent and the polymer. The Sylceramide) or Zwitterionic Surfactants (e.g., sphingomy Solvent blend containing the dissolved agent and polymer is elin, phosphatidylcholine, palmitoyl carnitine) are optionally dispersed in an aqueous solution to form droplets. The result used to prepare nanoparticles. ing emulsion is then added to an aqueous extraction medium 0666. The auris-acceptable phospholipids are chosen, by preferably containing at least one of the solvents of the blend, way of example, from natural, synthetic or semi-synthetic whereby the rate of extraction of each solvent is controlled, phospholipids; lecithins (phosphatidylcholine) Such as, for whereupon the biodegradable microspheres containing the example, purified egg or soya lecithins (lecithin E100, leci pharmaceutically active agent are formed. This process has thin E80 and phospholipons, for example phospholipon 90), the advantage that less extraction medium is required because phosphatidylethanolamine, phosphatidylserine, phosphati the solubility of one solvent in water is substantially indepen dylinositol, phosphatidylglycerol, dipalmitoylphosphatidyl dent of the other and solvent selection is increased, especially choline, dipalmitoylglycerophosphatidylcholine, dimyris with solvents that are particularly difficult to extract. toylphosphatidylcholine, distearoylphosphatidylcholine and 0662 Nanoparticles are also contemplated for use with the phosphatidic acid or mixtures thereof are used more particu otic structure modulating agent or innate immune system larly. modulating agents disclosed herein. Nanoparticles are mate 0667 Fatty acids for use with the auris-acceptable com rial structures of about 100 nm or less in size. One use of positions are chosen from, by way of example, lauric acid, nanoparticles in pharmaceutical compositions is the forma mySristic acid, palmitic acid, Stearic acid, isostearic acid, tion of Suspensions as the interaction of the particle Surface arachidic acid, behenic acid, oleic acid, myristoleic acid, with solvent is strong enough to overcome differences in palmitoleic acid, linoleic acid, alpha-linoleic acid, arachi density. Nanoparticle Suspensions are sterilized as the nano donic acid, eicosapentaenoic acid, erucic acid, docosa particles are small enough to be subjected to sterilizing filtra hexaenoic acid, and the like. tion (see, e.g., U.S. Pat. No. 6,139,870, herein incorporated 0668 Suitable auris-acceptable surfactants are selected by reference for such disclosure). Nanoparticles comprise at from known organic and inorganic pharmaceutical excipi least one hydrophobic, water-insoluble and water-indispers ents. Such excipients include various polymers, low molecu ible polymer or copolymer emulsified in a solution or aque lar weight oligomers, natural products, and Surfactants. Pre ous dispersion of Surfactants, phospholipids or fatty acids. ferred Surface modifiers include nonionic and ionic The otic structure modulating agent or innate immune system Surfactants. Two or more Surface modifiers are used in com modulating agent is optionally introduced with the polymer bination. or the copolymer into the nanoparticles. 0669 Representative examples of auris-acceptable sur 0663 Lipid nanocapsules as controlled-release structures, factants include cetyl pyridinium chloride, gelatin, casein, as well for penetrating the round window membrane and lecithin (phosphatides), dextran, glycerol, gum acacia, cho reaching auris interna and/or auris media targets, is also con lesterol, tragacanth, Stearic acid, calcium Stearate, glycerol templated herein. Lipid nanocapsules are optionally formed monostearate, cetostearyl alcohol, cetomacrogolemulsifying by emulsifying capric and caprylic acid triglycerides (La wax, Sorbitan esters, polyoxyethylene alkyl ethers, polyoxy brafacWL 1349; avg. mw 512), soybean lecithin (LIPOID(R) ethylene castor oil derivatives, polyoxyethylene sorbitan fatty S75-3; 69% phosphatidylcholine and other phospholipids), acid esters; dodecyl trimethyl ammonium bromide, polyoxy surfactant (for example, Solutol HS15), a mixture of polyeth ethylenestearates, colloidal silicon dioxide, phosphates, ylene glycol 660 hydroxystearate and free polyethylene gly Sodium dodecylsulfate, carboxymethylcellulose calcium, col 660; NaCl and water. The mixture is stirred at room hydroxypropyl cellulose (HPC, HPC-SL, and HPC-L), temperature to obtain an oil emulsion in water. After progres hydroxypropyl methylcellulose (HPMC), carboxymethylcel sive heating at a rate of 4°C./min under magnetic stirring, a lulose sodium, methylcellulose, hydroxyethylcellulose, short interval of transparency should occur close to 70° C. hydroxypropylcellulose, hydroxypropylmethyl-cellulose and the inverted phase (water droplets in oil) obtained at 85° phthalate, noncrystalline cellulose, magnesium aluminum C. Three cycles of cooling and heating is then applied silicate, triethanolamine, polyvinyl alcohol (PVA), polyvi between 85°C. and 60° C. at the rate of 4°C/min, and a fast nylpyrrolidone (PVP), 4-(1,1,3,3-tetaamethylbutyl)-phenol dilution in cold water at a temperature close to 0° C. to polymer with ethylene oxide and formaldehyde (also known produce a suspension of nanocapsules. To encapsulate the as tyloxapol, Superione, and triton), poloxamers, poloxam otic structure modulating agent or innate immune system ines, a charged phospholipid such as dimyristoylphophatidyl modulating agents, the agent is optionally added just prior to glycerol, dioctylsulfosuccinate (DOSS); Tetronic R. 1508, the dilution with cold water. dialkylesters of sodium sulfosuccinic acid, Duponol P. Tri US 2010/0021416 A1 Jan. 28, 2010 54 tons X-200, Crodestas F-110, p-isononylphenoxypoly-(gly containing nanoparticles. Various SEC media, Such as Super cidol), Crodestas SL-40 (Croda, Inc.); and SA9CHCO, which dex 200, Superose 6, Sephacryl 1000 are commercially avail is C.H.CH (CON(CH) CH (CHOH) (CH, OH), able and are employed for the size-based fractionation of such (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-de mixtures. Additionally, nanoparticles are optionally purified cyl B-D-glucopyranoside; n-decyl B-D-maltopyranoside; by centrifugation, membrane filtration and by use of other n-dodecyl B-D-glucopyranoside; n-dodecyl B-D-maltoside; molecular sieving devices, crosslinked gels/materials and heptanoyl-N-methylglucamide; n-heptyl-B-D-glucopyrano membranes. side; n-heptyl B-D-thioglucoside; n-hexyl B-D-glucopyrano side; nonanoyl-N-methylglucamide; n-noyl B-D-glucopyra Auris-Acceptable Cyclodextrin and Other Stabilizing Com noside; octanoyl-N-methylglucamide; n-octyl-f-D- positions glucopyranoside; octyl B-D-thioglucopyranoside; and the 0674. In a specific embodiment, the auris-acceptable for like. Most of these Surfactants are known pharmaceutical mulations alternatively comprise a cyclodextrin. Cyclodex excipients and are described in detail in the Handbook of trins are cyclic oligosaccharides containing 6, 7, or 8 glucopy Pharmaceutical Excipients, published jointly by the Ameri ranose units, referred to as C-cyclodextrin, B-cyclodextrin, or can Pharmaceutical Association and The Pharmaceutical Y-cyclodextrin respectively. Cyclodextrins have a hydrophilic Society of Great Britain (The Pharmaceutical Press, 1986), exterior, which enhances water-solublility, and a hydropho specifically incorporated by reference for such disclosure. bic interior, which forms a cavity. In an aqueous environment, 0670. The hydrophobic, water-insoluble and water-indis hydrophobic portions of other molecules often enter the persible polymer or copolymer may be chosen from biocom hydrophobic cavity of cyclodextrin to form inclusion com patible and biodegradable polymers, for example lactic or pounds. Additionally, cyclodextrins are capable of other glycolic acid polymers and copolymers thereof, or polylactic/ types of nonbonding interactions with molecules that are not polyethylene (or polypropylene) oxide copolymers, prefer inside the hydrophobic cavity. Cyclodextrins have three free ably with molecular weights of between 1000 and 200,000, hydroxyl groups for each glucopyranose unit, or 18 hydroxyl polyhydroxybutyric acid polymers, polylactones of fatty groups on C-cyclodextrin, 21 hydroxyl groups on B-cyclo acids containing at least 12 carbonatoms, or polyanhydrides. dextrin, and 24 hydroxyl groups on Y-cyclodextrin. One or 0671 The nanoparticles may be obtained by coacervation, more of these hydroxyl groups can be reacted with any of a or the technique of evaporation of solvent, from an aqueous number of reagents to form a large variety of cyclodextrin dispersion or solution of phospholipids and of an oleic acid derivatives, including hydroxypropyl ethers, Sulfonates, and Salt into that is added an immiscible organic phase comprising sulfoalkylethers. Shown below is the structure off-cyclodex the active principle and the hydrophobic, water-insoluble and trin and the hydroxypropyl-3-cyclodextrin (HPBCD). water-indispersible polymer or copolymer. The mixture is pre-emulsified and then Subjected to homogenization and evaporation of the organic solvent to obtain an aqueous Sus RO pension of very Small-sized nanoparticles. 0672 A variety of methods are optionally employed to RO O O fabricate the otic structure modulating nanoparticles that are p ORO within the scope of the embodiments. These methods include OR RO vaporization methods, such as free jet expansion, laser vapor O OR ization, spark erosion, electro explosion and chemical vapor O OR RO deposition; physical methods involving mechanical attrition OR (e.g., “pearlmilling technology, Elan NanoSystems), Super O O critical CO2 and interfacial deposition following solvent dis placement. In one embodiment, the solvent displacement RO RO method is used. The size of nanoparticles produced by this OR O method is sensitive to the concentration of polymer in the RO organic solvent; the rate of mixing; and to the Surfactant O OR employed in the process. Continuous flow mixers provide the R OR V necessary turbulence to ensure Small particle size. One type O OR OO O of continuous flow mixing device that is optionally used to O prepare nanoparticles has been described (Hansen et al.JPhys Chem 92, 2189-96, 1988). In other embodiments, ultrasonic RO devices, flow through homogenizers or supercritical CO2 devices may be used to prepare nanoparticles. 0673. If suitable nanoparticle homogeneity is not obtained R = H B-clclodextrin on direct synthesis, then size-exclusion chromatography is R = CH3CH(OH)CH used to produce highly uniform drug-containing particles that hydroxypropyl 3-cyclodextrin are freed of other components involved in their fabrication. Size-exclusion chromatography (SEC) techniques, such as gel-filtration chromatography, is used to separate particle 0675. In some embodiments, the use of cyclodextrins in bound otic structure modulating agent or innate immune sys the pharmaceutical compositions described herein improves tem modulating agent or other pharmaceutical compound the solubility of the drug. Inclusion compounds are involved from free otic structure modulating agent or innate immune in many cases of enhanced solubility; however other interac system modulating agent or other pharmaceutical compound, tions between cyclodextrins and insoluble compounds also or to select a suitable size range of otic structure modulating improves solubility. Hydroxypropyl-f-cyclodextrin (HP US 2010/0021416 A1 Jan. 28, 2010

BCD) is commercially available as a pyrogen free product. It 0679. Additional useful otic structure modulating agent or is a nonhygroscopic white powder that readily dissolves in innate immune system modulating agent auris-acceptable water. HPBCD is thermally stable and does not degrade at compositions include one or more anti-aggregation additives neutral pH. Thus, cyclodextrins improve the solubility of a to enhance stability of a otic structure modulating composi therapeutic agent in a composition. Accordingly, in some tions by reducing the rate of protein aggregation. The anti embodiments, cyclodextrins are included to increase the solu aggregation additive selected depends upon the nature of the bility of the auris-acceptable otic structure modulating agent conditions to that the otic structure modulating agent or or innate immune system modulating agents within the com innate immune system modulating agents, for example otic positions described herein. In other embodiments, cyclodex structure modulating agent or innate immune system modu trins in addition serve as controlled-release excipients within lating agent antibodies are exposed. For example, certain the compositions described herein. compositions undergoing agitation and thermal stress require 0676 By way of example only, cyclodextrin derivatives a different anti-aggregation additive than a composition for use include C-cyclodextrin, B-cyclodextrin, Y-cyclodex undergoing lyophilization and reconstitution. Useful anti trin, hydroxyethyl 3-cyclodextrin, hydroxypropyl Y-cyclo aggregation additives include, by way of example only, urea, dextrin, Sulfated B-cyclodextrin, Sulfated C-cyclodextrin, Sul guanidinium chloride, simple amino acids such as glycine or fobutyl ether f3-cyclodextrin. arginine, Sugars, polyalcohols, polysorbates, polymers such 0677. The concentration of the cyclodextrin used in the as polyethylene glycol and dextrans, alkyl saccharides. Such compositions and methods disclosed herein varies according as alkyl glycoside, and Surfactants. to the physiochemical properties, pharmacokinetic proper 0680. Other useful compositions optionally include one or ties, side effect or adverse events, composition consider more auris-acceptable antioxidants to enhance chemical sta ations, or other factors associated with the therapeutically bility where required. Suitable antioxidants include, by way active agent, or a salt or prodrug thereof, or with the properties of example only, ascorbic acid, methionine, Sodium thiosul of other excipients in the composition. Thus, in certain cir fate and Sodium metabisulfite. In one embodiment, antioxi cumstances, the concentration or amount of cyclodextrin dants are selected from metal chelating agents, thiol contain used in accordance with the compositions and methods dis ing compounds and other general stabilizing agents. closed herein will vary, depending on the need. When used, 0681 Still other useful compositions include one or more the amount of cyclodextrins needed to increase solubility of auris-acceptable Surfactants to enhance physical stability or the otic structure modulating agent or innate immune system for other purposes. Suitable nonionic surfactants include, but modulating agent and/or function as a controlled-release are not limited to, polyoxyethylene fatty acid glycerides and excipient in any of the compositions described herein is Vegetable oils, e.g., polyoxyethylene (60) hydrogenated cas selected using the principles, examples, and teachings tor oil; and polyoxyethylene alkylethers and alkylphenyl described herein. ethers, e.g., Octoxynol 10, octoxynol 40. 0678. Other stabilizers that are useful in the auris-accept 0682. In some embodiments, the auris-acceptable phar able compositions disclosed herein include, for example, maceutical compositions described herein are stable with fatty acids, fatty alcohols, alcohols, long chain fatty acid respect to compound degradation over a period of any of at esters, long chain ethers, hydrophilic derivatives of fatty least about 1 day, at least about 2 days, at least about 3 days, acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl at least about 4 days, at least about 5 days, at least about 6 alcohols, hydrocarbons, hydrophobic polymers, moisture-ab days, at least about 1 week, at least about 2 weeks, at least Sorbing polymers, and combinations thereof. In some about 3 weeks, at least about 4 weeks, at least about 5 weeks, embodiments, amide analogues of stabilizers are also used. In at least about 6 weeks, at least about 7 weeks, at least about 8 further embodiments, the chosen stabilizer changes the weeks, at least about 3 months, at least about 4 months, at hydrophobicity of the composition (e.g., oleic acid, waxes), least about 5 months, or at least about 6 months. In other or improves the mixing of various components in the compo embodiments, the compositions described herein are stable sition (e.g., ethanol), controls the moisture level in the for with respect to compound degradation overa period of at least mula (e.g., PVP or polyvinyl pyrrolidone), controls the about 1 week. Also described herein are compositions that are mobility of the phase (Substances with melting points higher stable with respect to compound degradation over a period of than room temperature Such as long chain fatty acids, alco at least about 1 month. hols, esters, ethers, amides etc. or mixtures thereof, waxes), 0683. In other embodiments, an additional surfactant (co and/or improves the compatibility of the formula with encap Surfactant) and/or buffering agent is combined with one or Sulating materials (e.g., oleic acid or wax). In another more of the pharmaceutically acceptable vehicles previously embodiment some of these stabilizers are used as solvents/ described herein so that the surfactant and/or buffering agent co-solvents (e.g., ethanol). In other embodiments, stabilizers maintains the product at an optimal pH for stability. Suitable are present in Sufficient amounts to inhibit the degradation of co-Surfactants include, but are not limited to: a) natural and the otic structure modulating agent or innate immune system synthetic lipophilic agents, e.g., phospholipids, cholesterol, modulating agent. Examples of Such stabilizing agents, and cholesterol fatty acid esters and derivatives thereof, b) include, but are not limited to: (a) about 0.5% to about 2% w/v. nonionic Surfactants, which include for example, polyoxyeth glycerol, (b) about 0.1% to about 1% w/v methionine, (c) ylene fatty alcohol esters, Sorbitan fatty acid esters (Spans), about 0.1% to about 2% w/v monothioglycerol, (d) about 1 polyoxyethylene Sorbitan fatty acid esters (e.g., polyoxyeth mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v. ylene (20) sorbitan monooleate (Tween 80), polyoxyethylene ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, sorbitan monolaurate (Tween 20) and other Tweens, sorbitan (i) heparin, () dextran Sulfate, (k) cyclodextrins, (1) pentosan esters, glycerol esters, e.g., Myr and glycerol triacetate (tri polysulfate and other heparinoids, (m) divalent cations such acetin), polyethylene glycols, cetyl alcohol, cetostearyl alco as magnesium and Zinc, or (n) combinations thereof. hol, Stearyl alcohol, polysorbate 80, poloxamers, poloxam US 2010/0021416 A1 Jan. 28, 2010 56 ines, polyoxyethylene castor oil derivatives (e.g., contains preservatives to prevent microbial growth. Suitable Cremophor(R) RH40, Cremphor A25, Cremphor A20, Cremo auris-acceptable preservatives for use in the enhanced viscos phor(REL) and other Cremophors, sulfosuccinates, alkylsul ity compositions described herein include, but are not limited phates (SLS); PEG glyceryl fatty acid esters such as PEG-8 to benzoic acid, boric acid, p-hydroxybenzoates, alcohols, glyceryl caprylate/caprate (Labrasol), PEG-4 glyceryl capry quarternary compounds, stabilized chlorine dioxide, mercu late/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl rials, such as merfen and thiomersal, mixtures of the forego laurate (Gelucire 444/14), PEG-6 glyceryl mono oleate (La ing and the like. brafil M. 1944CS), PEG-6 glyceryllinoleate (Labrafil M2125 0689. In a further embodiment, the preservative is, by way CS); propylene glycol mono- and di-fatty acid esters, such as of example only, an antimicrobial agent, within the auris propylene glycol laurate, propylene glycol caprylate/caprate; acceptable compositions presented herein. In one embodi BrijR 700, ascorbyl-6-palmitate, stearylamine, sodium lauryl ment, the composition includes a preservative such as by way Sulfate, polyoxethyleneglycerol triricinoleate, and any com of example only, methyl paraben, Sodium bisulfite, sodium binations or mixtures thereof; c) anionic Surfactants include, thiosulfate, ascorbate, chorobutanol, thimerosal, parabens, but are not limited to, calcium carboxymethylcellulose, benzyl alcohol, phenylethanol and others. In another embodi Sodium carboxymethylcellulose, Sodium SulfoSuccinate, dio ment, the methyl paraben is at a concentration of about 0.05% ctyl, Sodium alginate, alkyl polyoxyethylene Sulfates, sodium to about 1.0%, about 0.1% to about 0.2%. Inafurther embodi lauryl Sulfate, triethanolamine Stearate, potassium laurate, ment, the gel is prepared by mixing water, methylparaben, bile salts, and any combinations or mixtures thereof, and d) hydroxyethylcellulose and sodium citrate. In a further cationic Surfactants such as cetyltrimethylammonium bro embodiment, the gel is prepared by mixing water, methylpa mide, and lauryldimethylbenzyl-ammonium chloride. raben, hydroxyethylcellulose and sodium acetate. In a further 0684. In a further embodiment, when one or more co embodiment, the mixture is sterilized by autoclaving at 120° Surfactants are utilized in the auris-acceptable compositions C. for about 20 minutes, and tested for pH, methylparaben of the present disclosure, they are combined, e.g., with a concentration and Viscosity before mixing with the appropri pharmaceutically acceptable vehicle and is present in the final ate amount of the otic structure modulating agent or innate composition, e.g., in an amount ranging from about 0.1% to immune system modulating agent disclosed herein. about 20%, from about 0.5% to about 10%. 0690 Suitable auris-acceptable water soluble preserva 0685. In one embodiment, the surfactant has an HLB value tives that are employed in the drug delivery vehicle include of 0 to 20. In additional embodiments, the surfactant has an sodium bisulfite, sodium thiosulfate, ascorbate, chorobu HLB value of 0 to 3, of 4 to 6, of 7 to 9, of 8 to 18, of 13 to 15, tanol, thimerosal, parabens, benzyl alcohol. Butylated of 10 to 18. hydroxytoluene (BHT), phenylethanol and others. These 0686. In one embodiment, diluents are also used to stabi agents are present, generally, in amounts of about 0.001% to lize the otic structure modulating agent or innate immune about 5% by weight or, in the amount of about 0.01 to about system modulating agent or other pharmaceutical com 2% by weight. In some embodiments, auris-compatible com pounds because they provide a more stable environment. positions described herein are free of preservatives. Salts dissolved in buffered solutions (that also can provide pH control or maintenance) are utilized as diluents, including, Round Window Membrane Penetration Enhancers but not limited to a phosphate buffered saline solution. In 0691. In another embodiment, the composition further other embodiments, the gel composition is isotonic with the comprises one or more round window membrane penetration endolymph or the perilymph: depending on the portion of the enhancers. Penetration across the round window membrane is cochlea that the otic structure modulating agent or innate enhanced by the presence of round window membrane pen immune system modulating agent composition is targeted. etration enhancers. Round window membrane penetration Isotonic compositions are provided by the addition of a tonic enhancers are chemical entities that facilitate transport of ity agent. Suitable tonicity agents include, but are not limited coadministered substances across the round window mem to any pharmaceutically acceptable Sugar, Salt or any combi brane. Round window membrane penetration enhancers are nations or mixtures thereof. Such as, but not limited to dex grouped according to chemical structure. Surfactants, both trose and sodium chloride. In further embodiments, the tonic ionic and non-ionic, such as sodium lauryl Sulfate, Sodium ity agents are present in an amount from about 100 mOsm/kg laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium to about 500 mOsm/kg. In some embodiments, the tonicity dodecylsulfate, dioctyl Sodium SulfoSuccinate, polyoxyethyl agent is present in an amount from about 200 mOsm/kg to ene-9-lauryl ether (PLE), Tween R. 80, nonylphenoxypolyeth about 400 mOsm/kg, from about 280 mOsm/kg to about 320 ylene (NP POE), polysorbates and the like, function as mOsm/kg. The amount of tonicity agents will depend on the round window membrane penetration enhancers. Bile salts target structure of the pharmaceutical composition, as (such as sodium glycocholate, Sodium deoxycholate, sodium described herein. taurocholate, Sodium taurodihydrofusidate, Sodium glycodi 0687 Useful tonicity compositions also include one or hydrofusidate and the like), fatty acids and derivatives (such more salts in an amount required to bring osmolality of the as oleic acid, caprylic acid, mono- and di-glycerides, lauric composition into an acceptable range for the perilymph or the acids, acylcholines, caprylic acids, acylcarnitines, sodium endolymph. Such salts include those having sodium, potas caprates and the like), chelating agents (such as EDTA, citric sium or ammonium cations and chloride, citrate, ascorbate, acid, Salicylates and the like), Sulfoxides (such as dimethyl borate, phosphate, bicarbonate, sulfate, thiosulfate or sulfoxide (DMSO), decylmethyl sulfoxide and the like), and bisulfite anions; suitable salts include sodium chloride, potas alcohols (such as ethanol, isopropanol, glycerol, propanediol sium chloride, sodium thiosulfate, sodium bisulfite and and the like) also function as round window membrane pen ammonium Sulfate. etration enhancers. 0688. In some embodiments, the auris-acceptable gel 0692. In some embodiments, the auris acceptable penetra compositions disclosed herein alternatively or additionally tion enhancer is a Surfactant comprising an alkyl-glycoside US 2010/0021416 A1 Jan. 28, 2010 57 wherein the alkyl glycoside is tetradecyl-B-D-maltoside. In The amount of lipophilic additive used range from 0.5 to 8%, Some embodiments, the auris acceptable penetration preferably from 1.5 to 4% and in particular is about 2%. enhancer is a surfactant comprising an alkyl-glycoside Generally, the ratio of the amount of lipophilic additive to the wherein the alkyl glycoside is dodecyl-maltoside. In certain amount of phospholipid ranges from about 1:8 to about 1:12 instances, the penetration enhancing agent is a hyaluronidase. and in particular is about 1:10. Said phospholipid, lipophilic In certain instances, a hyaluronidase is a human or bovine additive and the otic structure modulating agent or innate hyaluronidase. In some instances, a hyaluronidase is a human immune system modulating agent and other pharmaceutical hyaluronidase (e.g., hyaluronidase found in human sperm, compounds are employed in conjunction with a non-toxic, PH20 (Halozyme), Hyelenex R (Baxter International, Inc.)). pharmaceutically acceptable organic solvent system that dis In some instances, a hyaluronidase is a bovine hyaluronidase Solve said ingredients. Said solvent system not only must (e.g., bovine testicular hyaluronidase, Amphadase R (Am dissolve the otic structure modulating agentorinnate immune phastar Pharmaceuticals), Hydase R (PrimaPharm, Inc). In system modulating agent completely, but it also has to allow Some instances, a hyaluronidase is an ovine hyaluronidase, the composition of stable single bilayered liposomes. The Vitrase(R) (ISTA Pharmaceuticals). In certain instances, a Solvent system comprises dimethylisosorbide and tetraglycol hyaluronidase described herein is a recombinant hyalu (glycofurol, tetrahydrofurfuryl alcohol polyethylene glycol ronidase. In some instances, a hyaluronidase described herein ether) in an amount of about 8 to about 30%. In said solvent is a humanized recombinant hyaluronidase. In some system, the ratio of the amount of dimethylisosorbide to the instances, a hyaluronidase described herein is a pegylated amount of tetraglycol range from about 2:1 to about 1:3, in hyaluronidase (e.g., PEGPH20 (Halozyme)). In addition, the particular from about 1:1 to about 1:2.5 and preferably is peptide-like penetration enhancers described in U.S. Pat. about 1:2. The amount of tetraglycol in the final composition Nos. 7,151,191, 6,221,367 and 5,714,167, herein incorpo thus vary from 5 to 20%, in particular from 5 to 15% and rated by references for Such disclosure, are contemplated as preferably is approximately 10%. The amount of dimethyli an additional embodiment. These penetration enhancers are sosorbide in the final composition thus range from 3 to 10%, amino-acid and peptide derivatives and enable drug absorp in particular from 3 to 7% and preferably is approximately tion by passive transcellular diffusion without affecting the 5%. integrity of membranes or intercellular tight junctions. 0696. The term “organic component as used hereinafter refers to mixtures comprising said phospholipid, lipophilic Round Window Membrane Permeable Liposomes additives and organic Solvents. The otic structure modulating 0693 Liposomes or lipid particles may also be employed agent or innate immune System modulating agent may be to encapsulate the otic structure modulating compositions or dissolved in the organic component, or other means to main compositions. Phospholipids that are gently dispersed in an tain full activity of the agent. The amount of anotic structure aqueous medium form multilayer vesicles with areas of modulating agent or innate immune system modulating agent entrapped aqueous media separating the lipid layers. Sonica in the final composition may range from 0.1 to 5.0%. In tion, or turbulent agitation, of these multilayer vesicles results addition, other ingredients such as anti-oxidants may be in the formation of single layer vesicles, commonly referred added to the organic component. Examples include toco to as liposomes, with sizes of about 10-1000 nm. These lipo pherol, butylated hydroxyanisole, butylated hydroxytoluene, Somes have many advantages as otic structure modulating ascorbyl palmitate, ascorbyl oleate and the like. agent or innate immune system modulating agents or other 0697 Liposomal compositions are alternatively prepared, pharmaceutical agent carriers. They are biologically inert, for otic structure modulating agent or innate immune system biodegradable, non-toxic and non-antigenic. Liposomes are modulating agents or other pharmaceutical agents that are formed in various sizes and with varying compositions and moderately heat-resistant, by (a) heating the phospholipid Surface properties. Additionally, they are able to entrap a wide and the organic solvent system to about 60-80°C. in a vessel, variety of agents and release the agent at the site of liposome dissolving the active ingredient, then adding any additional collapse. formulating agents, and stirring the mixture until complete 0694 Suitable phospholipids for use in auris-acceptable dissolution is obtained; (b) heating the aqueous solution to liposomes here are, for example, phosphatidylcholines, etha 90-95°C. in a second vessel and dissolving the preservatives nolamines and serines, sphingomyelins, cardiolipins, plas therein, allowing the mixture to cool and then adding the malogens, phosphatidic acids and cerebrosides, in particular remainder of the auxiliary formulating agents and the remain those that are soluble together with the otic structure modu der of the water, and stirring the mixture until complete dis lating agent or innate immune system modulating agents Solution is obtained; thus preparing the aqueous component; herein in non-toxic, pharmaceutically acceptable organic Sol (c) transferring the organic phase directly into the aqueous vents. Preferred phospholipids are, for example, phosphatidyl component, while homogenizing the combination with a high choline, phosphatidyl ethanolmine, phosphatidyl serine, performance mixing apparatus, for example, a high-shear phosphatidyl inositol, lysophosphatidylcholine, phosphati mixer, and (d) adding a viscosity enhancing agent to the dyl glycerol and the like, and mixtures thereof especially resulting mixture while further homogenizing. The aqueous lecithin, e.g. Soya lecithin. The amount of phospholipid used component is optionally placed in a Suitable vessel that is in the present composition range from about 10 to about 30%, equipped with a homogenizer and homogenization is effected preferably from about 15 to about 25% and in particular is by creating turbulence during the injection of the organic about 20%. component. Any mixing means or homogenizer that exerts 0695 Lipophilic additives may be employed advanta high shear forces on the mixture may be employed. Generally, geously to modify selectively the characteristics of the lipo a mixer capable of speeds from about 1,500 to 20,000 rpm, in somes. Examples of such additives include by way of particular from about 3,000 to about 6,000 rpm may be example only, Stearylamine, phosphatidic acid, tocopherol, employed. Suitable viscosity enhancing agents for use in cholesterol, cholesterol hemisuccinate and lanolin extracts. process step (d) are for example, Xanthan gum, hydroxypro US 2010/0021416 A1 Jan. 28, 2010 pyl cellulose, hydroxypropyl methylcellulose or mixtures the percentage of an otic structure modulating agent or innate thereof. The amount of viscosity enhancing agent depends on immune system modulating agent is variedbetween about 1% the nature and the concentration of the other ingredients and and about 95%, between about 5% and about 80%, between in general ranges from about 0.5 to 2.0%, or approximately about 10% and about 60% or more of the weight or volume of 1.5%. In order to prevent degradation of the materials used the total pharmaceutical composition. In some embodiments, during the preparation of the liposomal composition, it is the amount of the compound(s) in each therapeutically useful advantageous to purge all solutions with an inert gas Such as otic structure modulating agent or innate immune system nitrogen or argon, and to conduct all steps under an inert modulating agent composition is prepared in Such a way that a suitable dosage will be obtained in any given unit dose of the atmosphere. Liposomes prepared by the above described compound. Factors such as solubility, bioavailability, bio method usually contain most of the active ingredient bound in logical half-life, route of administration, product shelflife, as the lipid bilayer and separation of the liposomes from unen well as other pharmacological considerations are contem capsulated material is not required. plated herein. 0698. In other embodiments, the auris-acceptable compo 0703. If desired, the auris-acceptable pharmaceutical gels sitions, including gel compositions and Viscosity-enhanced also contain co-solvents, preservatives, cosolvents, ionic compositions, further include excipients, other medicinal or strength and osmolality adjustors and other excipients in pharmaceutical agents, carriers, adjuvants, such as preserv addition to buffering agents. Suitable auris-acceptable water ing, stabilizing, wetting or emulsifying agents, solution pro soluble buffering agents are alkali or alkaline earth metal moters, salts, solubilizers, an antifoaming agent, an antioxi carbonates, phosphates, bicarbonates, citrates, borates, dant, a dispersing agent, a wetting agent, a Surfactant, and acetates, Succinates and the like, Such as Sodium phosphate, combinations thereof. citrate, borate, acetate, bicarbonate, carbonate and 0699 Suitable carriers for use in an auris-acceptable com tromethamine (TRIS). These agents are present in amounts position described herein include, but are not limited to, any sufficient to maintain the pH of the system at 7.4+0.2 and pharmaceutically acceptable solvent compatible with the tar preferably, 7.4. As such, the buffering agent is as much as 5% geted auris structure's physiological environment. In other on a weight basis of the total composition. embodiments, the base is a combination of a pharmaceuti 0704. Cosolvents are used to enhance otic structure modu cally acceptable Surfactant and solvent. lating agent or innate immune system modulating agent solu 0700. In some embodiments, other excipients include, bility, however, some otic structure modulating agent or Sodium Stearyl fumarate, diethanolamine cetyl sulfate, isos innate immune system modulating agents or other pharma tearate, polyethoxylated castor oil, nonoxyl 10, octoxynol 9, ceutical compounds are insoluble. These are often suspended Sodium lauryl Sulfate, Sorbitan esters (Sorbitan monolaurate, in the polymer vehicle with the aid of suitable suspending or Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan Viscosity enhancing agents. monostearate, Sorbitan sesquioleate, Sorbitan trioleate, Sorbi 0705 Moreover, some pharmaceutical excipients, dilu tan tristearate, Sorbitan laurate, Sorbitan oleate, Sorbitan ents or carriers are potentially ototoxic. For example, benza palmitate, Sorbitan Stearate, Sorbitan dioleate, Sorbitan ses Ikonium chloride, a common preservative, is ototoxic and qui-isostearate, Sorbitan sesquistearate, Sorbitan tri-isostear therefore potentially harmful if introduced into the vestibular ate), lecithin pharmaceutical acceptable salts thereof and or cochlear structures. In formulating a controlled-release combinations or mixtures thereof. otic structure modulating agent or innate immune system 0701. In other embodiments, the carrier is a polysorbate. modulating agent composition, it is advised to avoid or com Polysorbates are nonionic surfactants of sorbitan esters. bine the appropriate excipients, diluents or carriers to lessen Polysorbates useful in the present disclosure include, but are or eliminate potential ototoxic components from the compo not limited to polysorbate 20, polysorbate 40, polysorbate 60, sition, or to decrease the amount of Such excipients, diluents polysorbate 80 (Tween 80) and any combinations or mixtures or carriers. Optionally, a controlled-release otic structure thereof. In further embodiments, polysorbate 80 is utilized as modulating agent or innate immune system modulating agent the pharmaceutically acceptable carrier. composition includes otoprotective agents, such as antioxi 0702. In one embodiment, water-soluble glycerin-based dants, alpha lipoic acid, calcium, fosfomycin or iron chela auris-acceptable enhanced viscosity compositions utilized in tors, to counteract potential ototoxic effects that may arise the preparation of pharmaceutical delivery vehicles comprise from the use of specific therapeutic agents or excipients, an otic structure modulating agent or innate immune system diluents or carriers. modulating agent containing at least about 0.1% of the water 0706 The following are examples of therapeutically soluble glycerin compound or more. In some embodiments, acceptable otic compositions:

Example Composition Example Characteristics Chitosan tunable degradation of matrix in vitro glycerophosphate (CGP) tunable TACE inhibitor release in vitro: e.g., ~50% of drug released after 24 hrs biodegradable compatible with drug delivery to the inner ear Suitable for macromolecules and hydrophobic drugs PEG-PLGA-PEG tribock tunable high stability: e.g., maintains mechanical integrity polymers >1 month in vitro tunable fast release of hydrophilic drugs: e.g., ~50% of drug released after 24 hrs, and remainder released over ~5 days US 2010/0021416 A1 Jan. 28, 2010 59

-continued Example Composition Example Characteristics tunable slow release of hydrophobic drugs: e.g., ~80% released after 8 weeks biodegradable Subcutaneous injection of solution: e.g., gel forms within seconds and is intact after 1 month PEO-PPO-PEO triblock Tunable sol-gel transition temperature: e.g., decreases copolymers (e.g., with increasing F127 concentration Pluronic or Poloxameres) (e.g., F127) Chitosan CGP composition tolerates liposomes: e.g., up to 15 uM/ml glycerophosphate with liposomes. drug-loaded liposomes liposomes tunably reduce drug release time (e.g., up to 2 weeks in vitro). increase in liposome diameter optionally reduces drug release kinetics (e.g., liposome size between 100 and 300 nm) release parameters are controlled by changing composition of liposomes

0707. The compositions disclosed herein alternatively embodiment, the internal diameter of the needle can be encompass an otoprotectant agent in addition to the at least increased by reducing the wall thickness of the needle (com one active agent and/or excipients, including but not limited monly referred as thin wall or extra thin wall needles) to to Such agents as antioxidants, alpha lipoic acid, calcium, reduce the possibility of needle clogging while maintaining fosfomycin or iron chelators, to counteract potential ototoxic an adequate needle gauge. effects that may arise from the use of specific therapeutic 0712. In another embodiment, the needle is a hypodermic agents or excipients, diluents or carriers. needle used for instant delivery of the gel composition. The hypodermic needle may be a single use needle or a disposable Modes of Treatment needle. In some embodiments, a syringe may be used for delivery of the pharmaceutically acceptable gel-based otic (0708. Dosing Methods and Schedules structure modulating agent or innate immune system modu 0709 Drugs delivered to the inner ear have been adminis lating agent-containing compositions as disclosed herein tered systemically via oral, intravenous or intramuscular wherein the Syringe has a press-fit (Luer) or twist-on (Luer routes. However, systemic administration for pathologies lock) fitting. In one embodiment, the Syringe is a hypodermic local to the inner ear increases the likelihood of systemic Syringe. In another embodiment, the Syringe is made of plas toxicities and adverse side effects and creates a non-produc tic or glass. In yet another embodiment, the hypodermic tive distribution of drug in that high levels of drug are found Syringe is a single use Syringe. In a further embodiment, the in the serum and correspondingly lower levels are found at the glass syringe is capable of being sterilized. In yet a further inner ear. embodiment, the sterilization occurs through an autoclave. In 0710 Intratympanic injection of therapeutic agents is the another embodiment, the Syringe comprises a cylindrical technique of injecting a therapeutic agent behind the tym Syringe body wherein the gel composition is stored before panic membrane into the middle and/or inner ear. In one use. In other embodiments, the Syringe comprises a cylindri embodiment, the compositions described herein are admin cal Syringe body wherein the otic structure modulating agent istered directly onto the round window membrane via tran or innate immune system modulating agent pharmaceutically stympanic injection. In another embodiment, the otic struc acceptable gel-based compositions as disclosed herein is ture modulating agent or innate immune system modulating stored before use that conveniently allows for mixing with a agent auris-acceptable compositions described herein are suitable pharmaceutically acceptable buffer. In other embodi administered onto the round window membrane via a non ments, the Syringe may contain other excipients, stabilizers, transtympanic approach to the inner ear. In additional Suspending agents, diluents or a combination thereof to sta embodiments, the composition described herein is adminis bilize or otherwise stably store the otic structure modulating tered onto the round window membrane via a Surgical agent or innate immune system modulating agent or other approach to the round window membrane comprising modi pharmaceutical compounds contained therein. fication of the crista fenestrae cochleae. 0713. In some embodiments, the syringe comprises a 0711. In one embodiment the delivery system is a syringe cylindrical Syringe body wherein the body is compartmental and needle apparatus that is capable of piercing the tympanic ized in that each compartment is able to store at least one membrane and directly accessing the round window mem component of the auris-acceptable otic structure modulating brane or crista fenestrae cochleae of the auris interna. In some agent or innate immune system modulating agent gel com embodiments, the needle on the syringe is wider than a 18 position. In a further embodiment, the Syringe having a com gauge needle. In another embodiment, the needle gauge is partmentalized body allows for mixing of the components from 18 gauge to 31 gauge. In a further embodiment, the prior to injection into the auris media or auris interna. In other needle gauge is from 25 gauge to 30 gauge. Depending upon embodiments, the delivery system comprises multiple the thickness or viscosity of the otic structure modulating Syringes, each syringe of the multiple syringes contains at compositions or compositions, the gauge level of the Syringe least one component of the gel composition Such that each or hypodermic needle may be varied accordingly. In another component is pre-mixed prior to injection or is mixed Subse US 2010/0021416 A1 Jan. 28, 2010 60 quent to injection. In a further embodiment, the Syringes example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, disclosed herein comprise at least one reservoir wherein the at 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, least one reservoir comprises an otic structure modulating 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, agent or innate immune system modulating agent, or a phar 250 days, 280 days, 300 days, 320 days, 350 days, and 365 maceutically acceptable buffer, or a viscosity enhancing days. The dose reduction during a drug holiday may be from agent, Such as a gelling agent or a combination thereof. Com 10%-100%, including by way of example only 10%, 15%, mercially available injection devices are optionally employed 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, in their simplest form as ready-to-use plastic syringes with a 70%, 75%, 80%, 85%, 90%, 95%, and 100%. Syringe barrel, needle assembly with a needle, plunger with a 0719. Once improvement of the patient's otic conditions plunger rod, and holding flange, to perform an intratympanic has occurred, a maintenance otic structure modulating agent injection. or innate immune system modulating agent dose is adminis 0714. In some embodiments, the delivery device is an tered if necessary. Subsequently, the dosage or the frequency apparatus designed for administration of therapeutic agents to of administration, or both, is optionally reduced, as a function the middle and/or inner ear. By way of example only: GYRUS of the symptoms, to a level at that the improved disease, Medical Gmbh offers micro-otoscopes for visualization of disorder or condition is retained. In certain embodiments, and drug delivery to the round window niche; Arenberg has patients require intermittent treatment on a long-term basis described a medical treatment device to deliver fluids to inner upon any recurrence of symptoms. ear structures in U.S. Pat. Nos. 5,421,818; 5,474,529; and 0720. The amount of anotic structure modulating agent or 5,476,446, each of that is incorporated by reference hereinfor innate immune system modulating agent that will correspond such disclosure. U.S. patent application Ser. No. 08/874,208, to Such an amount will vary depending upon factors such as which is incorporated herein by reference for such disclosure, the particular compound, disease condition and its severity, describes a Surgical method for implanting a fluid transfer according to the particular circumstances Surrounding the conduit to deliver therapeutic agents to the inner ear. U.S. case, including, e.g., the specific otic structure modulating Patent Application Publication 2007/0167918, which is agent or innate immune system modulating agent being incorporated herein by reference for such disclosure, further administered, the route of administration, the condition being describes a combinedotic aspirator and medication dispenser treated, the target area being treated, and the Subject or host for intratympanic fluid sampling and medicament applica being treated. In general, however, doses employed for adult tion. human treatment will typically be in the range of 0.02-50 mg 0715. The compositions described herein, and modes of per administration, preferably 1-15 mg per administration. administration thereof, are also applicable to methods of The desired dose is presented in a single dose or as divided direct instillation or perfusion of the inner ear compartments. doses administered simultaneously (or over a short period of Thus, the compositions described hereinare useful in Surgical time) or at appropriate intervals. procedures including, by way of non-limiting examples, 0721. In some embodiments, the initial administration is a cochleostomy, labyrinthotomy, mastoidectomy, stapedec particular otic structure modulating agent or innate immune tomy, endolymphatic sacculotomy or the like. system modulating agent and the Subsequent administration a 0716. The auris-acceptable compositions or compositions different composition or otic structure modulating agent or containing the otic structure modulating agent or innate innate immune system modulating agent. immune system modulating agent compound(s) described 0722 Implants of Exogenous Materials herein are administered for prophylactic and/or therapeutic 0723. In some embodiments, the pharmaceutical formula treatments. In therapeutic applications, the otic structure tions, compositions and devices described herein are used in modulating compositions are administered to a patient combination with (e.g., implantation, short-term use, long already Suffering from a disorder disclosed herein, in an term use, or removal of) the implantation of an exogenous amount Sufficient to cure or at least partially arrest the Symp material (e.g., a medical device or a plurality of cells (e.g., toms of the disease, disorder or condition. Amounts effective stem cells)). As used herein, the term “exogenous material for this use will depend on the severity and course of the includes auris-interna or auris-media medical devices (e.g., disease, disorder or condition, previous therapy, the patient's hearing sparing devices, hearing improving devices, short health status and response to the drugs, and the judgment of electrodes, micro-prostheses or piston-like prostheses); the treating physician. needles; drug delivery devices, and cells (e.g., stem cells). In 0717. In the case wherein the patient's condition does not Some instances, the implants of exogenous materials are used improve, upon the doctor's discretion the administration of in conjunction with a patient experiencing hearing loss. In the otic structure modulating agent or innate immune system Some instances, the hearing loss is present at birth. In some modulating agent compounds may be administered chroni instances, the hearing loss is associated with conditions that cally, which is, for an extended period of time, including develop or progress after birth (e.g., Merniere's disease) throughout the duration of the patient's life in order to ame resulting in osteoneogenesis, nerve damage, obliteration of liorate or otherwise control or limit the symptoms of the cochlear structures, or combinations thereof. patient's disease or condition. 0724. In some instances, the exogenous material is a plu 0718. In the case wherein the patient's status does rality of cells. In some instances, the exogenous material is a improve, upon the doctor's discretion the administration of plurality of stem cells. the otic structure modulating agent or innate immune system 0725. In some instances, the exogenous material is an modulating agent compounds may be given continuously; electronic device. In some embodiments, the electronic alternatively, the dose of drug being administered may be device has an external portion placed behind the ear, and a temporarily reduced or temporarily Suspended for a certain second portion that is Surgically placed under the skin that length of time (i.e., a "drug holiday'). The length of the drug helps provide a sense of Sound to a person who is profoundly holiday varies between 2 days and 1 year, including by way of deaf or severely hard-of-hearing. By way of example only, US 2010/0021416 A1 Jan. 28, 2010

Such medical device implants bypass damaged portions of the such embodiments, the formulations described hereincontain ear and directly stimulate the auditory nerve. In some less than 2% of the extended release components (e.g., gelling instances cochlear implants are used in single sided deafness. components such as polyoxyethylene-polyoxypropylene tri In some instances cochlear implants are used for deafness in block copolymers) by weight of the formulation. In some of both ears. such embodiments, the formulations described hereincontain 0726. In some embodiments, administration of an active less than 1% of the extended release components (e.g., gelling agent described herein in combination with the implantation components such as polyoxyethylene-polyoxypropylene tri of an exogenous material (e.g., a medical device implant or a block copolymers) by weight of the formulation. In some of stem cell transplant) delays or prevents damage of auris struc Such embodiments, a composition described herein that is tures, e.g., irritation, cell death osteoneogeneis and/or further used for perfusion of a Surgical area contains Substantially no neuronal degeneration, caused by installation of an external gelling component. device and/or a plurality cells (e.g., stem cells) in the ear. In Some embodiments, administration of a composition or device described herein in combination with an implant Viscosity allows for a more effective restoration of hearing loss com 0731. In further embodiments, the auris gel formulation pared to an implant alone. contains a viscosity enhancing agent sufficient to provide a 0727. In some embodiments, administration of an active viscosity of between about 500 and 1,000,000 centipoise, agent described herein reduces damage to auris structures caused by underlying conditions allowing for Successful between about 750 and 1,000,000 centipoise; between about implantation. In some embodiments, administration of an 1000 and 1,000,000 centipoise; between about 1000 and 400, active agent described herein, in conjunction Surgery and/or 000 centipoise; between about 2000 and 100,000 centipoise: with the implantation of an exogenous material reduces or between about 3000 and 50,000 centipoise; between about prevents negative side-effects (e.g., cell death). 4000 and 25,000 centipoise; between about 5000 and 20,000 0728. In some embodiments, administration of an active centipoise; or between about 6000 and 15,000 centipoise. In agent described herein in conjunction with the implantation Some embodiments, the auris gel formulation contains a vis of an exogenous material has a trophic effect (i.e., promotes cosity enhancing agent Sufficient to provide a viscosity of healthy growth of cells and healing of tissue in the area of an between about 50,0000 and 1,000,000 centipoise. implant or transplant). In some embodiments, a trophic effect 0732. In some embodiments, the compositions or devices is desirable during otic Surgery or during intratympanic injec described herein are low viscosity compositions or devices at tion procedures. In some embodiments, a trophic effect is body temperature. In some embodiments, low viscosity com desirable after installation of a medical device or after a cell positions or devices contain from about 1% to about 10% of (e.g., stem cell) transplant. In some of such embodiments, the a Viscosity enhancing agent (e.g., gelling components such as compositions or devices described herein are administered polyoxyethylene-polyoxypropylene copolymers). In some via direct cochlear injection, through a chochleostomy or via embodiments, low viscosity compositions or devices contain deposition on the round window from about 2% to about 10% of a viscosity enhancing agent 0729. In some embodiments, administration of an active (e.g., gelling components such as polyoxyethylene-polyox agent described herein reduces inflammation and/or infec ypropylene copolymers). In some embodiments, low viscos tions associated with otic Surgery, or implantation of an exog ity compositions or devices contain from about 5% to about enous material (e.g., a medical device or a plurality of cells 10% of a viscosity enhancing agent (e.g., gelling components (e.g., stem cells)). In some instances, perfusion of a Surgical Such as polyoxyethylene-polyoxypropylene copolymers). In area with a formulation described herein reduces or elimi Some embodiments, low viscosity compositions or devices nates post-Surgical and/or post-implantation complications are Substantially free of a viscosity enhancing agent (e.g., (e.g., inflammation, hair cell damage, neuronal degeneration, gelling components such as polyoxyethylene-polyoxypropy osteoneogenesis or the like). In some instances, perfusion of lene copolymers). In some embodiments, a low viscosity otic a Surgical area with a formulation described herein reduces structure modulating or complement modulating composi post-Surgery or post-implantation recuperation time. tion or device described herein provides an apparent viscosity 0730. In one aspect, the formulations described herein, of from about 100 cP to about 10,000 cP. In some embodi and modes of administration thereof, are applicable to meth ments, a low viscosity otic structure modulating or comple ods of direct perfusion of the inner ear compartments. Thus, ment modulating composition or device described herein pro the formulations described herein are useful in combination vides an apparent viscosity of from about 500 cp to about with Surgical procedures including, by way of non-limiting 10,000 cp. In some embodiments, a low viscosity otic struc examples, cochleostomy, labyrinthotomy, mastoidectomy, ture modulating or complement modulating composition or stapedectomy, Stapedotomy, endolymphatic sacculotomy or device described herein provides an apparent viscosity of the like. In some embodiments, the inner ear compartments from about 1000 cP to about 10,000 cP. In some of such are perfused with a formulation described herein prior to otic embodiments, a low viscosity otic structure modulating or Surgery, during otic Surgery, afterotic Surgery, or a combina complement modulating composition or device is adminis tion thereof. In some of such embodiments, the formulations tered in combination with an external otic intervention, e.g., a described herein are substantially free of extended release Surgical procedure including but not limited to middle ear components (e.g., gelling components such as polyoxyethyl Surgery, inner ear Surgery, typanostomy, cochleostomy, laby ene-polyoxypropylene copolymers). In some of Such rinthotomy, mastoidectomy, stapedectomy, stapedotomy, embodiments, the formulations described herein contain less endolymphatic sacculotomy or the like. In some of Such than 5% of the extended release components (e.g., gelling embodiments, a low viscosity otic structure modulating or components such as polyoxyethylene-polyoxypropylene tri complement modulating composition or device is adminis block copolymers) by weight of the formulation. In some of tered during anotic intervention. In other such embodiments, US 2010/0021416 A1 Jan. 28, 2010 62 a low viscosity otic structure modulating or complement immune system modulating agent. Additional embodiments modulating composition or device is administered before the of the composition may also include an agent that enhances otic intervention. the Viscosity of the compositions included herein. 0733. In some embodiments, the compositions or devices 0736. In other or further embodiments, the composition described herein are high viscosity compositions or devices at provides an extended release composition of an otic structure body temperature. In some embodiments, high viscosity modulating agent or innate immune system modulating compositions or devices contain from about 10% to about agent. In certain embodiments, diffusion of an otic structure 25% of a viscosity enhancing agent (e.g., gelling components modulating agent or innate immune system modulating agent Such as polyoxyethylene-polyoxypropylene copolymers). In from the composition occurs for a time period exceeding 5 Some embodiments, high viscosity compositions or devices minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, contain from about 14% to about 22% of a viscosity enhanc or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 ing agent (e.g., gelling components such as polyoxyethylene days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or polyoxypropylene copolymers). In some embodiments, high 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 viscosity compositions or devices contain from about 15% to days, or 45 days, or 2 months or 3 months or 4 months or 5 about 21% of a viscosity enhancing agent (e.g., gelling com months or 6 months or 9 months or 1 year. In other embodi ponents such as polyoxyethylene-polyoxypropylene copoly ments, a therapeutically effective amount of an otic structure mers). In some embodiments, a high Viscosity otic structure modulating agent or innate immune system modulating agent modulating or complement modulating composition or is released from the composition for a time period exceeding device described herein provides an apparent viscosity of 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, from about 100,000 cP to about 1,000,000 cP. or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 0734. In some embodiments, a high viscosity otic struc days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or ture modulating or complement modulating composition or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 device described herein provides an apparent viscosity of days, or 45 days, or 2 months or 3 months or 4 months or 5 from about 150,000 cP to about 500,000 cP. In some embodi months or 6 months or 9 months or 1 year. ments, a high viscosity otic structure modulating or comple 0737. In other embodiments, the composition provides ment modulating composition or device described herein pro both an immediate release and an extended release composi vides an apparent viscosity of from about 250,000 cp to about tion of an otic structure modulating agent or innate immune 500,000 cp. In some of such embodiments, a high viscosity system modulating agent. In yet other embodiments, the com composition or device is a liquid at room temperature and gels position contains a 0.25:1 ratio, or a 0.5:1 ratio, or a 1:1 ratio, at about between room temperature and body temperature or a 1:2 ratio, or a 1:3, or a 1:4 ratio, or a 1:5 ratio, or a 1:7 (including an individual with a serious fever, e.g., up to about ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:20 ratio of imme 42°C.). In some embodiments, an otic structure modulating diate release and extended release compositions. In a further or complement modulating high Viscosity composition or embodiment the composition provides an immediate release device is administered as monotherapy for treatment of an of a first otic structure modulating agent or innate immune otic disease or condition described herein. In some embodi system modulating agent and an extended release of a second ments, an otic structure modulating or complement modulat otic structure modulating agent or innate immune system ing high Viscosity composition or device is administered in modulating agent or other therapeutic agent. In yet other combination with an external otic intervention, e.g., a Surgical embodiments, the composition provides an immediate procedure including but not limited to middle ear Surgery, release and extended release composition of an otic structure inner ear Surgery, typanostomy, cochleostomy, labyrintho modulating agent or innate immune system modulating tomy, mastoidectomy, stapedectomy, stapedotomy, endolym agent, and at least one therapeutic agent. In some embodi phatic sacculotomy or the like. In some of such embodiments, ments, the composition provides a 0.25:1 ratio, or a 0.5:1 a high viscosity otic structure modulating or complement ratio, or a 1:1 ratio, or a 1:2 ratio, or a 1:3, or a 1:4 ratio, or a modulating composition or device is administered after the 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:20 otic intervention. In other such embodiments, a high viscosity ratio of immediate release and extended release compositions otic structure modulating or complement modulating compo of a first otic structure modulating agent or innate immune sition or device is administered before the otic intervention. system modulating agent and second therapeutic agent, respectively. Pharmacokinetics of Controlled-Release Compositions 0738. In a specific embodiment the composition provides 0735. In one embodiment, the compositions disclosed a therapeutically effective amount of an otic structure modu herein additionally provides an immediate release of an otic lating agent or innate immune system modulating agent at the structure modulating agent or innate immune system modu site of disease with essentially no systemic exposure. In an lating agent from the composition, or within 1 minute, or additional embodiment the composition provides a therapeu within 5 minutes, or within 10 minutes, or within 15 minutes, tically effective amount of an otic structure modulating agent or within 30 minutes, or within 60 minutes or within 90 or innate immune system modulating agent at the site of minutes. In other embodiments, a therapeutically effective disease with essentially no detectable systemic exposure. In amount of an otic structure modulating agent or innate other embodiments, the composition provides a therapeuti immune system modulating agent is released from the com cally effective amount of an otic structure modulating agent position immediately, or within 1 minute, or within 5 minutes, or innate immune system modulating agent at the site of or within 10 minutes, or within 15 minutes, or within 30 disease with little or no detectable systemic exposure. minutes, or within 60 minutes or within 90 minutes. In certain 0739 The combination of immediate release, delayed embodiments the composition comprises an auris-pharma release and/or extended release otic structure modulating ceutically acceptable gel composition providing immediate compositions or compositions may be combined with other release of an otic structure modulating agent or innate pharmaceutical agents, as well as the excipients, diluents, US 2010/0021416 A1 Jan. 28, 2010

stabilizers, tonicity agents and other components disclosed the dissolution mechanism and b is the axis intercept, char herein. As such, depending upon the otic structure modulat acterizing the initial burst release mechanism wherein n=1 ing agent or innate immune system modulating agent used, characterizes an erosion controlled mechanism. The mean the thickness or viscosity desired, or the mode of delivery dissolution time (MDT) is the sum of different periods of time chosen, alternative aspects of the embodiments disclosed the drug molecules stay in the matrix before release, divided herein are combined with the immediate release, delayed by the total number of molecules and is optionally calculated release and/or extended release embodiments accordingly. by: 0740. In certain embodiments, the pharmacokinetics of the otic structure modulating compositions described herein are determined by injecting the composition on or near the DT = nklin round window membrane of a test animal (including by way n + 1 of example, a guinea pig or a chinchilla). At a determined period of time (e.g., 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days for testing the pharmaco 0744. For example,p a linear relationshipp between the mean kinetics of a composition over a 1 week period), the test dissolution time (MDT) of a composition or device and the animal is euthanized and a 5 mL sample of the perilymph fluid concentration of the gelling agent (e.g., poloxamer) indicates is tested. The inner ear removed and tested for the presence of that the otic agent is released due to the erosion of the polymer the otic structure modulating agent or innate immune system gel (e.g., poloxamer) and not via diffusion. In another modulating agent. As needed, the level of an otic structure example, a non-linear relationship indicates release of otic modulating agent or innate immune system modulating agent agent via a combination of diffusion and/or polymer gel deg is measured in other organs. In addition, the systemic level of radation. In another example, a faster gel elimination time the otic structure modulating agent or innate immune system course of a composition or device (a faster release of active modulating agent is measured by withdrawing a blood agent) indicates lower mean dissolution time (MDT). The sample from the test animal. In order to determine whether concentration of gelling components and/or active agent in a the composition impedes hearing, the hearing of the test composition are tested to determine Suitable parameters for animal is optionally tested. MDT. In some embodiments, injection volumes are also 0741. Alternatively, an inner ear is provided (as removed tested to determine suitable parameters for preclinical and from a test animal) and the migration of the otic structure clinical studies. The gel strength and concentration of the modulating agent or innate immune system modulating agent active agent affects release kinetics of an otic agent from the is measured. As yet another alternative, an in vitro model of a composition. At low poloxamer concentration, elimination round window membrane is provided and the migration of the rate is accelerated (MDT is lower). An increase in otic agent otic structure modulating agent or innate immune system concentration in the composition or device prolongs resi modulating agent is measured. dence time and/or MDT of the otic agent in the ear. 0742. As described herein, compositions comprising 0745. In some embodiments, the MDT for poloxamer micronized otic agents provide extended release overalonger from a composition or device described herein is at least 6 period of time compared to compositions comprising non hours. In some embodiments, the MDT for poloxamer from a micronized otic agents. In some instances, the micronized composition or device described herein is at least 10 hours. otic agent provides a steady Supply (e.g., +/-20%) of active 0746. In some embodiments, the MDT for an active agent agent via slow degradation and serves as a depot for the active from a composition or device described herein is from about agent; such a depot effect increases residence time of the otic 30 hours to about 48 hours. In some embodiments, the MDT agent in the ear. In specific embodiments, selection of an for an active agent from a composition or device described appropriate particle size of the active agent (e.g., micronized herein is from about 30 hours to about 96 hours. In some active agent) in combination with the amount of gelling agent embodiments, the MDT for an active agent from a composi in the composition provides tunable extended release charac tion or device described herein is from about 30 hours to teristics that allow for release of an active agent over a period about 1 week. In some embodiments, the MDT for a compo of hours, days, weeks or months. sition or device described herein is from about 1 week to 0743. In some embodiments, the viscosity of any formu about 6 weeks. lation described herein is designed to provide a suitable rate 0747. In some embodiments, the mean residence time of release from anotic compatible gel. In some embodiments, (MRT) for an active agent in a composition or device the concentration of a thickening agent (e.g., gelling compo described herein is from about 20 hours to about 48 hours. In nents such as polyoxyethylene-polyoxypropylene copoly some embodiments, the MRT for an active agent from a mers) allows for a tunable mean dissolution time (MDT). The composition or device described herein is from about 20 MDT is inversely proportional to the release rate of an active agent from a composition or device described herein. Experi hours to about 96 hours. In some embodiments, the MRT for mentally, the released otic agent is optionally fitted to the an active agent from a composition or device described herein Korsmeyer-Peppas equation is from about 20 hours to about 1 week. 0748. In some embodiments, the MRT for an active agent is about 20 hours. In some embodiments, the MRT for an active agent is about 30 hours. In some embodiments, the MRT for an active agent is about 40 hours. In some embodi ments, the MRT for an active agent is about 50 hours. In some embodiments, the MRT for an active agent is about 60 hours. where Q is the amount of otic agent released at time t, Q, is In some embodiments, the MRT for an active agent is about the overall released amount of otic agent, k is a release con 70 hours. In some embodiments, the MRT for an active agent stant of the nth order, n is a dimensionless number related to is about 80 hours. US 2010/0021416 A1 Jan. 28, 2010 64

0749. In some embodiments, the MRT for an active agent agent. In some of Such embodiments, the composition is is about 90 hours. In some embodiments, the MRT for an useful in perfusion of otic structures, e.g., during Surgery. active agent is about 1 week. In some embodiments, the MRT 0753. In some embodiments, a composition described for an active agent is about 90 hours. In some embodiments, herein is a solution that is Substantially free of gelling com the MRT for a composition or device described herein is from ponents and comprises micronized otic agent. In some of such about 1 week to about 6 weeks. In some embodiments, the embodiments, the composition provides intermediate release MRT for an active agent is about 1 week. In some embodi of an active agent from about 2 day to about 4 days. 0754. In some embodiments, a composition described ments, the MRT for an active agent is about 2 weeks. In some herein comprises a gelling agent (e.g., poloxamer 407) and embodiments, the MRT for an active agent is about 3 weeks. provides release of an active agent over a period of from about In some embodiments, the MRT for an active agent is about 4 1 day to about 3 days. In some embodiments, a composition weeks. In some embodiments, the MRT for an active agent is described herein comprises a gelling agent (e.g., poloxamer about 5 weeks. The half life of an otic agent and mean resi 407) and provides release of an active agent over a period of dence time of the otic agent are determined for each formu from about 1 day to about 5 days. In some embodiments, a lation by measurement of concentration of the otic agent in composition described herein comprises agelling agent (e.g., the perilymph using procedures described herein. poloxamer 407) and provides release of an active agent over 0750. In certain embodiments, any controlled release otic a period of from about 2 days to about 7 days. formulation described herein increases the exposure of an 0755. In some embodiments, a composition described otic agent and increases the Area Under the Curve (AUC) in herein comprises a gelling agent (e.g., poloxamer 407) in otic fluids (e.g., endolymph and/or perilymph) by about 30%, combination with micronized otic agent and provides about 40%, about 50%, about 60%, about 70%, about 80% or extended Sustained release. In some embodiments, a compo about 90% compared to a formulation that is not a controlled sition described herein comprises (a) about 14-17% of a gel release otic formulation. In certain embodiments, any con ling agent (e.g., poloxamer 407) and (b) a micronized otic trolled release otic formulation described herein increases the agent; and provides extended Sustained release over a period exposure time of an otic agent and decreases the C in otic of from about 1 week to about 3 weeks. In some embodi fluids (e.g., endolymph and/or perilymph) by about 40%, ments, a composition described herein comprises (a) about about 30%, about 20%, or about 10%, compared to a formu 16% of a gelling agent (e.g., poloxamer 407) and (b) a lation that is not a controlled release otic formulation. In micronized otic agent; and provides extended Sustained certain embodiments, any controlled release otic formulation release over a period of from about 3 weeks. In some embodi described herein alters (e.g. reduces) the ratio of C to C, ments, a composition described herein comprises (a) about compared to a formulation that is not a controlled release otic 18-21% of a gelling agent (e.g., poloxamer 407) and (b) a formulation. In certain embodiments, any controlled release micronized otic agent; and provides extended Sustained otic formulation described herein increases the exposure of release over a period of from about 3 weeks to about 6 weeks. anotic agent and increases the length of time that the concen In some embodiments, a composition described herein com tration of an otic agent is above C by about 30%, about prises (a) about 20% of a gelling agent (e.g., poloxamer 407) 40%, about 50%, about 60%, about 70%, about 80% or about and (b) a micronized otic agent; and provides extended Sus 90% compared to a formulation that is not a controlled release tained release over a period of from about 6 weeks. In some otic formulation. In certain instances, controlled release for embodiments, the amount of gelling agent in a composition, mulations described herein delay the time to C. In certain and the particle size of anotic agent are tunable to the desired instances, the controlled steady release of a drug prolongs the release profile of an otic agent from the composition. time the concentration of the drug will stay above the C. In 0756. In specific embodiments, compositions comprising Some embodiments, auris compositions described herein pro micronized otic agents provide extended release over alonger long the residence time of a drug in the inner ear and provide period of time compared to compositions comprising non a stable drug exposure profile. In some instances, an increase micronized otic agents. In specific embodiments, selection of in concentration of an active agent in the composition Satu an appropriate particle size of the active agent (e.g., micron rates the clearance process and allows for a more rapid and ized active agent) in combination with the amount of gelling stable steady state to be reached. agent in the composition provides tunable extended release 0751. In certain instances, once drug exposure (e.g., con characteristics that allow for release of an active agent over a centration in the endolymph or perilymph) of a drug reaches period of hours, days, weeks or months. steady state, the concentration of the drug in the endolymph or perilymph stays at or about the therapeutic dose for an Kits/Articles of Manufacture extended period of time (e.g., one day, 2 days, 3 days, 4 days, 0757. The disclosure also provides kits for preventing, 5 days, 6 days, or 1 week, 3 weeks, 6 weeks, 2 months). In treating orameliorating the symptoms of a disease or disorder Some embodiments, the steady state concentration of active in a mammal. Such kits generally will comprise one or more agent released from a controlled release formulation of the otic structure modulating agent or innate immune sys described herein is about 20 to about 50 times the steady state tem modulating agent controlled-release compositions or concentration of an active agent released from a formulation devices disclosed herein, and instructions for using the kit. that is not a controlled release formulation. The disclosure also contemplates the use of one or more of the 0752. The release of an active agent from any formulation, otic structure modulating agent or innate immune system composition or device described herein is optionally tunable modulating agent controlled-release compositions, in the to the desired release characteristics. In some embodiments, a manufacture of medicaments for treating, abating, reducing, composition described herein is a solution that is Substan or ameliorating the symptoms of a disease, dysfunction, or tially free of gelling components. In Such instances, the com disorder in a mammal. Such as a human that has, is Suspected position provides essentially immediate release of an active of having, or at risk for developing an inner ear disorder. US 2010/0021416 A1 Jan. 28, 2010

0758. In some embodiments, kits include a carrier, pack EXAMPLES age, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the Example 1 container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for Preparation of a Methotrexate/Hyaluronidase Ther example, bottles, vials, Syringes, and test tubes. In other moreversible Gel Formulation embodiments, the containers are formed from a variety of materials such as glass or plastic. 0762 0759. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packag ing pharmaceutical products are also presented herein. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Quantity (mgg of Examples of pharmaceutical packaging materials include, Ingredient formulation) but are not limited to, blister packs, bottles, tubes, inhalers, Methylparaben 1.O pumps, bags, vials, containers, Syringes, bottles, and any HPMC 1O.O packaging material Suitable for a selected composition and Poloxamer 407 18O.O intended mode of administration and treatment. A wide array TRIS HCl buffer (0.1M) 808.O of a otic structure modulating compositions provided herein Hyaluronidase 1.O are contemplated as are a variety of treatments for any dis Thimerosal O.1 ease, disorder, or condition that would benefit by controlled release administration of an otic structure modulating agent or innate immune system modulating agent to the inner ear. 0763. A 10-g batch of gel formulation containing 0.1% of 0760. In some embodiments, a kit includes one or more hyaluronidase is prepared by Suspending 1.80g of Poloxamer additional containers, each with one or more of various mate 407 (BASF Corp.) in 5.00 g of TRISHC1 buffer (0.1 M) and rials (such as reagents, optionally in concentrated form, and/ the components are mixed under agitation overnight at 4°C. or devices) desirable from a commercial and user standpoint for use of a composition described herein. Non-limiting to ensure complete dissolution. The hydroxypropylmethyl examples of such materials include, but not limited to, buff cellulose (100.0 mg), methylparaben (10 mg) and additional ers, diluents, filters, needles, Syringes; carrier, package, con TRIS HCl buffer (0.1 M) (3.08 g) are added and further tainer, vial and/or tube labels listing contents and/or instruc stirring allowed until complete dissolution is observed. Meth tions for use and package inserts with instructions for use. A otrexate (10 mg) is added and mixed in order to solubilize. set of instructions is optionally included. In a further embodi The mixture is maintained below room temperature until use. ment, a label is on or associated with the container. In yet a further embodiment, a label is on a container when letters, Example 2 numbers or other characters forming the label are attached, moldedoretched into the container itself a label is associated with a container when it is present within a receptacle or Preparation of a Collagen Mucoadhesive. Thermor carrier that also holds the container, e.g., as a package insert. eversible Gel Formulation In other embodiments a label is used to indicate that the contents are to be used for a specific therapeutic application. 0764 In yet another embodiment, a label also indicates directions for use of the contents, such as in the methods described herein. Quantity (mgg of 0761. In certain embodiments, the pharmaceutical com Ingredient formulation) positions are presented in a pack or dispenser device that Collagen 1O.O contains one or more unit dosage forms containing a com Methylparaben 1.O pound provided herein. In another embodiment, the pack for HPMC 1O.O example contains metal or plastic foil. Such as ablister pack. Carbopol 934P 2.O In a further embodiment, the pack or dispenser device is Poloxamer 407 18O.O accompanied by instructions for administration. In yet a fur TRIS HCl buffer (0.1M) 797.0 ther embodiment, the pack or dispenser is also accompanied Thimerosal O.1 with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture, use, or 0765. A 10-g batch of a mucoadhesive, gel formulation sale of pharmaceuticals, which notice is reflective of approval containing 1.0% of collagen is prepared by Suspending 20.0 by the agency of the form of the drug for human or veterinary mg of Carbopol 934P and 1.80 g of Poloxamer 407 (BASF administration. In another embodiment, such notice, for example, is the labeling approved by the U.S. Food and Drug Corp.) in 5.00 g of TRIS HCl buffer (0.1 M) and the compo Administration for prescription drugs, or the approved prod nents are mixed under agitation overnight at 4°C. to ensure uct insert. In yet another embodiment, compositions contain complete dissolution. The hydroxypropylmethylcellulose ing a compound provided hereinformulated in a compatible (100.0 mg), methylparaben (10 mg) and additional TRISHC1 pharmaceutical carrier are also prepared, placed in an appro buffer (0.1M)(2.97g) are added and further stirring allowed priate container, and labeled for treatment of an indicated until complete dissolution is observed. The mixture is main condition. tained below room temperature until use. US 2010/0021416 A1 Jan. 28, 2010 66

Example 3 Preparation of a Thermoreversible Gel KCNQ -continued Modulator/Hyaluronidase Formulation Quantity (mgg of Ingredient formulation) 0766 Poloxamer 407 18O.O Carbopol 934P 2.O TRIS HCl buffer (0.1M) 316.O Quantity (mgg of Thimerosal O.1 Ingredient formulation) Retigabine 18.0 0771. The Carbopol 934P and Poloxamer 407 (BASF Hyaluronidase 2.0 Corp.) is first suspended in the TRISHC1 buffer (0.1 M) and methylparaben 1.O the components are mixed under agitation overnight at 4°C. HPMC 1O.O to ensure complete dissolution. The methylparaben is added Poloxamer 407 18O.O and further stirring allowed until complete dissolution is TRIS HCl buffer (0.1M) 789.O observed. The collagenase is mixed in while maintaining stirring to produce a 0.2% collagenase mucoadhesive, ther 0767 A 10-g batch of gel formulation containing 1.8% of moreversible gel formulation. The mixture is maintained retigabine, 0.2% hyaluronidase is prepared by Suspending below room temperature until use. 1.80g of Poloxamer 407 (BASF Corp.) in 5.00g of TRISHC1 0772 Viscosity determinations of the pharmaceutical buffer (0.1 M) and the components are mixed under agitation compositions described herein are performed at room tem overnight at 4°C. to ensure complete dissolution. The retiga perature and 37° C. and are made using a Brookfield (spindle bine (200.0 mg), hydroxypropylmethylcellulose (100.0 mg), and cup) viscometer at 20 rpm. methylparaben (10 mg) and additional TRISHC1 buffer (0.1 M) (2.89 g) is added and further stirring allowed until com Example 6 plete dissolution is observed. The mixture is maintained below room temperature until use. Preparation of a Keratin Mucoadhesive-Based For mulation Example 4 (0773) Preparation of a Hyaluronidase Mucoadhesive-Based Formulation 0768 Quantity (mgg of Ingredient formulation) Keratin 1OOO Quantity (mgg of Sodium citrate 6.75 Ingredient formulation) Sodium ascorbate 4.32 Hyaluronidase 1O.O Paraffin oil SOO.O Sodium citrate 1.25 Trihydroxystearate S4.O Sodium ascorbate O.8 Cetyl dimethicon copolyol 1620 Paraffin oil 2OO Water qsad 1000 Trihydroxystearate 10 Phosphate buffer pH 7.4 qs pH 7.4 Cetyl dimethicon copolyol 30 Water qsad 1000 Phosphate buffer pH 7.4 qs pH 7.4 0774 The cream-type formulation is first prepared by gen tly mixing a keratin with a buffer. A second system is prepared by mixing paraffin oil, trihydroxyStearate and cetyl dimethi 0769 The cream-type formulation is first prepared by gen tly mixing a hyaluronidase with a buffer. A second system is con copolyol with warming to 60°C. Upon cooling to room prepared by mixing paraffin oil, trihydroxy Stearate and cetyl temperature, the lipid system is mixed with the aqueous phase dimethicon copolyol with warming to 60°C. Upon cooling to for 30 minutes. room temperature, the lipid system is mixed with the aqueous Example 7 phase for 30 minutes. Preparation of a Gel/Liposome Thyme Oil Formula Example 5 tion Preparation of a Collagenase Mucoadhesive. Ther 0775 moreversible Gel Formulation (0770 Ingredient Quantity Thyme oil 20.0 mg/g Quantity (mgg of Liposomes 15 umol/ml Ingredient formulation) Chitosan-Glycerophosphate 100.0 mg/g Collagenase 1O.O Methylparaben 1.O 0776 The liposomes are prepared in the presence of the thyme oil by the reversed-phase evaporation method, where US 2010/0021416 A1 Jan. 28, 2010 67 lipids in chloroform or chloroform-methanol (2:1, v/v) are 0781. The liquid formulation is first prepared by gently deposited on the sides of a tube by evaporation of the organic mixing PH20 with a buffer. A second system is prepared by solvent. The lipid film is redissolved in diethyl ether and the mixing poloxamer 188, Sodium chloride, edetate disodium aqueous phase (pH 7.4 300 mOsm/kg) containing 20 mM and calcium chloride in water with warming to 60° C. The Hepes and 144 mM NaCl is added. The mixture is sonicated to obtain a homogeneous emulsion, and then the organic PH20 solution is added to the second system and mixed well. Solvent is removed under vacuum. The preparation is extruded to obtain the required liposome size and free com Example 10 ponents removed by size-exclusion chromatography using a Sephadex G-50 column (Amersham Pharmacia Biotech, Preparation of a Bisphosphonate Mucoadhesive Uppsala, Sweden). Based Formulation 0777 To prepare the chitosan-glycerophosphate formula tion, a 5 ml solution of acetic acid is titrated to a pH of about 0782 4.0. The chitosan is added to achieve a pH of about 5.5. This solution is sterilized by filtration. A 5 ml aqueous solution of glycerophosphate disodium is also prepared and sterilized. The two solutions are mixed and within2 hat 37°C., and the desired gel is formed. The chitosan-glycerophosphate solu Quantity (mgg of tion is gently mixed with the liposomes at room temperature. Ingredient formulation) risedronate 1O.O Example 8 Sodium citrate 1.25 Preparation of a Bisphosphonate Thermoreversible Sodium ascorbate O.8 Gel Formulation Paraffin oil 200 Hydroxypropyl methylcellulose 10 0778 Cetyl dimethicon copolyol 30 Water qsad 1000 Phosphate buffer pH 7.4 qs pH 7.4 Quantity (mgg of Ingredient formulation) Alendronate Sodium 1O.O 0783 The cream-type formulation is first prepared by gen Sodium citrate 1.25 tly mixing risedronate with a buffer. A second system is Sodium ascorbate O.8 prepared by mixing paraffin oil, hydroxypropyl methylcellu Hyaluronidase PH2O 10 Poloxamer 407 15 lose and cetyl dimethicon copolyol with warming to 60° C. Water qsad 1000 Upon cooling to room temperature, the lipid system is mixed Phosphate buffer pH 7.4 qs pH 7.4 with the aqueous phase for 30 minutes. 0779. The liquid formulation is prepared by mixing alen Example 11 dronate sodium and hyaluronidase PH20 with a buffer to form a first Solution. A second system is prepared by mixing poloX Preparation of a Parathyroid Hormone Mucoadhe amer 407, sodium citrate, and sodium ascorbate in water with sive-Based Formulation warming to 60° C. The first solution is added to the second system and mixed well. 0784) Example 9 Preparation of a Hyaluronidase Thermoreversible Quantity (mgg of Gel Formulation Ingredient formulation) Parathyroid Hormone 1OOO 0780 Sodium citrate 6.75 Sodium ascorbate 4.32 Paraffin oil SOO.O Trihydroxystearate S4.O Cetyl dimethicon copolyol 1620 Quantity (mgg of Water qsad 1000 Ingredient formulation) Phosphate buffer pH 7.4 qs pH 7.4 Hyaluronidase PH2O 2OO Sodium chloride 10 Edetate disodium 1.2 0785. The cream-type formulation is first prepared by gen Calcium chloride O.S Poloxamer 188 12 tly mixing a parathyroid hormone with a buffer. A second Water qsad 1000 system is prepared by mixing paraffin oil, trihydroxyStearate Phosphate buffer pH 7.4 qs pH 7.4 and cetyl dimethicon copolyol with warming to 60°C. Upon cooling to room temperature, the lipid system is mixed with the aqueous phase for 30 minutes. US 2010/0021416 A1 Jan. 28, 2010

Example 12 Example 14 Preparation of a TKIXc Mucoadhesive-Based For Preparation of a FUT-175 Thermoreversible Gel For mulation mulation 0790 0786)

Quantity (mgg of Ingredient formulation) Quantity (mgg of TKIXc 2SO Ingredient formulation) Sodium citrate 3.12S Sodium ascorbate 2.0 Paraffin oil SOO.O Methylparaben 3.0 Trihydroxystearate 2SO Cetyl dimethicon copolyol 75.0 HPMC 3O.O Water qsad 1000 Poloxamer 407 S4O.O Phosphate buffer pH 7.4 qs pH 7.4 TRIS HCl buffer (0.1M) 2424.O FUT-175 3.0 0791. The cream-type formulation is first prepared by gen tly mixing a TKIXc with a buffer. A second system is prepared by mixing paraffin oil, trihydroxyStearate and cetyl dimethi 0787. A 10-g batch of gel formulation containing 0.1% of con copolyol with warming to 60°C. Upon cooling to room FUT-175 is prepared by suspending 1.80 g of Poloxamer 407 temperature, the lipid system is mixed with the aqueous phase (BASF Corp.) in 5.00 g of TRISHC1 buffer (0.1 M) and the for 30 minutes. components are mixed under agitation overnight at 4°C. to Example 15 ensure complete dissolution. The hydroxypropylmethylcel lulose (100.0 mg), methylparaben (10 mg) and additional Preparation of a Heparin Mucoadhesive. Thermor TRIS HCl buffer (0.1 M) (3.08 g) are added and further eversible Gel Formulation stirring allowed until complete dissolution is observed. The 0792 mixture is maintained below room temperature until use.

Example 13 Quantity (mgg of Ingredient formulation) Preparation of a TKIXc Mucoadhesive, Thermor Heparin 1O.O eversible Gel Formulation Methylparaben 1.O Poloxamer 407 18O.O Carbopol 934P 2.O 0788 TRIS HCl buffer (0.1M) 316.O Thimerosal O.1

0793. The Carbopol 934P and Poloxamer 407 (BASF Quantity (mgg of Corp.) is first suspended in the TRISHC1 buffer (0.1 M) and Ingredient formulation) the components are mixed under agitation overnight at 4°C. to ensure complete dissolution. The methylparaben is added TKIXc 4S.O and further stirring allowed until complete dissolution is Methylparaben 4.5 observed. The heparin is mixed in while maintaining stirring HPMC 4S.O to produce a 0.2% collagenase mucoadhesive, thermorevers Carbopol 934P 9.0 ible gel formulation. The mixture is maintained below room Poloxamer 407 810.O temperature until use. TRIS HCl buffer (0.1M) 3586.5 0794. Viscosity determinations of the pharmaceutical compositions described herein are performed at room tem perature and 37° C. and are made using a Brookfield (spindle 0789. A 10-g batch of a mucoadhesive, gel formulation and cup) viscometer at 20 rpm. containing 1.0% of TKIXc is prepared by suspending 20.0 mg of Carbopol 934P and 1.80g of Poloxamer 407 (BASF Corp.) Example 16 in 5.00 g of TRISHC1 buffer (0.1 M) and the components are Application of an Enhanced Viscosity Otic Agent mixed under agitation overnight at 4°C. to ensure complete Formulation onto the Round Window Membrane dissolution. The hydroxypropylmethylcellulose (100.0 mg), 0795. A formulation according to Example 2 is prepared methylparaben (10 mg) and additional TRISHC1 buffer (0.1 and loaded into 5 ml Siliconized glass Syringes attached to a M) (2.97g) are added and further stirring allowed until com 15-gauge luer lock disposable needle. Lidocaine is topically plete dissolution is observed. The mixture is maintained applied to the tympanic membrane, and a small incision made below room temperature until use. to allow visualization into the middle ear cavity. The needle US 2010/0021416 A1 Jan. 28, 2010 69 tip is guided into place over the round window membrane, then 17.05 g of poloxamer 407NF (SPECTRUM CHEMI and the otic agent formulation applied directly onto the CALS) is sprinkled into the cold solution while mixing. The round-window membrane. mixture is further mixed until the poloxamer is completely dissolved. The pH for this solution is measured. Example 17 (0801 17% poloxamer 407/2% otic agent in PBS pH of 5.3. Take an aliquot (approximately 30 mL) of the above Preparation of a Gel/Liposome sOR1-SLe Formula solution and adjust the pH to 5.3 by the addition of 1 MHC1. tion (0802 17% poloxamer 407/2% otic agent in PBS pH of 0796 8.0. Take an aliquot (approximately 30 mL) of the above stock solution and adjust the pH to 8.0 by the addition of 1 M NaOH. (0803 A PBS buffer (pH 7.3) is prepared by dissolving Ingredient Quantity 805.5 mg of sodium chloride (Fisher Scientific), 606 mg of SCR1-SLe 20.0 mgg sodium phosphate dibasic anhydrous (Fisher Scientific), 247 Liposomes 15 umol/ml mg of Sodium phosphate monobasic anhydrous (Fisher Sci Chitosan-Glycerophosphate 100.0 mgg entific), then QS to 200 g with sterile filtered DI water. (0804. A 2% solution of an otic agent in PBS pH 7.3 is 0797 The liposomes are prepared in the presence of the prepared by dissolving an appropriate amount of the otic SCR1-SLe' by the reversed-phase evaporation method, where agent in the PBS buffer and QS to 10 g with PBS buffer. lipids in chloroform or chloroform-methanol (2:1, v/v) are 0805 One mL samples are individually placed in 3 mL deposited on the sides of a tube by evaporation of the organic screw cap glass vials (with rubber lining) and closed tightly. solvent. The lipid film is redissolved in diethyl ether and the The vials are placed in a Market Forge-sterilmatic autoclave aqueous phase (pH 7.4 300 mOsm/kg) containing 20 mM (settings, slow liquids) and sterilized at 250 F. for 15 min Hepes and 144 mM NaCl is added. The mixture is sonicated utes. After the autoclave the samples are left to cool down to to obtain a homogeneous emulsion, and then the organic room temperature and then placed in refrigerator. The Solvent is removed under vacuum. The preparation is samples are homogenized by mixing the vials while cold. extruded to obtain the required liposome size and free com 0806. Appearance (e.g., discoloration and/or precipita ponents removed by size-exclusion chromatography using a tion) is observed and recorded. HPLC analysis is performed Sephadex G-50 column (Amersham Pharmacia Biotech, using an Agilent 1200 equipped with a Luna C18(2)3 um, Uppsala, Sweden). 100 A, 250x4.6 mm column) using a 30-80 acetonitrilegra 0798. To prepare the chitosan-glycerophosphate formula dient (1-10 min) of (water-acetonitrile mixture containing tion, a 5 ml solution of acetic acid is titrated to a pH of about 0.05%TFA), for a total run of 15 minutes. Samples are diluted 4.0. The chitosan is added to achieve a pH of about 5.5. This by taking 30 uL of sample and dissolved with 1.5 mL of a 1:1 solution is sterilized by filtration. A 5 ml aqueous solution of acetonitrile water mixture. Purity of the otic agent in the glycerophosphate disodium is also prepared and sterilized. autoclaved samples is recorded. The two solutions are mixed and within2 hat 37°C., and the 0807. In general the composition should not have any indi desired gel is formed. The chitosan-glycerophosphate solu vidual impurity (e.g., degradation product of otic agent) of tion is gently mixed with the liposomes at room temperature. more than 2% and more preferably not more than one percent. In addition, the composition should not precipitate during Example 18 storage or change in color after manufacturing and storage. 0808 Compositions comprising alprazolam, clonazepam, Application of an Enhanced Viscosity Otic Agent diazepam, or micronized diazepam, prepared according to the Formulation onto the Round Window Membrane procedure in Example 6, are tested using the above procedure 0799. A formulation according to example 2 is prepared to determine the effect of pH on degradation during the auto and loaded into 5 ml Siliconized glass Syringes attached to a claving step. 15-gauge luer lock disposable needle. Lidocaine is topically applied to the tympanic membrane, and a small incision made Example 20 to allow visualization into the middle ear cavity. The needle Effect of Autoclaving on the Release Profile and Vis tip is guided into place over the round window membrane, cosity of a 17% Poloxamer 407NF/2% Otic Agent in and the otic agent formulation applied directly onto the PBS round-window membrane. 0809. An aliquot of the sample from example 6 (auto Example 19 claved and not autoclaved) is evaluated for release profile and Effect of pH on Degradation Products for Auto Viscosity measurement to evaluate the impact of heat steril claved 17% Poloxamer 407NF/2% Otic Agent in ization on the properties of the gel. PBS Buffer 0810 Dissolution is performed at 37°C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 (0800. A stock solution of a 17% poloxamer 407/2% otic um). 0.2 mL of gel is placed into Snapwell and left to harden, agent is prepared by dissolving 351.4 mg of sodium chloride then 0.5 mL is placed into reservoir and shaken using a (Fisher Scientific), 302.1 mg of sodium phosphate dibasic Labline orbit shaker at 70 rpm. Samples are taken every hour anhydrous (Fisher Scientific), 122.1 mg of sodium phosphate (0.1 mL withdrawn and replace with warm buffer). Samples monobasic anhydrous (Fisher Scientific) and an appropriate are analyzed for poloxamer concentration by UV at 624 nm amount of anotic agent with 79.3 g of sterile filtered DI water. using the cobalt thiocyanate method, against an external cali The solution is cooled down in a ice chilled water bath and bration standard curve. In brief, 20 uL of the sample is mixed US 2010/0021416 A1 Jan. 28, 2010 70 with 1980 uL of a 15 mM cobalt thiocyanate solution and (settings, slow liquids) and sterilized at 250 F. for 25 min absorbance measured at 625 nm, using a Evolution 160 utes. After autoclaving the sample is left to cool down to room UV/Vis spectrophotometer (Thermo Scientific). temperature and then placed in refrigerator. The sample is 0811. The released otic agent is fitted to the Korsmeyer homogenized by mixing while the vials are cold. Peppas equation 0817 Precipitation or discoloration are observed after autoclaving. HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2)3 um, 100 A, 250x4.6 mm 9 = k + b column) using a 30-80 acetonitrile gradient (1-10 min) of (water-acetonitrile mixture containing 0.05% TFA), for a total run of 15 minutes. Samples are diluted by taking 30 ul of sample and dissolving with 1.5 mL of a 1:1 acetonitrile where Q is the amount of otic agent released at time t, Q is water mixture. Purity of the otic agent in the autoclaved the overall released amount of otic agent, k is a release con samples is recorded. stant of the nth order, n is a dimensionless number related to 0818 Viscosity measurements are performed using a the dissolution mechanism and b is the axis intercept, char Brookfield viscometer RVDV-II+P with a CPE-51 spindle acterizing the initial burst release mechanism wherein n=1 rotated at 0.08 rpm (shear rate of 0.31 s), equipped with a characterizes an erosion controlled mechanism. The mean water jacketed temperature control unit (temperature ramped dissolution time (MDT) is the sum of different periods of time from 15-34°C. at 1.6°C./min). Tgel is defined as the inflec the drug molecules stay in the matrix before release, divided tion point of the curve where the increase in Viscosity occurs by the total number of molecules and is calculated by: due to the Sol-gel transition. 0819 Dissolution is performed at 37° C. for the non-au klin toclaved sample in Snapwells (6.5 mm diameter polycarbon DT = ate membrane with a pore size of 0.4 um), 0.2 mL of gel is in + 1 placed into snapwell and left to harden, then 0.5 mL is placed into reservoir and shaken using a Labline orbit shaker at 70 0812 Viscosity measurements are performed using a rpm. Samples are taken every hour (0.1 mL withdrawn and Brookfield viscometer RVDV-II+P with a CPE-51 spindle replaced with warm buffer). Samples are analyzed for otic rotated at 0.08 rpm (shear rate of 0.31 s), equipped with a agent concentration by UV at 245 nm, against an external water jacketed temperature control unit (temperature ramped calibration standard curve. from 15-34°C. at 1.6°C/min). Tgel is defined as the inflec 0820 Compositions comprising collagen, keratin, colla tion point of the curve where the increase in Viscosity occurs genase, or micronized collagen are tested using the above due to the sol-gel transition. procedure to determine the effect addition of a secondary 0813 Compositions comprising collagen, keratin, colla polymer on the degradation products and Viscosity of a com genase, or micronized collagen prepared according to the position containing 2% otic agent and 17% poloxamer 407NF procedure in Example 6, are tested using the procedure after heat sterilization (autoclaving). described above to determine Tgel. Example 22 Example 21 Effect of Buffer Type on the Degradation Products Effect of Addition of a Secondary Polymer on the for Compositions Containing Poloxamer 407NF Degradation Products and Viscosity of a Composi after Heat Sterilization (Autoclaving) tion Containing 2% Otic Agent and 17% Poloxamer 407NF after Heat Sterilization (Autoclaving) 0821. A TRIS buffer is made by dissolving 377.8 mg of sodium chloride (Fisher Scientific), and 602.9 mg of 0814 Solution A. A solution of pH 7.0 comprising sodium Tromethamine (Sigma Chemical Co.) then QS to 100 g with carboxymethylcellulose (CMC) in PBS buffer is prepared by sterile filtered DI water, pH is adjusted to 7.4 with 1M HC1. dissolving 178.35 mg of sodium chloride (Fisher Scientific), 300.5 mg of sodium phosphate dibasic anhydrous (Fisher Stock Solution Containing 25% Poloxamer 407 Solution in Scientific), 126.6 mg of sodium phosphate monobasic anhy Tris Buffer: drous (Fisher Scientific) dissolved with 78.4 of sterile filtered DI water, then 1 g of Blanose 7M65 CMC (Hercules, viscos 0822. Weigh 45 g of TRIS buffer, chill in an ice chilled ity of 5450cP(a) 2%) is sprinkled into the buffer solution and bath then sprinkle into the buffer, while mixing, 15 g of heated to aid dissolution, and the solution is then cooled poloxamer 407 NF (Spectrum Chemicals). The mixture is down. further mixed until all the poloxamer is completely dissolved. 0815. A solution of pH 7.0 comprising 17% poloxamer 0823. A series of compositions is prepared with the above 407NF/1% CMC/2% otic agent in PBS buffer is made by stock Solution. An appropriate amount of otic agent (or salt or cooling down 8.1 g of solution A in a ice chilled water bath prodrug thereof) and/or otic agent as micronized/coated/lipo and then adding an appropriate amount of an otic agent fol Somal particles (or salt or prodrug thereof) is used for all lowed by mixing. 1.74 g of poloxamer 407NF (Spectrum experiments. Chemicals) is sprinkled into the cold solution while mixing. The mixture is further mixed until all the poloxamer is com Stock Solution (pH 7.3) Containing 25% Poloxamer 407 pletely dissolved. Solution in PBS Buffer: 0816 Two mL of the above sample is placed in a 3 mL 0824 PBS buffer is prepared by dissolving 704 mg of screw cap glass vial (with rubber lining) and closed tightly. sodium chloride (Fisher Scientific), 601.2 mg of sodium The vial is placed in a Market Forge-sterilmatic autoclave phosphate dibasic anhydrous (Fisher Scientific), 242.7 mg of US 2010/0021416 A1 Jan. 28, 2010

Sodium phosphate monobasic anhydrous (Fisher Scientific) rotated at 0.08 rpm (shear rate of 0.31 s), equipped with a with 140.4 g of sterile filtered DI water. The solution is cooled water jacketed temperature control unit (temperature ramped down in an ice chilled water bath and then 50g of poloxamer from 15-34°C. at 1.6°C./min). Tgel is defined as the inflec 407NF (SPECTRUM CHEMICALS) is sprinkled into the tion point of the curve where the increase in Viscosity occurs cold solution while mixing. The mixture is further mixed until due to the sol-gel transition. Only compositions that show no the poloxamer is completely dissolved. change after autoclaving are analyzed. 0825. A series of compositions is prepared with the above 0830 Compositions comprising Compositions compris stock Solution. An appropriate amount of otic agent (or salt or prodrug thereof) and/or otic agent as micronized/coated/lipo ing collagen, keratin, collagenase, or micronized collagen are Somal particles (or salt or prodrug thereof) is used for all tested using the above procedure to determine the effect addi experiments. tion of a secondary polymer on the degradation products and 0826 Tables 2 and 3 list samples prepared using the pro Viscosity of a composition containing 2% otic agent and 17% cedures described above. An appropriate amount of otic agent poloxamer 407NF after heat sterilization (autoclaving). Sta is added to each sample to provide a final concentration of 2% bility of compositions containing micronized otic agent is otic agent in the sample. compared to non-micronized otic agent composition counter parts. TABLE 2 Preparation of samples containing TRIS buffer Example 23 25% Stock Pulsed Release Otic Compositions Solution TRIS Buffer Sample pH (g) (g) 0831. Diazepam is used to prepare a pulsed release otic 20% P407/2% otic agent/TRIS 7.45 8.O1 1.82 agent composition using the procedures described herein. A 18% P407/2% otic agent/TRIS 7.45 7.22 2.61 16% P407/2% otic agent/TRIS 7.45 6.47 3.42 17% poloxamer solution is prepared by dissolving 351.4 mg 18% P4O72% otic agent/TRIS 7.4 7.18 2.64 of sodium chloride (Fisher Scientific), 302.1 mg of sodium 4% otic agent TRIS 7.5 9.7 phosphate dibasic anhydrous (Fisher Scientific), 122.1 mg of 2% otic agentTRIS 7.43 5 1% otic agentTRIS 7.35 5 Sodium phosphate monobasic anhydrous (Fisher Scientific) 2% otic agentTRIS 7.4 4.9 and an appropriate amount of an otic agent with 79.3 g of (Suspension) sterile filtered DI water. The solution is cooled down in a ice chilled water bath and then 17.05 g of poloxamer 407NF (SPECTRUMCHEMICALS) is sprinkled into the cold solu TABLE 3 tion while mixing. The mixture is further mixed until the poloxamer is completely dissolved. The pH for this solution Preparation of samples containing PBS buffer (pH of 7.3 is measured. 20% of the delivered dose of diazepam is solu 25% Stock Solution bilized in the 17% poloxamer solution with the aid of beta Sample in PBS (g) PBS Buffer (g) cyclodextrins. The remaining 80% of the otic agent is then added to the mixture and the final composition is prepared 20% P407/2% otic agent? 8.03 1.82 PBS using any procedure described herein. 18% P407/2% otic agent? 7.1 2.63 0832 Pulsed release compositions comprising Composi PBS 16% P407/2% otic agent? 6.45 3.44 tions comprising collagen, keratin, collagenase, or micron PBS ized collagen prepared according to the procedures and 18% P407/2% otic agent? 2.63 examples described herein, are tested using procedures PBS 2% otic agent/PBS 4.9 described herein to determine pulse release profiles.

0827. One mL samples are individually placed in 3 mL Example 24 screw cap glass vials (with rubber lining) and closed tightly. The vials are placed in a Market Forge-sterilmatic autoclave Preparation of a 17% Poloxamer 407/2% Otic Agent/ (setting, slow liquids) and sterilized at 250°F. for 25 minutes. 78 Ppm Evans Blue in PBS After the autoclaving the samples are left to cool down to room temperature. The vials are placed in the refrigerator and 0833. A Stock solution of Evans Blue (5.9 mg/mL) in PBS mixed while cold to homogenize the samples. buffer is prepared by dissolving 5.9 mg of Evans Blue (Sigma 0828 HPLC analysis is performed using an Agilent 1200 Chemical Co) with 1 mL of PBS buffer. PBS buffer is pre equipped with a Luna C18(2) 3 um, 100 A, 250x4.6 mm pared by dissolving 704 mg of sodium chloride (Fisher Sci column) using a 30-80 acetonitrile gradient (1-10 min) of entific), 601.2 mg of sodium phosphate dibasic anhydrous (water-acetonitrile mixture containing 0.05% TFA), for a (Fisher Scientific), 242.7 mg of sodium phosphate monobasic total run of 15 minutes. Samples are diluted by taking 30 ul anhydrous (Fisher Scientific) with 140.4 g of sterile filtered of sample and dissolving with 1.5 mL of a 1:1 acetonitrile DI water. water mixture. Purity of the otic agent in the autoclaved 0834. A Stock solution containing 25% Poloxamer 407 samples is recorded. The stability of compositions in TRIS solution in PBS buffer (as in Example 9) is used in this study. and PBS buffers is compared. An appropriate amount of an otic agent is added to the 25% 0829. Viscosity measurements are performed using a Poloxamer 407 solution stock solution to prepare composi Brookfield viscometer RVDV-II+P with a CPE-51 spindle tions comprising 2% of an otic agent (Table 4). US 2010/0021416 A1 Jan. 28, 2010 72

utes. After the autoclaving the samples are left to cool downto TABLE 4 room temperature and then placed in refrigeration. The vials are placed in the refrigerator and mixed while cold to homog Preparation of poloxamer 407 samples containing Evans Blue enize the samples. Sample discoloration or precipitation after 25% P4O7in Evans Blue autoclaving is recorded. Sample ID PBS (g) PBS Buffer (g) Solution (IL) 0843 HPLC analysis is performed using an Agilent 1200 17% P407/2% otic agent? 13.6 6 26S equipped with a Luna C18(2) 3 m, 100 A, 250x4.6 mm EB column) using a 30-95 methanol:acetate buffer pH 4 gradient 20% P407/2% otic agent? 16.019 3.62 26S (1-6 min), then isocratic for 11 minutes, for a total run of 22 EB minutes. Samples are diluted by taking 30 ul of sample and 25% P407/2% otic agent? 1963 26S dissolved with 0.97 mL of water. The main peaks are recorded EB in the table below. Purity before autoclaving is always greater than 99% using this method. 0835 Compositions comprising collagen, keratin, colla 0844 Viscosity measurements are performed using a genase, or micronized collagen are prepared according to the Brookfield viscometer RVDV-II+P with a CPE-51 spindle procedures in Example 12 and are sterile filtered through 0.22 rotated at 0.08 rpm (shear rate of 0.31 s), equipped with a um PVDF syringe filters (Millipore corporation), and auto water jacketed temperature control unit (temperature ramped claved. from 15-34°C. at 1.6°C./min). Tgel is defined as the inflec 0836. The above compositions are dosed to guinea pigs in tion point of the curve where the increase in Viscosity occurs the middle ear by procedures described herein and the ability due to the Sol-gel transition. of compositions to gel upon contact and the location of the gel 0845 Compositions comprising collagen, keratin, colla is identified after dosing and at 24 hours after dosing. genase, or micronized collagen prepared according to the procedure in Example 11, are tested using the above proce Example 25 dures to determine stability of the compositions. Terminal Sterilization of Poloxamer 407 Composi Example 26 tions with and without a Visualization Dye In Vitro Comparison of Release Profile 0837, 17% poloxamer 407/2% otic agent/in phosphate buffer, pH 7.3: Dissolve 709 mg of sodium chloride (Fisher 0846 Dissolution is performed at 37°C. in snapwells (6.5 Scientific), 742 mg of sodium phosphate dibasic dehydrate mm diameter polycarbonate membrane with a pore size of 0.4 USP (Fisher Scientific), 251.1 mg of sodium phosphate um), 0.2 mL of a gel composition described herein is placed monobasic monohydrate USP (Fisher Scientific) and an into snapwell and left to harden, then 0.5 mL buffer is placed appropriate amount of an otic agent with 158.1 g of sterile into reservoir and shaken using a Labline orbit shaker at 70 filtered DI water. The solution is cooled down in an ice chilled rpm. Samples are taken every hour (0.1 mL withdrawn and water bath and then 34.13 g of poloxamer 407NF (Spectrum replace with warm buffer). Samples are analyzed for otic chemicals) is sprinkled into the cold solution while mixing. agent concentration by UV at 245 nm against an external The mixture is further mixed until the poloxamer is com calibration standard curve. Pluronic concentration is ana pletely dissolved. lyzed at 624 nm using the cobalt thiocyanate method. Relative 0838 17% poloxamer 407/2% otic agent/59 ppm Evans rank-order of mean dissolution time (MDT) as a function of blue in phosphate buffer: Take two mL of the 17% poloxamer % P407 is determined. A linear relationship between the 407/2% otic agent/in phosphate buffer solution and add 2 mL compositions mean dissolution time (MDT) and the P407 of a 5.9 mg/mL Evans blue (Sigma-Aldrich chemical Co) concentration indicates that the otic agent is released due to Solution in PBS buffer. the erosion of the polymer gel (poloxamer) and not via dif 0839 25% poloxamer 407/2% otic agent/in phosphate fusion. A non-linear relationship indicates release of otic buffer: Dissolve 330.5 mg of sodium chloride (Fisher Scien agent via a combination of diffusion and/or polymer gel deg tific), 334.5 mg of sodium phosphate dibasic dehydrate USP radation. (Fisher Scientific), 125.9 mg of sodium phosphate monobasic 0847. Alternatively, samples are analyzed using the monohydrate USP (Fisher Scientific) and an appropriate method described by Li Xin-Yu paper Acta Pharmaceutica amount of anotic agent with 70.5g of sterile filtered DI water. Sinica 2008, 43(2):208-203 and Rank-order of mean disso 0840. The solution is cooled down in an ice chilled water lution time (MDT) as a function of% P407 is determined. bath and then 25.1 g of poloxamer 407NF (Spectrum chemi 0848 Compositions comprising collagen, keratin, colla cals) is sprinkled into the cold solution while mixing. The genase, or micronized collagen prepared according to the mixture is further mixed until the poloxamer is completely procedures described herein, are tested using the above pro dissolved. cedure to determine the release profile of the otic agents. 0841 25% poloxamer 407/2% otic agent/59 ppm Evans blue in phosphate buffer: Take two mL of the 25% poloxamer Example 27 407/2% otic agent/in phosphate buffer solution and add 2 mL In Vitro Comparison of Gelation Temperature of a 5.9 mg/mL Evans blue (Sigma-Aldrich chemical Co) Solution in PBS buffer. 0849. The effect of Poloxamer 188 and anotic agent on the 0842 Place 2 mL of composition into a 2 mL glass vial gelation temperature and viscosity of Poloxamer 407 compo (Wheaton serum glass vial) and seal with 13 mm butyl str sitions is evaluated with the purpose of manipulating the (kimble stoppers) and crimp with a 13 mm aluminum seal. gelation temperature. The vials are placed in a Market Forge-sterilmatic autoclave 0850. A 25% Poloxamer 407 stock solution in PBS buffer (settings, slow liquids) and sterilized at 250 F. for 25 min (as in Example 9) and a PBS solution (as in Example 11) are US 2010/0021416 A1 Jan. 28, 2010

used. Poloxamer 188NF from BASF is used. An appropriate Example 29 amount of otic agent is added to the solutions described in Table 5 to provide a 2% composition of the otic agent. Determination of Manufacturing Conditions TABLE 5 0859 Preparation of Samples containing poloxaner 407 poloxamer 188 TABLE 6 25% P407 Stock Poloxamer PBS Buffer Viscosity of potential compositions at Sample Solution (g) 188 (mg) (g) manufacturing/filtration conditions. 16% P4O7.10% P188 3.2O7 5O1 1.3036 17% P4O7.10% P188 3.4089 500 1.1056 Apparent Viscosity (CP Temperature (a) 18% P4O7.10% P188 3.61S6 5O2 O.9072 19% P4O7.10% P188 3.8183 500 0.7050 Sample 5° C. below Tgel 20° C. 100 CP 20% P4O7.10% P188 4.008 5O1 OSO32 20% P4O7.5% P188 4.01 256 0.770 Placebo 52 cP (a) 17° C. 120 cp 19° C. 17% P4O7.20 otic 90 cP (a) 18° C. 147 CF 18.5° C. agent 17% P4O7.6% otic 142 cP (a) 22°C. 105 cF 19.7 C. 0851 Mean dissolution time, viscosity and gel tempera agent ture of the above compositions are measured using proce dures described herein. Viscosity measured at a shear rate of 37.5 s 0852. An equation is fitted to the data obtained and can be 0860. An 8 liter batch of a 17% P407 placebo is manufac utilized to estimate the gelation temperature of F127/F68 tured to evaluate the manufacturing/filtration conditions. The mixtures (for 17-20% F127 and 0-10% F68). placebo is manufactured by placing 6.4 liters of DI water in a 3 gallon SS pressure vessel, and left to cool down in the 0853. An equation is fitted to the data obtained and can be refrigerator overnight. The following morning the tank was utilized to estimate the Mean Dissolution Time (hr) based on taken out (water temperature 5°C., RT 18°C.) and 48g of the gelation temperature of F127/F68 mixtures (for 17-25% sodium chloride, 29.6 g of sodium phosphate dibasic dehy F127 and 0-10% F68), using results obtained in example 13 drate and 10g of sodium phosphate monobasic monohydrate and 15. is added and dissolved with an overhead mixer (IKARW20 (a) 1720 rpm). Half hour later, once the buffer is dissolved (solution temperature 8°C., RT 18°C.), 1.36 kg of poloxamer 0854 Compositions comprising collagen, keratin, colla genase, or micronized collagen are prepared by addition of an 407 NF (spectrum chemicals) is slowly sprinkled into the appropriate amount of otic agents to the Solutions described buffer solution in a 15 minute interval (solution temperature in Table 5. The gel temperature of the compositions is deter 12°C., RT 18°C.), then speed is increased to 2430 rpm. After mined using the procedure described above. an additional one hour mixing, mixing speed is reduced to 1062 rpm (complete dissolution). Example 28 0861. The temperature of the room is maintained below 25°C. to retain the temperature of the solution at below 19°C. Determination of Temperature Range for Sterile Fil The temperature of the solution is maintained at below 19°C. tration up to 3 hours of the initiation of the manufacturing, without the need to chill/cool the container. 0855. The viscosity at low temperatures is measured to help guide the temperature range at that the Sterile filtration 0862 Three different Sartoscale (Sartorius Stedim) filters needs to occur to reduce the possibility of clogging. with a surface area of 17.3 cm are evaluated at 20 psi and 14° 0856 Viscosity measurements are performed using a C. of solution Brookfield viscometer RVDV-II+P with a CPE-40 spindle 0863. 1) Sartopore 2, 0.2 pm 5445307HS-FF (PES), flow rotated at 1, 5 and 10 rpm (shear rate of 7.5, 37.5 and 75 s), rate of 16 mL/min equipped with a waterjacketed temperature control unit (tem 0864. 2) Sartobran P, 0.2 um 5235307HS-FF (cellulose perature ramped from 10-25°C. at 1.6°C./min). ester), flow rate of 12 mL/min 0857. The Tgel of a 17% Pluronic P407 is determined as a 0865 3) Sartopore 2 XLI, 0.2 pm 5445307IS-FF (PES), function of increasing concentration of otic agent. The flow rate of 15 mL/min increase in Tgel for a 17% pluronic composition is estimated by: 0866 Sartopore 2 filter 5441307H4-SS is used, filtration is carried out at the Solution temperature using a 0.45, 0.2 um AT=0.93% otic agent Sartopore 2 150 sterile capsule (Sartorius Stedim) with a 0858 Compositions comprising collagen, keratin, colla surface area of 0.015 m at a pressure of 16 psi. Flow rate is genase, or micronized collagen prepared according to proce measured at approximately 100 mL/min at 16 psi, with no dures described herein, are tested using the above procedure change in flow rate while the temperature is maintained in the to determine the temperature range for sterile filtration. The 6.5-14° C. range. Decreasing pressure and increasing tem effect of addition of increased amounts of otic agent on the perature of the solution causes a decrease in flow rate due to Tgel, and the apparent viscosity of the compositions is an increase in the viscosity of the solution. Discoloration of recorded. the solution is monitored during the process. US 2010/0021416 A1 Jan. 28, 2010 74

buffer containing 2% PEG-40 hydrogenated castor oil TABLE 7 (BASF) to enhance otic agent solubility. Samples are ana lyzed for otic agent concentration by UV at 245 nm againstan Predicted filtration time for a 17% poloxamer 407 placebo at a external calibration standard curve. The release rate is com solution temperature range of 6.5-14°C. using Sartopore 2, 0.2 in filters at a pressure of 16 psi of pressure. pared to other compositions disclosed herein. MDT time is calculated for each sample. Estimated flow rate Time to filter 8 L 0871 Solubilization of otic agent in the 17% poloxamer Filter Size (m) (mL/min) (estimated) system is evaluated by measuring the concentration of the otic Sartopore 2, size 4 O.O15 100 mL/min 80 min agent in the Supernatant after centrifuging samples at 15,000 Sartopore 2, size 7 O.OS 330 mL/min 24 min rpm for 10 minutes using an eppendorf centrifuge 5424. otic Sartopore 2, size 8 O.1 670 mL/min 12 min agent concentration in the Supernatant is measured by UV at 245 nm against an external calibration standard curve. 0867 Viscosity, Tgel and UV/Vis absorption is check 0872 Compositions comprising collagen, keratin, colla before filtration evaluation. Pluronic UV/Vis spectra are genase, or micronized collagen prepared according to the obtained by a Evolution 160 UV/Vis (Thermo Scientific). A procedures described herein, are tested using the above pro peak in the range of 250-300 nm is attributed to BHT stabi cedures to determine release rate of the otic agent from each lizer present in the raw material (poloxamer). Table 8 lists composition. physicochemical properties of the above solutions before and after filtration. Example 31 Release Rate or MDT and Viscosity of Composition TABLE 8 Containing Sodium Carboxymethyl Cellulose Physicochemical properties of 17% poloxamer 407 placebo solution before and after filtration 0873. 17% poloxamer 407/2% otic agent/1% CMC (Her cules Blanose 7M): A sodium carboxymethylcellulose Viscosity' (a) 19°C. Absorbance (a) (CMC) solution (pH 7.0) in PBS buffer is prepared by dis Sample Tgel ( C.) (cP) 274 mm solving 205.6 mg of sodium chloride (Fisher Scientific), Before filtration 22 1OO O.3181 372.1 mg of sodium phosphate dibasic dihydrate (Fisher Sci After filtration 22 1OO O3O81 entific), 106.2 mg of sodium phosphate monobasic monohy drate (Fisher Scientific) in 78.1 g of sterile filtered DI water. Viscosity measured at a shear rate of 37.5 s 1 g of Blanose 7MCMC (Hercules, viscosity of 533cP(a) 2%) 0868. The above process is applicable for manufacture of is sprinkled into the buffer solution and heated to ease solu 17% P407 compositions, and includes temperature analysis tion, solution is then cooled down and 17.08 g poloxamer of the room conditions. Preferably, a maximum temperature 407NF (Spectrum Chemicals) is sprinkled into the cold solu of 19°C. reduces cost of cooling the container during manu tion while mixing. A composition comprising 17% poloX facturing. In some instances, a jacketed container is used to amer 407NF/1% CMC/2% otic agent in PBS buffer is made further control the temperature of the solution to ease manu adding/dissolving an appropriate amount of otic agent to 9.8 facturing concerns. g of the above Solution, and mixing until all the otic agent is completely dissolved. Example 30 0874) 17% poloxamer 407/2% otic agent/0.5% CMC (B1 anose 7M65): A sodium carboxymethylcellulose (CMC) In Vitro Release of Otic Agent from an Autoclaved solution (pH 7.2) in PBS buffer is prepared by dissolving 257 Micronized Sample mg of sodium chloride (Fisher Scientific), 375 mg of sodium 0869 17% poloxamer 407/1.5% otic agentin TRIS buffer: phosphate dibasic dihydrate (Fisher Scientific), 108 mg of 250.8 mg of sodium chloride (Fisher Scientific), and 302.4 Sodium phosphate monobasic monohydrate (Fisher Scien mg of Tromethamine (Sigma Chemical Co.) is dissolved in tific) in 78.7 g of sterile filtered DI water. 0.502 g of Blanose 39.3 g of sterile filtered DI water, pH is adjusted to 7.4 with 7M65 CMC (Hercules, viscosity of 5450cP (a) 2%) is 1M HCl. 4.9 g of the above solution is used and an appropriate sprinkled into the buffer solution and heated to ease solution, amount of micronized otic agent is Suspended and dispersed solution is then cooled down and 17.06 g poloxamer 407NF well. 2 mL of the composition is transferred into a 2 mL glass (Spectrum Chemicals) is sprinkled into the cold solution vial (Wheaton serum glass vial) and sealed with 13 mm butyl while mixing. A 17% poloxamer 407NF/1% CMC/2% otic styrene (kimble stoppers) and crimped with a 13 mm alumi agent solution in PBS buffer is made adding/dissolving an num seal. The vial is placed in a Market Forge-sterilmatic appropriate amount of otic agent to 9.8g of the above solu autoclave (settings, slow liquids) and sterilized at 250°F. for tion, and mixing until the otic agent is completely dissolved. 25 minutes. After the autoclaving the sample is left to cool 0875) 17% poloxamer 407/2% otic agent/0.5% CMC (B1 down to room temperature. The vial is placed in the refrig anose 7H9): A sodium carboxymethylcellulose (CMC) solu erator and mixed while cold to homogenize the sample. tion (pH 7.3) in PBS buffer is prepared by dissolving 256.5 Sample discoloration or precipitation after autoclaving is mg of sodium chloride (Fisher Scientific), 374 mg of sodium recorded. phosphate dibasic dihydrate (Fisher Scientific), 107 mg of 0870 Dissolution is performed at 37° C. in snapwells (6.5 Sodium phosphate monobasic monohydrate (Fisher Scien mm diameter polycarbonate membrane with a pore size of 0.4 tific) in 78.6 g of sterile filtered DI water, then 0.502 g of um), 0.2 mL of gel is placed into Snapwell and left to harden, Blanose 7H9 CMC (Hercules, viscosity of 5600cP(a) 1%) is then 0.5 mL PBS buffer is placed into reservoir and shaken sprinkled to the buffer solution and heated to ease solution, using a Labline orbit shaker at 70 rpm. Samples are taken solution is then cooled down and 17.03 g poloxamer 407NF every hour 0.1 mL withdrawn and replaced with warm PBS (Spectrum Chemicals) is sprinkled into the cold solution US 2010/0021416 A1 Jan. 28, 2010 while mixing. A 17% poloxamer 407NF/1% CMC/2% otic 17% Pluronic F-127 composition buffered at 280 mOsm/kg agent solution in PBS buffer is made adding/dissolving an and containing 1.5% to 4.5% of an otic structure modulating appropriate amount of otic agent to 9.8 of the above solution, agent or innate immune system modulating agent by weight and mixing until the otic agent is completely dissolved. of the composition. Animals are dosed on day 1. The release 0876 Viscosity measurements are performed using a profile for the compositions is determined based on analysis Brookfield viscometer RVDV-II+P with a CPE-40 spindle of the perilymph. rotated at 0.08 rpm (shear rate of 0.6 s), equipped with a water jacketed temperature control unit (temperature ramped Example 35 from 10-34°C. at 1.6°C/min). Tgel is defined as the inflec tion point of the curve where the increase in Viscosity occurs Effect of Poloxamer Concentration and Active Agent due to the sol-gel transition. Concentration on Release Kinetics 0877 Dissolution is performed at 37° C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 0882. A series of compositions comprising varying con um). 0.2 mL of gel is placed into Snapwell and left to harden, centrations of a gelling agent and micronized dexamethasone then 0.5 mL PBS buffer is placed into reservoir and shaken was prepared using procedures described above. The mean using a Labline orbit shaker at 70 rpm. Samples are taken dissolution time (MDT) for each composition in Table 9 was every hour, 0.1 mL withdrawn and replaced with warm PBS determined using procedures described above. buffer. Samples are analyzed for otic agent concentration by UV at 245 nm against an external calibration standard curve. TABLE 9 MDT time is calculated for each of the above compositions. Preparation of poloxanerotic agent compositions 0878 Compositions comprising collagen, keratin, colla genase, or micronized collagen prepared according to proce Sample pH MDT dures described above, are tested using the above procedures 15.5% P4O71.5% dexamethasone, PBS 7.4 46h to determine relationship between release rate and/or mean 16% P4O71.5% dexamethasone, PBS 7.4 40 h. dissolution time and Viscosity of composition containing 17% P4O71.5% dexamethasone, PBS 7.4 39 15.5% P4O7. 4.5% dexamethasone, PBS 7.4 >7 days sodium carboxymethyl cellulose. Any correlation between 16% P4O7. 4.5% dexamethasone, PBS 7.4 >7 days the mean dissolution time (MDT) and the apparent viscosity 17% P4O7. 4.5% dexamethasone, PBS 7.4 >7 days (measured at 2° C. below the gelation temperature) is recorded. 0883. The effect of gel strength and otic agent concentra Example 32 tion on release kinetics of an otic agent from the composition Application of an Enhanced Viscosity Otic Structure or device was determined by measurement of the MDT for Modulating Agent or Innate Immune System Modu poloxamer, and measurement of MDT for otic agent. The half lating Agent Composition onto the Round Window life of the otic agent and mean residence time of the otic agent was also determined for each formulation by measurement of Membrane concentration of the otic agent in the perilymph. 0879. A composition according to Example 2 is prepared 0884 The apparent viscosity of each composition was and loaded into 5 ml Siliconized glass Syringes attached to a measured as described above. A thermoreversible polymer 15-gauge luer lock disposable needle. Lidocaine is topically gel concentration of about 15.5% in a composition or device applied to the tympanic membrane, and a small incision made described above provided an apparent viscosity of about 270, to allow visualization into the middle ear cavity. The needle 000 cp. A thermoreversible polymer gel concentration of tip is guided into place over the round window membrane, about 16% in a composition or device described above pro and the composition applied directly onto the round-window vided an apparent viscosity of about 360,000 cp. A thermor membrane. eversible polymer gel concentration of about 17% in a com position or device described above provided an apparent Example 33 viscosity of about 480,000 cB. In Vivo Testing of Intratympanic Injection of a Otic 0885 Compositions comprising collagen, keratin, colla Structure Modulating Composition in a Guinea Pig genase, or micronized collagen, prepared according to the 0880. A cohort of 21 guinea pigs (Charles River, females procedures described herein, are tested using the above pro weighing 200-300 g) is intratympanically injected with 50LL cedure to determine release rate of the otic agent from each of different P407-DSP compositions described herein, con composition. taining 0 to 6% of an otic agent. The gel elimination time course for each composition is determined. A faster gel elimi Example 36 nation time course of a composition indicates lower mean dissolution time (MDT). Thus the injection volume and the Evaluation of Otic Agent Formulations in an Otitis concentration of an otic structure modulating agent or innate Media Animal Model immune system modulating agent in a composition are tested 0886 Induction of Otitis Media to determine optimal parameters for preclinical and clinical 0887 Healthy adult chinchillas weight 400 to 600 g with studies. normal middle ears, ascertained by otoscopy and tympanom Example 34 etry are used for these studies. Eustachian tube obstruction is performed 24 hours before inoculation to prevent the inocu In Vivo Extended Release Kinetics lum from flowing out of the eustachian tube. One milliliter of 0881. A cohort of 21 guinea pigs (Charles River, females type 3 S. pneumoniae Strain at 4-h-log phase (containing weighing 200-300 g) is intratympanically injected with 50LL approximately 40 colony forming units (CFU)) is placed US 2010/0021416 A1 Jan. 28, 2010 76 directly into both middle ear hypotympanic bullae of the histological analysis and stained with AZure or tartrate resis chinhillas. Control mice are inoculated with one milliliter tant acid phosphatase stain, which evaluates osteoclast activ Sterile PBS. 0888 Treatment 0889. S. pneumoniae inoculated and control mice are Example 39 Sorted into two groups (n=10 in each group). Otic agent formulation of Example 3 containing hyaluronidase is Clinical Trials of Hyaluronidase in Otitis Media with applied to the walls of the tympanic cavity of one group of Effusion Patients animals. Control formulation containing no hyaluronidase is applied to the second group. The hyaluronidase and control (0894 Study Objective formulations are reapplied three days after the initial appli 0895. The primary objective of this study will be to assess cation. The animals are sacrificed after the seventh day of the safety and efficacy of hyaluronidase compared with that treatment. of placebo in ameliorating otitis media with effusion symp (0890 Analysis of Results toms in afflicted patients. 0891. The amount of auris media ear fluid (MEF) is mea sured at 12, 24, 48, 72, 96, 120, and 148 hours after pneu Methods moccal inocualtion. Hearing analysis is also performed at 12, (0896 Study Design 24, 48, 72.96, 120, and 148 hours after pneumoccal inocual (0897. This will be a phase 3, multicentre, double-blind, tion. Finally, balance analysis is performed at 12, 24, 48,72, randomised, placebo-controlled, three-arm study comparing 96, 120, and 148 hours after pneumoccal inocualtion. TKIXc (100 mg and 200 mg) to placebo in the treatment of otitis media with effusion symptoms. Approximately 150 Example 37 subjects will be enrolled in this study, and randomised (1:1) to 1 of 3 treatment groups based on a randomisation sequence Evaluation of Otic Agent Formulations in Tympanic prepared by sponsor. Each group will receive 200 mg con Membrane Perforation Animal Model trolled release hyaluronidase, 400 mg controlled release hyaluronidase, or controlled release placebo formulation. 0892. Otic agent formulations of Example 3 are tested in a 0898. After a 1-week baseline phase, patients from each tympanic membrane perforation animal model described in group will be randomized to a 16 week double treatment Amoils, C. P. et al. Otolaryngol Head Neck Surg. (1992), period (8-week treatment followed by an 8-week mainte 106,47-55. A cohort of 20 Chinchillas is divided into control/ nance period). Primary efficacy will be measured as a per untreated and test/treated groups for comparison of the effect centage change in the amount of fluids (i.e. effusions) seen in of the otic agent formulation on tympanic membrane healing. the ears of the subjects. The animals are subjected to thermal myringectomy followed by medial infolding of tympanic membrane microflaps, resulting in permanent Subtotal chronic tympanic membrane Example 40 perforations. The animals are kept under observation for 6-8 Clinical Trials of Bisphosphonates in Patients Suffer weeks to ensure chronicity of tympanic membrane perfora ing from Otosclerosis tions. Any animal demonstrating otitis externa, or otitis media are discarded. Any animal with spontaneous closure of the (0899 Study Objective perforation is excluded from the study. At the end of the 0900. The primary objective of this study will be to assess observation period, the animals are treated with the compo the safety and efficacy of bisphosphonates compared with sition of Example 1 once a day for three weeks. The animals that of placebo in improving hearing in afflicted patients. are examined by visual otologic exam weekly for closure of the perforation. Progression of healing is also recorded. Methods Example 38 (0901 Study Design 0902. This will be a phase 3, multicentre, double-blind, Evaluation of Otic Agent Formulations in an Oto randomised, placebo-controlled, three-arm study comparing sclerosis Animal Model the efficacy of risendronate (100 mg and 200 mg) to placebo in the treatment of otosclerosis. Approximately 150 subjects 0893. Otic agent formulations of Example 8 are tested in will be enrolled in this study, and randomised (1:1) to 1 of 3 an otosclerosis animal model described in ARO abstracts, treatment groups based on a randomisation sequence pre 2008, abstract 352, Bisphosphonates Inhibit Bone Remodel pared by sponsor. Each group will receive 200 mg of risen ing in the Otic Capsule of Osteoprotegerin Deficient Mouse, dronate mucoadhesive formulation, 400 mg of risendronate an Animal Model of Otosclerosis. Three week old OPG mucoadhesive formulation, or mucoadhesive placebo formu knockout mice are treated with the formulation of Example 8 lation. Inclusion criteria include otosclerosis where Surgery is (100 microgram/kg/day, 6 days, or 500 microgram/kg/day, 6 planned, air/bone gap larger than 20 dB and normal middle days) and sacrificed 9 and 18 weeks later. Prior to sacrifice, ear status. Exclusion criteria are pregnancy, deafness on other hearing is evaluated with auditory brainstem evoked response ear or stapedectomy previously performed on ear. and distortion product otoacoustic emissions. Bone remodel 0903. After a 1-week baseline phase, patients from each ing is evaluated as follows: temporal bones are processed for group will be randomized to a 16 week double treatment US 2010/0021416 A1 Jan. 28, 2010 77 period (8-week treatment followed by an 8-week mainte ments are provided by way of example only. Various alterna nance period). Primary efficacy will be measured as a change tives to the embodiments described herein are optionally in hearing thresholds. employed in practicing the inventions. It is intended that the following claims define the scope of the invention and that Example 41 methods and structures within the scope of these claims and Evaluation of Otic Agent Formulations in an Otitis their equivalents be covered thereby. Media Animal Model We claim: 0904 Induction of Otitis Media 1. A pharmaceutical composition or device, comprising: a (0905 Healthy adult chinchillas weight 400 to 600 g with therapeutically effective amount of a otic structure degrading normal middle ears, ascertained by otoscopy and tympanom agent having Substantially low degradation products; and etry are used for these studies. Eustachian tube obstruction is wherein the composition or device comprises two or more performed 24 hours before inoculation to prevent the inocu characteristics selected from: lum from flowing out of the eustachian tube. One milliliter of (i) between about 0.1% to about 10% by weight of the otic type 3 S. pneumoniae Strain at 4-h-log phase (containing structure degrading agent, or pharmaceutically accept approximately 40 colony forming units (CFU)) is placed able prodrug or salt thereof; directly into both middle ear hypotympanic bullae of the (ii) between about 14% to about 21% by weight of a poly chinhillas. Control mice are inoculated with one milliliter oxyethylene-polyoxypropylene triblock copolymer of Sterile PBS. general formula E106 P70 E106: 0906 Treatment (iii) sterile water, q.s., buffered to provide a pH between 0907 S. pneumoniae inoculated and control mice are about 5.5 and about 8.0: Sorted into two groups (n=10 in each group). Otic agent (iv) multiparticulate otic structure degrading agent; formulation of Example 3 is applied to the walls of the tym (v) a gelation temperature between about 19°C. to about panic cavity of one group of animals. A control formulation 42°C.; containing no active agent is applied to the second group. The (vi) less than about 50 colony forming units (cfu) of micro formulations are reapplied three days after the initial appli biological agents per gram of composition; cation. The animals are sacrificed after the seventh day of treatment. (vii) less than about 5 endotoxin units (EU) per kg of body (0908 Analysis of Results weight of a Subject; (0909. The amount of auris media ear fluid (MEF) is mea (viii) a mean dissolution time of about 30 hours for the otic sured at 12, 24, 48, 72, 96, 120, and 148 hours after pneu Structure degrading agent; and moccal inocualtion. Hearing analysis is also performed at 12, (ix) an apparent viscosity of about 100,000 cp to about 24, 48, 72.96, 120, and 148 hours after pneumoccal inocual 500,000 cP. tion. Finally, balance analysis is performed at 12, 24, 48,72, 2. The pharmaceutical composition or device of claim 1, 96, 120, and 148 hours after pneumoccal inocualtion. wherein the composition or device comprises: (i) between about 0.1% to about 10% by weight of the otic Example 42 structure degrading agent, or pharmaceutically accept able prodrug or salt thereof; Clinical Trials of TKIXc in Otitis Media Patients (ii) between about 14% to about 21% by weight of a poly (0910 Study Objective oxyethylene-polyoxypropylene triblock copolymer of 0911. The primary objective of this study will be to assess general formula E106 P70 E106: the safety and efficacy of TKIXc compared with that of pla (iii) multiparticulate the otic structure degrading agent; and cebo in ameliorating otitis media with effusion symptoms in (iv) a gelation temperature between about 19°C. to about afflicted patients. 42O C. 3. The pharmaceutical composition or device of claim 1 Methods wherein the composition or device provides a practical osmo (0912 Study Design larity between about 200 and 400 mOsm/L. 0913. This will be a phase 3, multicentre, double-blind, 4. The pharmaceutical composition or device of claim 1, randomised, placebo-controlled, three-arm study comparing wherein the otic structure degrading agent is released for a TKIXc (100 mg and 200 mg) to placebo in the treatment of period of at least 3 days. otitis media with effusion symptoms. Approximately 150 5. The pharmaceutical composition or device of claim 1, subjects will be enrolled in this study, and randomised (1:1) to wherein the pharmaceutical composition is an auris-accept 1 of 3 treatment groups based on a randomisation sequence able thermoreversible gel. prepared by sponsor. Each group will receive 200 mg con 6. The pharmaceutical composition or device of claim 1, trolled release TKIXc, 400 mg controlled release TKIXc, or further comprising a dye. controlled release placebo formulation. 7. The pharmaceutical composition or device of claim 1, 0914. After a 1-week baseline phase, patients from each wherein the otic structure degrading agent is an alcohol, an group will be randomized to a 16 week double treatment alkanol, an essential oil, a fatty acid, a glycol, laurocapram, a period (8-week treatment followed by an 8-week mainte pyrrolidone, a Sulfoxide, a Surfactant, an enzyme, or a com nance period). Primary efficacy will be measured as a per bination thereof. In some embodiments, the enzyme is a pro centage change in the amount of fluids (i.e. effusions) seen in tease, a glycosidase, protease, a glycosidase, an actinase, a the ears of the subjects. caseinase, a chondroitinase, a collagenase, a dermatanase, an (0915. While preferred embodiments of the present disclo elastase, a gelatinase, a heparanase, a hyaluronidase, a kera sure have been shown and described herein, such embodi tinase, a lipase, a metalloproteinase (e.g. matrix metallopro US 2010/0021416 A1 Jan. 28, 2010

teinase), a staphylokinase, a streptokinase, chymotrypsin, (ii) between about 14% to about 21% by weight of a poly endopeptidase V8, trypsin, thermolysin, pepsin, plasmin, or oxyethylene-polyoxypropylene triblock copolymer of combinations thereof. general formula E106 P70 E106: 8. The pharmaceutical composition or device of claim 1, (iii) sterile water, q.s., buffered to provide a pH between wherein the otic structure degrading agent comprises multi about 5.5 and about 8.0: particulates. (iv) multiparticulate otic structure degrading agent; 9. The pharmaceutical composition or device of claim 1, (v) a gelation temperature between about 19°C. to about 42°C.; wherein the otic structure degrading agent is essentially in the (vi) less than about 50 colony forming units (cfu) of micro form of micronized particles. biological agents per gram of composition, and 10. The pharmaceutical composition or device of claim 1, (vii) less than about 5 endotoxin units (EU) per kg of body wherein the pH of the composition or device is between about weight of a Subject; 6.0 to about 7.6. (viii) a mean dissolution time of about 30 hours for the otic 11. The pharmaceutical composition or device of claim 1, Structure degrading agent; and wherein the otic disease or condition is otitis externa, otitis (ix) an apparent viscosity of about 100,000 cp to about media, mastoiditis, sensorineural hearing loss, ototoxicity, 500,000 cP. endolymphatic hydrops, labyrinthitis, Meniere's disease, 13. The method of claim 12, wherein the otic structure Meniere's syndrome, microvascular compression syndrome, degrading agent is released from the composition for a period vestibular neuronitis, acoustic trauma, presbycusis, choleste of at least 3 days. atoma, otosclerosis, Scheibe syndrome, Mondini-Michelle 14. The method of claim 12, wherein the otic structure syndrome, Waardenburg's syndrome, Michel Syndrome, degrading agent is essentially in the form of micronized par Alexander's ear deformity, hypertelorism, Jervell-Lange ticles. Nielson syndrome, Refsum's syndrome, Usher's syndrome, 15. The method of claim 12, wherein the otic structure or combinations thereof. degrading agent degrades bone. 12. A method of treating an otic disease or condition char 16. The method of claim 12, wherein the otic structure acterized by excess otic structures comprising administering degrading agent degrades a neuron. to an individual in need thereofan intratympanic composition 17. The method of claim 12, wherein the otic structure or device comprising: atherapeutically effective amount of an degrading agent degrades a membrane. otic structure degrading agent having Substantially low deg 18. The method of claim 12, wherein the otic structure radation products; and wherein the composition or device degrading agent degrades liquor puris. comprises two or more characteristics selected from: 19. The method of claim 12, wherein the otic structure (i) between about 0.1% to about 10% by weight of the otic degrading agent degrades endolymph or perilymph. structure degrading agent, or pharmaceutically accept able prodrug or salt thereof; c c c c c