Patent Publication Number: US-2019192425-A1

Title: Controlled release delivery devices for the treatment of otic disorders

Description:
CROSS-REFERENCE 
     This application is a continuation of U.S. application Ser. No. 12/506,573, filed 21 Jul. 2009, which claims the benefit of U.S. Provisional Application No. 61/082,450, filed 21 Jul. 2008; U.S. Provisional Application No. 61/094,384, filed 4 Sep. 2008; U.S. Provisional Application No. 61/101,112, filed 29 Sep. 2008; U.S. Provisional Application No. 61/140,033, filed 22 Dec. 2008; all of which are incorporated by reference herein in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     Vertebrates have a pair of ears, placed symmetrically on opposite sides of the head. The ear serves as both the sense organ that detects sound and the organ that maintains balance and body position. The ear is generally divided into three portions: the outer ear, auris media (or middle ear) and the auris interna (or inner ear). 
     SUMMARY OF THE INVENTION 
     Described herein, in certain embodiments, are delivery devices for the controlled-release of an active agent to at least one structure or region of the ear. 
     The delivery devices described herein have numerous advantages that overcome the previously-unrecognized limitations of delivery devices and therapeutic methods described in prior art. 
     Sterility 
     The environment of the inner ear is an isolated environment. The endolymph and the perilymph are static fluids and are not in contiguous contact with the circulatory system. The blood-labyrinth-barrier (BLB), which includes a blood-endolymph barrier and a blood-perilymph barrier, consists of tight junctions between specialized epithelial cells in the labyrinth spaces (i.e., the vestibular and cochlear spaces). The presence of the BLB limits delivery of an active agent to the isolated microenvironment of the inner ear. Auris hair cells are bathed in endolymphatic or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is infected, there is an influx of leukocytes and/or immunoglobulins (e.g. in response to a microbial infection) into the endolymph and/or the perilymph and the ionic composition of inner ear fluids is upset by the influx of leukocytes and/or immunoglobulins. In certain instances, a change in the ionic composition of inner ear fluids results in hearing loss, loss of balance and/or ossification of auditory structures. In certain instances, trace amounts of pyrogens and/or microbes trigger infections and related physiological changes in the isolated microenvironment of the inner ear. 
     Due to the susceptibility of the inner ear to infections, the delivery devices for active agents require a level of sterility that has not been recognized hitherto in prior art. Provided herein, in certain embodiments, are delivery devices for active agents that are sterilized with stringent sterility requirements and are suitable for administration to the middle and/or inner ear. In some embodiments, the delivery devices described herein are substantially free of pyrogens and/or microbes. 
     Compatibility with Inner Ear Environment 
     Described herein are delivery devices for active agents with an ionic balance that is compatible with the perilymph and/or the endolymph and does not cause a change in cochlear potential. In specific embodiments, osmolarity/osmolality of the present devices is adjusted, for example, by the use of appropriate salt concentrations (e.g., concentration of sodium salts) or the use of tonicity agents that render a delivery device disclosed herein endolymph-compatible and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph). In some instances, the endolymph-compatible and/or perilymph-compatible delivery devices described herein cause minimal disturbance to the environment of the inner ear and cause minimum discomfort (e.g., vertigo) to a subject (e.g., a human) upon administration. Further, a delivery device disclosed herein comprises polymers that are biodegradable and/or dispersible, and/or otherwise non-toxic to the inner ear environment. In some embodiments, a delivery device disclosed herein is free of preservatives and cause minimal disturbance (e.g., change in pH or osmolarity, irritation) in auditory structures. In some embodiments, a delivery device disclosed herein comprises antioxidants that are non-irritating and/or non-toxic to otic structures. 
     Dosing Frequency 
     The current standard of care for treatment of an otic disorder requires multiple administrations of drops or injections (e.g. intratympanic injections) over several days (e.g., up to two weeks), including schedules of receiving multiple injections per day. In some embodiments, the delivery devices described herein are controlled-release devices and are administered at reduced dosing frequency compared to the current standard of care. In certain instances, when an active agent is administered via intratympanic injection of a delivery device disclosed herein, a reduced frequency of administration alleviates discomfort caused by multiple intratympanic injections in individuals undergoing treatment for a middle and/or inner ear disease, disorder or condition. In certain instances, a reduced frequency of administration reduces the risk of permanent damage (e.g., perforation) to the tympanic membrane. A delivery device disclosed herein provides a constant, sustained, extended, delayed or pulsatile rate of release of an active agent into the inner ear environment and thus avoids any variability in drug exposure in treatment of otic disorders. 
     Therapeutic Index 
     The delivery devices described herein are administered into the ear canal, or in the vestibule of the ear. In some embodiments, access to the vestibular and cochlear apparatus occurs through the auris media (e.g., the round window membrane, the oval window/stapes footplate, thenular ligament and through the otic capsule/temporal bone). Administration of an active agent by use of the delivery device a delivery device described herein avoids toxicity associated with systemic administration (e.g., hepatotoxicity, cardiotoxicity, gastrointestinal side effects, renal toxicity) of the active agents. In some instances, localized administration in the ear allows an active agent to reach a target (e.g., the inner ear) in the absence of systemic accumulation of the active agent. In some instances, local administration to the ear provides a higher therapeutic index for an active agent that would otherwise have dose-limiting systemic toxicity. 
     Prevention of Drainage into Eustachian Tube 
     In some instances, a disadvantage of liquid delivery devices (e.g., liquid delivery devices of an active agent) is their propensity to drip into the eustachian tube and cause rapid clearance of the delivery device from the inner ear. Provided herein, in certain embodiments, are delivery devices comprising polymers that gel at body temperature and remain in contact with the target auditory surfaces (e.g., the round window) for extended periods of time. In some embodiments, a delivery device disclosed herein further comprises a mucoadhesive that allows the delivery device to adhere to otic mucosal surfaces. In some instances, the delivery devices described herein avoid attenuation of therapeutic benefit due to drainage or leakage of active agents via the eustachian tube. 
     Description of Certain Embodiments 
     Described herein, in certain embodiments, are controlled-release delivery devices for treating otic disorders comprising (a) a therapeutically-effective amount of an active agent, (b) a controlled-release auris-acceptable excipient and (c) an auris-acceptable vehicle. In one aspect, the controlled-release auris-acceptable excipient is chosen from an auris-acceptable polymer, an auris-acceptable viscosity enhancing agent, an auris-acceptable gel, an auris-acceptable microsphere or microparticle, an auris-acceptable hydrogel, an auris-acceptable liposome, an auris-acceptable nanocapsule or nanosphere, an auris-acceptable thermoreversible gel or combinations thereof. In further embodiments, the auris-acceptable viscosity enhancing agent is a cellulose, a cellulose ether, alginate, polyvinylpyrrolidone, a gum, a cellulosic polymer or combinations thereof. In yet another embodiment, the auris-acceptable viscosity enhancing agent is present in an amount sufficient to provide a viscosity of between about 1000 to about 1,000,000 centipoise. In still another aspect, the auris-acceptable viscosity enhancing agent is present in an amount sufficient to provide a viscosity of between about 50,000 to about 1,000,000 centipoise. 
     In some embodiments, a delivery device disclosed herein is formulated for a pH that ensures that they are compatible with the targeted auris structure. In some embodiments, a delivery device disclosed herein is formulated for a practical osmolality and/or osmolarity that ensures that homeostasis of the target auris structure is maintained. A perilymph-suitable osmolarity/osmolality is a practical osmolarity/osmolality that maintains the homeostasis of the target auris structure during administration of the delivery device. 
     For example, the osmolarity of the perilymph is between about 270-300 mOsm/L and a delivery device disclosed herein is optionally formulated to provide a practical osmolarity of about 150 to about 1000 mOsm/L. In certain embodiments, a delivery device disclosed herein provides a practical osmolarity within about 150 to about 500 mOsm/L at the target site of action (e.g., the inner ear and/or the perilymph and/or the endolymph). In certain embodiments, a delivery device disclosed herein provides a practical osmolarity within about 200 to about 400 mOsm/L at the target site of action (e.g., the inner ear and/or the perilymph and/or the endolymph). In certain embodiments, a delivery device disclosed herein provides a practical osmolarity within about 250 to about 320 mOsm/L at the target site of action (e.g., the inner ear and/or the perilymph and/or the endolymph). In certain embodiments, a delivery device disclosed herein provides a perilymph-suitable osmolarity within about 150 to about 500 mOsm/L, about 200 to about 400 mOsm/L or about 250 to about 320 mOsm/L at the target site of action (e.g., the inner ear and/or the perilymph and/or the endolymph). In certain embodiments, a delivery device disclosed herein provides a perilymph-suitable osmolality within about 150 to about 500 mOsm/kg, about 200 to about 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 and/or the endolymph). Similarly, the pH of the perilymph is about 7.2-7.4, and the pH of the present delivery devices is formulated (e.g., with the use of buffers) to provide a perilymph-suitable pH of about 5.5 to about 9.0, about 6.0 to about 8.0 or about 7.0 to about 7.6. In certain embodiments, the pH of a delivery device disclosed herein is within about 6.0 to about 7.6. In certain instances, the pH of the endolymph is about 7.2-7.9, and the pH of the present delivery device is formulated (e.g., with the use of buffers) to be within about 5.5 to about 9.0, within about 6.5 to about 8.0 or within about 7.0 to about 7.6. 
     In some aspects, the controlled-release auris-acceptable excipient is biodegradable and/or bioeliminated (e.g., degraded and/or eliminated through urine, feces or other routes of elimination). In another aspect, the delivery device further comprises an auris-acceptable mucoadhesive, an auris-acceptable penetration enhancer or an auris-acceptable bioadhesive. 
     In one aspect, the delivery device is administered using a needle and syringe, a pump, a microinjection device, and in situ forming spongy material or combinations thereof. In some embodiments, active agent of the delivery device has limited or no systemic release, is toxic when administered systemically, has poor pK characteristics, or combinations thereof. 
     Also disclosed herein, in certain embodiments, is a method for treating an otic disorder comprising administering a delivery device disclosed herein at least once every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days; at least once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks; or at least once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once every twelve months. In particular embodiments, the delivery devices described herein provide a sustained dose of an active agent to the inner ear between subsequent doses of the delivery device. That is, taking one example only, if the delivery device is administered via intratympanic injection to the round window membrane every 10 days, then the delivery device provides an effective dose of an active agent to the inner ear (e.g., across the round window membrane) during that 10-day period. 
     In one aspect, the delivery device is administered so that the delivery device is in contact with the  crista  fenestrae  cochleae , the round window membrane or the tympanic cavity. In one aspect the delivery device is administered by intratympanic injection. 
     Provided herein, in certain embodiments, are delivery devices for use in the treatment of an otic disease or condition formulated to provide a therapeutically effective amount of an active agent, the delivery devices comprising substantially low degradation products of the active agent, the delivery devices further comprising two or more characteristics selected from:
         (i) between about 0.1% to about 10% by weight of the active agent, or pharmaceutically acceptable prodrug or salt thereof;   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0;   (iv) multiparticulate active agent;   (v) a gelation temperature between about 19° C. to about 42° C.;   (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of delivery device;   (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject;   (viii) a mean dissolution time of about 30 hours for the active agent; and   (ix) an apparent viscosity of about 100,000 cP to about 500,000 cP.       

     In some embodiments, the pharmaceutical composition comprises at least three of the aforementioned characteristics. In some embodiments, the pharmaceutical composition comprises at least four of the aforementioned characteristics. In some embodiments, the pharmaceutical composition comprises at least five of the aforementioned characteristics. In some embodiments, the pharmaceutical composition comprises at least six of the aforementioned characteristics. In some embodiments, the pharmaceutical composition comprises at least seven of the aforementioned characteristics. In some embodiments, the pharmaceutical composition comprises all of the aforementioned characteristics. 
     In some embodiments, a delivery device described herein comprises:
         (i) between about 0.1% to about 10% by weight of the active agent, or pharmaceutically acceptable prodrug or salt thereof;   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106; and   (iii) multiparticulate active agent.       

     In some embodiments, a delivery device described herein comprises:
         (i) between about 0.1% to about 10% by weight of the active agent, or pharmaceutically acceptable prodrug or salt thereof;   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) multiparticulate active agent; and   (iv) a gelation temperature between about 19° C. to about 42° C.       

     In some embodiments, a delivery device described herein comprises:
         (i) between about 0.1% to about 10% by weight of the active agent, or pharmaceutically acceptable prodrug or salt thereof;   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) multiparticulate active agent; and   (iv) an apparent viscosity of about 100,000 cP to about 500,000 cP.       

     In some embodiments, a delivery device described herein provides a practical osmolarity between about 150 and 500 mOsm/L. In some embodiments, a delivery device described herein provides a practical osmolarity between about 200 and 400 mOsm/L. In some embodiments, a delivery device described herein provides a practical osmolarity between about 250 and 320 mOsm/L. 
     In some embodiments, the active agent is released from a delivery device disclosed herein for a period of at least 3 days. In some embodiments, the active agent is released from a delivery device disclosed herein for a period of at least 5 days. In some embodiments, the active agent is released from a delivery device disclosed herein for a period of at least 10 days. In some embodiments, the active agent is released from a delivery device disclosed herein for a period of at least 14 days. In some embodiments, the active agent is released from a delivery device disclosed herein for a period of at least one month. 
     In some embodiments, a delivery device described herein comprises an active agent as multiparticulates. In some embodiments, a delivery device described herein comprises an active agent in the form of micronized particles. In some embodiments, a delivery device described herein comprises an active agent as micronized powder. 
     In some embodiments, a delivery device described herein comprises about 10% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106 by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 15% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106 by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 20% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106 by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 25% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106 by weight of the delivery device. 
     In some embodiments, a delivery device described herein comprises about 1% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 2% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 3% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 4% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 5% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 10% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 15% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 20% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 25% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 30% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 40% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 50% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 60% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 70% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 80% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. In some embodiments, a delivery device described herein comprises about 90% of an active agent, or pharmaceutically acceptable prodrug or salt thereof, by weight of the delivery device. 
     In some embodiments, a delivery device described herein has a pH between about 5.5 and about 8.0. In some embodiments, a delivery device described herein has a pH between about 6.0 and about 8.0. In some embodiments, a delivery device described herein has a pH between about 6.0 and about 7.6. 
     In some embodiments, a delivery device described herein contains less than 100 colony forming units (cfu) of microbiological agents per gram of delivery device. In some embodiments, a delivery device described herein contains less than 50 colony forming units (cfu) of microbiological agents per gram of delivery device. In some embodiments, a delivery device described herein contains less than 10 colony forming units (cfu) of microbiological agents per gram of delivery device. 
     In some embodiments, a delivery device described herein contains less than 5 endotoxin units (EU) per kg of body weight of a subject. In some embodiments, a delivery device described herein contains less than 4 endotoxin units (EU) per kg of body weight of a subject. 
     In some embodiments, a delivery device described herein provides a gelation temperature between about between about 19° C. to about 42° C. In some embodiments, a delivery device described herein provides a gelation temperature between about between about 19° C. to about 37° C. In some embodiments, a delivery device described herein provides a gelation temperature between about between about 19° C. to about 30° C. 
     In some embodiments, the delivery device is an auris-acceptable thermoreversible gel. In some embodiments, the polyoxyethylene-polyoxypropylene triblock copolymer is biodegradable and/or bioeliminated (e.g., the copolymer is eliminated from the body by a biodegradation process, e.g., elimination in the urine, the feces or the like). In some embodiments, a delivery device described herein further comprises a mucoadhesive. In some embodiments, a delivery device described herein further comprises a penetration enhancer. In some embodiments, a delivery device described herein further comprises a thickening agent. In some embodiments, a delivery device described herein further comprises a dye. 
     In some embodiments, a delivery device described herein further comprises a drug delivery device selected from a needle and syringe, a pump, a microinjection device, a wick, an in situ forming spongy material or combinations thereof. 
     In some embodiments, the active agent, or pharmaceutically acceptable salt thereof, has limited or no systemic release, systemic toxicity, poor PK characteristics, or combinations thereof. In some embodiments, the active agent is in the form of a neutral molecule, a free base, a free acid, a salt, a prodrug, or a combination thereof. In some embodiments, the active agent is administered in the form of a phosphate or ester prodrug. In some embodiments, a delivery device described herein comprises an active agent, or pharmaceutically acceptable salt thereof, prodrug or combination thereof as an immediate release agent. 
     In some embodiments, delivery devices described herein further comprise a second active agent. 
     In some embodiments, a delivery device described herein has a pH between about 6.0 and about 7.6. 
     In some embodiments, the ratio of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106 to a thickening agent is from about 40:1 to about 5:1. In some embodiments, the thickening agent is carboxymethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose. 
     Also provided herein is a method of treating an otic disease or condition comprising administering to an individual in need thereof an intratympanic delivery device comprising a therapeutically effective amount of an active agent, the delivery device comprising substantially low degradation products of an active agent, the delivery device further comprising two or more characteristics selected from:
         (i) between about 0.1% to about 10% by weight of the, or pharmaceutically acceptable prodrug or salt thereof;   (ii) between about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106;   (iii) sterile water, q.s., buffered to provide a pH between about 5.5 and about 8.0;   (iv) multiparticulate active agent;   (v) a gelation temperature between about 19° C. to about 42° C.;   (vi) less than about 50 colony forming units (cfu) of microbiological agents per gram of delivery device, and   (vii) less than about 5 endotoxin units (EU) per kg of body weight of a subject.       

     In some embodiments, the active agent is released from the delivery device for a period of at least 3 days. In some embodiments, the active agent is released from the delivery device for a period of at least 4 days. In some embodiments, the active agent is released from the delivery device for a period of at least 5 days. In some embodiments, the active agent is released from the delivery device for a period of at least 6 days. In some embodiments, the active agent is released from the delivery device for a period of at least 7 days. In some embodiments, the active agent is released from the delivery device for a period of at least 8 days. In some embodiments, the active agent is released from the delivery device for a period of at least 9 days. In some embodiments, the active agent is released from the delivery device for a period of at least 10 days. In some embodiments, the active agent is essentially in the form of micronized particles. 
    
    
     
       BRIEF DESCRIPTION OF FIGURES 
         FIG. 1  illustrates a comparison of non-sustained release and sustained release delivery devices. 
         FIG. 2  illustrates the effect of concentration on the viscosity of aqueous solutions of Blanose refined CMC. 
         FIG. 3  illustrates the effect of concentration on the viscosity of aqueous solutions of Methocel. 
         FIG. 4  provides an illustrative representation of anatomy of the ear. 
         FIG. 5  illustrates tunable release of an active agent from four delivery devices. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Provided herein, in certain embodiments, are controlled-release auris compatible delivery devices to facilitate or enable the treatment of an otic disease, disorder, or condition. 
     Benefits of the Current Delivery Device Over the Prior Art 
     Local Delivery Vs. Systemic Delivery 
     Many of the current methods of treating an otic disorder involve delivery of an active agent via systemic routes (e.g., oral, intravenous or intramuscular routes). However, there are many drawbacks to systemic administration of an active agent. 
     First, systemic drug administration creates an inequality in drug concentration with higher circulating levels in the serum, and lower levels in the target auris media and auris interna organ structures. As a result, fairly large amounts of drug are required to overcome this inequality in order to deliver sufficient, therapeutically effective quantities to the inner ear. 
     Second, systemic drug administration increases the likelihood of systemic toxicities and adverse side effects as a result of the high serum amounts required to effectuate sufficient local delivery to the target site. Systemic toxicities may also occur as a result of liver breakdown and processing of the active agents, forming toxic metabolites that effectively erase a benefit attained from the administered therapeutic. 
     To overcome the negative side effects of systemic delivery, disclosed herein are delivery devices that enable local delivery of active agents to targeted auris structures. Access to, for example, the vestibular and cochlear apparatus will occur through the auris media including round window membrane, the oval window/stapes footplate, annular ligament and through the otic capsule/temporal bone. 
     Provided herein, in certain embodiments, are controlled-release auris compatible delivery devices to locally treat targeted auris structures, thereby avoiding side effects as a result of systemic administration of the auris compatible delivery devices. The locally applied auris compatible delivery devices and devices are compatible with the targeted auris structures, and administered either directly to the desired targeted auris structure (e.g., the cochlear region, the tympanic cavity or the external ear), or administered to a structure in direct communication with areas of the auris interna (e.g., the round window membrane, the  crista  fenestrae  cochleae  or the oval window membrane). By specifically targeting an auris structure, adverse side effects as a result of systemic treatment are avoided. Moreover, clinical studies have shown the benefit of having long term exposure of drug to the perilymph of the cochlea, for example with improved clinical efficacy of sudden hearing loss when the active agent is given on multiple occasions. Thus, by providing a controlled-release auris compatible delivery device to treat otic disorders, a constant, variable and/or extended source of an active agent is provided to the subject suffering from an otic disorder, reducing or eliminating uncertainty in treatment. Accordingly, one embodiment disclosed herein is to provide a delivery device that enables an active agent to be released in therapeutically effective doses either at variable or constant rates such as to ensure a continuous release of an active agent. In some embodiments, an active agent disclosed herein is administered as an immediate release delivery device. In other embodiments, an active agent is administered as a sustained release delivery device, released either continuously, variably or in a pulsatile manner, or variants thereof. In still other embodiments, an active agent delivery device is administered as both an immediate release and sustained release delivery device, released either continuously, variably or in a pulsatile manner, or variants thereof. The release is optionally dependent on environmental or physiological conditions, for example, the external ionic environment (see, e.g. Oros® release system, Johnson &amp; Johnson). 
     In addition, localized treatment of the targeted auris structure also affords the use of previously undesired active agents, including agents with poor pK profiles, poor uptake, low systemic release and/or toxicity issues. Because of the localized targeting that follows from use of a device disclosed herein, as well as the biological blood barrier present in the auris interna, the risk of adverse effects will be reduced as a result of treatment with previously characterized toxic or ineffective otic active agent. Accordingly, also contemplated within the scope of the embodiments herein is the use of otic active agent in the treatment of disorders that have been previously rejected by practitioners because of adverse effects or ineffectiveness of the active agent. 
     Prevention of Drainage into Eustachian Tube 
     In certain instances, medical practitioners attempt to deliver an active agent to an auris structure via local administration. Currently, local administration of an active agent to an auris structure involves the use of a liquid delivery device. However, liquid delivery devices present several draw backs. 
     First, liquid delivery devices demonstrate a propensity to drip into the eustachian tube. This results in cause rapid clearance of the delivery device and the active agent from the inner ear. Further, drainage of the delivery device and active agent may result in irritation to the throat and stomach. 
     Provided herein, in certain embodiments, are delivery devices comprising polymers that gel at body temperature and remain in contact with the target auditory surfaces (e.g., the round window) for extended periods of time. In some embodiments, a delivery device disclosed herein further comprises a mucoadhesive that allows the delivery device to adhere to otic mucosal surfaces. In some instances, the delivery devices described herein avoid attenuation of therapeutic benefit due to drainage or leakage of active agents via the eustachian tube. 
     Unrecognized Physiological Requirements of a Human Otic Compatible Delivery Device 
     Intratympanic injection of active agents is the technique of injecting an active agent behind the tympanic membrane into the auris media and/or auris interna. However, intra-tympanic injections create several unrecognized problems not addressed by currently available treatment regimens. One of the reasons the art may not have recognized these problems is that there are no approved intra-tympanic delivery devices: the inner ear provides  sui  generis delivery challenges. Additionally, there is wide anatomical disparity between the ears of animals across species. A consequence of the inter-species differences in auditory structures is that animal models of inner ear disease are often unreliable as a tool for testing therapeutics that are being developed for clinical approval. 
     Sterility 
     The first unrecognized challenge presented by intra-tympanic injections is the absolute need for sterility. The environment of the inner ear is an isolated environment. The endolymph and the perilymph are static fluids and are not in contiguous contact with the circulatory system. The blood-labyrinth-barrier (BLB), which includes a blood-endolymph barrier and a blood-perilymph barrier, consists of tight junctions between specialized epithelial cells in the labyrinth spaces (i.e., the vestibular and cochlear spaces). The presence of the BLB limits delivery of an active agent to the isolated microenvironment of the inner ear. Auris hair cells are bathed in endolymphatic or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is infected, there is an influx of leukocytes and/or immunoglobulins (e.g. in response to a microbial infection) into the endolymph and/or the perilymph and the ionic composition of inner ear fluids is upset by the influx of leukocytes and/or immunoglobulins. In certain instances, a change in the ionic composition of inner ear fluids results in hearing loss, loss of balance and/or ossification of auditory structures. In certain instances, trace amounts of pyrogens and/or microbes trigger infections and related physiological changes in the isolated microenvironment of the inner ear. 
     Due to the susceptibility of the inner ear to infections, the delivery devices for active agents require a level of sterility that has not been recognized hitherto in prior art. Provided herein, in certain embodiments, are delivery devices for active agents that are sterilized with stringent sterility requirements and are suitable for administration to the middle and/or inner ear. In some embodiments, the delivery devices described herein are substantially free of pyrogens and/or microbes. 
     Osmolarity 
     The second unregognized challenge presented by intra-tympanic injections is the absolute need for the device to have the proper osmolarity. Described herein are delivery devices for active agents with an ionic balance that is compatible with the perilymph and/or the endolymph and does not cause a change in cochlear potential. In specific embodiments, osmolarity/osmolality of the present devices is adjusted, for example, by the use of appropriate salt concentrations (e.g., concentration of sodium salts) or the use of tonicity agents that render a delivery device disclosed herein endolymph-compatible and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph). In some instances, the endolymph-compatible and/or perilymph-compatible delivery devices described herein cause minimal disturbance to the environment of the inner ear and cause minimum discomfort (e.g., vertigo) to a subject (e.g., a human) upon administration. Further, a delivery device disclosed herein comprises polymers that are biodegradable and/or dispersible, and/or otherwise non-toxic to the inner ear environment. In some embodiments, a delivery device disclosed herein is free of preservatives and cause minimal disturbance (e.g., change in pH or osmolarity, irritation) in auditory structures. In some embodiments, a delivery device disclosed herein comprises antioxidants that are non-irritating and/or non-toxic to otic structures. 
     Provided herein, in certain embodiments, are delivery devices for active agents that meet stringent criteria for pH, osmolarity, ionic balance, sterility, endotoxin and/or pyrogen levels. The delivery devices described herein are compatible with the microenvironment of the inner ear (e.g., the perilymph) and are suitable for administration to humans. 
     Viscosity 
     A third unrecognized challenge presented by intra-tympanic injections is the potential for inducing vertigo or dizziness. The inner ear is critical to maintaining balance. The semi-circular canals and the vestibule form the vestibular labyrinth. When the head moves, fluid within the vestibular labyrinth moves and stimulates nerve endings that send impulses along the balance nerve to the brain. 
     When the pressure of the inner ear (or the pressure on the vestibular labrynth) is changed suddenly, vertigo and dizziness occur. In certain instances, adding a foreign object (e.g., a delivery device) to the inner ear increases the pressure in the inner ear and the pressure on the vestibular labrynth. With regards to a fluidic delivery device, in certain instances, the pressure on the inner ear environment increases as the viscosity of the fluid increases. 
     Provided herein, in certain embodiments, are delivery devices for active agents that meet the requirements (e.g., viscosity requirements) necessary to minimize changes in inner ear pressure, while minimizing the amount of the delivery device that flows out of the Eustachian tube. In some embodiments, the viscosity of the delivery device increases as the temperature of the delivery device increases (for example, due to warming from the inner ear environment). The delivery devices described herein are compatible with the pressure requirements of the inner ear and are suitable for administration to humans. 
     Further Physiological Requirements of a Human Otic Compatible Delivery Device 
     Intratympanic injection of delivery devices creates several additional problems that must also be addressed before the delivery device can be administered. For example, there are many excipients that are ototoxic. While these excipients can be used when formulating an active agent for delivery by another method (e.g., topical), their use should be limited, reduced or eliminated when formulating a delivery device to be administered to the ear due to their ototoxic effects. 
     By way of non-limiting example, the use of the following commonly used solvents should be limited, reduced or eliminated when formulating agents for administration to the ear: alcohols, propylene glycol, and cyclohexane. Thus, in some embodiments, a device disclosed herein is free or substantially free of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of alcohols, propylene glycol, and cyclohexane. 
     Further, by way of non-limiting example, the use of the following commonly utilized preservatives should be limited, reduced or eliminated when formulating agents for administration to the ear: Benzethonium chloride, Benzalkonium chloride, and Thiomersal. Thus, in some embodiments, a device disclosed herein is free or substantially free of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. 
     Certain antiseptics used to disinfect components of therapeutic preparations (or the devices utilized to administer the preparations) should be limited, reduced, or eliminated in otic preparations. For example, acetic acid, iodine, and merbromin are all known to be ototoxic. Additionally, chlorhexidene, a commonly used antiseptic, should be limited, reduced or eliminated to disinfect any component of an otic preparation (including devices used to administer the preparation) as it is highly ototoxic in minute concentrations (e.g., 0.05%). Thus, in some embodiments, a device disclosed herein is free or substantially free of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. 
     Further, otic preparations require particularly low concentrations of several potentially-common contaminants that are known to be ototoxic. Other dosage forms, while seeking to limit the contamination attributable to these compounds, do not require the stringent precautions that otic preparations require. For example, the following contaminants should be absent or nearly absent from otic preparations: arsnic, lead, mercury, and tin. Thus, in some embodiments, a device disclosed herein is free or substantially free of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of arsnic, lead, mercury, and tin. 
     Certain Definitions 
     The term “auris-acceptable” with respect to a composition, composition or ingredient, as used herein, includes having no persistent detrimental effect on the auris media (or middle ear) and the auris interna (or inner ear) of the subject being treated. By “auris-pharmaceutically acceptable,” as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound in reference to the auris media (or middle ear) and the auris interna (or inner ear), and is relatively or is reduced in toxicity to the auris media (or middle ear) and the auris interna (or inner ear), i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in that it is contained. 
     As used herein, amelioration or lessening of the symptoms of a particular otic disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any decrease of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that is attributed to or associated with administration of the compound or composition. 
     “Antioxidants” are auris-pharmaceutically acceptable antioxidants, and include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required. Antioxidants are also used to counteract the ototoxic effects of certain therapeutic agents, including agents that are used in combination with the otic structure modulating agent or innate immune system modulating agents disclosed herein. 
     “Auris interna” refers to the inner ear, including the cochlea and the vestibular labyrinth, and the round window that connects the cochlea with the middle ear. 
     “Auris-bioavailability” or “Auris-interna bioavailability” or “Auris-media bioavailability” or “Auris-externa bioavailability” refers to the percentage of the administered dose of compounds disclosed herein that becomes available in the targeted auris structure of the animal or human being studied. 
     “Auris media” refers to the middle ear, including the tympanic cavity, auditory ossicles and oval window, which connects the middle ear with the inner ear. 
     “Auris externa” refers to the outer ear, including the pinna, the auditory canal, and the tympanic membrane, which connects the outer ear with the middle ear. 
     “Blood plasma concentration” refers to the concentration of compounds provided herein in the plasma component of blood of a subject. 
     “Carrier materials” are excipients that are compatible with otic structure modulating agent or innate immune system modulating agent(s), the targeted auris structure(s) and the release profile properties of the auris-acceptable pharmaceutical compositions. Such carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Auris-pharmaceutically compatible carrier materials” include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. 
     The term “diluent” refers to chemical compounds that are used to dilute the otic structure modulating agent or innate immune system modulating agent prior to delivery and that are compatible with the targeted auris structure(s). 
     “Dispersing agents,” and/or “viscosity modulating agents” are materials that control the diffusion and homogeneity of the otic structure modulating agent or innate immune system modulating agent through liquid media. Examples of diffusion facilitators/dispersing agents include but are not limited to hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronic F127®, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose are also be used as dispersing agents. Optional dispersing agents useful in liposomal dispersions and self-emulsifying dispersions of the otic structure modulating agent or innate immune system modulating agents disclosed herein are dimyristoyl phosphatidyl choline, phosphatidyl cholines (c8-c18), phosphatidylethanolamines (c8-c18), phosphatidyl glycerols (c8-c18), natural phosphatidyl choline from eggs or soy, natural phosphatidyl glycerol from eggs or soy, cholesterol and isopropyl myristate. 
     “Drug absorption” or “absorption” refers to the process of movement of the otic structure modulating agent or innate immune system modulating agent(s) from the localized site of administration, by way of example only, the round window membrane of the inner ear, and across a barrier (the round window membranes, as described below) into the auris interna or inner ear structures. The terms “co-administration” or the like, as used herein, are meant to encompass administration of the otic structure modulating agent or innate immune system modulating agents to a single patient, and are intended to include treatment regimens in that the otic structure modulating agent or innate immune system modulating agents are administered by the same or different route of administration or at the same or different time. 
     The term “inhibiting” includes preventing, slowing, or reversing the development of a condition, for example, otitis externa, or advancement of a condition in a patient necessitating treatment. 
     The terms “kit” and “article of manufacture” are used as synonyms. 
     As used herein, the term “otic intervention” means an external insult or trauma to one or more auris structures and includes implants, otic surgery, injections, cannulations, or the like. Implants include auris-interna or auris-media medical devices, examples of which include cochlear implants, hearing sparing devices, hearing-improvement devices, short electrodes, micro-prostheses or piston-like prostheses; needles; stem cell transplants; drug delivery devices; any cell-based therapeutic; or the like. Otic surgery includes middle ear surgery, inner ear surgery, typanostomy, cochleostomy, labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy, tympanostomy, endolymphatic sacculotomy or the like. Injections include intratympanic injections, intracochlear injections, injections across the round window membrane or the like. Cannulations include intratympanic, intracochlear, endolymphatic, perilymphatic or vestibular cannulations or the like. 
     “Pharmacokinetics” refers to the factors that determine the attainment and maintenance of the appropriate concentration of drug at the desired site within the targeted auris structure. 
     In prophylactic applications, compositions containing the agents described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition, for otitis externa, otitis media, mastoiditis, sensorineural hearing loss, ototoxicity, endolymphatic hydrops, labyrinthitis, Meniere&#39;s disease, Meniere&#39;s syndrome, microvascular compression syndrome, vestibular neuronitis, acoustic trauma, presbycusis, cholesteatoma, otosclerosis, Scheibe syndrome, Mondini-Michelle syndrome, Waardenburg&#39;s syndrome, Michel syndrome, Alexander&#39;s ear deformity, hypertelorism, Jervell-Lange Nielson syndrome, Refsum&#39;s syndrome, and Usher&#39;s syndrome. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient&#39;s state of health, weight, and the like. As used herein, a “pharmaceutical device” includes any composition described herein that, upon administration to an ear, provides a reservoir for extended release of an active agent described herein. 
     A “prodrug” refers to the otic structure modulating agent or innate immune system modulating agent that is converted into the parent drug in vivo. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. In one embodiment, the prodrug is designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, or to alter other characteristics or properties of a drug. Compounds provided herein, in some embodiments, are derivatized into suitable prodrugs. 
     “Round window membrane” is the membrane in humans that covers the fenestrae cochlea (also known as the circular window, fenestrae rotunda, or round window). In humans, the thickness of round window membrane is about 70 micron. 
     “Solubilizers” refers to auris-acceptable compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium caprate, sucrose esters, alkylglucosides, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like. 
     “Stabilizers” refers to compounds such as any antioxidation agents, buffers, acids, preservatives and the like that are compatible with the environment of the targeted auris structure. Stabilizers include but are not limited to agents that will do any of (1) improve the compatibility of excipients with a container, or a delivery system, including a syringe or a glass bottle, (2) improve the stability of a component of the composition, or (3) improve composition stability. 
     As used herein, the term “substantially low degradation products” means less than 5% by weight of the active agent are degradation products of the active agent. In further embodiments, the term means less than 3% by weight of the active agent are degradation products of the active agent. In yet further embodiments, the term means less than 2% by weight of the active agent are degradation products of the active agent. In further embodiments, the term means less than 1% by weight of the active agent are degradation products of the active agent. 
     As used herein “essentially in the form of micronized powder” includes, by way of example only, greater than 70% by weight of the active agent is in the form of micronized particles of the active agent. In further embodiments, the term means greater than 80% by weight of the active agent is in the form of micronized particles of the active agent. In yet further embodiments, the term means greater than 90% by weight of the active agent is in the form of micronized particles of the active agent. 
     “Steady state,” as used herein, is when the amount of drug administered to the targeted auris structure is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant levels of drug exposure within the targeted structure. 
     The mean residence time (MRT) is the average time that molecules of an active agent reside in an otic structure after a dose. 
     As used herein, the term “subject” is used to mean any animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably. Neither term is to be interpreted as requiring the supervision of a medical professional (e.g., a doctor, nurse, physician&#39;s assistant, orderly, hospice worker). 
     “Surfactants” refers to compounds that are auris-acceptable, such as sodium lauryl sulfate, sodium docusate, Tween® 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants are included to enhance physical stability or for other purposes. 
     The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. 
     Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, which the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only. 
     Anatomy of the Ear 
     As shown in  FIG. 4 , the outer ear is the external portion of the organ and is composed of the pinna (auricle), the auditory canal (external auditory meatus) and the outward facing portion of the tympanic membrane, also known as the ear drum. The pinna, which is the fleshy part of the external ear that is visible on the side of the head, collects sound waves and directs them toward the auditory canal. Thus, the function of the outer ear, in part, is to collect and direct sound waves towards the tympanic membrane and the middle ear. 
     The middle ear is an air-filled cavity, called the tympanic cavity, behind the tympanic membrane. The tympanic membrane, also known as the ear drum, is a thin membrane that separates the external ear from the middle ear. The middle ear lies within the temporal bone, and includes within this space the three ear bones (auditory ossicles): the malleus, the incus and the stapes. The auditory ossicles are linked together via tiny ligaments, which form a bridge across the space of the tympanic cavity. The malleus, which is attached to the tympanic membrane at one end, is linked to the incus at its anterior end, which in turn is linked to the stapes. The stapes is attached to the oval window, one of two windows located within the tympanic cavity. A fibrous tissue layer, known as thenular ligament connects the stapes to the oval window. Sound waves from the outer ear first cause the tympanic membrane to vibrate. The vibration is transmitted across to the cochlea through the auditory ossicles and oval window, which transfers the motion to the fluids in the auris interna. Thus, the auditory ossicles are arranged to provide a mechanical linkage between the tympanic membrane and the oval window of the fluid-filled auris interna, where sound is transformed and transduced to the auris interna for further processing. Stiffness, rigidity or loss of movement of the auditory ossicles, tympanic membrane or oval window leads to hearing loss, e.g. otosclerosis, or rigidity of the stapes bone. 
     The tympanic cavity also connects to the throat via the eustachian tube. The eustachian tube provides the ability to equalize the pressure between the outside air and the middle ear cavity. The round window, a component of the auris interna but that is also accessible within the tympanic cavity, opens into the cochlea of the auris interna. The round window is covered by round window membrane, which consists of three layers: an external or mucous layer, an intermediate or fibrous layer, and an internal membrane, which communicates directly with the cochlear fluid. The round window, therefore, has direct communication with the auris interna via the internal membrane. 
     Movements in the oval and round window are interconnected, i.e. as the stapes bone transmits movement from the tympanic membrane to the oval window to move inward against the auris interna fluid, the round window (round window membrane) is correspondingly pushed out and away from the cochlear fluid. This movement of the round window allows movement of fluid within the cochlea, which leads in turn to movement of the cochlear inner hair cells, allowing hearing signals to be transduced. Stiffness and rigidity in round window membrane leads to hearing loss because of the lack of ability of movement in the cochlear fluid. Recent studies have focused on implanting mechanical transducers onto the round window, which bypasses the normal conductive pathway through the oval window and provides amplified input into the cochlear chamber. 
     Auditory signal transduction takes place in the auris interna. The fluid-filled auris interna, or inner ear, consists of two major components: the cochlear and the vestibular apparatus. The auris interna is located in part within the osseous or bony labyrinth, an intricate series of passages in the temporal bone of the skull. The vestibular apparatus is the organ of balance and consists of the three semi-circular canals and the vestibule. The three semi-circular canals are arranged relative to each other such that movement of the head along the three orthogonal planes in space can be detected by the movement of the fluid and subsequent signal processing by the sensory organs of the semi-circular canals, called the  crista ampullaris . The  crista ampullaris  contains hair cells and supporting cells, and is covered by a dome-shaped gelatinous mass called the cupula. The hairs of the hair cells are embedded in the cupula. The semi-circular canals detect dynamic equilibrium, the equilibrium of rotational or angular movements. 
     When the head turns rapidly, the semicircular canals move with the head, but endolymph fluid located in the membranous semi-circular canals tends to remain stationary. The endolymph fluid pushes against the cupula, which tilts to one side. As the cupula tilts, it bends some of the hairs on the hair cells of the  crista ampullaris , which triggers a sensory impulse. Because each semicircular canal is located in a different plane, the corresponding  crista ampullaris  of each semi-circular canal responds differently to the same movement of the head. This creates a mosaic of impulses that are transmitted to the central nervous system on the vestibular branch of the vestibulocochlear nerve. The central nervous system interprets this information and initiates the appropriate responses to maintain balance. Of importance in the central nervous system is the cerebellum, which mediates the sense of balance and equilibrium. 
     The vestibule is the central portion of the auris interna and contains mechanoreceptors bearing hair cells that ascertain static equilibrium, or the position of the head relative to gravity. Static equilibrium plays a role when the head is motionless or moving in a straight line. The membranous labyrinth in the vestibule is divided into two sac-like structures, the utricle and the saccule. Each structure in turn contains a small structure called a macula, which is responsible for maintenance of static equilibrium. The macula consists of sensory hair cells, which are embedded in a gelatinous mass (similar to the cupula) that covers the macula. Grains of calcium carbonate, called otoliths, are embedded on the surface of the gelatinous layer. 
     When the head is in an upright position, the hairs are straight along the macula. When the head tilts, the gelatinous mass and otoliths tilts correspondingly, bending some of the hairs on the hair cells of the macula. This bending action initiates a signal impulse to the central nervous system, which travels via the vestibular branch of the vestibulocochlear nerve, which in turn relays motor impulses to the appropriate muscles to maintain balance. 
     The cochlea is the portion of the auris interna related to hearing. The cochlea is a tapered tube-like structure that is coiled into a shape resembling a snail. The inside of the cochlea is divided into three regions, which is further defined by the position of the vestibular membrane and the basilar membrane. The portion above the vestibular membrane is the scala vestibuli, which extends from the oval window to the apex of the cochlea and contains perilymph fluid, an aqueous liquid low in potassium and high in sodium content. The basilar membrane defines the scala tympani region, which extends from the apex of the cochlea to the round window and also contains perilymph. The basilar membrane contains thousands of stiff fibers, which gradually increase in length from the round window to the apex of the cochlea. The fibers of the basement membrane vibrate when activated by sound. In between the scala vestibuli and the scala tympani is the cochlear duct, which ends as a closed sac at the apex of the cochlea. The cochlear duct contains endolymph fluid, which is similar to cerebrospinal fluid and is high in potassium. 
     The organ of  Corti , the sensory organ for hearing, is located on the basilar membrane and extends upward into the cochlear duct. The organ of  Corti  contains hair cells, which have hairlike projections that extend from their free surface, and contacts a gelatinous surface called the tectorial membrane. Although hair cells have no axons, they are surrounded by sensory nerve fibers that form the cochlear branch of the vestibulocochlear nerve (cranial nerve VIII). 
     As discussed, the oval window, also known as the elliptical window communicates with the stapes to relay sound waves that vibrate from the tympanic membrane. Vibrations transferred to the oval window increases pressure inside the fluid-filled cochlea via the perilymph and scala vestibuli/scala tympani, which in turn causes the round window membrane to expand in response. The concerted inward pressing of the oval window/outward expansion of the round window allows for the movement of fluid within the cochlea without a change of intra-cochlear pressure. However, as vibrations travel through the perilymph in the scala vestibuli, they create corresponding oscillations in the vestibular membrane. These corresponding oscillations travel through the endolymph of the cochlear duct, and transfer to the basilar membrane. When the basilar membrane oscillates, or moves up and down, the organ of  Corti  moves along with it. The hair cell receptors in the Organ of  Corti  then move against the tectorial membrane, causing a mechanical deformation in the tectorial membrane. This mechanical deformation initiates the nerve impulse that travels via the vestibulocochlear nerve to the central nervous system, mechanically transmitting the sound wave received into signals that are subsequently processed by the central nervous system. 
     General Methods of Sterilization 
     Provided herein, in certain embodiments, are delivery devices for active agents that ameliorate or lessen otic disorders described herein. In some embodiments, a delivery device disclosed herein is sterilized. Included within the embodiments disclosed herein are means and processes for sterilization of a delivery device disclosed herein for use in humans. The goal is to provide a safe pharmaceutical product, relatively free of infection causing micro-organisms. The U. S. Food and Drug Administration has provided regulatory guidance in the publication “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing” available at: http://www.fda.gov/cder/guidance/5882fnl.htm, which is incorporated herein by reference in its entirety. 
     As used herein, “sterilization” means a process used to destroy or remove microorganisms that are present in a product or packaging. Any suitable method available for sterilization is contemplated for use with a delivery device disclosed herein. Available methods for the inactivation of microorganisms include, but are not limited to, the application of extreme heat, lethal chemicals, or gamma radiation. Disclosed herein, in some embodiments, are processes for the preparation of an otic compatible delivery device comprising: subjecting the delivery device to a sterilization method selected from heat sterilization, chemical sterilization, radiation sterilization or filtration sterilization. The method used depends largely upon the nature of the delivery device to be sterilized. Detailed descriptions of many methods of sterilization are given in Chapter 40 of Remington: The Science and Practice of Pharmacy published by Lippincott, Williams &amp; Wilkins, and is incorporated by reference with respect to this subject matter. 
     Sterilization by Heat 
     Many methods are available for sterilization by the application of extreme heat. One method is through the use of a saturated steam autoclave. In this method, saturated steam at a temperature of at least 121° C. is allowed to contact the object to be sterilized. The transfer of heat is either directly to the microorganism, in the case of an object to be sterilized, or indirectly to the microorganism by heating the bulk of an aqueous solution to be sterilized. This method is widely practiced as it allows flexibility, safety and economy in the sterilization process. 
     Dry heat sterilization is a method that is used to kill microorganisms and perform depyrogenation at elevated temperatures. This process takes place in an apparatus suitable for heating HEPA-filtered microorganism-free air to temperatures of at least 130-180° C. for the sterilization process and to temperatures of at least 230-250° C. for the depyrogenation process. Water to reconstitute concentrated or powdered delivery devices is also sterilized by autoclave. In some embodiments, a delivery device described herein comprises micronized pharmaceutical that are sterilized by dry heating, e.g., heating for about 7-11 hours at internal powder temperatures of 130-140° C., or for 1-2 hours at internal temperatures of 150-180° C. 
     Chemical Sterilization 
     Chemical sterilization methods are an alternative for products that do not withstand the extremes of heat sterilization. In this method, a variety of gases and vapors with germicidal properties, such as ethylene oxide, chlorine dioxide, formaldehyde or ozone are used. The germicidal activity of ethylene oxide, for example, arises from its ability to serve as a reactive alkylating agent. Thus, the sterilization process requires the ethylene oxide vapors to make direct contact with the product to be sterilized. 
     Radiation Sterilization 
     One advantage of radiation sterilization is the ability to sterilize many types of products without heat degradation or other damage. The radiation commonly employed is beta radiation or alternatively, gamma radiation from a  60 Co source. The penetrating ability of gamma radiation allows its use in the sterilization of many product types, including solutions, delivery devices and heterogeneous mixtures. The germicidal effects of irradiation arise from the interaction of gamma radiation with biological macromolecules. This interaction generates charged species and free radicals. Subsequent chemical reactions, such as rearrangements and cross-linking processes, result in the loss of normal function for these biological macromolecules. A delivery device described herein is optionally sterilized using beta irradiation. 
     Filtration 
     Filtration sterilization is a method used to remove but not destroy microorganisms from solutions. Membrane filters are used to filter heat-sensitive solutions. Such filters are thin, strong, homogenous polymers of mixed cellulosic esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE) and have pore sizes ranging from 0.1 to 0.22 μm. Solutions of various characteristics are optionally filtered using different filter membranes. For example, PVF and PTFE membranes are well suited to filtering organic solvents while aqueous solutions are filtered through PVF or MCE membranes. Filter apparatus are available for use on many scales ranging from the single point-of-use disposable filter attached to a syringe up to commercial scale filters for use in manufacturing plants. The membrane filters are sterilized by autoclave or chemical sterilization. Validation of membrane filtration systems is performed following standardized protocols (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3. Washington, D.C: Health Industry Manufacturers Association, 1981) and involve challenging the membrane filter with a known quantity (ca. 10 7 /cm 2 ) of unusually small microorganisms, such as  Brevundimonas diminuta  (ATCC 19146). 
     A delivery device disclosed herein is optionally sterilized by passing through membrane filters. Delivery devices comprising nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2):144-50) are amenable to sterilization by filtration through 0.22 μm filters without destroying their organized structure. 
     In some embodiments, a delivery device disclosed herein (or components thereof) is sterilized by means of filtration sterilization. In some embodiments, a delivery device disclosed herein comprises a plurality of particles wherein the particles are suitable for filtration sterilization. In some embodiments, the particles are less than 300 nm in size, less than 200 nm in size, or less than 100 nm in size. In some embodiments, a delivery device disclosed herein comprises a plurality of particles wherein the sterility of the particles is ensured by sterile filtration of the precursor components. In some embodiments, a delivery device disclosed herein comprises a plurality of particles wherein the sterility of the particles is ensured by low temperature sterile filtration. In a further embodiment, low temperature sterile filtration is carried out at a temperature between 0 and 30° C., between 0 and 20° C., between 0 and 10° C., between 10 and 20° C., or between 20 and 30° C. 
     In some embodiments, a delivery device disclosed herein is sterilized by: filtering the delivery device at low temperature through a sterilization filter; lyophilizing the delivery device; and reconstituting the delivery device with sterile water prior to administration. In some embodiments, a delivery device disclosed herein delivery device disclosed herein is manufactured as a suspension in a single vial delivery device containing the micronized active agent. A single vial o the delivery device is prepared by aseptically mixing a sterile poloxamer solution with sterile micronized active ingredient (e.g., PD98059) and transferring the delivery device to a sterile pharmaceutical container. In some embodiments, a single vial containing a delivery device disclosed herein delivery device disclosed herein as a suspension is resuspended before dispensing and/or administration. 
     In specific embodiments, filtration and/or filling procedures are carried out at about 5° C. below the gel temperature (T gel ) of a delivery device disclosed herein delivery device disclosed herein and with viscosity below a theoretical value of 100 cP to allow for filtration in a reasonable time using a peristaltic pump. 
     In some embodiments, the delivery device comprises a plurality of nanoparticles wherein the plurality of nanoparticles is suitable for filtration sterilization. In some embodiments, the plurality of nanoparticles comprises nanoparticles of less than 300 nm in size, of less than 200 nm in size, or of less than 100 nm in size. 
     In some embodiments, a delivery device disclosed herein comprises a plurality of microspheres wherein the sterility of the microspheres is ensured by sterile filtration of the precursor organic solution and aqueous solutions. In some embodiments, a delivery device disclosed herein comprises a thermoreversible gel composition wherein the sterility of the gel composition is ensured by low temperature sterile filtration. In a further embodiment, the low temperature sterile filtration occurs at a temperature between 0 and 30° C., or between 0 and 20° C., or between 0 and 10° C., or between 10 and 20° C., or between 20 and 30° C. In some embodiments, a delivery device disclosed herein is prepared by: filtering the aqueous solution containing the thermoreversible gel components at low temperature through a sterilization filter; lyophilizing the sterile solution; and reconstituting the thermoreversible gel composition with sterile water prior to administration. 
     In certain embodiments, an active agent is dissolved in a suitable vehicle (e.g. a buffer) and sterilized separately (e.g. by heat treatment, filtration, gamma radiation). In some instances, an active agent is sterilized separately in a dry state. In some instances, an active agent is sterilized as a suspension or as a colloidal suspension. The remaining excipients (e.g., fluid gel components present in the delivery devices) are sterilized in a separate step by a suitable method (e.g. filtration and/or irradiation of a cooled mixture of excipients); the two components that are separately sterilized are then mixed aseptically to provide the delivery device. In some instances, the final aseptic mixing is performed just prior to administration of a delivery device disclosed herein. 
     In some instances, certain methods of sterilization (e.g., heat treatment (e.g., in an autoclave), gamma irradiation, filtration) lead to irreversible degradation of polymeric components (e.g., thermosetting, gelling or mucoadhesive polymer components) and/or the active agent in the delivery device. In some instances, sterilization of a delivery device disclosed herein by filtration through a membrane (e.g., 0.2 μM membrane) is not possible if the delivery device comprises thixotropic polymers that gel during the process of filtration. 
     Accordingly, provided herein, in certain embodiments, are methods for sterilization of the delivery devices that prevent degradation of polymeric components (e.g., thermosetting and/or gelling and/or mucoadhesive polymer components) and/or the active agent during the process of sterilization. In some embodiments, degradation of the active agent is reduced or eliminated through the use of specific pH ranges for buffer components and specific proportions of gelling agents in a delivery device. In some embodiments, the choice of an appropriate gelling agent and/or thermosetting polymer allows for sterilization of delivery devices described herein by filtration. In some embodiments, the use of an appropriate thermosetting polymer and an appropriate copolymer (e.g., a gelling agent) in combination with a specific pH range for the delivery device allows for high temperature sterilization of delivery devices described with substantially no degradation of the active agent or the polymeric excipients. An advantage of the methods of sterilization provided herein is that, in certain instances, a delivery device are subjected to terminal sterilization via autoclaving without a loss of the active agent and/or excipients and/or polymeric components during the sterilization step and are rendered substantially free of microbes and/or pyrogens. 
     Microorganisms 
     Provided herein, in certain embodiments, are auris-acceptable delivery devices that ameliorate or lessen otic disorders. Further provided herein, in certain embodiments, are methods comprising the administration of said delivery devices. In some embodiments, a delivery device disclosed herein is substantially free of microorganisms. Acceptable sterility levels are based on applicable standards that define therapeutically acceptable the delivery devices, including but not limited to United States Pharmacopeia Chapters &lt;1111&gt; et seq. For example, acceptable sterility levels include about 10 colony forming units (cfu) per gram of delivery device, about 50 cfu per gram of delivery device, about 100 cfu per gram of delivery device, about 500 cfu per gram of delivery device or about 1000 cfu per gram of delivery device. In some embodiments, acceptable sterility levels for delivery devices include less than 10 cfu/mL, less that 50 cfu/mL, less than 500 cfu/mL or less than 1000 cfu/mL microbial agents. In addition, acceptable sterility levels include the exclusion of specified objectionable microbiological agents. By way of example, specified objectionable microbiological agents include but are not limited to  Escherichia coli  ( E. coli ),  Salmonella  sp.,  Pseudomonas aeruginosa  ( P. aeruginosa ) and/or other specific microbial agents. 
     Sterility of delivery device disclosed herein is confirmed through a sterility assurance program in accordance with United States Pharmacopeia Chapters &lt;61&gt;, &lt;62&gt; and &lt;71&gt;. A key component of the sterility assurance quality control, quality assurance and validation process is the method of sterility testing. Sterility testing, by way of example only, is performed by two methods. The first is direct inoculation wherein a sample of the delivery device to be tested is added to growth medium and incubated for a period of time up to 21 days. Turbidity of the growth medium indicates contamination. Drawbacks to this method include the small sampling size of bulk materials that reduces sensitivity, and detection of microorganism growth based on a visual observation. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter paper. The filter paper is then placed into media to promote the growth of microorganisms. This method has the advantage of greater sensitivity as the entire bulk product is sampled. The commercially available Millipore Steritest sterility testing system is optionally used for determinations by membrane filtration sterility testing. For the filtration testing of creams or ointments Steritest filter system No. TLHVSL210 are used. For the filtration testing of emulsions or viscous products Steritest filter system No. TLAREM210 or TDAREM210 are used. For the filtration testing of pre-filled syringes Steritest filter system No. TTHASY210 are used. For the filtration testing of material dispensed as an aerosol or foam Steritest filter system No. TTHVA210 are used. For the filtration testing of soluble powders in ampoules or vials Steritest filter system No. TTHADA210 or TTHADV210 are used. 
     Testing for  E. coli  and  Salmonella  includes the use of lactose broths incubated at 30-35° C. for 24-72 hours, incubation in MacConkey and/or EMB agars for 18-24 hours, and/or the use of Rappaport medium. Testing for the detection of  P. aeruginosa  includes the use of NAC agar. United States Pharmacopeia Chapter &lt;62&gt; further enumerates testing procedures for specified objectionable microorganisms. 
     In certain embodiments, a delivery device disclosed herein has less than about 60 colony forming units (CFU), less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 colony forming units of microbial agents per gram of delivery device. In certain embodiments, the delivery devices described herein are formulated to be isotonic with the endolymph and/or the perilymph. 
     Endotoxins 
     Provided herein, in certain embodiments, are auris-acceptable delivery devices that ameliorate or lessen otic disorders. Further provided herein, in certain embodiments, are methods comprising the administration of said delivery devices. In some embodiments, a delivery device disclosed herein is substantially free of endotoxins. A second aspect of the sterilization process is the removal of by-products from the killing of microorganisms (hereinafter, “Product”). The process of depyrogenation removes pyrogens from the sample. Pyrogens are endotoxins or exotoxins that induce an immune response. An example of an endotoxin is the lipopolysaccharide (LPS) molecule found in the cell wall of gram-negative bacteria. While sterilization procedures such as autoclaving or treatment with ethylene oxide kill the bacteria, the LPS residue induces a proinflammatory immune response, such as septic shock. Because the molecular size of endotoxins can vary widely, the presence of endotoxins is expressed in “endotoxin units” (EU). One EU is equivalent to 100 picograms of  E. coli  LPS. Humans can develop a response to as little as 5 EU/kg of body weight. The sterility is expressed in any units as recognized in the art. In certain embodiments, delivery devices described herein contain lower endotoxin levels (e.g. &lt;4 EU/kg of body weight of a subject) when compared to conventionally acceptable endotoxin levels (e.g., 5 EU/kg of body weight of a subject). In some embodiments, a delivery device disclosed herein has less than about 5 EU/kg of body weight of a subject. In other embodiments, a delivery device disclosed herein has less than about 4 EU/kg of body weight of a subject. In additional embodiments, a delivery device disclosed herein has less than about 3 EU/kg of body weight of a subject. In additional embodiments, a delivery device disclosed herein has less than about 2 EU/kg of body weight of a subject. 
     In some embodiments, a delivery device disclosed herein has less than about 5 EU/kg of delivery device. In other embodiments, a delivery device disclosed herein has less than about 4 EU/kg of delivery device. In additional embodiments, a delivery device disclosed herein has less than about 3 EU/kg of delivery device. In some embodiments, a delivery device disclosed herein has less than about 5 EU/kg of delivery device. In other embodiments, a delivery device disclosed herein has less than about 1 EU/kg of delivery device. In additional embodiments, a delivery device disclosed herein has less than about 0.2 EU/kg of delivery device. In some embodiments, a delivery device disclosed herein has less than about 5 EU/g of delivery device. In other embodiments, a delivery device disclosed herein has less than about 4 EU/g of delivery device. In additional embodiments, a delivery device disclosed herein has less than about 3 EU/g of delivery device. In some embodiments, a delivery device disclosed herein has less than about 5 EU/mg of delivery device. In other embodiments, a delivery device disclosed herein has less than about 4 EU/mg of delivery device. In additional embodiments, a delivery device disclosed herein has less than about 3 EU/mg of delivery device. In certain embodiments, a delivery device disclosed herein comprises from about 1 to about 5 EU/mL of delivery device. In certain embodiments, delivery devices for active agents described herein contain from about 2 to about 5 EU/mL of delivery device, from about 3 to about 5 EU/mL of delivery device, or from about 4 to about 5 EU/mL of delivery device. 
     In certain embodiments, a delivery device disclosed herein contains lower endotoxin levels (e.g. &lt;0.5 EU/mL of delivery device) when compared to conventionally acceptable endotoxin levels (e.g., 0.5 EU/mL of delivery device). In some embodiments, a delivery device disclosed herein has less than about 0.5 EU/mL of delivery device. In other embodiments, a delivery device disclosed herein has less than about 0.4 EU/mL of delivery device. In additional embodiments, a delivery device disclosed herein has less than about 0.2 EU/mL of delivery device. 
     Pyrogen detection, by way of example only, is performed by several methods. Suitable tests for sterility include tests described in United States Pharmacopoeia (USP) &lt;71&gt; Sterility Tests (23rd edition, 1995). The rabbit pyrogen test and the Limulus amebocyte lysate test are both specified in the United States Pharmacopeia Chapters &lt;85&gt; and &lt;151&gt; (USP23/NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, Md., 1995). Alternative pyrogen assays have been developed based upon the monocyte activation-cytokine assay. Uniform cell lines suitable for quality control applications have been developed and have demonstrated the ability to detect pyrogenicity in samples that have passed the rabbit pyrogen test and the Limulus amebocyte lysate test (Taktak et al, J. Pharm. Pharmacol. (1990), 43:578-82). In some embodiments, a delivery device disclosed herein is subject to depyrogenation. In some embodiments, the process for the manufacture of a delivery device disclosed herein comprises testing the delivery device for pyrogenicity. In certain embodiments, a delivery device described herein is substantially free of pyrogens. 
     Limitations on Excipients 
     Intratympanic injection of delivery devices creates several additional problems that must also be addressed before the delivery device can be administered. For example, there are many excipients that are ototoxic. While these excipients can be used when formulating an active agent for delivery by another method (e.g., topical), their use should be limited, reduced or eliminated when formulating a delivery device to be administered to the ear due to their ototoxic effects. 
     By way of non-limiting example, the use of the following commonly used solvents should be limited, reduced or eliminated when formulating agents for administration to the ear: alcohols, propylene glycol, and cyclohexane. Thus, in some embodiments, a device disclosed herein is free or substantially free of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of alcohols, propylene glycol, and cyclohexane. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of alcohols, propylene glycol, and cyclohexane. 
     Further, by way of non-limiting example, the use of the following commonly utilized preservatives should be limited, reduced or eliminated when formulating agents for administration to the ear: benzethonium chloride, benzalkonium chloride, and thiomersal. Thus, in some embodiments, a device disclosed herein is free or substantially free of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal. 
     Certain antiseptics used to disinfect components of therapeutic preparations (or the devices utilized to administer the preparations) should be limited, reduced, or eliminated in otic preparations. For example, acetic acid, iodine, and merbromin are all known to be ototoxic. Additionally, chlorhexidene, a commonly used antiseptic, should be limited, reduced or eliminated to disinfect any component of an otic preparation (including devices used to administer the preparation) as it is highly ototoxic in minute concentrations (e.g., 0.05%). Thus, in some embodiments, a device disclosed herein is free or substantially free of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene. 
     Further, otic preparations require particularly low concentrations of several potentially-common contaminants that are known to be ototoxic. Other dosage forms, while seeking to limit the contamination attributable to these compounds, do not require the stringent precautions that otic preparations require. For example, the following contaminants should be absent or nearly absent from otic preparations: arsnic, lead, mercury, and tin. Thus, in some embodiments, a device disclosed herein is free or substantially free of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 50 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 25 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 20 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 10 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 5 ppm of each of arsnic, lead, mercury, and tin. In some embodiments, a device disclosed herein comprises less than about 1 ppm of each of arsnic, lead, mercury, and tin. 
     pH and Practical Osmolarity 
     In some embodiments, an otic delivery device disclosed herein is formulated to provide an ionic balance that is compatible with inner ear fluids (e.g., endolymph and/or perilymph). 
     In certain instances, the ionic composition of the endolymph and perilymph regulate the electrochemical impulses of hair cells and thus hearing. In certain instances, changes in the conduction of electrochemical impulses along otic hair cells results in hearing loss. In certain instances, changes in the ionic balance of the endolymph or perilymph results in complete hearing loss. In certain instances, changes in the ionic balance of the endolymph or perilymph results in partial hearing loss. In certain instances, changes in the ionic balance of the endolymph or perilymph results in permanent hearing loss. In certain instances, changes in the ionic balance of the endolymph or perilymph results in temporary hearing loss. 
     In some embodiments, a delivery device disclosed herein is formulated in order to not disrupt the ionic balance of the endolymph. In some embodiments, a delivery device disclosed herein has an ionic balance that is the same as or substantially the same as the endolymph. In some embodiments, a delivery device disclosed herein does not does not disrupt the ionic balance of the endolymph so as to result in parital or complete hearing loss. In some embodiments, a delivery device disclosed herein does not does not disrupt the ionic balance of the endolymph so as to result in temporary or permanent hearing loss. 
     In some embodiments, a delivery device disclosed herein does not substantially disrupt the ionic balance of the perilymph. In some embodiments, a delivery device disclosed herein has an ionic balance that is the same as or substantially the same as the perilymph. In some embodiments, a delivery device disclosed herein does not result in parital or complete hearing loss as the delivery device does not disrupt the ionic balance of the perilymph. In some embodiments, a delivery device disclosed herein does not result in temporary or permanent hearing loss as the delivery device does not disrupt the ionic balance of the perilymph. 
     As used herein, “practical osmolarity/osmolality” or “deliverable osmolarity/osmolality” means the osmolarity/osmolality of a delivery device as determined by measuring the osmolarity/osmolality of the active agent and all excipients except the gelling and/or the thickening agent (e.g., polyoxyethylene-polyoxypropylene copolymers, carboxymethylcellulose or the like). The practical osmolarity of a delivery device disclosed herein is measured by a suitable method, e.g., a freezing point depression method as described in Viegas et. al.,  Int. J. Pharm.,  1998, 160, 157-162. In some instances, the practical osmolarity of a delivery device disclosed herein is measured by vapor pressure osmometry (e.g., vapor pressure depression method) that allows for determination of the osmolarity of a delivery device at higher temperatures. In some instances, vapor pressure depression method allows for determination of the osmolarity of a delivery device comprising a gelling agent (e.g., a thermoreversible polymer) at a higher temperature wherein the gelling agent is in the form of a gel. 
     In some embodiments, the osmolarity at a target site of action (e.g., the perilymph) is about the same as the delivered osmolarity (i.e., osmolarity of materials that cross or penetrate the round window membrane) of a delivery device described herein. In some embodiments, a delivery device described herein has a deliverable osmolarity of about 150 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 280 mOsm/L to about 370 mOsm/L or about 250 mOsm/L to about 320 mOsm/L. 
     The practical osmolality of an otic delivery device disclosed herein is from about 100 mOsm/kg to about 1000 mOsm/kg, from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, or from about 250 mOsm/kg to about 320 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg or from about 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, a delivery device described herein has a practical osmolarity of about 100 mOsm/L to about 1000 mOsm/L, about 200 mOsm/L to about 800 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 250 mOsm/L to about 320 mOsm/L, or about 280 mOsm/L to about 320 mOsm/L. 
     The endolymph and the perilymph have a pH that is close to the physiological pH of blood. The endolymph has a pH range of about 7.2-7.9; the perilymph has a pH range of about 7.2-7.4. The in situ pH of the proximal endolymph is about 7.4 while the pH of distal endolymph is about 7.9. 
     In some embodiments, the pH of a delivery device disclosed herein is adjusted (e.g., by use of a buffer) to an endolymph-compatible pH range of about 5.5 to 9.0. In specific embodiments, the pH of a delivery device disclosed herein is adjusted to a perilymph-suitable pH range of about 5.5 to about 9.0. In some embodiments, the pH of a delivery device disclosed herein is adjusted to a perilymph-suitable range of about 5.5 to about 8.0, about 6 to about 8.0 or about 6.6 to about 8.0. In some embodiments, the pH of a delivery device disclosed herein is adjusted to a perilymph-suitable pH range of about 7.0-7.6. 
     In some embodiments, a delivery device disclosed herein further comprises one or more pH adjusting agents or buffering agents. Suitable pH adjusting agents or buffers include, but are not limited to acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof and combinations or mixtures thereof. 
     In one embodiment, when one or more buffers are utilized in a delivery device of the present disclosure, they are combined (e.g., with a pharmaceutically acceptable vehicle) and are present in the final delivery device (e.g., in an amount ranging from about 0.1% to about 20%, from about 0.5% to about 10%). In certain embodiments of the present disclosure, the amount of buffer included in a delivery device is an amount such that the pH of the delivery device does not interfere with the body&#39;s natural buffering system. 
     In one embodiment, diluents are also used to stabilize a delivery device disclosed herein because they can provide a more stable environment. Salts dissolved in buffered solutions (that also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. 
     In some embodiments, a delivery device disclosed herein has a pH that allows for sterilization (e.g., by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) of a delivery device without degradation of the pharmaceutical agent or the polymers comprising the gel. In order to reduce hydrolysis and/or degradation of the active agent and/or the gel polymer during sterilization, the buffer pH is designed to maintain pH of the delivery device in the 7-8 range during the process of sterilization (e.g., high temperature autoclaving). 
     In specific embodiments, a delivery device disclosed herein has a pH that allows for terminal sterilization (e.g., by heat treatment and/or autoclaving) of a delivery device without degradation of the pharmaceutical agent or the polymers comprising the gel. For example, in order to reduce hydrolysis and/or degradation of the active agent and/or the gel polymer during autoclaving, the buffer pH is designed to maintain pH of the delivery device in the 7-8 range at elevated temperatures. Any appropriate buffer is used depending on the active agent used in the delivery device. In some instances, since pK a  of TRIS decreases as temperature increases at approximately −0.03/° C. and pK a  of PBS increases as temperature increases at approximately 0.003/° C., autoclaving at 250° F. (121° C.) results in a significant downward pH shift (i.e. more acidic) in the TRIS buffer whereas a relatively much less upward pH shift in the PBS buffer and therefore much increased hydrolysis and/or degradation of an active agent in TRIS than in PBS. Degradation of an active agent is reduced by the use of an appropriate combination of a buffer and polymeric additives (e.g. P407, CMC) as described herein. 
     In some embodiments, a pH of between about 5.0 and about 9.0, between about 5.5 and about 8.5, between about 6.0 and about 7.6, between about 7 and about 7.8, between about 7.0 and about 7.6, between about 7.2 and 7.6, or between about 7.2 and about 7.4 is suitable for sterilization (e.g., by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) of the delivery devices described herein. In specific embodiments, a delivery device pH of about 6.0, about 6.5, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6 is suitable for sterilization (e.g., by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) of a delivery device described herein. 
     In some embodiments, a delivery device has a pH as described herein, and further comprises a thickening agent (e.g., a viscosity enhancing agent) such as, by way of non-limiting example, a cellulose based thickening agent described herein. In some instances, the addition of a secondary polymer (e.g., a thickening agent) and a pH as described herein, allows for sterilization of a delivery device disclosed herein without substantial degradation of the active agent and/or the polymer components in the delivery device. In some embodiments, the ratio of a thermoreversible poloxamer to a thickening agent in a delivery device that has a pH as described herein, is about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1 about 10:1, or about 5:1. For example, in certain embodiments, a sustained and/or extended release delivery device disclosed herein comprises a combination of poloxamer 407 (pluronic F127) and carboxymethylcellulose (CMC) in a ratio of about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 10:1 or about 5:1. 
     In some embodiments, the amount of thermoreversible polymer in a delivery device disclosed herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35% or about 40% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer in a delivery device disclosed herein is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24% or about 25% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 7.5% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 10% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 11% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 12% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 13% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 14% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 15% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 16% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 17% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 18% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 19% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 20% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 21% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 23% of the total weight of the delivery device. In some embodiments, the amount of thermoreversible polymer (e.g., pluronic F127) in a delivery device disclosed herein is about 25% of the total weight of the delivery device. 
     In some embodiments, the amount of thickening agent (e.g., a gelling agent) in a delivery device disclosed herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the delivery device. In some embodiments, the amount of thickening agent (e.g., a gelling agent) in a delivery device disclosed herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the delivery device. 
     In some embodiments, a delivery device disclosed herein is stable with respect to pH over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, a delivery device described herein is stable with respect to pH over a period of at least about 1 week. Also described herein are delivery devices that are stable with respect to pH over a period of at least about 1 month. 
     Tonicity Agents 
     In general, the endolymph has a higher osmolality than the perilymph. For example, the endolymph has an osmolality of about 304 mOsm/kg H 2 O while the perilymph has an osmolality of about 294 mOsm/kg H 2 O. In certain embodiments, tonicity agents are added to a delivery device described herein in an amount as to provide a practical osmolality of about 100 mOsm/kg to about 1000 mOsm/kg, from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg or from about 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, a delivery device described herein has a practical osmolarity of about 100 mOsm/L to about 1000 mOsm/L, about 200 mOsm/L to about 800 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 280 mOsm/L to about 320 mOsm/L or about 250 mOsm/L to about 320 mOsm/L. 
     In some embodiments, the deliverable osmolarity of a delivery device disclosed herein is designed to be isotonic with the targeted otic structure (e.g., endolymph, perilymph or the like). In specific embodiments, a delivery devices described herein is formulated to provide a delivered perilymph-suitable osmolarity at the target site of action of about 250 to about 320 mOsm/L (osmolality of about 250 to about 320 mOsm/kg H 2 O); and preferably about 270 to about 320 mOsm/L (osmolality of about 270 to about 320 mOsm/kg H 2 O). In specific embodiments, the deliverable osmolarity/osmolality of a delivery device (i.e., the osmolarity/osmolality of the delivery device in the absence of gelling or thickening agents (e.g., thermoreversible gel polymers)) is adjusted, for example, by the use of appropriate salt concentrations (e.g., concentration of potassium or sodium salts) or the use of tonicity agents that renders a delivery device endolymph-compatible and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph) upon delivery at the target site. The osmolarity of a delivery device comprising a thermoreversible gel polymer is an unreliable measure due to the association of varying amounts of water with the monomeric units of the polymer. The practical osmolarity of a delivery device is a reliable measure and is measured by any suitable method (e.g., freezing point depression method, vapor depression method). In some instances, a delivery device described herein provide a deliverable osmolarity (e.g., at a target site (e.g., perilymph)) that causes minimal disturbance to the environment of the inner ear and causes minimum discomfort (e.g., vertigo and/or nausea) to a mammal upon administration. 
     In some embodiments, a delivery device disclosed herein is isotonic with the perilymph and/or endolymph. Isotonic delivery devices are provided by the addition of a tonicity agent. Suitable tonicity agents include, but are not limited to a pharmaceutically acceptable sugar, salt or combinations or mixtures thereof, such as, but not limited to dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. 
     In some embodiments, a delivery device disclosed herein further comprises a salt in an amount required to bring the osmolality of the delivery device into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, salts and/or other tonicity agents used in delivery devices described herein are non-ototoxic. 
     In some embodiments, a delivery device disclosed herein has a pH and/or practical osmolarity as described herein, and has a concentration of active pharmaceutical ingredient between about 1 mM and about 10 mM, between about 1 mM and about 100 mM, between about 0.1 mM and about 100 mM, between about 0.1 mM and about 100 nM. In some embodiments, a delivery device disclosed herein has a pH and/or practical osmolarity as described herein, and have a concentration of active pharmaceutical ingredient between about 0.01%-about 20%, between about 0.01%-about 10%., between about 0.01%-about 7.5%, between about 0.01%-6%, between about 0.01-5%, between about 0.1-about 10%, or between about 0.1-about 6% of the active ingredient by weight of the delivery device. In some embodiments, a delivery device disclosed herein has a pH and/or practical osmolarity as described herein, and has a concentration of active pharmaceutical ingredient between about 0.1 and about 70 mg, between about 1 mg and about 70 mg/mL, between about 1 mg and about 50 mg/mL, between about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL to about 10 mg/mL, between about 1 mg/mL to about 5 mg/mL, or between about 0.5 mg/mL to about 5 mg/mL of the active agent by volume of the delivery device. In some embodiments, a delivery device disclosed herein has a pH and/or practical osmolarity as described herein, and has a concentration of active pharmaceutical ingredient between about 1 μg/mL and about 500 μg/mL, between about 1 μg/mL and about 250 μg/mL, between about 1 μg and about 100 μg/mL, between about 1 μg/mL and about 50 μg/mL, or between about 1 μg/mL and about 20 μg/mL of the active agent by volume of the delivery device. 
     Delivery Devices 
     Provided herein, in certain embodiments, are delivery devices that include an active agent and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In some embodiments, a delivery device disclosed herein further comprises a second active agent, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. Such carriers, adjuvants, and other excipients will be compatible with the environment in the targeted auris structure(s). Specifically contemplated are carriers, adjuvants and excipients that lack ototoxicity or are minimally ototoxic in order to allow effective treatment of the otic disorders contemplated herein with minimal side effects in the targeted regions or areas. To prevent ototoxicity, a delivery device disclosed herein are optionally targeted to distinct regions of the targeted auris structures, including but not limited to the tympanic cavity, vestibular bony and membranous labyrinths, cochlear bony and membranous labyrinths and other anatomical or physiological structures located within the auris interna. 
     Some pharmaceutical excipients, diluents or carriers are potentially ototoxic. For example, benzalkonium chloride, a common preservative, is ototoxic and therefore potentially harmful if introduced into the vestibular or cochlear structures. In formulating a controlled-release auris compatible delivery device, it is advised to avoid or combine the appropriate excipients, diluents or carriers to lessen or eliminate potential ototoxic components from the delivery device, or to decrease the amount of such excipients, diluents or carriers. Optionally, a controlled-release auris compatible delivery device further comprises otoprotective agents, such as antioxidants, alpha lipoic acid, calcium, fosfomycin or iron chelators, to counteract potential ototoxic effects that may arise from the use of specific active agents or excipients, diluents or carriers. 
     In some embodiments, a delivery device disclosed herein further comprises a dye to help enhance the visualization of the gel when applied. In some embodiments, dyes that are compatible with a delivery device disclosed herein include Evans blue (e.g., 0.5% of the total weight of an the delivery device), Methylene blue (e.g., 1% of the total weight of an the delivery device), Isosulfan blue (e.g., 1% of the total weight of an the delivery device), Trypan blue (e.g., 0.15% of the total weight of an the delivery device), and/or indocyanine green (e.g., 25 mg/vial). Other common dyes, e.g., FD&amp;C red 40, FD&amp;C red 3, FD&amp;C yellow 5, FD&amp;C yellow 6, FD&amp;C blue 1, FD&amp;C blue2, FD&amp;C green 3, fluorescence dyes (e.g., Fluorescein isothiocyanate, rhodamine, Alexa Fluors, DyLight Fluors) and/or dyes that are visualizable in conjunction with non-invasive imaging techniques such as MRI, CAT scans, PET scans or the like. Gadolinium-based MRI dyes, iodine-base dyes, barium-based dyes or the like are also contemplated for use with a delivery device described herein. Other dyes that are compatible with a delivery device disclosed herein are listed in the Sigma-Aldrich catalog under dyes (that is included herein by reference for such disclosure). 
     A delivery device described herein is administered by contacting the delivery device with the  crista  fenestrae cochlea, the round window, the tympanic cavity, the tympanic membrane, the auris media or the auris externa. 
     In some embodiments, a delivery device disclosed herein comprises a gel matrix, also referred to herein as “auris acceptable gel compositions,” “auris interna-acceptable gel compositions,” “auris media-acceptable gel compositions,” “auris externa-acceptable gel compositions”, “the delivery device” or variations thereof. All of the components of the delivery device must be compatible with the targeted auris structure. Further, the delivery device provides controlled-release of the active agent to the desired site within the targeted auris structure; in some embodiments, the delivery device also has an immediate or rapid release component for delivery of the active agent to the desired target site. In other embodiments, the delivery device has a sustained release component for delivery of the active agent. In some embodiments, the delivery device comprises a multiparticulate (e.g., micronized) active agent. In some embodiments, the delivery device is biodegradable. In other embodiments, the delivery device further comprises a mucoadhesive excipient to allow adhesion to the external mucous layer of the round window membrane. In yet other embodiments, the delivery device further comprises a penetration enhancer excipient; in further embodiments, the auris gel composition contains a viscosity enhancing agent sufficient to provide a viscosity of between about 500 and 1,000,000 centipoise, between about 750 and 1,000,000 centipoise; between about 1000 and 1,000,000 centipoise; between about 1000 and 400,000 centipoise; between about 2000 and 100,000 centipoise; between about 3000 and 50,000 centipoise; between about 4000 and 25,000 centipoise; between about 5000 and 20,000 centipoise; or between about 6000 and 15,000 centipoise. In some embodiments, the auris gel composition contains a viscosity enhancing agent sufficient to provide a viscosity of between about 50,0000 and 1,000,000 centipoise. 
     In some embodiments, a delivery device disclosed herein is a hydrogel. In some embodiments, a delivery device disclosed herein is a thermoreversible gel such that upon preparation of the gel at room temperature or below, the delivery device is a fluid, but upon application of the gel into or near the auris interna and/or auris media target site, including the tympanic cavity, round window membrane or the  crista  fenestrae  cochleae , the auris-pharmaceutical delivery device stiffens or hardens into a gel-like substance. 
     In some embodiments, a delivery device disclosed herein is capable of being administered on or near the round window membrane via intratympanic injection. In some embodiments, a delivery device disclosed herein is administered on or near the round window or the  crista  fenestrae  cochleae  through entry via a post-auricular incision and surgical manipulation into or near the round window or the  crista  fenestrae  cochleae  area. In some embodiments, a delivery device disclosed herein is applied via syringe and needle, wherein the needle is inserted through the tympanic membrane and guided to the area of the round window or  crista  fenestrae  cochleae . The delivery device is then deposited on or near the round window or  crista  fenestrae  cochleae  for localized treatment. In some embodiments, a delivery device disclosed herein is applied via microcatheters implanted into the patient. In some embodiments, a delivery device disclosed herein is administered via a pump device onto or near the round window membrane. In some embodiments, a delivery device disclosed herein is applied at or near the round window membrane via a microinjection device. In some embodiments, a delivery device disclosed herein is applied in the tympanic cavity. In some embodiments, a delivery device disclosed herein is applied on the tympanic membrane. In some embodiments, a delivery device disclosed herein is applied onto or in the auditory canal. 
     In further specific embodiments, a delivery device disclosed herein comprises a multiparticulate active agent in a liquid matrix (e.g., a liquid composition for intratympanic injection, or otic drops). In some embodiments, a delivery device disclosed herein comprises a multiparticulate active agent in a solid matrix. 
     Controlled-Release Delivery Devices 
     In general, controlled-release delivery devices impart control over the release of drug with respect to site of release and time of release within the body. As discussed herein, controlled-release refers to immediate release, delayed release, sustained release, extended release, variable release, pulsatile release and bi-modal release. Many advantages are offered by controlled-release. First, controlled-release of a pharmaceutical agent allows less frequent dosing and thus minimizes repeated treatment. Second, controlled-release treatment results in more efficient drug utilization and less of the compound remains as a residue. Third, controlled-release offers the possibility of localized drug delivery by placement of a delivery device at the site of disease. Still further, controlled-release offers the opportunity to administer and release two or more different drugs, each having a unique release profile, or to release the same drug at different rates or for different durations, by means of a single dosage unit. 
     Accordingly, one aspect of the embodiments disclosed herein is to provide a controlled-release auris-compatible delivery device. The controlled-release aspect of a delivery device disclosed herein is imparted through a variety of agents, including but not limited to excipients, agents or materials that are acceptable for use in the auris interna or other otic structure. By way of example only, such excipients, agents or materials include an auris-acceptable polymer, an auris-acceptable viscosity enhancing agent, an auris-acceptable gel, an auris-acceptable microsphere or microparticle, an auris-acceptable hydrogel, an auris-acceptable thermoreversible gel, or combinations thereof. 
     Gels 
     Gels, sometimes referred to as jellies, have been defined in various ways. For example, the United States Pharmacopoeia defines gels as semisolid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid. Gels include a single-phase or a two-phase system. A single-phase gel consists of organic macromolecules distributed uniformly throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecules and the liquid. Some single-phase gels are prepared from synthetic macromolecules (e.g., carbomer) or from natural gums, (e.g., tragacanth). In some embodiments, single-phase gels are generally aqueous, but will also be made using alcohols and oils. Two-phase gels consist of a network of small discrete particles. 
     Gels can also be classified as being hydrophobic or hydrophilic. In certain embodiments, the base of a hydrophobic gel consists of a liquid paraffin with polyethylene or fatty oils gelled with colloidal silica, or aluminum or zinc soaps. In contrast, the base of hydrophobic gels usually consists of water, glycerol, or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth, starch, cellulose derivatives, carboxyvinylpolymers, and magnesium-aluminum silicates). In certain embodiments, the rheology of a delivery device disclosed herein is disclosed herein is pseudo plastic, plastic, thixotropic, or dilatant. 
     In some embodiments, a delivery device disclosed herein is not a liquid at room temperature. In certain embodiments, the enhanced viscosity delivery device is characterized by a phase transition between room temperature and body temperature (including an individual with a serious fever, e.g., up to about 42° C.). In some embodiments, the phase transition occurs at 1° C. below body temperature, at 2° C. below body temperature, at 3° C. below body temperature, at 4° C. below body temperature, at 6° C. below body temperature, at 8° C. below body temperature, or at 10° C. below body temperature. In some embodiments, the phase transition occurs at about 15° C. below body temperature, at about 20° C. below body temperature or at about 25° C. below body temperature. In specific embodiments, the gelation temperature (Tgel) of a delivery device disclosed herein is about 20° C., about 25° C., or about 30° C. In certain embodiments, the gelation temperature (Tgel) of a delivery device disclosed herein is about 35° C., or about 40° C. In one embodiment, administration of a delivery device disclosed herein at about body temperature reduces or inhibits vertigo associated with intratympanic administration of the delivery devices. Included within the definition of body temperature is the body temperature of a healthy individual, or an unhealthy individual, including an individual with a fever (up to −42° C.). In some embodiments, a delivery device disclosed herein is a liquid at about room temperature and is administered at or at about room temperature, reducing or ameliorating side effects such as, for example, vertigo. 
     Polymers composed of polyoxypropylene and polyoxyethylene form thermoreversible gels when incorporated into aqueous solutions. These polymers have the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful delivery devices that are applied to the targeted auris structure(s). The liquid state-to-gel state phase transition is dependent on the polymer concentration and the ingredients in the solution. 
     Poloxamer 407 (PF-127) is a nonionic surfactant composed of polyoxyethylene-polyoxypropylene copolymers. Other poloxamers include 188 (F-68 grade), 237 (F-87 grade), 338 (F-108 grade). Aqueous solutions of poloxamers are stable in the presence of acids, alkalis, and metal ions. PF-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106 P70 E106, with an average molar mass of 13,000. The polymer can be further purified by suitable methods that will enhance gelation properties of the polymer. It contains approximately 70% ethylene oxide, which accounts for its hydrophilicity. It is one of the series of poloxamer ABA block copolymers, whose members share the chemical formula shown below. 
     
       
         
         
             
             
         
       
     
     PF-127 is of particular interest since concentrated solutions (&gt;20% w/w) of the copolymer are transformed from low viscosity transparent solutions to solid gels on heating to body temperature. This phenomenon, therefore, suggests that when placed in contact with the body, the gel preparation will form a semi-solid structure and a sustained release depot. Furthermore, PF-127 has good solubilizing capacity, low toxicity and is, therefore, considered a good medium for drug delivery systems. 
     In an alternative embodiment, the thermogel is a PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature (1997), 388:860-2; Jeong et al, J. Control. Release (2000), 63:155-63; Jeong et al, Adv. Drug Delivery Rev. (2002), 54:37-51). The polymer exhibits sol-gel behavior over a concentration of about 5% w/w to about 40% w/w. Depending on the properties desired, the lactide/glycolide molar ratio in the PLGA copolymer ranges from about 1:1 to about 20:1. The resulting copolymers are soluble in water and form a free-flowing liquid at room temperature, but form a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Ingelheim. This material is composed of a PLGA copolymer of 50:50 poly(DL-lactide-co-glycolide) and is 10% w/w of PEG and has a molecular weight of about 6000. 
     ReGel® is a tradename of MacroMed Incorporated for a class of low molecular weight, biodegradable block copolymers having reverse thermal gelation properties as described in U.S. Pat. Nos. 6,004,573, 6,117,949, 6,201,072, and 6,287,588. It also includes biodegradable polymeric drug carriers disclosed in pending U.S. patent application Ser. Nos. 09/906,041, 09/559,799 and 10/919,603. The biodegradable drug carrier comprises ABA-type or BAB-type triblock copolymers or mixtures thereof, wherein the A-blocks are relatively hydrophobic and comprise biodegradable polyesters or poly(orthoester)s, and the B-blocks are relatively hydrophilic and comprise polyethylene glycol (PEG), said copolymers having a hydrophobic content of between 50.1 to 83% by weight and a hydrophilic content of between 17 to 49.9% by weight, and an overall block copolymer molecular weight of between 2000 and 8000 Daltons. The drug carriers exhibit water solubility at temperatures below normal mammalian body temperatures and undergo reversible thermal gelation to then exist as a gel at temperatures equal to physiological mammalian body temperatures. The biodegradable, hydrophobic A polymer block comprises a polyester or poly(ortho ester), in that the polyester is synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, ε-hydroxyhexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and copolymers thereof and having an average molecular weight of between about 600 and 3000 Daltons. The hydrophilic B-block segment is preferably polyethylene glycol (PEG) having an average molecular weight of between about 500 and 2200 Daltons. 
     Additional biodegradable thermoplastic polyesters include AtriGel® (provided by Atrix Laboratories, Inc.) and/or those disclosed, e.g., in U.S. Pat. Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194; wherein the suitable biodegradable thermoplastic polyester is disclosed as a thermoplastic polymer. Examples of suitable biodegradable thermoplastic polyesters include polylactides, polyglycolides, polycaprolactones, copolymers thereof, terpolymers thereof, and combinations thereof. In some such embodiments, the suitable biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymer thereof, a terpolymer thereof, or a combination thereof. In one embodiment, the biodegradable thermoplastic polyester is 50/50 poly(DL-lactide-co-glycolide) having a carboxy terminal group; is present in about 30 wt. % to about 40 wt. % of the delivery device; and has an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without a carboxy terminal group; is present in about 40 wt. % to about 50 wt. % of the delivery device; and has an average molecular weight of about 15,000 to about 24,000. In further or alternative embodiments, the terminal groups of the poly(DL-lactide-co-glycolide) are either hydroxyl, carboxyl, or ester depending upon the method of polymerization. Polycondensation of lactic or glycolic acid provides a polymer with terminal hydroxyl and carboxyl groups. Ring-opening polymerization of the cyclic lactide or glycolide monomers with water, lactic acid, or glycolic acid provides polymers with the same terminal groups. However, ring-opening of the cyclic monomers with a monofunctional alcohol such as methanol, ethanol, or 1-dodecanol provides a polymer with one hydroxyl group and one ester terminal groups. Ring-opening polymerization of the cyclic monomers with a diol such as 1,6-hexanediol or polyethylene glycol provides a polymer with only hydroxyl terminal groups. 
     Since the polymer systems of thermoreversible gels dissolve more completely at reduced temperatures, methods of solubilization include adding the required amount of polymer to the amount of water to be used at reduced temperatures. Generally after wetting the polymer by shaking, the mixture is capped and placed in a cold chamber or in a thermostatic container at about 0-10° C. in order to dissolve the polymer. The mixture is stirred or shaken to bring about a more rapid dissolution of the thermoreversible gel polymer. The active agent and various additives such as buffers, salts, and preservatives are subsequently added and dissolved. In some instances the active agent and/or other pharmaceutically active agent is suspended if it is insoluble in water. The pH is modulated by the addition of appropriate buffering agents. Round window membrane mucoadhesive characteristics are optionally imparted to a thermoreversible gel by incorporation of round window membrane mucoadhesive carbomers, such as Carbopol® 934P, to the delivery device (Majithiya et al, AAPS PharmSciTech (2006), 7(3), p. E1; EP0551626, both of that is incorporated herein by reference for such disclosure). 
     In some embodiments, a delivery device disclosed herein does not require the use of an added viscosity enhancing agent. Such delivery devices incorporate at least one pharmaceutically acceptable buffer. In some embodiments, the delivery device comprises an active agent and a pharmaceutically acceptable buffer. In another embodiment, the pharmaceutically acceptable excipient or carrier is a gelling agent. 
     In other embodiments, a delivery device disclosed herein further comprises one or more pH adjusting agents or buffering agents to provide an endolymph or perilymph suitable pH. Suitable pH adjusting agents or buffers include, but are not limited to acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof and combinations or mixtures thereof. Such pH adjusting agents and buffers are included in an amount required to maintain pH of the delivery device between a pH of about 5 and about 9, in one embodiment a pH between about 6.5 to about 7.5, and in yet another embodiment at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5. In one embodiment, when one or more buffers are utilized in a delivery device of the present disclosure, they are combined, e.g., with a pharmaceutically acceptable vehicle and are present in the final delivery device, e.g., in an amount ranging from about 0.1% to about 20%, from about 0.5% to about 10%. In certain embodiments of the present disclosure, the amount of buffer included in a delivery device is an amount such that the pH of delivery device does not interfere with the natural buffering system of the auris media or auris interna, or does not interfere with the natural pH of the endolymph or perilymph: depending on where in the cochlea the active agent delivery device is targeted. In some embodiments, from about 10 mM to about 200 mM concentration of a buffer is present in a delivery device disclosed herein. In certain embodiments, from about a 5 mM to about a 200 mM concentration of a buffer is present. In certain embodiments, from about a 20 mM to about a 100 mM concentration of a buffer is present. In one embodiment is a buffer such as acetate or citrate at slightly acidic pH. In one embodiment the buffer is a sodium acetate buffer having a pH of about 4.5 to about 6.5. In one embodiment the buffer is a sodium citrate buffer having a pH of about 5.0 to about 8.0, or about 5.5 to about 7.0. 
     In an alternative embodiment, the buffer used is tris(hydroxymethyl)aminomethane, bicarbonate, carbonate or phosphate at slightly basic pH. In one embodiment, the buffer is a sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or about 7.0 to about 8.0. In some embodiments, the buffer is a sodium phosphate dibasic buffer having a pH of about 6.0 to about 9.0. 
     Also described herein are controlled-release delivery devices comprising an active agent and a viscosity enhancing agent. Suitable viscosity-enhancing agents include by way of example only, gelling agents and suspending agents. In one embodiment, the enhanced viscosity delivery device does not include a buffer. In other embodiments, the enhanced viscosity delivery device further comprises a pharmaceutically acceptable buffer. Sodium chloride or other tonicity agents are optionally used to adjust tonicity, if necessary. 
     By way of example only, the auris-acceptable viscosity agent includes hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate. Other viscosity enhancing agents compatible with the targeted auris structure include, but are not limited to, acacia (gum arabic), agar, aluminum magnesium silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, Carbopol, xanthan, cellulose, microcrystalline cellulose (MCC),  ceratonia , chitin, carboxymethylated chitosan, chondrus, dextrose, furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, xanthum gum, gum tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose) or combinations thereof. In specific embodiments, the viscosity-enhancing excipient is a combination of MCC and CMC. In another embodiment, the viscosity-enhancing agent is a combination of carboxymethylated chitosan, or chitin, and alginate. The combination of chitin and alginate with an active agent restricts the diffusion of an active agents from the delivery device. Moreover, the combination of carboxymethylated chitosan and alginate is optionally used to assist in increasing the permeability of the active agents through the round window membrane. 
     In some embodiments, is an enhanced viscosity delivery device, comprising from about 0.1 mM and about 100 mM of active agent, a pharmaceutically acceptable viscosity agent, and water for injection, the concentration of the viscosity agent in the water being sufficient to provide an enhanced viscosity delivery device with a final viscosity from about 100 to about 100,000 cP. In certain embodiments, the viscosity of the gel is in the range from about 100 to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000 cP to about 500,000 cP, about 15,000 cP to about 1,000,000 cP. In other embodiments, when an even more viscous medium is desired, the biocompatible gel comprises at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, or even at least about 80% or so by weight of the active agent. In highly concentrated samples, the biocompatible enhanced viscosity delivery device comprises at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, at least about 90% or at least about 95% or more by weight of the active agent. 
     In some embodiments, the viscosity of a delivery device disclosed herein is measured by any suitable method. For example, in some embodiments, an LVDV-II+CP Cone Plate Viscometer and a Cone Spindle CPE-40 is used to calculate the viscosity of a delivery device disclosed herein. In other embodiments, a Brookfield (spindle and cup) viscometer is used to calculate the viscosity of a delivery device disclosed herein. In some embodiments, the viscosity ranges referred to herein are measured at room temperature. In other embodiments, the viscosity ranges referred to herein are measured at body temperature (e.g., at the average body temperature of a healthy human). 
     In one embodiment, the pharmaceutically acceptable enhanced viscosity auris-acceptable delivery device comprises an active agent and at least one gelling agent. Suitable gelling agents for use in preparation of a delivery device disclosed herein include, but are not limited to, celluloses, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan, paraffin, petrolatum and combinations or mixtures thereof. In some other embodiments, hydroxypropylmethylcellulose (Methocel®) is utilized as the gelling agent. In certain embodiments, the viscosity enhancing agents described herein are also utilized as the gelling agent for a delivery device disclosed herein. 
     In some embodiments, the auris-acceptable gel comprises substantially all of the weight of the delivery device. In some embodiments, the auris-acceptable gel comprises as much as about 98% or about 99% of the delivery device by weight. This is desirous when a substantially non-fluid, or substantially viscous delivery device is needed. In a further embodiment, when slightly less viscous, or slightly more fluid delivery devices are desired, the biocompatible gel portion of the delivery device comprises at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, or even at least about 80% or 90% by weight of the delivery device. All intermediate integers within these ranges are contemplated to fall within the scope of this disclosure, and in some alternative embodiments, even more fluid (and consequently less viscous) delivery devices are formulated, such as for example, those in that the gel or matrix component of the mixture comprises not more than about 50% by weight, not more than about 40% by weight, not more than about 30% by weight, or even those than comprise not more than about 15% or about 20% by weight of the delivery device. 
     Auris-Acceptable Suspending Agents 
     In one embodiment, the delivery device further comprises at least one suspending agent, wherein the suspending agent assists in imparting controlled-release characteristics to the delivery device. In some embodiments, suspending agents also serve to increase the viscosity of the auris compatible delivery devices. 
     Suspending agents include, by way of example only, compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. In some embodiments, useful aqueous suspensions also contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. 
     In one embodiment, the present disclosure provides auris-acceptable delivery devices comprising a therapeutically effective amount of an active agent in a hydroxyethyl cellulose gel. Hydroxyethyl cellulose (HEC) is obtained as a dry powder that is reconstituted in water or an aqueous buffer solution to give the desired viscosity (generally about 200 cps to about 30,000 cps, corresponding to about 0.2 to about 10% HEC). In one embodiment the concentration of HEC is between about 1% and about 15%, about 1% and about 2%, or about 1.5% to about 2%. 
     In other embodiments, a delivery device disclosed herein further comprises excipients, other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts, solubilizers, an antifoaming agent, an antioxidant, a dispersing agent, a wetting agent, a surfactant, and combinations thereof. 
     Round Window Membrane Mucoadhesives 
     Also contemplated within the scope of the embodiments is the addition of a round window membrane mucoadhesive to the auris compatible delivery devices. The term ‘mucoadhesion’ is used for materials that bind to the mucin layer of a biological membrane, such as the external membrane of the 3-layered round window membrane. To serve as round window membrane mucoadhesive polymers, the polymers possess some general physiochemical features such as predominantly anionic hydrophilicity with numerous hydrogen bond forming groups, suitable surface property for wetting mucus/mucosal tissue surfaces or sufficient flexibility to penetrate the mucus network. 
     Round window membrane mucoadhesive agents that are used with a delivery device disclosed herein include, but are not limited to, at least one soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer; a crosslinked poly(acrylic acid) (e.g. Carbopol® 947P); a carbomer homopolymer; a carbomer copolymer; a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alignate gum gel, a water-dispersible polycarboxylated vinyl polymer, at least two particulate components selected from the group consisting of titanium dioxide, silicon dioxide, and clay, or a mixture thereof. The round window membrane mucoadhesive agent is optionally used in combination with an auris-acceptable viscosity increasing excipient, or used alone to increase the interaction of the delivery device with the mucosal layer target otic component. In one non-limiting example, the mucoadhesive agent is maltodextrin and/or an alginate gum. When used, the round window membrane mucoadhesive character imparted to the delivery device is at a level that is sufficient to deliver an effective amount of the active agent to, for example, the mucosal layer of round window membrane or the  crista  fenestrae  cochleae  in an amount that coats the mucosal membrane, and thereafter deliver the active agent to the affected areas, including by way of example only, the vestibular and/or cochlear structures of the auris interna. When used, the mucoadhesive characteristics of a delivery device provided herein are determined, and using this information (along with the other teachings provided herein), the appropriate amounts are determined. One method for determining sufficient mucoadhesiveness includes monitoring changes in the interaction of the delivery device with a mucosal layer, including but not limited to measuring changes in residence or retention time of the delivery device in the absence and presence of the mucoadhesive excipient. 
     Mucoadhesive agents have been described, for example, in U.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028, 6,348,502, 6,319,513, 6,306,789, 5,814,330, and 4,900,552, each of that is hereby incorporated by reference for such disclosure. 
     In another non-limiting example, a mucoadhesive agent is, for example, at least two particulate components selected from titanium dioxide, silicon dioxide, and clay, wherein the delivery device is not further diluted with a liquid prior to administration and the level of silicon dioxide, if present, is from about 3% to about 15%, by weight of the delivery device. Silicon dioxide, if present, includes fumed silicon dioxide, precipitated silicon dioxide, coacervated silicon dioxide, gel silicon dioxide, and mixtures thereof. Clay, if present, includes kaolin minerals, serpentine minerals, smectites, illite or a mixture thereof. For example, clay includes laponite, bentonite, hectorite, saponite, montmorillonites or a mixture thereof. 
     In one non-limiting example, the round window membrane mucoadhesive agent is maltodextrin. Maltodextrin is a carbohydrate produced by the hydrolysis of starch that is optionally derived from corn, potato, wheat or other plant products. Maltodextrin is optionally used either alone or in combination with other round window membrane mucoadhesive agents to impart mucoadhesive characteristics to a delivery device disclosed herein. In one embodiment, a combination of maltodextrin and a carbopol polymer are used to increase the round window membrane mucoadhesive characteristics of a delivery device disclosed herein. 
     In another embodiment, the round window membrane mucoadhesive agent is an alkyl-glycoside and/or a saccharide alkyl ester. As used herein, an “alkyl-glycoside” means a compound comprising a hydrophilic saccharide (e.g. sucrose, maltose, or glucose) linked to a hydrophobic alkyl. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkyl-glycoside comprises a sugar linked to a hydrophobic alkyl (e.g., an alkyl comprising about 6 to about 25 carbon atoms) by an amide linkage, an amine linkage, a carbamate linkage, an ether linkage, a thioether linkage, an ester linkage, a thioester linkage, a glycosidic linkage, a thioglycosidic linkage, and/or a ureide linkage. In some embodiments, the round window membrane mucoadhesive agent is a hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl α- or β-D-maltoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl α- or β-D-glucoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl α- or β-D-sucroside; hexyl-, heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; heptyl- or octyl-1-thio-α- or β-D-glucopyranoside; alkyl thiosucroses; alkyl maltotriosides; long chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers; derivatives of palatinose or isomaltamine linked by an amide linkage to an alkyl chain and derivatives of isomaltamine linked by urea to an alkyl chain; long chain aliphatic carbonic acid ureides of sucrose β-amino-alkyl ethers and long chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkyl glycoside is maltose, sucrose, glucose, or a combination thereof linked by a glycosidic linkage to an alkyl chain of 9-16 carbon atoms (e.g., nonyl-, decyl-, dodecyl- and tetradecyl sucroside; nonyl-, decyl-, dodecyl- and tetradecyl glucoside; and nonyl-, decyl-, dodecyl- and tetradecyl maltoside). In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkyl glycoside is dodecylmaltoside, tridecylmaltoside, and tetradecylmaltoside. 
     In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkyl-glycoside is a disaccharide with at least one glucose. In some embodiments, the auris acceptable penetration enhancer is a surfactant comprising α-D-glucopyranosyl-β-glycopyranoside, n-Dodecyl-4-O-α-D-glucopyranosyl-β-glycopyranoside, and/or n-tetradecyl-4-O-α-D-glucopyranosyl-β-glycopyranoside. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkyl-glycoside has a critical miscelle concentration (CMC) of less than about 1 mM in pure water or in aqueous solutions. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein an oxygen atom within the alkyl-glycoside is substituted with a sulfur atom. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkylglycoside is the β anomer. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein the alkylglycoside comprises 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.5%, or 99.9% of the β anomer. 
     Auris-Acceptable Controlled-Release Particles 
     In some embodiments, a delivery device disclosed herein further comprises controlled-release particles. In some embodiments, an active agent is incorporated within controlled-release particles, lipid complexes, liposomes, nanoparticles, microparticles, microspheres, coacervates, nanocapsules or other agents that enhance or facilitate the localized delivery of the active agent. In some embodiments, the delivery device is a single enhanced viscosity; while in other embodiments, the delivery device comprises a mixture of two or more distinct enhanced viscosities. In some embodiments, combinations of sols, gels and/or biocompatible matrices is employed to provide desirable characteristics of the controlled-release auris compatible delivery devices. In certain embodiments, the controlled-release auris compatible delivery devices are cross-linked by one or more agents to alter or improve the properties of the delivery device. 
     Examples of microspheres relevant to a delivery device disclosed herein disclosed herein include: Luzzi, L. A., J. Pharm. Psy. 59:1367 (1970); U.S. Pat. No. 4,530,840; Lewis, D. H., “Controlled-release of Bioactive Agents from Lactides/Glycolide Polymers” in Biodegradable Polymers as Drug Delivery Systems, Chasin, M. and Langer, R., eds., Marcel Decker (1990); U.S. Pat. No. 4,675,189; Beck et al., “Poly(lactic acid) and Poly(lactic acid-co-glycolic acid) Contraceptive Delivery Systems,” in Long Acting Steroid Contraception, Mishell, D. R., ed., Raven Press (1983); U.S. Pat. Nos. 4,758,435; 3,773,919; 4,474,572. Examples of protein therapeutics formulated as microspheres include: U.S. Pat. Nos. 6,458,387; 6,268,053; 6,090,925; 5,981,719; and 5,578,709, and are herein incorporated by reference for such disclosure. 
     Microspheres usually have a spherical shape, although irregularly-shaped microparticles are possible. Microspheres may vary in size, ranging from submicron to 1000 micron diameters. Microspheres suitable for use with a delivery device disclosed herein are submicron to 250 micron diameter microspheres, allowing administration by injection with a standard gauge needle. The auris-acceptable microspheres are prepared by a method that produces microspheres in a size range acceptable for use in an injectable delivery device. Injection is optionally accomplished with standard gauge needles used for administering liquid delivery devices. 
     Suitable examples of polymeric matrix materials for use in the auris-acceptable controlled-release particles herein include poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxonene, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polydioxonene, polyanhydrides, polyphosphazines, and natural polymers including albumin, casein, and some waxes, such as, glycerol mono- and distearate, and the like. Various commercially available poly (lactide-co-glycolide) materials (PLGA) are optionally used in the method disclosed herein. For example, poly (d,l-lactic-co-glycolic acid) is commercially available from Boehringer-Ingelheim as RESOMER RG 503 H. This product has a mole percent composition of 50% lactide and 50% glycolide. These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid. One embodiment further comprises the use of the polymer poly(d,l-lactide-co-glycolide). The molar ratio of lactide to glycolide in such a copolymer includes the range of from about 95:5 to about 50:50. 
     The molecular weight of the polymeric matrix material is of some importance. The molecular weight should be high enough so that it forms satisfactory polymer coatings, i.e., the polymer should be a good film former. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 Daltons. The molecular weight of a polymer is also important from the point of view that molecular weight influences the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade. The drug is also released from the microparticles as the polymeric excipient bioerodes. By an appropriate selection of polymeric materials a delivery device is made such that the resulting microspheres exhibit both diffusional release and biodegradation release properties. This is useful in affording multiphasic release patterns. 
     A variety of methods are known suitable for encapsulating an active agent in microspheres. In these methods, the active agent is generally dispersed or emulsified, using stirrers, agitators, or other dynamic mixing techniques, in a solvent containing a wall-forming material. Solvent is then removed from the microspheres, and thereafter the microsphere product is obtained. 
     In one embodiment, a delivery device is formed through the incorporation of the active agents and/or other pharmaceutical agents into ethylene-vinyl acetate copolymer matrices. (See U.S. Pat. No. 6,083,534, incorporated herein for such disclosure). In another embodiment, active agents are incorporated into poly (lactic-glycolic acid) or poly-L-lactic acid microspheres. Id. In yet another embodiment, the active agents are encapsulated into alginate microspheres. (See U.S. Pat. No. 6,036,978, incorporated herein for such disclosure). Biocompatible methacrylate-based polymers to an active agent are optionally used in a delivery device and methods disclosed herein. A wide range of methacrylate-based polymer systems are commercially available, such as the EUDRAGIT polymers marketed by Evonik. One useful aspect of methacrylate polymers is that the properties of the delivery device are varied by incorporating various co-polymers. For example, poly(acrylic acid-co-methylmethacrylate) microparticles exhibit enhanced mucoadhesion properties as the carboxylic acid groups in the poly(acrylic acid) form hydrogen bonds with mucin (Park et al, Pharm. Res. (1987) 4(6):457-464). Variation of the ratio between acrylic acid and methylmethacrylate monomers serves to modulate the properties of the co-polymer. Methacrylate-based microparticles have also been used in protein therapeutic delivery devices (Naha et al, Journal of Microencapsulation 4 Feb. 2008 (online publication)). In one embodiment, the enhanced viscosity auris-acceptable delivery devices described herein comprises microspheres wherein the microspheres are formed from a methacrylate polymer or copolymer. In an additional embodiment, the enhanced viscosity delivery device disclosed herein comprises active agent microspheres wherein the microspheres are mucoadhesive. Other controlled-release systems, including incorporation or deposit of polymeric materials or matrices onto solid or hollow spheres containing active agents, are also explicitly contemplated within the embodiments disclosed herein. The types of controlled-release systems available without significantly losing activity of the active agent are determined using the teachings, examples, and principles disclosed herein 
     An example of a conventional microencapsulation process for pharmaceutical preparations is shown in U.S. Pat. No. 3,737,337, incorporated herein by reference for such disclosure. The active agent to be encapsulated or embedded are dissolved or dispersed in the organic solution of the polymer (phase A), using conventional mixers, including (in the preparation of dispersion) vibrators and high-speed stirrers, etc. The dispersion of phase (A), containing the core material in solution or in suspension, is carried out in the aqueous phase (B), again using conventional mixers, such as high-speed mixers, vibration mixers, or even spray nozzles, in that case the particle size of the microspheres will be determined not only by the concentration of phase (A), but also by the emulsate or microsphere size. With conventional techniques for the microencapsulation of active agents, the microspheres form when the solvent containing an active agent and a polymer is emulsified or dispersed in an immiscible solution by stirring, agitating, vibrating, or some other dynamic mixing technique, often for a relatively long period of time. 
     Methods for the construction of microspheres are also described in U.S. Pat. Nos. 4,389,330, and 4,530,840, incorporated herein by reference for such disclosure. The desired active agent is dissolved or dispersed in an appropriate solvent. To the agent-containing medium is added the polymeric matrix material in an amount relative to the active ingredient that gives a product of the desired loading of active agent. Optionally, all of the ingredients are be blended in the solvent medium together. Suitable solvents for the agent and the polymeric matrix material include organic solvents such as acetone, halogenated hydrocarbons such as chloroform, methylene chloride and the like, aromatic hydrocarbon compounds, halogenated aromatic hydrocarbon compounds, cyclic ethers, alcohols, ethyl acetate and the like. 
     The mixture of ingredients in the solvent is emulsified in a continuous-phase processing medium; the continuous-phase medium being such that a dispersion of microdroplets containing the indicated ingredients is formed in the continuous-phase medium. Naturally, the continuous-phase processing medium and the organic solvent must be immiscible, and includes water although nonaqueous media such as xylene and toluene and synthetic oils and natural oils are optionally used. Optionally, a surfactant is added to the continuous-phase processing medium to prevent the microparticles from agglomerating and to control the size of the solvent microdroplets in the emulsion. A preferred surfactant-dispersing medium combination is a 1 to 10 wt. % poly (vinyl alcohol) in water mixture. The dispersion is formed by mechanical agitation of the mixed materials. An emulsion is optionally formed by adding small drops of the active agent-wall forming material solution to the continuous phase processing medium. The temperature during the formation of the emulsion is not especially critical but influences the size and quality of the microspheres and the solubility of the drug in the continuous phase. It is desirable to have as little of the agent in the continuous phase as possible. Moreover, depending on the solvent and continuous-phase processing medium employed, the temperature must not be too low or the solvent and processing medium will solidify or the processing medium will become too viscous for practical purposes, or too high that the processing medium will evaporate, or that the liquid processing medium will not be maintained. Moreover, the temperature of the medium cannot be so high that the stability of the particular agent being incorporated in the microspheres is adversely affected. Accordingly, the dispersion process is conducted at a temperature that maintains stable operating conditions, which preferred temperature being about 15° C. to 60° C., depending upon the drug and excipient selected. 
     The dispersion that is formed is a stable emulsion and from this dispersion the organic solvent immiscible fluid is optionally partially removed in the first step of the solvent removal process. The solvent is removed by techniques such as heating, the application of a reduced pressure or a combination of both. The temperature employed to evaporate solvent from the microdroplets is not critical, but should not be that high that it degrades the active agent employed in the preparation of a given microparticle, nor should it be so high as to evaporate solvent at such a rapid rate to cause defects in the wall forming material. Generally, from 5 to 75%, of the solvent is removed in the first solvent removal step. 
     After the first stage, the dispersed microparticles in the solvent immiscible fluid medium are isolated from the fluid medium by a convenient means of separation. Thus, for example, the fluid is decanted from the microsphere or the microsphere suspension is filtered. Still other, various combinations of separation techniques are used if desired. 
     Following the isolation of the microspheres from the continuous-phase processing medium, the remainder of the solvent in the microspheres is removed by extraction. In this step, the microspheres are suspended in the same continuous-phase processing medium used in step one, with or without surfactant, or in another liquid. The extraction medium removes the solvent from the microspheres and yet does not dissolve the microspheres. During the extraction, the extraction medium with dissolved solvent is optionally removed and replaced with fresh extraction medium. This is best done on a continual basis. The rate of extraction medium replenishment of a given process is a variable that is determined at the time the process is performed and, therefore, no precise limits for the rate must be predetermined. After the majority of the solvent has been removed from the microspheres, the microspheres are dried by exposure to air or by other conventional drying techniques such as vacuum drying, drying over a desiccant, or the like. This process is very efficient in encapsulating the active agent since core loadings of up to 80 wt. %, preferably up to 60 wt. % are obtained. 
     Alternatively, controlled-release microspheres containing an active agent is prepared through the use of static mixers. Static or motionless mixers consist of a conduit or tube in that is received a number of static mixing agents. Static mixers provide homogeneous mixing in a relatively short length of conduit, and in a relatively short period of time. With static mixers, the fluid moves through the mixer, rather than some part of the mixer, such as a blade, moving through the fluid. 
     A static mixer is optionally used to create an emulsion. When using a static mixer to form an emulsion, several factors determine emulsion particle size, including the density and viscosity of the various solutions or phases to be mixed, volume ratio of the phases, interfacial tension between the phases, static mixer parameters (conduit diameter; length of mixing element; number of mixing elements), and linear velocity through the static mixer. Temperature is a variable because it affects density, viscosity, and interfacial tension. The controlling variables are linear velocity, sheer rate, and pressure drop per unit length of static mixer. 
     In order to create microspheres containing an active agent using a static mixer process, an organic phase and an aqueous phase are combined. The organic and aqueous phases are largely or substantially immiscible, with the aqueous phase constituting the continuous phase of the emulsion. The organic phase includes an active agent as well as a wall-forming polymer or polymeric matrix material. The organic phase is prepared by dissolving an active agent in an organic or other suitable solvent, or by forming a dispersion or an emulsion containing the active agent. The organic phase and the aqueous phase are pumped so that the two phases flow simultaneously through a static mixer, thereby forming an emulsion that comprises microspheres containing the active agent encapsulated in the polymeric matrix material. The organic and aqueous phases are pumped through the static mixer into a large volume of quench liquid to extract or remove the organic solvent. Organic solvent is optionally removed from the microspheres while they are washing or being stirred in the quench liquid. After the microspheres are washed in a quench liquid, they are isolated, as through a sieve, and dried. 
     In one embodiment, microspheres are prepared using a static mixer. The process is not limited to the solvent extraction technique discussed above, but is used with other encapsulation techniques. For example, the process is optionally used with a phase separation encapsulation technique. To do so, an organic phase is prepared that comprises an active agent suspended or dispersed in a polymer solution. The non-solvent second phase is free from solvents for the polymer and active agent. A preferred non-solvent second phase is silicone oil. The organic phase and the non-solvent phase are pumped through a static mixer into a non-solvent quench liquid, such as heptane. The semi-solid particles are quenched for complete hardening and washing. The process of microencapsulation includes spray drying, solvent evaporation, a combination of evaporation and extraction, and melt extrusion. 
     In another embodiment, the microencapsulation process involves the use of a static mixer with a single solvent. This process is described in detail in U.S. application Ser. No. 08/338,805, herein incorporated by reference for such disclosure. An alternative process involves the use of a static mixer with co-solvents. In this process, biodegradable microspheres comprising a biodegradable polymeric binder and an active agent are prepared, which comprises a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons to dissolve both the agent and the polymer. The solvent blend containing the dissolved agent and polymer is dispersed in an aqueous solution to form droplets. The resulting emulsion is then added to an aqueous extraction medium preferably containing at least one of the solvents of the blend, whereby the rate of extraction of each solvent is controlled, whereupon the biodegradable microspheres containing the pharmaceutically active agent are formed. This process has the advantage that less extraction medium is required because the solubility of one solvent in water is substantially independent of the other and solvent selection is increased, especially with solvents that are particularly difficult to extract. 
     Nanoparticles are also contemplated for use with the active agents disclosed herein. Nanoparticles are material structures of about 100 nm or less in size. One use of nanoparticles in a delivery device disclosed herein is the formation of suspensions as the interaction of the particle surface with solvent is strong enough to overcome differences in density. Nanoparticle suspensions are sterilized as the nanoparticles are small enough to be subjected to sterilizing filtration (see, e.g., U.S. Pat. No. 6,139,870, herein incorporated by reference for such disclosure). Nanoparticles comprise at least one hydrophobic, water-insoluble and water-indispersible polymer or copolymer emulsified in a solution or aqueous dispersion of surfactants, phospholipids or fatty acids. The active agent is optionally introduced with the polymer or the copolymer into the nanoparticles. 
     Lipid nanocapsules as controlled-release structures, as well for penetrating the round window membrane and reaching auris interna and/or auris media targets, is also contemplated herein. Lipid nanocapsules are optionally formed by emulsifying capric and caprylic acid triglycerides (Labrafac WL 1349; avg. mw 512), soybean lecithin (LIPOID® S75-3; 69% phosphatidylcholine and other phospholipids), surfactant (for example, Solutol HS15), a mixture of polyethylene glycol 660 hydroxystearate and free polyethylene glycol 660; NaCl and water. The mixture is stirred at room temperature to obtain an oil emulsion in water. After progressive heating at a rate of 4° C./min under magnetic stirring, a short interval of transparency should occur close to 70° C., and the inverted phase (water droplets in oil) obtained at 85° C. Three cycles of cooling and heating is then applied between 85° C. and 60° C. at the rate of 4° C./min, and a fast dilution in cold water at a temperature close to 0° C. to produce a suspension of nanocapsules. To encapsulate the active agents, the agent is optionally added just prior to the dilution with cold water. 
     Active agents are also inserted into the lipid nanocapsules by incubation for 90 minutes with an aqueous micellar solution of the auris active agent. The suspension is then vortexed every 15 minutes, and then quenched in an ice bath for 1 minute. 
     Suitable auris-acceptable surfactants are, by way of example, cholic acid or taurocholic acid salts. Taurocholic acid, the conjugate formed from cholic acid and taurine, is a fully metabolizable sulfonic acid surfactant. An analog of taurocholic acid, tauroursodeoxycholic acid (TUDCA), is a naturally occurring bile acid and is a conjugate of taurine and ursodeoxycholic acid (UDCA). Other naturally occurring anionic (e.g., galactocerebroside sulfate), neutral (e.g., lactosylceramide) or zwitterionic surfactants (e.g., sphingomyelin, phosphatidyl choline, palmitoyl carnitine) are optionally used to prepare nanoparticles. 
     The auris-acceptable phospholipids are chosen, by way of example, from natural, synthetic or semi-synthetic phospholipids; lecithins (phosphatidylcholine) such as, for example, purified egg or soya lecithins (lecithin E100, lecithin E80 and phospholipons, for example phospholipon 90), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, dipalmitoylphosphatidylcholine, dipalmitoylglycerophosphatidylcholine, dimyristoylphosphatidylcholine, di stearoylphosphatidylcholine and phosphatidic acid or mixtures thereof are used more particularly. 
     Fatty acids for use with a delivery device disclosed herein are chosen from, by way of example, lauric acid, mysristic acid, palmitic acid, stearic acid, isostearic acid, arachidic acid, behenic acid, oleic acid, myristoleic acid, palmitoleic acid, linoleic acid, alpha-linoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, and the like. 
     Suitable auris-acceptable surfactants are selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and ionic surfactants. Two or more surface modifiers are used in combination. 
     Representative examples of auris-acceptable surfactants include cetyl pyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters; dodecyl trimethyl ammonium bromide, polyoxyethylenestearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 441,1,3,3-tetaamethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers, poloxamnines, a charged phospholipid such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic® 1508, dialkylesters of sodium sulfosuccinic acid, Duponol P, Tritons X-200, Crodestas F-110, p-isononylphenoxypoly-(glycidol), Crodestas SL-40 (Croda, Inc.); and SA9OHCO, which is C 18 H 37 CH 2  (CON(CH 3 )—CH 2  (CHOH) 4  (CH 2 OH) 2  (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucarmide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and the like. Most of these surfactants are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986), specifically incorporated by reference for such disclosure. 
     The hydrophobic, water-insoluble and water-indispersible polymer or copolymer may be chosen from biocompatible and biodegradable polymers, for example lactic or glycolic acid polymers and copolymers thereof, or polylactic/polyethylene (or polypropylene) oxide copolymers, preferably with molecular weights of between 1000 and 200,000, polyhydroxybutyric acid polymers, polylactones of fatty acids containing at least 12 carbon atoms, or polyanhydrides. 
     The nanoparticles may be obtained by coacervation, or the technique of evaporation of solvent, from an aqueous dispersion or solution of phospholipids and of an oleic acid salt into that is added an immiscible organic phase comprising the active principle and the hydrophobic, water-insoluble and 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 suspension of very small-sized nanoparticles. 
     A variety of methods are optionally employed to fabricate the nanoparticles that are within the scope of the embodiments. These methods include vaporization methods, such as free jet expansion, laser vaporization, spark erosion, electro explosion and chemical vapor deposition; physical methods involving mechanical attrition (e.g., “pearlmilling” technology, Elan Nanosystems), super critical CO2 and interfacial deposition following solvent displacement. In one embodiment, the solvent displacement method is used. The size of nanoparticles produced by this method is sensitive to the concentration of polymer in the organic solvent; the rate of mixing; and to the surfactant employed in the process. Continuous flow mixers provide the necessary turbulence to ensure small particle size. One type of continuous flow mixing device that is optionally used to prepare nanoparticles has been described (Hansen et al J Phys Chem 92, 2189-96, 1988). In other embodiments, ultrasonic devices, flow through homogenizers or supercritical CO2 devices may be used to prepare nanoparticles. 
     If suitable nanoparticle homogeneity is not obtained on direct synthesis, then size-exclusion chromatography is used to produce highly uniform drug-containing particles that are freed of other components involved in their fabrication. Size-exclusion chromatography (SEC) techniques, such as gel-filtration chromatography, is used to separate particle-bound active agent or other pharmaceutical compound from free active agent or other pharmaceutical compound, or to select a suitable size range of nanoparticles. Various SEC media, such as Superdex 200, Superose 6, Sephacryl 1000 are commercially available and are employed for the size-based fractionation of such mixtures. Additionally, nanoparticles are optionally purified by centrifugation, membrane filtration and by use of other molecular sieving devices, crosslinked gels/materials and membranes. 
     Auris-Acceptable Cyclodextrin and Other Stabilizing Compositions 
     In some embodiments, a delivery device disclosed herein comprises a cyclodextrin. Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin respectively. Cyclodextrins have a hydrophilic exterior, which enhances water-solublility, and a hydrophobic interior, which forms a cavity. In an aqueous environment, hydrophobic portions of other molecules often enter the hydrophobic cavity of cyclodextrin to form inclusion compounds. Additionally, cyclodextrins are capable of other types of nonbonding interactions with molecules that are not inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on α-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxyl groups on γ-cyclodextrin. One or more of these hydroxyl groups can be reacted with a of a number of reagents to form a large variety of cyclodextrin derivatives, including hydroxypropyl ethers, sulfonates, and sulfoalkylethers. Shown below is the structure of β-cyclodextrin and the hydroxypropyl-β-cyclodextrin (HPβCD). 
     
       
         
         
             
             
         
       
     
     In some embodiments, the use of cyclodextrins in a delivery device disclosed herein improves the solubility of the drug. Inclusion compounds are involved in many cases of enhanced solubility; however other interactions between cyclodextrins and insoluble compounds also improves solubility. Hydroxypropyl-β-cyclodextrin (HPβCD) is commercially available as a pyrogen free product. It is a nonhygroscopic white powder that readily dissolves in water. HPβCD is thermally stable and does not degrade at neutral pH. Thus, cyclodextrins improve the solubility of an active agent in a delivery device. Accordingly, in some embodiments, cyclodextrins are included to increase the solubility of the auris-acceptable active agents within a delivery device described herein. In other embodiments, cyclodextrins in addition serve as controlled-release excipients within a delivery device described herein. 
     By way of example only, cyclodextrin derivatives for use include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin. 
     The concentration of the cyclodextrin used in a delivery device and methods disclosed herein varies according to the physiochemical properties, pharmacokinetic properties, side effects or adverse events, delivery device considerations, or other factors associated with the therapeutically active agent, or a salt or prodrug thereof, or with the properties of other excipients in the delivery device. Thus, in certain circumstances, the concentration or amount of cyclodextrin used in accordance with a delivery device and methods disclosed herein will vary, depending on the need. When used, the amount of cyclodextrins needed to increase solubility of the active agent and/or function as a controlled-release excipient in any of the delivery devices described herein is selected using the principles, examples, and teachings described herein. 
     Other stabilizers that are useful in a delivery device disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and combinations thereof. In some embodiments, amide analogues of stabilizers are also used. In further embodiments, the chosen stabilizer changes the hydrophobicity of the delivery device (e.g., oleic acid, waxes), or improves the mixing of various components in the delivery device (e.g., ethanol), controls the moisture level in the formula (e.g., PVP or polyvinyl pyrrolidone), controls the mobility of the phase (substances with melting points higher than room temperature such as long chain fatty acids, alcohols, esters, ethers, amides etc. or mixtures thereof; waxes), and/or improves the compatibility of the formula with encapsulating materials (e.g., oleic acid or wax). In some embodiments, some of these stabilizers are used as solvents/co-solvents (e.g., ethanol). In other embodiments, stabilizers are present in sufficient amounts to inhibit the degradation of the active agent. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. 
     In some embodiments, a delivery device disclosed herein further comprises an anti-aggregation additives to enhance stability of the delivery devices by reducing the rate of protein aggregation. The anti-aggregation additive selected depends upon the nature of the conditions to that the active agents, for example active agent antibodies are exposed. For example, certain delivery devices undergoing agitation and thermal stress require a different anti-aggregation additive than a delivery device undergoing lyophilization and reconstitution. Useful anti-aggregation additives include, by way of example only, urea, guanidinium chloride, simple amino acids such as glycine or arginine, sugars, polyalcohols, polysorbates, polymers such as polyethylene glycol and dextrans, alkyl saccharides, such as alkyl glycoside, and surfactants. 
     Other useful delivery devices optionally include one or more auris-acceptable antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite. In one embodiment, antioxidants are selected from metal chelating agents, thiol containing compounds and other general stabilizing agents. 
     Still other useful delivery devices include one or more auris-acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. 
     In some embodiments, an auris-acceptable delivery device disclosed herein is stable with respect to compound degradation over a period of any of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, a delivery device described herein is stable with respect to compound degradation over a period of at least about 1 week. Also described herein are delivery devices that are stable with respect to compound degradation over a period of at least about 1 month. 
     In other embodiments, a second surfactant (co-surfactant) and/or buffering agent is combined with one or more of the pharmaceutically acceptable vehicles previously described herein so that the surfactant and/or buffering agent maintains the product at an optimal pH for stability. Suitable co-surfactants include, but are not limited to: a) natural and synthetic lipophilic agents, e.g., phospholipids, cholesterol, and cholesterol fatty acid esters and derivatives thereof; b) nonionic surfactants, which include for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens, sorbitan esters, glycerol esters, e.g., Myrj and glycerol triacetate (triacetin), polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oil derivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor A20, Cremophor® EL) and other Cremophors, sulfosuccinates, alkyl sulphates (SLS); PEG glyceryl fatty acid esters such as PEG-8 glyceryl caprylate/caprate (Labrasol), PEG-4 glyceryl caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 444/14), PEG-6 glyceryl mono oleate (Labrafil M 1944 CS), PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol mono- and di-fatty acid esters, such as propylene glycol laurate, propylene glycol caprylate/caprate; Brij ° 700, ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate, polyoxethyleneglycerol triricinoleate, and combinations or mixtures thereof; c) anionic surfactants include, but are not limited to, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium sulfosuccinate, dioctyl, sodium alginate, alkyl polyoxyethylene sulfates, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and combinations or mixtures thereof; and d) cationic surfactants such as cetyltrimethylammonium bromide, and lauryldimethylbenzyl-ammonium chloride. 
     In a further embodiment, when one or more co-surfactants are utilized in a delivery device disclosed herein, they are combined, e.g., with a pharmaceutically acceptable vehicle and is present in the final delivery device, e.g., in an amount ranging from about 0.1% to about 20%, from about 0.5% to about 10%. 
     In one embodiment, the surfactant has an HLB value of 0 to 20. In additional embodiments, the surfactant has an HLB value of 0 to 3, of 4 to 6, of 7 to 9, of 8 to 18, of 13 to 15, of 10 to 18. 
     In one embodiment, diluents are also used to stabilize the active agent because they provide a more stable environment. Salts dissolved in buffered solutions (that also can provide pH control or maintenance) are utilized as diluents, including, but not limited to a phosphate buffered saline solution. In other embodiments, a delivery device disclosed herein is isotonic with the endolymph or the perilymph: depending on the portion of the cochlea that the active agent delivery device is targeted. Isotonic delivery devices are provided by the addition of a tonicity agent. Suitable tonicity agents include, but are not limited to a pharmaceutically acceptable sugar, salt or combinations or mixtures thereof, such as, but not limited to dextrose and sodium chloride. In further embodiments, the tonicity agents are present in an amount from about 100 mOsm/kg to about 500 mOsm/kg. In some embodiments, the tonicity agent is present in an amount from about 200 mOsm/kg to about 400 mOsm/kg, from about 280 mOsm/kg to about 320 mOsm/kg. The amount of tonicity agents will depend on the target structure of the pharmaceutical delivery device, as described herein. 
     Useful tonicity delivery devices also include one or more salts in an amount required to bring osmolality of the delivery device into an acceptable range for the perilymph or the endolymph. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. 
     In some embodiments, the auris-acceptable delivery devices disclosed herein alternatively or additionally contain preservatives to prevent microbial growth. Suitable auris-acceptable preservatives for use in the enhanced viscosity delivery devices described herein include, but are not limited to benzoic acid, boric acid, p-hydroxybenzoates, alcohols, quarternary compounds, stabilized chlorine dioxide, mercurials, such as merfen and thiomersal, mixtures of the foregoing and the like. 
     In a further embodiment, the preservative is, by way of example only, an antimicrobial agent. In one embodiment, the delivery device further comprises a preservative such as by way of example only, methyl paraben, sodium bisulfite, sodium thiosulfate, ascorbate, chlorobutanol, thimerosal, parabens, benzyl alcohol, phenylethanol and others. In another embodiment, the methyl paraben is at a concentration of about 0.05% to about 1.0%, about 0.1% to about 0.2%. In a further embodiment, the gel is prepared by mixing water, methylparaben, hydroxyethylcellulose and sodium citrate. In a further embodiment, the gel is prepared by mixing water, methylparaben, hydroxyethylcellulose and sodium acetate. In a further embodiment, the mixture is sterilized by autoclaving at 120° C. for about 20 minutes, and tested for pH, methylparaben concentration and viscosity before mixing with the appropriate amount of the active agent disclosed herein. 
     Suitable auris-acceptable water soluble preservatives that are employed in the drug delivery vehicle include sodium bisulfate, sodium thiosulfate, ascorbate, chlorobutanol, thimerosal, parabens, benzyl alcohol, Butylated hydroxytoluene (BHT), phenylethanol and others. These agents are present, generally, in amounts of about 0.001% to about 5% by weight or, in the amount of about 0.01 to about 2% by weight. In some embodiments, auris-compatible delivery devices described herein are free of preservatives. 
     Round Window Membrane Penetration Enhancers 
     In another embodiment, the delivery device further comprises one or more round window membrane penetration enhancers. Penetration across the round window membrane is enhanced by the presence of round window membrane penetration enhancers. Round window membrane penetration enhancers are chemical entities that facilitate transport of coadministered substances across the round window membrane. Round window membrane penetration enhancers are grouped according to chemical structure. Surfactants, both ionic and non-ionic, such as sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecylsulfate, dioctyl sodium sulfosuccinate, polyoxyethylene-9-lauryl ether (PLE), Tween® 80, nonylphenoxypolyethylene (NP-POE), polysorbates and the like, function as round window membrane penetration enhancers. Bile salts (such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium glycodihydrofusidate and the like), fatty acids and derivatives (such as oleic acid, caprylic acid, mono- and di-glycerides, lauric acids, acylcholines, caprylic acids, acylcarnitines, sodium caprates and the like), chelating agents (such as EDTA, citric acid, salicylates and the like), sulfoxides (such as dimethyl sulfoxide (DMSO), decylmethyl sulfoxide and the like), and alcohols (such as ethanol, isopropanol, glycerol, propanediol and the like) also function as round window membrane penetration enhancers. 
     In some embodiments, the auris acceptable penetration enhancer is a surfactant comprising an alkyl-glycoside wherein the alkyl glycoside is tetradecyl-β-D-maltoside. In some embodiments, the auris acceptable penetration enhancer is a surfactant comprising an alkyl-glycoside wherein the alkyl glycoside is dodecyl-maltoside. In certain instances, the penetration enhancing agent is a hyaluronidase. In certain instances, a hyaluronidase is a human or bovine hyaluronidase. In some instances, a hyaluronidase is a human hyaluronidase (e.g., hyaluronidase found in human sperm, PH20 (Halozyme), Hyelenex® (Baxter International, Inc.)). In some instances, a hyaluronidase is a bovine hyaluronidase (e.g., bovine testicular hyaluronidase, Amphadase® (Amphastar Pharmaceuticals), Hydase® (PrimaPharm, Inc). In some instances, a hyaluronidase is an ovine hyaluronidase, Vitrase® (ISTA Pharmaceuticals). In certain instances, a hyaluronidase described herein is a recombinant hyaluronidase. In some instances, a hyaluronidase described herein is a humanized recombinant hyaluronidase. In some instances, a hyaluronidase described herein is a pegylated hyaluronidase (e.g., PEGPH20 (Halozyme)). In addition, the peptide-like penetration enhancers described in U.S. Pat. Nos. 7,151,191, 6,221,367 and 5,714,167, herein incorporated by references for such disclosure, are contemplated as an additional embodiment. These penetration enhancers are amino-acid and peptide derivatives and enable drug absorption by passive transcellular diffusion without affecting the integrity of membranes or intercellular tight junctions. 
     Round Window Membrane Permeable Liposomes 
     In some embodiments, liposomes or lipid particles are employed to encapsulate the auris compatible delivery devices. Phospholipids that are gently dispersed in an aqueous medium form multilayer vesicles with areas of entrapped aqueous media separating the lipid layers. Sonication, or turbulent agitation, of these multilayer vesicles results in the formation of single layer vesicles, commonly referred to as liposomes, with sizes of about 10-1000 nm. These liposomes have many advantages as active agents or other pharmaceutical agent carriers. They are biologically inert, biodegradable, non-toxic and non-antigenic. Liposomes are formed in various sizes and with varying properties. Additionally, they are able to entrap a wide variety of agents and release the agent at the site of liposome collapse. 
     Suitable phospholipids for use in auris-acceptable liposomes here are, for example, phosphatidyl cholines, ethanolamines and serines, sphingomyelins, cardiolipins, plasmalogens, phosphatidic acids and cerebrosides, in particular those that are soluble together with the active agents herein in non-toxic, pharmaceutically acceptable organic solvents. Preferred phospholipids are, for example, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, lysophosphatidyl choline, phosphatidyl glycerol and the like, and mixtures thereof especially lecithin, e.g. soya lecithin. The amount of phospholipid used in the present delivery devices ranges from about 10 to about 30%, preferably from about 15 to about 25% and in particular is about 20%. 
     Lipophilic additives may be employed advantageously to modify selectively the characteristics of the liposomes. Examples of such additives include by way of example only, stearylamine, phosphatidic acid, tocopherol, cholesterol, cholesterol hemisuccinate and lanolin extracts. The amount of lipophilic additive used range from 0.5 to 8%, preferably from 1.5 to 4% and in particular is about 2%. Generally, the ratio of the amount of lipophilic additive to the amount of phospholipid ranges from about 1:8 to about 1:12 and in particular is about 1:10. Said phospholipid, lipophilic additive and the active agent and other pharmaceutical compounds are employed in conjunction with a non-toxic, pharmaceutically acceptable organic solvent system that dissolve said ingredients. Said solvent system not only must dissolve the active agent completely, but it also has to allow a delivery device of stable single bilayered liposomes. The solvent system comprises dimethylisosorbide and tetraglycol (glycofurol, tetrahydrofurfuryl alcohol polyethylene glycol ether) in an amount of about 8 to about 30%. In said solvent system, the ratio of the amount of dimethylisosorbide to the amount of tetraglycol range from about 2:1 to about 1:3, in particular from about 1:1 to about 1:2.5 and preferably is about 1:2. The amount of tetraglycol in the final delivery device thus varies from 5 to 20%, in particular from 5 to 15% and preferably is approximately 10%. The amount of dimethylisosorbide in the final delivery device thus ranges from 3 to 10%, in particular from 3 to 7% and preferably is approximately 5%. 
     The term “organic component” as used hereinafter refers to mixtures comprising said phospholipid, lipophilic additives and organic solvents. The active agent may be dissolved in the organic component, or other means to maintain full activity of the agent. The amount of an active agent in the final delivery device may range from 0.1 to 5.0%. In addition, other ingredients such as anti-oxidants may be added to the organic component. Examples include tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, ascorbyl oleate and the like. 
     Liposomal delivery devices are alternatively prepared, for active agents or other pharmaceutical agents that are moderately heat-resistant, by (a) heating the phospholipid and the organic solvent system to about 60-80° C. in a vessel, dissolving the active ingredient, then adding an additional formulating agents, and stirring the mixture until complete dissolution is obtained; (b) heating the aqueous solution to 90-95° C. in a second vessel and dissolving the preservatives therein, allowing the mixture to cool and then adding the remainder of the auxiliary formulating agents and the remainder of the water, and stirring the mixture until complete dissolution is obtained; thus preparing the aqueous component; (c) transferring the organic phase directly into the aqueous component, while homogenizing the combination with a high performance mixing apparatus, for example, a high-shear mixer; and (d) adding a viscosity enhancing agent to the resulting mixture while further homogenizing. The aqueous component is optionally placed in a suitable vessel that is equipped with a homogenizer and homogenization is effected by creating turbulence during the injection of the organic component. Any mixing means or homogenizer that exerts high shear forces on the mixture may be employed. Generally, a mixer capable of speeds from about 1,500 to 20,000 rpm, in particular from about 3,000 to about 6,000 rpm may be employed. Suitable viscosity enhancing agents for use in process step (d) are for example, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose or mixtures thereof. The amount of viscosity enhancing agent depends on the nature and the concentration of the other ingredients and in general ranges from about 0.5 to 2.0%, or approximately 1.5%. In order to prevent degradation of the materials used during the preparation of the liposomal delivery device, it is advantageous to purge all solutions with an inert gas such as nitrogen or argon, and to conduct all steps under an inert atmosphere. Liposomes prepared by the above described method usually contain most of the active ingredient bound in the lipid bilayer and separation of the liposomes from unencapsulated material is not required. 
     Miscellaneous Excipients 
     In other embodiments, a delivery device disclosed herein further includes excipients, other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts, solubilizers, an antifoaming agent, an antioxidant, a dispersing agent, a wetting agent, a surfactant, and combinations thereof. 
     Suitable carriers for use in an auris-acceptable delivery device disclosed herein include, but are not limited to, a pharmaceutically acceptable solvent compatible with the targeted auris structure&#39;s physiological environment. In other embodiments, the base is a combination of a pharmaceutically acceptable surfactant and solvent. 
     In some embodiments, other excipients include, sodium stearyl fumarate, diethanolamine cetyl sulfate, isostearate, polyethoxylated castor oil, nonoxyl 10, octoxynol 9, sodium lauryl sulfate, sorbitan esters (sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan sesquistearate, sorbitan tri-isostearate), lecithin pharmaceutical acceptable salts thereof and combinations or mixtures thereof. 
     In other embodiments, the carrier is a polysorbate. Polysorbates are nonionic surfactants of sorbitan esters. Polysorbates useful in the present disclosure include, but are not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80) and combinations or mixtures thereof. In further embodiments, polysorbate 80 is utilized as the pharmaceutically acceptable carrier. 
     In one embodiment, water-soluble glycerin-based auris-acceptable enhanced viscosity delivery devices utilized in the preparation of pharmaceutical delivery vehicles comprise an active agent containing at least about 0.1% of the water-soluble glycerin compound or more. In some embodiments, the percentage of an active agent is varied between about 1% and about 95%, between about 5% and about 80%, between about 10% and about 60% or more of the weight or volume of the total pharmaceutical delivery device. In some embodiments, the amount of the compound(s) in each therapeutically useful active agent delivery device is prepared in such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations are contemplated herein. 
     If desired, the auris-acceptable pharmaceutical gels also contain co-solvents, preservatives, cosolvents, ionic strength and osmolality adjustors and other excipients in addition to buffering agents. Suitable auris-acceptable water soluble buffering agents are alkali or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and tromethamine (TRIS). These agents are present in amounts sufficient to maintain the pH of the system at 7.4±0.2 and preferably, 7.4. As such, the buffering agent is as much as 5% on a weight basis of the total delivery device. 
     Cosolvents are used to enhance active agent solubility; however, some active agents are insoluble. These are often suspended in the polymer vehicle with the aid of suitable suspending or viscosity enhancing agents. 
     Moreover, some pharmaceutical excipients, diluents or carriers are potentially ototoxic. For example, benzalkonium chloride, a common preservative, is ototoxic and therefore potentially harmful if introduced into the vestibular or cochlear structures. In formulating a controlled-release active agent delivery device, it is advised to avoid or combine the appropriate excipients, diluents or carriers to lessen or eliminate potential ototoxic components from the delivery device, or to decrease the amount of such excipients, diluents or carriers. Optionally, a delivery device disclosed herein further comprises otoprotective agents, such as antioxidants, alpha lipoic acid, calcium, fosfomycin or iron chelators, to counteract potential ototoxic effects that may arise from the use of specific active agents or excipients, diluents or carriers. 
     The following are examples of therapeutically acceptable the delivery devices: 
     
       
         
           
               
               
             
               
                   
               
               
                 Example Delivery 
                   
               
               
                 device 
                 Example Characteristics 
               
               
                   
               
             
            
               
                 Chitosan glycerophosphate 
                 tunable degradation of matrix in vitro 
               
               
                 (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 triblock 
                 tunable high stability: e.g., maintains mechanical integrity &gt;1 
               
               
                 polymers 
                 month in vitro 
               
               
                   
                 tunable fast release of hydrophilic drugs: e.g., ~50% of drug 
               
               
                   
                 released after 24 hrs, and remainder released over ~5 days 
               
               
                   
                 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 with 
               
               
                 copolymers (e.g., Pluronic 
                 increasing F127 concentration 
               
               
                 or Poloxameres) (e.g., 
               
               
                 F127) 
               
               
                 Chitosan glycerophosphate 
                 CGP delivery device tolerates liposomes: e.g., up to 15 uM/ml 
               
               
                 with drug-loaded liposomes 
                 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 delivery device 
               
               
                   
                 of liposomes 
               
               
                   
               
            
           
         
       
     
     A delivery device disclosed herein alternatively encompass an otoprotectant agent in addition to the at least one active agent and/or excipients, including but not limited to such agents as antioxidants, alpha lipoic acid, calcium, fosfomycin or iron chelators, to counteract potential ototoxic effects that may arise from the use of specific active agents or excipients, diluents or carriers. 
     Modes of Treatment 
     Dosing Methods and Schedules 
     Drugs delivered to the inner ear have been administered systemically via oral, intravenous or intramuscular routes. However, systemic administration for pathologies local to the inner ear increases the likelihood of systemic toxicities and adverse side effects and creates a non-productive distribution of drug in that high levels of drug are found in the serum and correspondingly lower levels are found at the inner ear. 
     Intratympanic injection of active agents is the technique of injecting an active agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, a delivery device described herein is administered directly onto the round window membrane via transtympanic injection. In another embodiment, the active agent auris-acceptable delivery devices described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the delivery device described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the  crista  fenestrae  cochleae.    
     In one embodiment, a delivery device disclosed herein is administered via a syringe and needle apparatus that is capable of piercing the tympanic membrane and directly accessing the round window membrane or  crista  fenestrae  cochleae  of the auris interna. In some embodiments, the needle on the syringe is wider than a 18 gauge needle. In another embodiment, the needle gauge is from 18 gauge to 31 gauge. In a further embodiment, the needle gauge is from 25 gauge to 30 gauge. Depending upon the thickness or viscosity of the auris compatible delivery device, the gauge level of the syringe or hypodermic needle may be varied accordingly. In another embodiment, the internal diameter of the needle can be increased by reducing the wall thickness of the needle (commonly referred as thin wall or extra thin wall needles) to reduce the possibility of needle clogging while maintaining an adequate needle gauge. 
     In another embodiment, the needle is a hypodermic needle used for instant administration of a delivery device disclosed herein. The hypodermic needle may be a single use needle or a disposable needle. In some embodiments, a syringe may be used for delivery of a delivery device disclosed herein wherein the syringe has a press-fit (Luer) or twist-on (Luer-lock) fitting. In one embodiment, the syringe is a hypodermic syringe. In another embodiment, the syringe is made of plastic or glass. In yet another embodiment, the hypodermic syringe is a single use syringe. In a further embodiment, the glass syringe is capable of being sterilized. In yet a further embodiment, the sterilization occurs through an autoclave. In another embodiment, the syringe comprises a cylindrical syringe body wherein a delivery device disclosed herein is stored before use. In other embodiments, the syringe comprises a cylindrical syringe body wherein the active agent pharmaceutically acceptable gel-based delivery devices as disclosed herein is stored before use that conveniently allows for mixing with a suitable pharmaceutically acceptable buffer. In other embodiments, the syringe may contain other excipients, stabilizers, suspending agents, diluents or a combination thereof to stabilize or otherwise stably store the active agent contained therein. 
     In some embodiments, the syringe comprises a cylindrical syringe body wherein the body is compartmentalized in that each compartment is able to store at least one component of the auris-acceptable active agent delivery device. In a further embodiment, the syringe having a compartmentalized body allows for mixing of the components prior to injection into the auris media or auris interna. In other embodiments, the delivery system comprises multiple syringes, each syringe of the multiple syringes contains at least one component of a delivery device disclosed herein such that each component is pre-mixed prior to injection or is mixed subsequent to injection. In a further embodiment, the syringes disclosed herein comprise at least one reservoir wherein the at least one reservoir comprises active agent, or a pharmaceutically acceptable buffer, or a viscosity enhancing agent, such as a gelling agent or a combination thereof. Commercially available injection devices are optionally employed in their simplest form as ready-to-use plastic syringes with a syringe barrel, needle assembly with a needle, plunger with a plunger rod, and holding flange, to perform an intratympanic injection. 
     In some embodiments, a delivery device disclosed herein is administered via an apparatus designed for administration of active agents to the middle and/or inner ear. By way of example only: GYRUS Medical Gmbh offers micro-otoscopes for visualization of and drug delivery to the round window niche; Arenberg has described a medical treatment device to deliver fluids to inner ear structures in U.S. Pat. Nos. 5,421,818; 5,474,529; and 5,476,446, each of that is incorporated by reference herein for such disclosure. U.S. patent application Ser. No. 08/874,208, which is incorporated herein by reference for such disclosure, describes a surgical method for implanting a fluid transfer conduit to deliver active agents to the inner ear. U.S. Patent Application Publication 2007/0167918, which is incorporated herein by reference for such disclosure, further describes a combined otic aspirator and medication dispenser for intratympanic fluid sampling and medicament application. 
     A delivery device described herein, and modes of administration thereof, are also applicable to methods of direct instillation or perfusion of the inner ear compartments. Thus, a delivery device described herein is useful in surgical procedures including, by way of non-limiting examples, cochleostomy, labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy, tympanostomy, endolymphatic sacculotomy or the like. 
     In some embodiments, a delivery device disclosed herein is administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the auris compatible delivery devices are administered to a patient already suffering from a disorder disclosed herein, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition. Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient&#39;s health status and response to the drugs, and the judgment of the treating physician. 
     In the case wherein the patient&#39;s condition does not improve, upon the doctor&#39;s discretion the administration of the active agent may be administered chronically, which is, for an extended period of time, including throughout the duration of the patient&#39;s life in order to ameliorate or otherwise control or limit the symptoms of the patient&#39;s disease or condition. 
     In the case wherein the patient&#39;s status does improve, upon the doctor&#39;s discretion the administration of the active agent may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday may be from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. 
     Once improvement of the patient&#39;s otic conditions has occurred, a maintenance active agent dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at that the improved disease, disorder or condition is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon a recurrence of symptoms. 
     The amount of an active agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific active agent being administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-50 mg per administration, preferably 1-15 mg per administration. The desired dose is presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals. 
     In some embodiments, the initial administration is a first active agent active agent and the subsequent administration a second active agent. 
     In some embodiments, an auris-acceptable controlled-release delivery device disclosed herein is administered to the target ear region and an oral dose of an active agent is additionally administered. In some embodiments, an oral dose of an active agent is administered before administration of the auris-acceptable controlled-release auris compatible delivery device, and then the oral dose is tapered off over the period of time that the controlled-release auris compatible delivery device is provided. Alternatively, an oral dose of an active agent is administered during administration of the controlled-release auris compatible delivery device, and then the oral dose is tapered off over the period of time that the controlled-release auris compatible delivery device is provided. Alternatively, an oral dose of an active agent is administered after administration of the controlled-release auris compatible delivery device, and then the oral dose is tapered off over the period of time that the controlled-release auris compatible delivery device is provided. 
     Implants of Exogenous Materials 
     In some embodiments, the delivery devices described herein are used in combination with (e.g., implantation, short-term use, long-term use, or removal of) the implantation of an exogenous material (e.g., a medical device or a plurality of cells (e.g., stem cells)). As used herein, the term “exogenous material” includes auris-interna or auris-media medical devices (e.g., hearing sparing devices, hearing improving devices, short electrodes, micro-prostheses or piston-like prostheses); needles; drug delivery devices, and cells (e.g., stem cells). In some instances, the implants of exogenous materials are used in conjunction with a patient experiencing hearing loss. In some instances, the hearing loss is present at birth. In some instances, the hearing loss is associated with conditions that develop or progress after birth (e.g., Meniere&#39;s disease) resulting in osteoneogenesis, nerve damage, obliteration of cochlear structures, or combinations thereof. 
     In some instances, the exogenous material is a plurality of cells. In some instances, the exogenous material is a plurality of stem cells. 
     In some instances, the exogenous material is an electronic device. In some embodiments, the electronic device has an external portion placed behind the ear, and a second portion that is surgically placed under the skin that helps provide a sense of sound to a person who is profoundly deaf or severely hard-of-hearing. By way of example only, such medical device implants bypass damaged portions of the ear and directly stimulate the auditory nerve. In some instances cochlear implants are used in single sided deafness. In some instances cochlear implants are used for deafness in both ears. 
     In some embodiments, administration of an active agent described herein in combination with the implantation of an exogenous material (e.g., a medical device implant or a stem cell transplant) delays or prevents damage to auris structures, e.g., irritation, cell death osteoneogenesis and/or further neuronal degeneration, caused by installation of an external device and/or a plurality cells (e.g., stem cells) in the ear. In some embodiments, administration of a delivery device described herein in combination with an implant allows for a more effective restoration of hearing loss compared to an implant alone. 
     In some embodiments, administration of an active agent described herein reduces damage to auris structures caused by underlying conditions allowing for successful implantation. In some embodiments, administration of an active agent described herein, in conjunction surgery and/or with the implantation of an exogenous material reduces or prevents negative side-effects (e.g., cell death). 
     In some embodiments, administration of an active agent described herein in conjunction with the implantation of an exogenous material has a trophic effect (i.e., promotes healthy growth of cells and healing of tissue in the area of an implant or transplant). In some embodiments, a trophic effect is desirable during otic surgery or during intratympanic injection procedures. In some embodiments, a trophic effect is desirable after installation of a medical device or after a cell (e.g., stem cell) transplant. In some embodiments, a delivery device disclosed herein is described herein are administered via direct cochlear injection, through a chochleostomy or via deposition on the round window. 
     In some embodiments, administration of an active agent described herein reduces inflammation and/or infections associated with otic surgery, or implantation of an exogenous material (e.g., a medical device or a plurality of cells (e.g., stem cells)). In some instances, perfusion of a surgical area with a delivery device described herein reduces or eliminates post-surgical and/or post-implantation complications (e.g., inflammation, hair cell damage, neuronal degeneration, osteoneogenesis or the like). In some instances, perfusion of a surgical area with a delivery device described herein reduces post-surgery or post-implantation recuperation time. 
     In one aspect, the delivery devices described herein, and modes of administration thereof, are applicable to methods of direct perfusion of the inner ear compartments. Thus, the delivery devices described herein are useful in combination with surgical procedures including, by way of non-limiting examples, cochleostomy, labyrinthotomy, mastoidectomy, tympanostomy, stapedectomy, stapedotomy, endolymphatic sacculotomy or the like. In some embodiments, the inner ear compartments are perfused with a delivery device described herein prior to otic surgery, during otic surgery, after otic surgery, or a combination thereof. In some of such embodiments, the delivery devices described herein are substantially free of extended release components (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some of such embodiments, the delivery devices described herein contain less than 5% of the extended release components (e.g., gelling components such as polyoxyethylene-polyoxypropylene triblock copolymers) by weight of the delivery device. In some of such embodiments, the delivery devices described herein contain less than 2% of the extended release components (e.g., gelling components such as polyoxyethylene-polyoxypropylene triblock copolymers) by weight of the delivery device. In some of such embodiments, the delivery devices described herein contain less than 1% of the extended release components (e.g., gelling components such as polyoxyethylene-polyoxypropylene triblock copolymers) by weight of the delivery device. In some embodiments, a delivery device disclosed herein that is used for perfusion of a surgical area contains substantially no gelling component. 
     Viscosity 
     In further embodiments, a delivery device disclosed herein contains a viscosity enhancing agent sufficient to provide a viscosity of between about 500 and 1,000,000 centipoise, between about 750 and 1,000,000 centipoise; between about 1000 and 1,000,000 centipoise; between about 1000 and 400,000 centipoise; between about 2000 and 100,000 centipoise; between about 3000 and 50,000 centipoise; between about 4000 and 25,000 centipoise; between about 5000 and 20,000 centipoise; or between about 6000 and 15,000 centipoise. In some embodiments, the auris gel delivery device contains a viscosity enhancing agent sufficient to provide a viscosity of between about 50,0000 and 1,000,000 centipoise. 
     In some embodiments, a delivery device disclosed herein has a low viscosity at body temperature. In some embodiments, low viscosity delivery devices contain from about 1% to about 10% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, low viscosity delivery devices contain from about 2% to about 10% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, low viscosity delivery devices contain from about 5% to about 10% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, low viscosity delivery devices are substantially free of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, a low viscosity delivery device described herein provides an apparent viscosity of from about 100 cP to about 10,000 cP. In some embodiments, a low viscosity delivery device described herein provides an apparent viscosity of from about 500 cP to about 10,000 cP. In some embodiments, a low viscosity delivery device described herein provides an apparent viscosity of from about 1000 cP to about 10,000 cP. In some of such embodiments, a low viscosity delivery device is administered in combination with an external otic intervention, e.g., a surgical procedure including but not limited to middle ear surgery, inner ear surgery, typanostomy, cochleostomy, labyrinthotomy, mastoidectomy, tympanostomy, stapedectomy, stapedotomy, endolymphatic sacculotomy or the like. In some of such embodiments, a low viscosity delivery device is administered during an otic intervention. In other such embodiments, a low viscosity delivery device is administered before the otic intervention. 
     In some embodiments, a delivery device disclosed herein has a high viscosity at body temperature. In some embodiments, high viscosity delivery devices contain from about 10% to about 25% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, high viscosity delivery devices contain from about 14% to about 22% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, high viscosity delivery devices contain from about 15% to about 21% of a viscosity enhancing agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, a high viscosity delivery device described herein provides an apparent viscosity of from about 100,000 cP to about 1,000,000 cP. In some embodiments, a high viscosity delivery device described herein provides an apparent viscosity of from about 150,000 cP to about 500,000 cP. In some embodiments, a high viscosity delivery device described herein provides an apparent viscosity of from about 250,000 cP to about 500,000 cP. In some of such embodiments, a high viscosity delivery device is a liquid at room temperature and gels at about between room temperature and body temperature (including an individual with a serious fever, e.g., up to about 42° C.). In some embodiments, an high viscosity delivery device is administered as monotherapy for treatment of an otic disease or condition described herein. In some embodiments, an high viscosity delivery device is administered in combination with an external otic intervention, e.g., a surgical procedure including but not limited to middle ear surgery, inner ear surgery, typanostomy, cochleostomy, labyrinthotomy, mastoidectomy, tympanostomy, stapedectomy, stapedotomy, endolymphatic sacculotomy or the like. In some of such embodiments, a high viscosity delivery device is administered after the otic intervention. In other such embodiments, a high viscosity delivery device is administered before the otic intervention. 
     Pharmacokinetics of Controlled-Release Delivery Devices 
     In one embodiment, a delivery device disclosed herein additionally provides an immediate release of an active agent from the delivery device, or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes or within 90 minutes. In other embodiments, a therapeutically effective amount of an active agent is released from the delivery device immediately, or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes or within 90 minutes. In certain embodiments the delivery device comprises an auris-pharmaceutically acceptable gel delivery device providing immediate release of active agent. Additional embodiments of the delivery device may also include an agent that enhances the viscosity of the delivery device. 
     In other or further embodiments, the delivery device provides an extended release delivery device of active agent. In certain embodiments, diffusion of an active agent from the delivery device occurs for a time period exceeding 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or 1 year. In other embodiments, a therapeutically effective amount of an active agent is released from the delivery device for a time period exceeding 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or 1 year. 
     In other embodiments, the delivery device provides both an immediate release and an extended release delivery device of active agent. In yet other embodiments, the delivery device contains a 0.25:1 ratio, or a 0.5:1 ratio, or a 1:1 ratio, or a 1:2 ratio, or a 1:3, or a 1:4 ratio, or a 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:20 ratio of immediate release and extended release delivery devices. In some embodiments, the delivery device provides an immediate release of a first active agent and an extended release of a second active agent or other active agent. In yet other embodiments, the delivery device provides an immediate release and extended release delivery device of active agent, and at least one active agent. In some embodiments, the delivery device provides a 0.25:1 ratio, or a 0.5:1 ratio, or a 1:1 ratio, or a 1:2 ratio, or a 1:3, or a 1:4 ratio, or a 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:20 ratio of immediate release and extended release delivery devices of a first active agent and second active agent, respectively. 
     In a specific embodiment the delivery device provides a therapeutically effective amount of an active agent at the site of disease with essentially no systemic exposure. In an additional embodiment the delivery device provides a therapeutically effective amount of an active agent at the site of disease with essentially no detectable systemic exposure. In other embodiments, the delivery device provides a therapeutically effective amount of an active agent at the site of disease with little or no detectable systemic exposure. 
     The combination of immediate release, delayed release and/or extended release auris compatible delivery devices may be combined with other pharmaceutical agents, as well as the excipients, diluents, stabilizers, tonicity agents and other components disclosed herein. As such, depending upon the active agent used, the thickness or viscosity desired, or the mode of delivery chosen, alternative aspects of the embodiments disclosed herein are combined with the immediate release, delayed release and/or extended release embodiments accordingly. 
     In certain embodiments, the pharmacokinetics of the auris compatible delivery devices described herein are determined by injecting the delivery device on or near the round window membrane of a test animal (including by way 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 pharmacokinetics of a delivery device over a 1 week period), the test animal is euthanized and a 5 mL sample of the perilymph fluid is tested. The inner ear removed and tested for the presence of the active agent. As needed, the level of an active agent is measured in other organs. In addition, the systemic level of the active agent is measured by withdrawing a blood sample from the test animal. In order to determine whether the delivery device impedes hearing, the hearing of the test animal is optionally tested. 
     Alternatively, an inner ear is provided (as removed from a test animal) and the migration of the active agent is measured. As yet another alternative, an in vitro model of a round window membrane is provided and the migration of the active agent is measured. 
     As described herein, delivery devices comprising micronized active agents provide extended release over a longer period of time compared to delivery devices comprising non-micronized active agents. In some instances, the micronized active agent provides a steady supply (e.g., +/−20%) of active agent via slow degradation and serves as a depot for the active agent; such a depot effect increases residence time of the active agent in the ear. In specific embodiments, selection of an appropriate particle size of the active agent (e.g., micronized active agent) in combination with the amount of gelling agent in the delivery device provides tunable extended release characteristics that allow for release of an active agent over a period of hours, days, weeks or months. 
     In some embodiments, the viscosity of a delivery device described herein is designed to provide a suitable rate of release from an otic compatible gel. In some embodiments, the concentration of a thickening agent (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers) allows for a tunable mean dissolution time (MDT). The MDT is inversely proportional to the release rate of an active agent from a delivery device described herein. Experimentally, the released active agent is optionally fitted to the Korsmeyer-Peppas equation 
     
       
         
           
             
               Q 
               
                 Q 
                 α 
               
             
             = 
             
               
                 kt 
                 n 
               
               + 
               b 
             
           
         
       
     
     where Q is the amount of active agent released at time t, Q α  is the overall released amount of active agent, k is a release constant of the nth order, n is a dimensionless number related to the dissolution mechanism and b is the axis intercept, characterizing the initial burst release mechanism wherein n=1 characterizes an erosion controlled mechanism. The mean dissolution time (MDT) is the sum of different periods of time the drug molecules stay in the matrix before release, divided by the total number of molecules and is optionally calculated by: 
     
       
         
           
             MDT 
             = 
             
               
                 nk 
                 
                   
                     - 
                     1 
                   
                   / 
                   n 
                 
               
               
                 n 
                 + 
                 1 
               
             
           
         
       
     
     For example, a linear relationship between the mean dissolution time (MDT) of a delivery device and the concentration of the gelling agent (e.g., poloxamer) indicates that the active agent is released due to the erosion of the polymer gel (e.g., poloxamer) and not via diffusion. In another example, a non-linear relationship indicates release of active agent via a combination of diffusion and/or polymer gel degradation. In another example, a faster gel elimination time course of a delivery device (a faster release of active agent) indicates lower mean dissolution time (MDT). The concentration of gelling components and/or active agent in a delivery device are tested to determine suitable parameters for MDT. In some embodiments, injection volumes are also tested to determine suitable parameters for preclinical and clinical studies. The gel strength and concentration of the active agent affects release kinetics of an active agent from the delivery device. At low poloxamer concentration, elimination rate is accelerated (MDT is lower). An increase in active agent concentration in the delivery device prolongs residence time and/or MDT of the active agent in the ear. 
     In some embodiments, the MDT for poloxamer from a delivery device described herein is at least 6 hours. In some embodiments, the MDT for poloxamer from a delivery device described herein is at least 10 hours. 
     In some embodiments, the MDT for an active agent from a delivery device described herein is from about 30 hours to about 48 hours. In some embodiments, the MDT for an active agent from a delivery device described herein is from about 30 hours to about 96 hours. In some embodiments, the MDT for an active agent from a delivery device described herein is from about 30 hours to about 1 week. In some embodiments, the MDT for a delivery device described herein is from about 1 week to about 6 weeks. 
     In some embodiments, the mean residence time (MRT) for an active agent in a composition or device described herein is from about 20 hours to about 48 hours. In some embodiments, the MRT for an active agent from a composition or device described herein is from about 20 hours to about 96 hours. In some embodiments, the MRT for an active agent from a composition or device described herein is from about 20 hours to about 1 week. 
     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 embodiments, the MRT for an active agent is about 50 hours. In some embodiments, the MRT for an active agent is about 60 hours. In some embodiments, the MRT for an active agent is about 70 hours. In some embodiments, the MRT for an active agent is about 80 hours. In some embodiments, the MRT for an active agent is about 90 hours. In some embodiments, the MRT for an active agent is about 1 week. In some embodiments, the MRT for an active agent is about 90 hours. In some embodiments, the MRT for a composition or device described herein is from about 1 week to about 6 weeks. In some embodiments, the MRT for an active agent is about 1 week. In some embodiments, the MRT for an active agent is about 2 weeks. In some embodiments, the MRT for an active agent is about 3 weeks. In some embodiments, the MRT for an active agent is about 4 weeks. In some embodiments, the MRT for an active agent is about 5 weeks. In some embodiments, the MRT for an active agent is about 6 weeks. In some embodiments, the MRT for an active agent is about 7 weeks. The half life of an otic agent and mean residence time of the otic agent are determined for each formulation by measurement of concentration of the otic agent in the perilymph using procedures described herein. 
     In certain embodiments, a controlled release otic delivery device described herein increases the exposure of an active agent and increases the Area Under the Curve (AUC) in otic fluids (e.g., endolymph and/or perilymph) by about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% compared to a delivery device that is not a controlled release otic delivery device. In certain embodiments, a controlled release otic delivery device described herein increases the exposure time of an active agent and decreases the C max  in otic fluids (e.g., endolymph and/or perilymph) by about 40%, about 30%, about 20%, or about 10%, compared to a delivery device that is not a controlled release otic delivery device. In certain embodiments, a controlled release otic delivery device described herein alters (e.g. reduces) the ratio of C max  to C min  compared to a delivery device that is not a controlled release otic delivery device. In certain embodiments, a controlled release otic delivery device described herein increases the exposure of an active agent and increases the length of time that the concentration of an active agent is above C min  by about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% compared to a delivery device that is not a controlled release otic delivery device. In certain instances, controlled release delivery devices described herein delay the time to C max . In certain instances, the controlled steady release of a drug prolongs the time the concentration of the drug will stay above the C min . In some embodiments, the delivery devices described herein prolong the residence time of a drug in the inner ear and provide a stable drug exposure profile. In some instances, an increase in concentration of an active agent in the delivery device saturates the clearance process and allows for a more rapid and stable steady state to be reached. 
     In certain instances, once drug exposure (e.g., concentration in the endolymph or perilymph) of a drug reaches steady state, the concentration of the drug in the endolymph or perilymph stays at or about the therapeutic dose for an extended period of time (e.g., one day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 3 weeks, 6 weeks, 2 months). In some embodiments, the steady state concentration of active agent released from a controlled release delivery device described herein is about 20 to about 50 times the steady state concentration of an active agent released from a delivery device that is not a controlled release delivery device. 
     The release of an active agent from a delivery device disclosed herein is optionally tunable to the desired release characteristics. In some embodiments, a delivery device disclosed herein is a solution that is substantially free of gelling components. In such instances, the delivery device provides essentially immediate release of an active agent. In some of such embodiments, the delivery device is useful in perfusion of otic structures, e.g., during surgery. 
     In some embodiments, a delivery device disclosed herein is a solution that is substantially free of gelling components and comprises micronized active agent. In some of such embodiments, the delivery device provides intermediate release of an active agent from about 2 day to about 4 days. 
     In some embodiments, a delivery device disclosed herein comprises a gelling agent (e.g., poloxamer 407) and provides release of an active agent over a period of from about 1 day to about 3 days. In some embodiments, a delivery device disclosed herein comprises a gelling agent (e.g., poloxamer 407) and provides release of an active agent over a period of from about 1 day to about 5 days. In some embodiments, a delivery device disclosed herein comprises a gelling agent (e.g., poloxamer 407) and provides release of an active agent over a period of from about 2 days to about 7 days. 
     In some embodiments, a delivery device disclosed herein comprises a gelling agent (e.g., poloxamer 407) in combination with micronized active agent and provides extended sustained release. In some embodiments, a delivery device disclosed herein comprises (a) about 14-17% of a gelling agent (e.g., poloxamer 407) and (b) a micronized active agent; and provides extended sustained release over a period of from about 1 week to about 3 weeks. In some embodiments, a delivery device disclosed herein comprises (a) about 16% of a gelling agent (e.g., poloxamer 407) and (b) a micronized active agent; and provides extended sustained release over a period of from about 3 weeks. In some embodiments, a delivery device disclosed herein comprises (a) about 18-21% of a gelling agent (e.g., poloxamer 407) and (b) a micronized active agent; and provides extended sustained release over a period of from about 3 weeks to about 6 weeks. In some embodiments, a delivery device disclosed herein comprises (a) about 20% of a gelling agent (e.g., poloxamer 407) and (b) a micronized active agent; and provides extended sustained release over a period of from about 6 weeks. In some embodiments, the amount of gelling agent in a delivery device, and the particle size of an active agent are tunable to the desired release profile of an active agent from the delivery device. 
     In specific embodiments, delivery devices comprising micronized active agents provide extended release over a longer period of time compared to delivery devices comprising non-micronized active agents. In specific embodiments, selection of an appropriate particle size of the active agent (e.g., micronized active agent) in combination with the amount of gelling agent in the delivery device provides tunable extended release characteristics that allow for release of an active agent over a period of hours, days, weeks or months. 
     Kits/Articles of Manufacture 
     The disclosure also provides kits for preventing, treating or ameliorating the symptoms of a disease or disorder in a mammal. Such kits generally will comprise one or more of the active agent controlled-release delivery devices disclosed herein, and instructions for using the kit. The disclosure also contemplates the use of one or more of the active agent controlled-release delivery devices, in the manufacture of medicaments for treating, abating, reducing, or ameliorating the symptoms of a disease, dysfunction, or disorder in a mammal, such as a human that has, is suspected of having, or at risk for developing an inner ear disorder. 
     In some embodiments, kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed from a variety of materials such as glass or plastic. 
     The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are also disclosed herein. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and a packaging material suitable for a selected delivery device and intended mode of administration and treatment. A wide array of delivery devices are contemplated, as are a variety of treatments for a disease, disorder, or condition that would benefit by controlled-release administration of an active agent to the inner ear. 
     In some embodiments, a kit further comprises one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a delivery device disclosed herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use and package inserts with instructions for use. A set of instructions is optionally included. In a further embodiment, a label is on or associated with the container. In yet a further embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In other embodiments a label is used to indicate that the contents are to be used for a specific therapeutic application. In yet another embodiment, a label also indicates directions for use of the contents, such as in the methods described herein. 
     In certain embodiments, a delivery device disclosed herein is presented in a pack or dispenser device that contains one or more unit dosage forms containing a compound provided herein. In another embodiment, the pack for example contains metal or plastic foil, such as a blister pack. In a further embodiment, the pack or dispenser device is accompanied by instructions for administration. In yet a further embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. In another embodiment, such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In yet another embodiment, delivery devices containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. 
     EXAMPLES 
     Example 1: Effect of pH on Degradation Products for Autoclaved 17% Poloxamer 407NF/2% Active Agent in PBS Buffer 
     A stock solution of a 17% poloxamer 407/2% active agent is prepared by dissolving 351.4 mg of sodium chloride (Fisher Scientific), 302.1 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 122.1 mg of sodium phosphate monobasic anhydrous (Fisher Scientific) and an appropriate amount of an active agent with 79.3 g of sterile filtered DI water. The solution is cooled down in an ice chilled water bath and then 17.05 g of poloxamer 407NF (SPECTRUM CHEMICALS) is sprinkled into the cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. The pH for this solution is measured. 
     17% poloxamer 407/2% active agent in PBS pH of 5.3. Take an aliquot (approximately 30 mL) of the above solution and adjust the pH to 5.3 by the addition of 1 M HCl. 
     17% poloxamer 407/2% active agent in PBS pH of 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. 
     A PBS buffer (pH 7.3) is prepared by dissolving 805.5 mg of sodium chloride (Fisher Scientific), 606 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 247 mg of sodium phosphate monobasic anhydrous (Fisher Scientific), then QS to 200 g with sterile filtered DI water. 
     A 2% solution of an active agent in PBS pH 7.3 is prepared by dissolving an appropriate amount of the active agent in the PBS buffer and QS to 10 g with PBS buffer. 
     One mL samples are individually placed in 3 mL screw cap glass vials (with rubber lining) and closed tightly. The vials are placed in a Market Forge-sterilmatic autoclave (settings, slow liquids) and sterilized at 250° F. for 15 minutes. After the autoclave the samples are left to cool down to room temperature and then placed in refrigerator. The samples are homogenized by mixing the vials while cold. 
     Appearance (e.g., discoloration and/or precipitation) is observed and recorded. HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2) 3 μm, 100 Å, 250×4.6 mm 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 304, of sample and dissolved with 1.5 mL of a 1:1 acetonitrile water mixture. Purity of the active agent in the autoclaved samples is recorded. 
     In general the delivery device should not have a individual impurity (e.g., degradation product of active agent) of more than 2% and more preferably not more than one percent. In addition, the delivery device should not precipitate during storage or change in color after manufacturing and storage. 
     Example 2: Effect of Autoclaving on the Release Profile and Viscosity of a 17% Poloxamer 407NF/2% Active Agent in PBS 
     An aliquot of the sample from example 6 (autoclaved and not autoclaved) is evaluated for release profile and viscosity measurement to evaluate the impact of heat sterilization on the properties of the gel. 
     Dissolution is performed at 37° C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm). 0.2 mL of gel is placed into snapwell and left to harden, then 0.5 mL is placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples are taken every hour (0.1 mL withdrawn and replace with warm buffer). Samples are analyzed for poloxamer concentration by UV at 624 nm using the cobalt thiocyanate method, against an external calibration standard curve. In brief, 204, of the sample is mixed with 19804, of a 15 mM cobalt thiocyanate solution and absorbance measured at 625 nm, using a Evolution 160 UV/Vis spectrophotometer (Thermo Scientific). 
     The released active agent is fitted to the Korsmeyer-Peppas equation 
     
       
         
           
             
               Q 
               
                 Q 
                 α 
               
             
             = 
             
               
                 kt 
                 n 
               
               + 
               b 
             
           
         
       
     
     where Q is the amount of active agent released at time t, Q α  is the overall released amount of active agent, k is a release constant of the nth order, n is a dimensionless number related to the dissolution mechanism and b is the axis intercept, characterizing the initial burst release mechanism wherein n=1 characterizes an erosion controlled mechanism. The mean dissolution time (MDT) is the sum of different periods of time the drug molecules stay in the matrix before release, divided by the total number of molecules and is calculated by: 
     
       
         
           
             MDT 
             = 
             
               
                 nk 
                 
                   
                     - 
                     1 
                   
                   / 
                   n 
                 
               
               
                 n 
                 + 
                 1 
               
             
           
         
       
     
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm (shear rate of 0.31 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 15-34° C. at 1.6° C./min). Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition. 
     Example 3: Effect of Addition of a Secondary Polymer on the Degradation Products and Viscosity of a Delivery Device Containing 2% Active Agent and 17% Poloxamer 407NF after Heat Sterilization (Autoclaving) 
     Solution A. A solution of pH 7.0 comprising sodium carboxymethylcellulose (CMC) in PBS buffer is prepared by dissolving 178.35 mg of sodium chloride (Fisher Scientific), 300.5 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 126.6 mg of sodium phosphate monobasic anhydrous (Fisher Scientific) dissolved with 78.4 of sterile filtered DI water, then 1 g of Blanose 7M65 CMC (Hercules, viscosity of 5450 cP @ 2%) is sprinkled into the buffer solution and heated to aid dissolution, and the solution is then cooled down. 
     A solution of pH 7.0 comprising 17% poloxamer 407NF/1% CMC/2% active agent in PBS buffer is made by cooling down 8.1 g of solution A in an ice chilled water bath and then adding an appropriate amount of an active agent followed by mixing. 1.74 g of poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold solution while mixing. The mixture is further mixed until all the poloxamer is completely dissolved. 
     Two mL of the above sample is placed in a 3 mL screw cap glass vial (with rubber lining) and closed tightly. The vial is placed in a Market Forge-sterilmatic autoclave (settings, slow liquids) and sterilized at 250° F. for 25 minutes. After autoclaving the sample is left to cool down to room temperature and then placed in refrigerator. The sample is homogenized by mixing while the vials are cold. 
     Precipitation or discoloration are observed after autoclaving. HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2) 3 μm, 100 Å, 250×4.6 mm 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 304, of sample and dissolving with 1.5 mL of a 1:1 acetonitrile water mixture. Purity of the active agent in the autoclaved samples is recorded. 
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm (shear rate of 0.31 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 15-34° C. at 1.6° C./min). Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition. 
     Dissolution is performed at 37° C. for the non-autoclaved sample in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm), 0.2 mL of gel is placed into snapwell and left to harden, then 0.5 mL is placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples are taken every hour (0.1 mL withdrawn and replaced with warm buffer). Samples are analyzed for active agent concentration by UV at 245 nm, against an external calibration standard curve. 
     Example 4: Effect of Buffer Type on the Degradation Products for Delivery Devices Containing Poloxamer 407NF after Heat Sterilization (Autoclaving) 
     A TRIS buffer is made by dissolving 377.8 mg of sodium chloride (Fisher Scientific), and 602.9 mg of Tromethamine (Sigma Chemical Co.) then QS to 100 g with sterile filtered DI water, pH is adjusted to 7.4 with 1M HCl. 
     Stock Solution Containing 25% Poloxamer 407 Solution in TRIS Buffer: 
     Weigh 45 g of TRIS buffer, chill in an ice chilled bath then sprinkle into the buffer, while mixing, 15 g of poloxamer 407 NF (Spectrum Chemicals). The mixture is further mixed until all the poloxamer is completely dissolved. 
     A series of delivery devices is prepared with the above stock solution. An appropriate amount of active agent (or salt or prodrug thereof) and/or active agent as micronized/coated/liposomal particles (or salt or prodrug thereof) is used for all experiments. 
     Stock Solution (pH 7.3) Containing 25% Poloxamer 407 Solution in PBS Buffer: 
     PBS buffer is prepared by dissolving 704 mg of sodium chloride (Fisher Scientific), 601.2 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 242.7 mg of sodium phosphate monobasic anhydrous (Fisher Scientific) with 140.4 g of sterile filtered DI water. The solution is cooled down in an ice chilled water bath and then 50 g of poloxamer 407NF (SPECTRUM CHEMICALS) is sprinkled into the cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. 
     A series of delivery devices is prepared with the above stock solution. An appropriate amount of active agent (or salt or prodrug thereof) and/or active agent as micronized/coated/liposomal particles (or salt or prodrug thereof) is used for all experiments. 
     Tables 2 and 3 list samples prepared using the procedures described herein. An appropriate amount of active agent is added to each sample to provide a final concentration of 2% active agent in the sample. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Preparation of samples containing TRIS buffer 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 25% Stock 
                 TRIS 
               
               
                 Sample 
                 pH 
                 Solution (g) 
                 Buffer (g) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 20% P407/2% active agent/TRIS 
                 7.45 
                 8.01 
                 1.82 
               
               
                 18% P407/2% active agent/TRIS 
                 7.45 
                 7.22 
                 2.61 
               
               
                 16% P407/2% active agent/TRIS 
                 7.45 
                 6.47 
                 3.42 
               
               
                 18% P4072 active agent/TRIS 
                 7.4 
                 7.18 
                 2.64 
               
               
                 4% active agent/TRIS 
                 7.5 
                 — 
                 9.7 
               
               
                 2% active agent/TRIS 
                 7.43 
                 — 
                 5 
               
               
                 1% active agent/TRIS 
                 7.35 
                 — 
                 5 
               
               
                 2% active agent/TRIS (suspension) 
                 7.4 
                 — 
                 4.9 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Preparation of samples containing PBS buffer (pH of 7.3) 
               
            
           
           
               
               
               
            
               
                   
                 25% Stock Solution 
                 PBS 
               
               
                 Sample 
                 in PBS (g) 
                 Buffer (g) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 20% P407/2% active agent/PBS 
                 8.03 
                 1.82 
               
               
                 18% P407/2% active agent/PBS 
                 7.1 
                 2.63 
               
               
                 16% P407/2% active agent/PBS 
                 6.45 
                 3.44 
               
               
                 18% P407/2% active agent/PBS 
                 — 
                 2.63 
               
               
                 2% active agent/PBS 
                 — 
                 4.9 
               
               
                   
               
            
           
         
       
     
     One mL samples are individually placed in 3 mL screw cap glass vials (with rubber lining) and closed tightly. The vials are placed in a Market Forge-sterilmatic autoclave (setting, slow liquids) and sterilized at 250° F. for 25 minutes. After the autoclaving the samples are left to cool down to room temperature. The vials are placed in the refrigerator and mixed while cold to homogenize the samples. 
     HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2) 3 μm, 100 Å, 250×4.6 mm 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 304, of sample and dissolving with 1.5 mL of a 1:1 acetonitrile water mixture. Purity of the active agent in the autoclaved samples is recorded. The stability of delivery devices in TRIS and PBS buffers is compared. 
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm (shear rate of 0.31 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 15-34° C. at 1.6° C./min). Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition. Only delivery devices that show no change after autoclaving are analyzed. 
     Example 5: Pulsed Release Delivery Device 
     Diazepam is used in a pulsed release delivery device prepared using the procedures described herein. A 17% poloxamer solution is prepared by dissolving 351.4 mg of sodium chloride (Fisher Scientific), 302.1 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 122.1 mg of sodium phosphate monobasic anhydrous (Fisher Scientific) and an appropriate amount of an active agent with 79.3 g of sterile filtered DI water. The solution is cooled down in an ice chilled water bath and then 17.05 g of poloxamer 407NF (SPECTRUM CHEMICALS) is sprinkled into the cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. The pH for this solution is measured. 20% of the delivered dose of diazepam is solubilized in the 17% poloxamer solution with the aid of beta-cyclodextrins. The remaining 80% of the active agent is then added to the mixture and the final delivery device is prepared using a procedure described herein. 
     Example 6: Preparation of a 17% Poloxamer 407/2% Active Agent/78 Ppm Evans Blue in PBS 
     A Stock solution of Evans Blue (5.9 mg/mL) in PBS buffer is prepared by dissolving 5.9 mg of Evans Blue (Sigma Chemical Co) with 1 mL of PBS buffer. PBS buffer is prepared by dissolving 704 mg of sodium chloride (Fisher Scientific), 601.2 mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 242.7 mg of sodium phosphate monobasic anhydrous (Fisher Scientific) with 140.4 g of sterile filtered DI water. 
     A Stock solution containing 25% Poloxamer 407 solution in PBS buffer (as in Example 9) is used in this study. An appropriate amount of an active agent is added to the 25% Poloxamer 407 solution stock solution to prepare delivery devices comprising 2% of an active agent (Table 4). 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Preparation of poloxamer 407 samples containing Evans Blue 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Evans Blue 
               
               
                   
                 25% P407in 
                 PBS 
                 Solution 
               
               
                 Sample ID 
                 PBS (g) 
                 Buffer (g) 
                 (μL) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 17% P407/2% active agent/EB 
                 13.6 
                 6 
                 265 
               
               
                 20% P407/2% active agent/EB 
                 16.019 
                 3.62 
                 265 
               
               
                 25% P407/2% active agent/EB 
                 19.63 
                 — 
                 265 
               
               
                   
               
            
           
         
       
     
     The above delivery devices are dosed to guinea pigs in the middle ear by procedures described herein and the ability of delivery devices to gel upon contact and the location of the gel is identified after dosing and at 24 hours after dosing. 
     Example 7: Terminal Sterilization of Poloxamer 407 Delivery Devices with and without a Visualization Dye 
     17% Poloxamer 407/2% Active Agent/in Phosphate Buffer, pH 7.3: 
     Dissolve 709 mg of sodium chloride (Fisher Scientific), 742 mg of sodium phosphate dibasic dehydrate USP (Fisher Scientific), 251.1 mg of sodium phosphate monobasic monohydrate USP (Fisher Scientific) and an appropriate amount of an active agent with 158.1 g of sterile filtered DI water. The solution is cooled down in an ice chilled water bath and then 34.13 g of poloxamer 407NF (Spectrum chemicals) is sprinkled into the cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. 
     17% Poloxamer 407/2% Active Agent/59 ppm Evans Blue in Phosphate Buffer: 
     Take two mL of the 17% poloxamer 407/2% active agent/in phosphate buffer solution and add 2 mL of a 5.9 mg/mL Evans blue (Sigma-Aldrich chemical Co) solution in PBS buffer. 
     25% Poloxamer 407/2% Active Agent/in Phosphate Buffer: 
     Dissolve 330.5 mg of sodium chloride (Fisher Scientific), 334.5 mg of sodium phosphate dibasic dehydrate USP (Fisher Scientific), 125.9 mg of sodium phosphate monobasic monohydrate USP (Fisher Scientific) and an appropriate amount of an active agent with 70.5 g of sterile filtered DI water. 
     The solution is cooled down in an ice chilled water bath and then 25.1 g of poloxamer 407NF (Spectrum chemicals) is sprinkled into the cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. 
     25% Poloxamer 407/2% Active Agent/59 ppm Evans Blue in Phosphate Buffer: 
     Take two mL of the 25% poloxamer 407/2% active agent/in phosphate buffer solution and add 2 mL of a 5.9 mg/mL Evans blue (Sigma-Aldrich chemical Co) solution in PBS buffer. 
     Place 2 mL of delivery device into a 2 mL glass vial (Wheaton serum glass vial) and seal with 13 mm butyl str (kimble stoppers) and crimp with a 13 mm aluminum seal. The vials are placed in a Market Forge-sterilmatic autoclave (settings, slow liquids) and sterilized at 250° F. for 25 minutes. After the autoclaving the samples are left to cool down to room temperature and then placed in refrigeration. The vials are placed in the refrigerator and mixed while cold to homogenize the samples. Sample discoloration or precipitation after autoclaving is recorded. 
     HPLC analysis is performed using an Agilent 1200 equipped with a Luna C18(2) 3 μm, 100 Å, 250×4.6 mm column) using a 30-95 methanol:acetate buffer pH 4 gradient (1-6 min), then isocratic for 11 minutes, for a total run of 22 minutes. Samples are diluted by taking 304, of sample and dissolved with 0.97 mL of water. The main peaks are recorded in the table below. Purity before autoclaving is always greater than 99% using this method. 
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm (shear rate of 0.31 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 15-34° C. at 1.6° C./min). Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition. 
     Example 8: In Vitro Comparison of Release Profile 
     Dissolution is performed at 37° C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm), 0.2 mL of a gel delivery device disclosed herein is placed into snapwell and left to harden, then 0.5 mL buffer is placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples are taken every hour (0.1 mL withdrawn and replace with warm buffer). Samples are analyzed for active agent concentration by UV at 245 nm against an external calibration standard curve. Pluronic concentration is analyzed at 624 nm using the cobalt thiocyanate method. Relative rank-order of mean dissolution time (MDT) as a function of % P407 is determined. A linear relationship between a delivery device mean dissolution time (MDT) and the P407 concentration indicates that the active agent is released due to the erosion of the polymer gel (poloxamer) and not via diffusion. A non-linear relationship indicates release of active agent via a combination of diffusion and/or polymer gel degradation. 
     Alternatively, samples are analyzed using the method described by Li Xin-Yu paper [Acta Pharmaceutica  Sinica  2008, 43(2):208-203] and Rank-order of mean dissolution time (MDT) as a function of % P407 is determined. 
     Example 9: In Vitro Comparison of Gelation Temperature 
     The effect of Poloxamer 188 and an active agent on the gelation temperature and viscosity of Poloxamer 407 delivery devices is evaluated with the purpose of manipulating the gelation temperature. 
     A 25% Poloxamer 407 stock solution in PBS buffer (as in Example 9) and a PBS solution (as in Example 11) are used. Poloxamer 188NF from BASF is used. An appropriate amount of active agent is added to the solutions described in Table 5 to provide a 2% delivery device of the active agent. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Preparation of samples containing poloxamer 407/poloxamer 188 
               
            
           
           
               
               
               
               
            
               
                   
                 25% P407 Stock 
                 Poloxamer 188 
                 PBS 
               
               
                 Sample 
                 Solution (g) 
                 (mg) 
                 Buffer (g) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 16% P407/10% P188 
                 3.207 
                 501 
                 1.3036 
               
               
                 17% P407/10% P188 
                 3.4089 
                 500 
                 1.1056 
               
               
                 18% P407/10% P188 
                 3.6156 
                 502 
                 0.9072 
               
               
                 19% P407/10% P188 
                 3.8183 
                 500 
                 0.7050 
               
               
                 20% P407/10% P188 
                 4.008 
                 501 
                 0.5032 
               
               
                 20% P407/5% P188 
                 4.01 
                 256 
                 0.770 
               
               
                   
               
            
           
         
       
     
     Mean dissolution time, viscosity and gel temperature of the above delivery devices are measured using procedures described herein. 
     An equation is fitted to the data obtained and can be utilized to estimate the gelation temperature of F127/F68 mixtures (for 17-20% F127 and 0-10% F68). 
         T   gel =−1.8(%  F 127)+1.3(%  F 68)+53
 
     An equation is fitted to the data obtained and can be utilized to estimate the Mean Dissolution Time (hr) based on the gelation temperature of F127/F68 mixtures (for 17-25% F127 and 0-10% F68), using results obtained in example 13 and 15. 
       MDT=−0.2( T   gel )+8
 
     Example 10: Determination of Temperature Range for Sterile Filtration 
     The viscosity at low temperatures is measured to help guide the temperature range at that the sterile filtration needs to occur to reduce the possibility of clogging. 
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-40 spindle rotated at 1, 5 and 10 rpm (shear rate of 7.5, 37.5 and 75 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 10-25° C. at 1.6° C./min). 
     The Tgel of a 17% Pluronic P407 is determined as a function of increasing concentration of active agent. The increase in Tgel for a 17% pluronic delivery device is estimated by: 
       Δ T   gel =0.93[% active agent]
 
     Example 11: Determination of Manufacturing Conditions 
       
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Viscosity of potential delivery devices 
               
               
                 at manufacturing/filtration conditions. 
               
            
           
           
               
               
            
               
                   
                 Temper- 
               
            
           
           
               
               
               
            
               
                   
                 Apparent Viscosity a  (cP) 
                 ature @ 
               
            
           
           
               
               
               
               
            
               
                 Sample 
                 5° C. below Tgel 
                 20° C. 
                 100 cP 
               
               
                   
               
               
                 Placebo 
                 52 cP @ 17° C. 
                 120 cP 
                     19° C. 
               
               
                 17% P407/2% active agent 
                 90 cP @ 18° C. 
                 147 cP 
                 18.5° C. 
               
               
                 17% P407/6% active agent 
                 142 cP @ 22° C.  
                 105 cP 
                 19.7° C. 
               
               
                   
               
               
                   a Viscosity measured at a shear rate of 37.5 s −1   
               
            
           
         
       
     
     An 8 liter batch of a 17% P407 placebo is manufactured to evaluate the manufacturing/filtration conditions. The 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 refrigerator overnight. The following morning the tank was taken out (water temperature 5° C., RT 18° C.) and 48 g of sodium chloride, 29.6 g of sodium phosphate dibasic dehydrate and 10 g of sodium phosphate monobasic monohydrate is added and dissolved with an overhead mixer (IKA RW20 @ 1720 rpm). Half hour later, once the buffer is dissolved (solution temperature 8° C., RT 18° C.), 1.36 kg of poloxamer 407 NF (spectrum chemicals) is slowly sprinkled into the buffer solution in a 15 minute interval (solution temperature 12° C., RT 18° C.), then speed is increased to 2430 rpm. After a second one hour mixing, mixing speed is reduced to 1062 rpm (complete dissolution). 
     The temperature of the room is maintained below 25° C. to retain the temperature of the solution at below 19° C. The temperature of the solution is maintained at below 19° C. up to 3 hours of the initiation of the manufacturing, without the need to chill/cool the container. 
     Three different Sartoscale (Sartorius Stedim) filters with a surface area of 17.3 cm 2  are evaluated at 20 psi and 14° C. of solution 
     1) Sartopore 2, 0.2 μm 5445307HS-FF (PES), flow rate of 16 mL/min 
     2) Sartobran P, 0.2 μm 5235307HS-FF (cellulose ester), flow rate of 12 mL/min 
     3) Sartopore 2 XLI, 0.2 μm 5445307IS-FF (PES), flow rate of 15 mL/min 
     Sartopore 2 filter 5441307H4-SS is used, filtration is carried out at the solution temperature using a 0.45, 0.2 μm Sartopore 2 150 sterile capsule (Sartorius Stedim) with a surface area of 0.015 m 2  at a pressure of 16 psi. Flow rate is measured at approximately 100 mL/min at 16 psi, with no change in flow rate while the temperature is maintained in the 6.5-14° C. range. Decreasing pressure and increasing temperature of the solution causes a decrease in flow rate due to an increase in the viscosity of the solution. Discoloration of the solution is monitored during the process. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Predicted filtration time for a 17% poloxamer 407 placebo 
               
               
                 at a solution temperature range of 6.5-14° C. using Sartopore 
               
               
                 2, 0.2 μm filters at a pressure of 16 psi of pressure. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Estimated flow rate 
                 Time to filter 8 L 
               
               
                 Filter 
                 Size (m 2 ) 
                 (mL/min) 
                 (estimated) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Sartopore 2, size 4 
                 0.015 
                 100 mL/min 
                 80 min 
               
               
                 Sartopore 2, size 7 
                 0.05 
                 330 mL/min 
                 24 min 
               
               
                 Sartopore 2, size 8 
                 0.1 
                 670 mL/min 
                 12 min 
               
               
                   
               
            
           
         
       
     
     Viscosity, Tgel and UV/Vis absorption is check before filtration evaluation. Pluronic UV/Vis spectra are obtained by a Evolution 160 UV/Vis (Thermo Scientific). A peak in the range of 250-300 nm is attributed to BHT stabilizer present in the raw material (poloxamer). Table 8 lists physicochemical properties of the above solutions before and after filtration. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Physicochemical properties of 17% poloxamer 407 
               
               
                 placebo solution before and after filtration 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Viscosity a  @ 
                 Absorbance @ 
               
               
                 Sample 
                 Tgel (° C.) 
                 19° C. (cP) 
                 274 nm 
               
               
                   
               
               
                 Before filtration 
                 22 
                 100 
                 0.3181 
               
               
                 After filtration 
                 22 
                 100 
                 0.3081 
               
               
                   
               
               
                   a Viscosity measured at a shear rate of 37.5 s −1   
               
            
           
         
       
     
     The above process is applicable for manufacture of 17% P407 delivery devices, and further comprises temperature analysis of the room conditions. Preferably, a maximum temperature of 19° C. reduces cost of cooling the container during manufacturing. In some instances, a jacketed container is used to further control the temperature of the solution to ease manufacturing concerns. 
     Example 12: In Vitro Release of Active Agent from an Autoclaved Micronized Sample 
     17% poloxamer 407/1.5% active agent in TRIS buffer: 250.8 mg of sodium chloride (Fisher Scientific), and 302.4 mg of Tromethamine (Sigma Chemical Co.) is dissolved in 39.3 g of sterile filtered DI water, pH is adjusted to 7.4 with 1M HCl. 4.9 g of the above solution is used and an appropriate amount of micronized active agent is suspended and dispersed well. 2 mL of the delivery device is transferred into a 2 mL glass vial (Wheaton serum glass vial) and sealed with 13 mm butyl styrene (kimble stoppers) and crimped with a 13 mm aluminum seal. The vial is placed in a Market Forge-sterilmatic autoclave (settings, slow liquids) and sterilized at 250° F. for 25 minutes. After the autoclaving the sample is left to cool down to room temperature. The vial is placed in the refrigerator and mixed while cold to homogenize the sample. Sample discoloration or precipitation after autoclaving is recorded. 
     Dissolution is performed at 37° C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm), 0.2 mL of gel is placed into snapwell and left to harden, then 0.5 mL PBS buffer is placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples are taken every hour [0.1 mL withdrawn and replaced with warm PBS buffer containing 2% PEG-40 hydrogenated castor oil (BASF) to enhance active agent solubility]. Samples are analyzed for active agent concentration by UV at 245 nm against an external calibration standard curve. The release rate is compared to other delivery devices disclosed herein. MDT time is calculated for each sample. 
     Solubilization of active agent in the 17% poloxamer system is evaluated by measuring the concentration of the active agent in the supernatant after centrifuging samples at 15,000 rpm for 10 minutes using an eppendorf centrifuge 5424. Active agent concentration in the supernatant is measured by UV at 245 nm against an external calibration standard curve. 
     Example 13: Release Rate or MDT and Viscosity of Delivery Device Containing Sodium Carboxymethyl Cellulose 
     17% poloxamer 407/2% active agent/1% CMC (Hercules Blanose 7M): A sodium carboxymethylcellulose (CMC) solution (pH 7.0) in PBS buffer is prepared by dissolving 205.6 mg of sodium chloride (Fisher Scientific), 372.1 mg of sodium phosphate dibasic dihydrate (Fisher Scientific), 106.2 mg of sodium phosphate monobasic monohydrate (Fisher Scientific) in 78.1 g of sterile filtered DI water. 1 g of Blanose 7M CMC (Hercules, viscosity of 533 cP @ 2%) is sprinkled into the buffer solution and heated to ease solution, solution is then cooled down and 17.08 g poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold solution while mixing. A delivery device comprising 17% poloxamer 407NF/1% CMC/2% active agent in PBS buffer is made adding/dissolving an appropriate amount of active agent to 9.8 g of the above solution, and mixing until all the active agent is completely dissolved. 
     17% Poloxamer 407/2% Active Agent/0.5% CMC (Blanose 7M65): 
     A sodium carboxymethylcellulose (CMC) solution (pH 7.2) in PBS buffer is prepared by dissolving 257 mg of sodium chloride (Fisher Scientific), 375 mg of sodium phosphate dibasic dihydrate (Fisher Scientific), 108 mg of sodium phosphate monobasic monohydrate (Fisher Scientific) in 78.7 g of sterile filtered DI water. 0.502 g of Blanose 7M65 CMC (Hercules, viscosity of 5450 cP @ 2%) is sprinkled into the buffer solution and heated to ease solution, solution is then cooled down and 17.06 g poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold solution while mixing. A 17% poloxamer 407NF/1% CMC/2% active agent solution in PBS buffer is made adding/dissolving an appropriate amount of active agent to 9.8 g of the above solution, and mixing until the active agent is completely dissolved. 
     17% Poloxamer 407/2% Active Agent/0.5% CMC (Blanose 7H9): 
     A sodium carboxymethylcellulose (CMC) solution (pH 7.3) in PBS buffer is prepared by dissolving 256.5 mg of sodium chloride (Fisher Scientific), 374 mg of sodium phosphate dibasic dihydrate (Fisher Scientific), 107 mg of sodium phosphate monobasic monohydrate (Fisher Scientific) in 78.6 g of sterile filtered DI water, then 0.502 g of Blanose 7H9 CMC (Hercules, viscosity of 5600 cP @ 1%) is sprinkled to the buffer solution and heated to ease solution, solution is then cooled down and 17.03 g poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold solution while mixing. A 17% poloxamer 407NF/1% CMC/2% active agent solution in PBS buffer is made adding/dissolving an appropriate amount of active agent to 9.8 of the above solution, and mixing until the active agent is completely dissolved. 
     Viscosity measurements are performed using a Brookfield viscometer RVDV-II+P with a CPE-40 spindle rotated at 0.08 rpm (shear rate of 0.6 s −1 ), equipped with a water jacketed temperature control unit (temperature ramped from 10-34° C. at 1.6° C./min). Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition. 
     Dissolution is performed at 37° C. in snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm). 0.2 mL of gel is placed into snapwell and left to harden, then 0.5 mL PBS buffer is placed into reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples are taken every hour, 0.1 mL withdrawn and replaced with warm PBS buffer. Samples are analyzed for active agent concentration by UV at 245 nm against an external calibration standard curve. MDT time is calculated for each of the above delivery devices. 
     Example 14: Application of an Enhanced Viscosity Active Agent Delivery Device onto the Round Window Membrane 
     A delivery device according to Example 2 is prepared and loaded into 5 ml siliconized glass syringes attached to a 15-gauge luer lock disposable needle. Lidocaine is topically applied to the tympanic membrane, and a small incision made to allow visualization into the middle ear cavity. The needle tip is guided into place over the round window membrane, and the delivery device applied directly onto the round-window membrane. 
     Example 15: In Vivo Testing of Intratympanic Injection of a Auris Compatible Delivery Device in a Guinea Pig 
     A cohort of guinea pigs (Charles River, females weighing 200-300 g) is intratympanically injected with 50 μL of different P407-DSP delivery devices described herein, containing 0 to 6% of an active agent. The gel elimination time course for each delivery device is determined. A faster gel elimination time course of a delivery device indicates lower mean dissolution time (MDT). Thus the injection volume and the concentration of an active agent in a delivery device are tested to determine optimal parameters for preclinical and clinical studies. 
     Example 16: In Vivo Extended Release Kinetics 
     A cohort of guinea pigs (Charles River, females weighing 200-300 g) is intratympanically injected with 50 μL 17% Pluronic F-127 delivery device buffered at 280 mOsm/kg and containing 1.5% to 4.5% of an active agent by weight of the delivery device. Animals are dosed on day 1. The release profile for a delivery device is determined based on analysis of the perilymph. 
     Example 17: Effect of Poloxamer Concentration and Active Agent Concentration on Release Kinetics 
     A series of delivery devices comprising varying concentrations of a gelling agent and micronized dexamethasone was prepared using procedures described herein. The mean dissolution time (MDT) for each delivery device in Table 9 was determined using procedures described herein. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Preparation of poloxamer/active agent delivery devices 
               
            
           
           
               
               
               
               
            
               
                   
                 Sample 
                 pH 
                 MDT 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 15.5% P407/1.5% dexamethasone/PBS 
                 7.4 
                 46 
                 h 
               
               
                   
                 16% P407/1.5% dexamethasone/PBS 
                 7.4 
                 40 
                 h 
               
               
                   
                 17% P407/1.5% dexamethasone/PBS 
                 7.4 
                 39 
                 h 
               
               
                   
                 15.5% P407/4.5% dexamethasone/PBS 
                 7.4 
                 &gt;7 
                 days 
               
               
                   
                 16% P407/4.5% dexamethasone/PBS 
                 7.4 
                 &gt;7 
                 days 
               
               
                   
                 17% P407/4.5% dexamethasone/PBS 
                 7.4 
                 &gt;7 
                 days 
               
               
                   
                   
               
            
           
         
       
     
     The effect of gel strength and active agent concentration on release kinetics of an active agent from the delivery device was determined by measurement of the MDT for poloxamer, and measurement of MDT for active agent. The half life of the active agent and mean residence time of the active agent was also determined for each delivery device by measurement of concentration of the active agent in the perilymph. 
     The apparent viscosity of each delivery device was measured as described herein. A thermoreversible polymer gel concentration of about 15.5% in a delivery device described herein provided an apparent viscosity of about 270,000 cP. A thermoreversible polymer gel concentration of about 16% in a delivery device described herein provided an apparent viscosity of about 360,000 cP. A thermoreversible polymer gel concentration of about 17% in a delivery device described herein provided an apparent viscosity of about 480,000 cP. 
     While preferred embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only. Various alternatives to the embodiments described herein are optionally employed in practicing the inventions. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.