TW200950787A - Controlled release corticosteroid compositions and methods for the treatment of otic disorders - Google Patents

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with steroid, NSAID, and/or adenosine triphosphatase ("ATPase") modulator agents. In these methods, the steroidal, NSAID, and/or ATPase compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of these compositions and formulations onto or via perfusion into the targeted auris structure(s).

Description

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200950787 VI. Description of the invention: [Technical field to which the invention pertains] A vertebrate animal has a pair of ears' whose symmetry is located on the opposite side of the head. The ear acts as an organ for measuring the sound receptor and maintaining the balance of the body position. The ear can be roughly divided into three parts: the outer ear, the middle ear (middle ear), and the inner ear (inside the ear). SUMMARY OF THE INVENTION The present invention discloses a controlled release composition, formulation, method of manufacture, treatment for at least a corticosteroid to at least one structure or region of the ear: a method of use, a kit, and a delivery device. The present invention discloses a controlled release formulation for delivering corticosteroids to the ear. In some implementations, the ear part of the ear is the middle ear or the middle of the ear. In some implementations, the ear portion of the ear is the inner ear or inside the ear. In other embodiments, the target portion of the ear is the middle ear and the inner ear. In certain embodiments, the controlled release formulation further comprises a fast or immediate release component for delivering a corticosteroid to the target ear structure. All formulations contain an acceptable carrier for the ear. The present invention also discloses methods and compositions for treating ear disorders by administration of a controlled release formulation containing a corticosteroid. In certain embodiments, the ear disorder is Meniere's disease, Meniere's syndrome, or sensorineural hearing loss. In still other embodiments, the ear disorder is an autoimmune inner ear disorder (AIED). The present invention also discloses local delivery of controlled release steroid compositions and formulations to suppress or improve hearing and vestibular damage due to AIED. The detainment may be triggered by other immune conditions, including ankylosing spondylitis, systemic lupus erythematosus (SLE), system, Hugh's (9) coffee, syndrome, c〇gan, s, ulceration Colitis, Wegner's granuloma (wegener s 140447.doc 200950787 granulomatosis), rheumatoid arthritis, inflamed bowel disease and cutaneous sclerosis and Bethel's disease disease 'also known as Bechet's disease-adamantiades). In other embodiments, the ear is dysfunctional to the middle ear. In another embodiment, 'ear disorders are vestibular neuronitis, postural dizziness, Ramsay Hum's Syndrome (herpes zoster infection), syphilis infection, drug-induced inner ear injury, auditory nerve tumor, Old age deafness, otosclerosis or ankle disease. The present invention discloses a controlled release composition for treating an otic disorder comprising a therapeutically effective amount of one of a corticosteroid, a controlled release auris-acceptable excipient, and an auris-acceptable carrier. In one aspect, the controlled release auris-acceptable excipient is selected from the group consisting of an auris-acceptable polymer, an auris-acceptable viscosity enhancer, an auris-acceptable (four), an auris-acceptable gel, an auris-acceptable thermoreversible gel Or a combination thereof. In certain embodiments, the pH of the composition and the actual osmotic pressure and/or volume of the osmotic concentration are formulated to ensure that the body structure of the target otic structure is maintained constant. For example, the volumetric osmotic concentration of the peripheral lymph is between about 27 〇 3 〇 () 111 〇 3 〇 1 ' and the composition disclosed herein is visibly modulated to provide an actual volume osmotic concentration of about 15 〇 to About U) 00 m〇sm/b In a particular embodiment, the formulations disclosed herein provide an actual volumetric osmotic concentration at the target location of action (eg, inner ear and/or peripheral lymph and/or endolymph) of about 150 Up to about 500 m〇sm/L. In a particular embodiment, the formulations disclosed herein provide an actual volumetric osmolality at the target site of action (e.g., inner ear and/or peripheral lymph and/or endolymph) of from about 2 (10) to about 100. In a particular embodiment, the presently disclosed formulation provides an actual volumetric osmolality at a location of 140447.doc 200950787 (eg, inner ear and/or peripheral lymph and/or endolymph) of from about 250 to about 350. Within mOsm/L. Similarly, the pH of the peripheral lymph is about 7.2-7.4, while the pH of the formulation of the invention (e.g., using a buffer) is between about 5.5 and about 9.0. In a particular embodiment, the pH of the formulation is between about 6.0 and about 7.6. In a particular embodiment, the pH of the endolymph is between about 7.2 and 7.9, and the pH of the formulation of the invention (e.g., using a buffer) is between about 5.5 and about 9.0, or between about 6.5 and about 8. · Daytime.

In certain aspects, the controlled release auris-acceptable excipient is biodegradable and/or bioremovable (e.g., degraded and/or removed via urine, feces or other drainage routes). In another aspect, the controlled release composition further comprises an Ear Acceptable Mucoadhesive, an Ear Acceptable Penetration Enhancer or an Ear Acceptable Bioadhesive. In one aspect, the controlled release composition is delivered using a drug delivery system which is a needle and syringe, pump, microinjection device, and in situ combination of materials or the like. In certain embodiments, the corticosteroid that controls the release of the composition has a limit, or is systemic, but is systemic, has poor pk characteristics, or the like when administered systemically. In still other aspects, the corticosteroid is methyl dehydrocorticosterol, shell cortisol, dehydrocortisol, methyl dehydrocortisol, deoxycorticosterone, n-deoxycorticosteroid, 18-mercosyl -11-decortisol, a combination of beci〇methas (tetra), triamian cortisol or the like. In another aspect, the corticosteroid is a steroid phosphate or a prodrug. In another aspect, the skin f steroid is a salt of a steroid. The method comprising the use of the present invention also discloses a method for treating an otic disorder 140447.doc 200950787 = exposed silk and formula order _ coffee: every 7 , S , 9 , 10 ' 】,] less - times, every two weeks at least - two = - times, one week to:: at least once every five weeks, at least - every six weeks; or - at least I for months; At least once a month, every three months, at least once, every four months, one at a time: at least five times a month, at least once every (10) months, at least once every eight months, at least once every eight months, every nine At least once a month, at least once every ten months, at least once every eleven months, or once every twelve months. In a specific implementation The subsequent dose of the controlled release formulation disclosed in the present invention is controlled to provide a sustained dose of corticosteroid to the inner ear. That is, as exemplified by the illustrative example, if the new dose of the corticosteroid controlled release formulation is 10 per 10 This controlled release formulation provides an effective dose of corticosteroids to the inner ear (eg, throughout the round window membrane) during the 10 days via intra-auricular injection into the round window membrane. In another aspect, the composition is administered The composition is contacted with a round window membrane. In one aspect, the composition is administered by intra-injection. The invention provides a pharmaceutical composition for treating an ear disease or condition modulated to provide a therapeutically effective amount Methyl dehydrocorticosterol, sulfhydryl dehydrocorticolysis or dehydrocortisol' composition comprising substantially low degradation products of sulfhydryl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, The composition further comprises two or more properties selected from the group consisting of: (i) sulfhydryl dehydrocorticosterol, decyl dehydrocortisol or between about 0.1 wt[deg.]/about 10 wt[deg.]/〇 Hydrocortisol, or a pharmaceutical acceptable prodrug or salt; 140447.doc 200950787 (11) a polyoxyethylene-polyoxypropylene tri-embedded copolymer of the formula E106 P70 E106 between about 16 Wt% and about 21 wt%; In) sterilized water 'appropriate buffer to provide a pH between about 5 5 and about 8.0; (iv) multiparticulate methyl dehydrocorticosteroid, mercapto dehydrocortisol or dehydrocortisol; · (V) - between about 19. (: to about 42. (: gelatinization temperature; _ (vi) less than about 5 colony forming units (cfu) per g of microbial formulation, and (Vii) - The individual has less than about 5 endotoxin units per kilogram of body weight. In certain embodiments, the pharmaceutical compositions described herein comprise: (1) between about 0.1% to about 10% by weight of methyl dehydrocorticosteroids. Alcohol, mercapto dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof; (Π) between about 16"% and about 21% by weight of the formula M〇6 p7〇ei〇 6 Refractory I oxyethylene-polyoxypropylene tri-polymer; and • (iv) multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrogenation. • In certain embodiments, the pharmaceutical compositions described herein comprise: methyl dechlorinated cortisol, deuterated dehydrocortisol or dehydrocortisol, having a ω between about 10% by weight of about 0.1%. Or a pharmaceutically acceptable prodrug or salt thereof; (1)) a polyoxyethylene-polyoxypropylene trimeric copolymer having a formula of E1〇6 P70 E106 of between about 16 Wt% and about 21 Wt%; 140447. Doc 200950787 (iii) Multiparticulate thiol dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol; and (iv) - a gelation temperature between about 19 ° C and about 42 ° C. In certain embodiments, the pharmaceutical compositions disclosed herein provide a delivery volume osmotic concentration of between about 250 and 3 20 mOsm/L. In certain embodiments, the thiol dehydrocorticosteroid, sulfhydryl dehydrocorticosteroid or dehydrocortisol is released from the formulation over a period of at least 3 days. In certain embodiments, the thiol dehydrocorticosteroid, decyl dehydrocortisol or dehydrocortisol is released from the formulation for at least 5 days. This methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol is released from the formulation for at least 1 day. In certain embodiments, the pharmaceutical composition is an ear-acceptable thermoreversible gel. In certain embodiments, the polyoxyethylene-polyoxypropylene triblock copolymer is biodegradable and/or bioremovable (eg, the copolymer can be biodegraded by the body, eg, in urine, Excreted in the stool or similar to remove). In certain embodiments, the composition further comprises a mucoadhesive. In certain embodiments, the formulation further comprises a penetration enhancer. In certain embodiments, the formulation further comprises a thickening agent. In certain embodiments, the formulation further comprises a dye. In still another embodiment, the present invention provides a formulation further comprising a drug delivery device selected from the group consisting of a needle and a syringe, a pump, a microinjection device, a core, a gel forming substance or a combination thereof. In certain embodiments, the compositions described herein are wherein the methyl dehydrocorticosterol, decyl dehydrocortisol or dehydrocortisol or a medicinal agent thereof is accommodating to 140447.doc 200950787 A composition that is free of systemic release, systemic toxicity, poor pK characteristics, or the like. In certain embodiments of the compositions described herein, the thiol dehydrocorticosteroid, decyl dehydrocortisol or dehydrocortisol is a free base, a free acid, a salt, a prodrug, or the like The form of the combination. In certain embodiments of the compositions described herein, the thiol dehydrocorticosteroid, decyl dehydrocortisol or dehydrocortisol is administered as a phosphate ester prodrug. In certain embodiments of the compositions described herein, such sterols are decyl dehydrocorticosteroid phosphate or sulfhydryl dehydrocorticosterol acetate. In certain embodiments, the compositions described herein comprise a thiol dehydrocorticosterol, methyl dehydrocortisol, dehydrocortisol, or a pharmaceutically acceptable salt thereof, a prodrug, or a combination thereof, Immediate release agent. In certain embodiments, the compositions described herein are compositions wherein the methyl dehydrocorticolysis, methyl dehydrocortisol or dehydrocortisol comprises multiple particles. In certain embodiments, the compositions described herein are those wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is substantially in the form of micronized particles. In certain embodiments of the compositions described herein, the methyl dehydrocorticosterol is in the form of a micro-mercapto dehydrocorticosteroid powder. In certain embodiments, the compositions described herein further comprise an additional therapeutic agent. In some implementations, this Essence (4) is a Na/K ATPase modulator, a chemotherapeutic agent, a collagen, a gamma globulin, an interferon, an antimicrobial agent, an antibiotic, a local An anesthetic, a platelet activating factor antagonist, an ear protectant, a nitric oxide synthase inhibitor, an anti-stun agent, a vasopressin antagonist, an antiviral agent, an anti-emetic agent 140447.doc 200950787 or A combination of the same. In certain embodiments, the compositions described herein are those wherein the pH of the composition is between about 6.0 and about 7.6. In certain embodiments of the compositions described herein, the ratio of polyoxyethylene-polyoxypropylene triblock copolymer having the formula E106 P70 E106 to a thickener is from about 40:1 to about 5: 1. In certain embodiments, the thickening agent is carboxymethylcellulose, propylpropylcellulose or hydroxypropylmethylcellulose. In certain embodiments, the ear disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging _ related to hearing loss, autoimmune ear disease, or tinnitus. The invention also provides a method of treating an otic disease or condition comprising administering to a subject in need of an in-ear composition comprising a therapeutically effective amount of methyl dehydrocorticosterol, thiol dehydrocortisol Or dehydrocortisol, the composition comprising a low degradation product of substantially sulfhydryl dehydrocorticosterol, decyl dehydrocortisol or dehydrocortisol, the composition further comprising two or two selected from the following characteristics: (1) thiol-dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.1 wt% and about 1 〇 wt 〇 /0; (11) a polyoxyethylene-polyoxypropylene trimeric co-polymer having a formula of E106 P70 E106 between about 16 wt% and about 21 wt%; (iii) sterilized water 'suitable buffering to provide between about 5.5 and about 8.0 pH; (iv) less than about 50 colony forming units (cfu) per g of formula, and 140447.doc 200950787 (V) - less than about 5 endotoxin units per kilogram of body weight of the individual.

In certain embodiments of the methods of the present invention, the methyl dehydrocorticosteroid, decyl dehydrocortisol or dehydrocortisol is released from the composition over a period of at least 3 days. In certain embodiments of the methods disclosed herein, the methyl dehydrocorticoic H1 alcohol, methyl dehydrogenated skin (tetra) or dehydrogenated skin (tetra) is released from the composition over a period of at least 5 days. In certain embodiments of the methods of the present invention, the methyl dehydrocorticosterol, methyl dehydropeno-l-alcohol or de-cortisol is released from the composition by at least 10 days. In certain embodiments of this method, the composition is administered throughout the inner ear window. In certain embodiments of the method, the ear disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging, hearing loss, autoimmune ear disease, or tinnitus. [Embodiment] The present invention provides a controlled release steroidal steroid composition and formulation for the treatment of otic diseases including Meniere's disease and sensorineural hearing loss. A small number of therapeutic calves can be obtained to treat otave disorders such as AIED; however, a systemic route of oral, intravenous or intramuscular injection, sputum is currently used to deliver such therapeutic agents. The administration of systemic drugs 潜在 The potential unevenness in the concentration of music is found to be lower in the serum and in the middle ear and inner ear structures in the serum. Therefore, it is necessary to respect the unequalness to overcome this inequality in order to deliver a sufficient, therapeutically effective amount of eucalyptus to the inner ear. In addition, the systemic drug administration increases the possibility of systemic and adverse side effects to perform adequate local delivery to light "...~ to sputum blood volume ~ hepatic breakdown and action of therapeutic agents, which form toxic metabolites致致140447.doc 200950787 Eliminates any advantages obtained by administration. a. In order to overcome the toxicity of delivery and accompanying side effects, the present invention discloses methods and compositions for the delivery of therapeutic agents to the ear structure. For example, in and out The court and the deafness organ will pass through the middle ear, which includes the inner ear round window membrane, the printed window/bellium panel, the annular horn band and the ear cartilage sac/tibia. Thus, the present invention provides a controlled release corticosteroid formulation and composition The topical treatment of the ear structure, thereby avoiding the side effects of the systemic administration of the corticosteroids. This topical application of corticosteroids is compatible with the target ear structure and can be directly administered to the intended ear region, ear. The tract or the outer ear, or the ritual, which is directly connected to the area, is included, but is not limited to a round window film, ear or printed window film. Given the alignment ear structure can be prevented from adverse side effects of the treatment system with rape. Further, judged clinically significant, advantage of the surrounding lymph, such as "heart treatment Xi 'time of exposure to the cochlea == clinical efficacy. Thus, by providing a controlled sputum, a corticosteroid formulation or composition for treating an otic disorder, providing a constant and/or prolonged source of corticosteroids to suffer from 'integration or patient reduction or removal of treatment The present invention provides a corticosteroid as disclosed in the present invention. Released. In the formulation or composition of the drug. In other embodiments, the alcohol-released modulator is administered in a sustained release formulation, in a pulsating manner or in a manner that varies in duration, variable or in another In an embodiment, 140447.doc 12 200950787 The corticosteroid formulation is administered in an immediate release and controlled release formulation which is sustained, variable or pulsed or a modified release thereof. ◎This release may optionally be dependent on environmental or physiological symptoms. For example, an external ionic environment (see, for example, the Oros® release system, j〇hnsori & Johnson) 〇

In addition, topical treatment of the subject's ear structure also provides the use of previously undesired therapeutic agents, including agents with poor PK profiles, poor absorption, low systemic release and/or toxicity issues. Because corticosteroid formulations and local targets of the composition, as well as the biological blood barrier present in the inner ear, reduce the risk of adverse effects caused by previously unique or unproductive corticosteroids. Accordingly, it is also contemplated in the context of the examples described herein that the use of a pebbled steroid which is rejected by a physician due to the adverse or non-effective effects of corticosteroids is used to treat ear disorders. The jujube is also disclosed. The u(7) collar 5T bucket 1 compatibilizer is combined with the corticosteroid formulation and composition disclosed in the present invention. When used, this agent helps to treat hearing loss or dysfunction due to autonomic dysfunction, including dizziness, deafness, smashing horses & loss of force, balance disorders, Infection or a combination thereof. Accordingly, an agent that improves or = 4%/distraction, tinnitus, hearing loss, balance disorder, infection, inflammatory response, or the like may also be combined with a corticosteroid, which includes Anti-TNF agent, anti-emetic agent, chemotherapeutic agent, including blood chemotherapeutic agent, acetylcholine. To earn 疋 疋 疋 7 7 7 (azathmfmne) or amine folic acid, 乂 collagen, egg yolk interferon, kepason The treatment of a combination of anesthetic, antibiotics, platelets _ live = agents, nitric oxide synthase inhibitors, and the like. . In addition, the ear can be controlled release corticosteroid formulation 140447.doc •13·200950787 and the treatment is provided to the ear region of the individual subject, which includes the inner ear, and the individual in need is additionally given an oral dose of corticosteroid . In certain embodiments, this oral dose of corticosteroid can be administered prior to administration of an acceptable controlled release corticosteroid formulation for the ear, so that the oral dose is reduced in time with which the controlled release corticosteroid formulation is provided. Alternatively, the oral dose of corticosteroid can be administered during the administration of an acceptable controlled release corticosteroid formulation for the ear, so the oral dose is reduced with the time available to provide acceptable control of the release of the corticosteroid formulation. Alternatively, this oral dose of corticosteroid can be administered after administration of an acceptable controlled release corticosteroid formulation for the ear, so the oral dose is reduced with the time available to provide an acceptable controlled release of the corticoplast formulation. Further, the corticosteroid pharmaceutical composition or formulation also includes a carrier, an adjuvant such as a preservative, a stabilizer, a moisturizing or emulsifying agent, a solution accelerating agent, and a salt and/or a buffer for adjusting the osmotic pressure. The carrier, adjuvant and other excipients are compatible with the environment of the standard ear structure. Accordingly, carriers, adjuvants, and excipients that are non-toxic or minimally toxic are specifically contemplated to allow for effective treatment of the ear disorders contemplated by the present invention with minimal side effects in the target area or portion. To prevent ototoxicity, the corticosteroid pharmaceutical compositions or formulations disclosed herein may be directed to different regions of the ear structure, including but not limited to auricular, vestibular bone and membrane labyrinth, cochlear bone and membrane labyrinth and others. An anatomical or physiological structure located in the inner ear. "Ear" is used in this article to define a formula or composition that does not have a continuing detrimental effect on a treated individual. 140447.doc 200950787 : and * * "Early acceptable for use in medicine" To refer to a substance f, such as a system or a diluent, which does not abolish the biological activity or property of the compound to the middle ear and inner ear 7, and is relatively or less toxic to the ear and inner ear, and the substance is administered to the individual. It does not cause undesired utility or interacts with the tissue containing material in four ways. . As used herein, administration of a particular compound or pharmaceutical composition is used

= or to alleviate the syndrome, disorder, or symptomatic attribution of a particular ear disease; or the reduction in severity achieved by administration of a compound or composition, the onset of delayed symptoms, the development of a slow course, or a shortened period, whether permanent or temporary , continuous or instantaneous. / Antioxidants are ear-medicinal acceptable antioxidants and include, for example, butylated toluene (bribet), sodium ascorbate, ascorbic acid, meta-dimer, U. acid and vitamin E. In a particular embodiment, the antioxidant promotes the need for a chemical ampoules to also counteract the ear of a particular therapeutic agent'! Effective for use' which includes agents for use in combination with the otic agents described herein. The inner ear means the inner ear, including the cochlea and vestibular labyrinth, and the inner ear round window of the connected cochlea and middle ear. "Auricular bioavailability" or "inner ear bioavailability" or "middle ear bioavailability" or "external ear bioavailability" means the administration of a compound disclosed by the present invention! Percentages are available in the ear structure of the animal or human being studied, respectively. The middle ear means the middle ear' which includes the tympanic cavity, the ossicular bone and the oval window which connects the middle ear and the inner ear. The outer part of the ear refers to the outer ear, including the ear flap, the ear canal and the eardrum. The eardrum 140447.doc 15 200950787 connects the outer ear to the middle ear. The blood ash crossing concentration refers to the concentration of the compound provided by the present invention in the plasma component of the plasma of a patient.

The carrier material is a topical agent that is compatible with the release profile properties of corticosteroids, standard ear structures, and ear-acceptable pharmaceutical formulations. Such carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Aur-medical compatible carrier materials" include, but are not limited to, gum arabic, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium citrate, polyvinylpyrrolidine Ketone (Pvp), cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phospholipid choline, sodium vapor, calcium triphosphate, potassium diphosphate, cellulose and cellulose conjugate, sugar hard Barium lactate, sodium staghorn, monoglyceride, diglycerin, pregelatinized powder and the like. The term "diluent" refers to a chemical compound that is used for dilution prior to delivery of a corticosteroid and is compatible with the standard ear structure.

"Dispersant" and / or "viscous modifier" are substances that control the diffusion and homogeneity of corticosteroids via a liquid medium. Examples of diffusion promoters/dispersants include, but are not limited to, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and sugar-based dispersants. For example, hydroxypropyl cellulose (such as HPC, HPC-SL and HPC-L), hydroxypropyl decyl cellulose (for example, HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethyl cellulose, Carboxymethylcellulose, methylcellulose, hydroxyl 140447.doc -16- 200950787 ethylcellulose, hydroxypropylcellulose, hydroxypropyl decyl cellulose o-dicarboxylic acid, hydroxypropyl fluorenyl cellulose acetate Stearate (HPMCAS), amorphous cellulose, aluminum magnesium niobate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone/ethylene acetate copolymer (S630), 4-(1,1, 3,3-Tetrabutylbutyl)-phenol polymers and ethylene oxide and furfural (also known as tetrabutyl phenolic), poloxamers (eg, Pluronic F127, Pluronics F68®, F88®, and F108) ®, which is a block copolymer of ethylene oxide and propylene oxide; and Poloxamines (eg Tetronic 908®) Also known as Poloxamine 908®, which is a tetrakid functional block copolymer derived from ethylene propylene oxide and ethylene bromide, which is derived from ethylene diamine (BASF, Pasbany, New Jersey, USA) , polyvinylpyrrolidone K12, polyethylene tons of each biting ketone K1 7, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K3 〇, polyethylene ° pyrrolidone / ethylene acetate copolymer (S- 630), polyethylene glycol (for example, polyethylene glycol having a molecular weight of from about 300 to about 6000, or from about 3,350 to about 4, biting from about 7,000 to about 5,400), sodium carboxymethyl cellulose, methyl Cellulose, Polysorbate-80, sodium alginate, gum (for example, tragacanth and gum arabic), silicone, tri-sac (including Sanxian gum), sugar, cellulose (eg sodium carboxymethyl) Cellulose, mercapto cellulose, sodium carboxymethyl cellulose), polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, pu A combination of ketones, carbons, polyvinyl alcohol (PVA), alginic acid vinegar, polyglucosamine, and dragons. Plasticizers such as cellulose or triethyl cellulose can also be used in (iv) eight powders. Lipids that can be selected for use in the skin steroids described herein = dispersants with autoemulsion dispersions are bismuth. The base is succinct = 140447.doc 200950787 base (C8-Cl8), phospholipid ethanolamine (c8_cl8), Phospholipid glycerol (c8_ci8), natural phospholipid choline from egg or ugly, natural phospholipid glycerol from egg or soybean, cholesterol and isopropyl myristyl ester. . "Pharmaceutical absorption" 4 "Absorption" refers to the process by which corticosteroids are moved from the local position of the administration, exemplified by the inner ear round window membrane and through the barrier (round window membrane, as described later) to the inner or inner ear structure. The term "co-administration" or its like as used herein is meant to encompass the administration of a corticosteroid to a patient and to include a treatment regimen of corticosteroids with the same or different routes of administration or at the same or different times. The term "effective amount" or "therapeutically effective amount" as used herein refers to a dose of a corticosteroid that is expected to slow down one or more symptomatic groups of the disease or condition being treated. For example, the administration of corticosteroids disclosed herein results in a reduction and/or alleviation of symptoms, syndromes or pathogens of AIED. For example, an "effective amount" for therapeutic use is the amount of corticosteroids which need to include the formulations disclosed herein to provide a reduction or amelioration of disease syndrome without undue adverse side effects. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a corticosteroid composition as described herein is effective to achieve the desired pharmaceutical effect or therapeutic improvement without undue adverse side effects. In certain embodiments, it is to be understood that "an effective amount" or "a therapeutically effective amount" is different from one another by the metabolism of the compound administered, the age, the weight, the general symptoms of the individual, the symptoms being treated. The severity of the symptoms being treated and the judgment of the physician. It should also be understood that based on pharmacokinetic and pharmacodynamic considerations, an "effective amount" in an extended-release dosage form may differ from an "effective amount" in an immediate-release dosage form. 140447.doc 200950787 "Promotion ( The term "enhancement" or "enhancing" means the increase or prolongation of the potential or duration of action of a corticosteroid, or the reduction of any adverse symptoms, such as local pain resulting from the administration of a therapeutic agent. For example, with regard to enhancing the utility of the corticosteroids disclosed herein, the term "promoting" means increasing or prolonging the utility of other therapeutic agents used in conjunction with the corticosteroids disclosed herein, whether in terms of potential or function. As used herein, "promoting-effective amount" means a setting of a corticosteroid or other therapeutic agent that is suitable for enhancing the utility of other therapeutic agents or corticosteroids in a contemplated system. When used in a patient, the amount of efficacy used is dependent on the severity and duration of the disease, disorders or symptoms, prior treatment, the patient's state of health and response to the drug, and the judgment of the treating physician. The term "inhibition" includes preventing, slowing or reversing the development of symptoms, such as AIED' or the progression of symptoms in a patient in need of treatment. The terms "kit" and "manufactured item" are used synonymously. "Pharmacodynamic" means a factor that determines the biological response of a relative drug concentration observed at a desired location within the target ear structure. "Pharmacokinetics" means the factor at which the appropriate concentration of the drug is determined and maintained at the desired location within the target ear structure. In prophylactic applications, a composition comprising a corticosteroid of the invention is administered to a patient susceptible to or at risk of a particular disease, disorder or symptom, such as Meniere's disease, or a patient suffering from an AIDD-related disease, including Examples of ankylosing spondylitis, systemic lupus erythematosus (SLE), Sjdgren's syndrome, Ke Gangshi (1) called deduction (nine), ulcerative colitis, Wegener's granulomatosis, inflammation Intestine 140447.doc -19· 200950787 Diseases 'Rheumatoid arthritis, cutaneous sclerosis and Bethel's disease (Beh9et,! This amount is defined as “preventive amount or dose”. Accurate summer in this use It is also dependent on the patient's state of health, weight, and the like. "Powder" is a corticosteroid that is converted into a parent drug in vivo. In a specific implementation, the prodrug is enzymatically metabolized by at least a step or process. To a biological, pharmaceutical or therapeutically active form of the compound. In order to produce a prodrug, the active compound is reconstituted so that the active compound will be reconstituted in vivo. In the examples, the prodrug is designed to alter metabolic stability or drug delivery characteristics, mask side effects or toxicity, or alter other properties or properties of the drug. In certain embodiments, the compounds provided herein are derivatized into suitable prodrugs. "Circular window film" covers the cochlear window in humans (also known as round window, round window (fenestrae rotunda), or round window). In humans, the thickness of the round window film is about 70 microns. "> "Glutamine" refers to the ear · acceptable compounds such as triethylene glycol glycerol, triethyl citrate, ethyl oleate, ethyl octanoate, sodium lauryl sulfate, sodium octyl sulfonate, vitamin Life E TPGS, dimercaptoacetamide, N-methyl pirone, N. thioethyl η ratio, ketone, polyethyl hydrazine, acetophenone, propyl methacrylate , hydroxypropyl cyclodextrin, ethanol, η·butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, tetrahydrofuran, southern glycol ether, Transcutol®, propylene glycol and dimethyl Isosorbide and its analogs. "Stabilizer" means a compound that is compatible with the standard structure of the ear structure. 140447.doc •20- 200950787 Hecaijihuazhai, including, liquid, acid, preservatives and the like. Stabilizers include, but are not limited to, the following agents: (1) Modified excipients and containers The compatibility of the sputum delivery system, including syringes or a glass bottle, (7) improving the stability of the components of the composition, or (3) improving the stability of the formulation. The "steady state" used herein is when the target is applied to the ear. The dose of the structure is equal to the amount of drug removed during the interval between the drug and the drug to cause a flat or constant dose exposure within the target structure. Φ Φ The term "individual" as used herein is used to refer to an animal. Preferably, the singular animal 'includes human or non-human. Words such as patients and individuals can be exchanged. "Factory surfactant" refers to the ear _ acceptable compounds, such as sodium lauryl sulfate, sodium docusate, Tween 6 〇 or 8 〇 'triacetyl glycerol, vitamin E TPGS, Lin lipid, printed Phospholipids, serotonin test (A, 1 lipoethanolamine (C8-C! 8), phospholipid glycerol (c8_cl 8), sorbitol liver monooleate, polyoxyethylene sorbitol oleic acid oleic acid, polysorbate Vinegar, ρ〇ι_milk, bile salts, glyceryl monostearate, epoxy epoxies and propylene propylene copolymers, such as P1_ni, (BASF), and the like. Some other surfactants include Polyoxyethylene fatty acid glycerin and vegetable oil, such as polyoxyethylene (6 〇) hydrogenated lotus oil '· and polyoxyethylene alkyl ether and alkyl phenyl ether, such as octyl polyether 10, octyl convergence 40. In certain embodiments, an intersex agent is included to enhance physical stability or for other purposes. "treat," "treating," or "treatment" as used herein. Words include reducing, attenuating or ameliorating a disease or symptom, syndrome, preventing additional syndromes' improvement or prevention Symptoms, depression 140447.doc -21 · 200950787 Potential metabolic causes of diseases or symptoms such as stopping the progression of a disease or condition, slow-release disease or symptoms, degenerative disease or symptoms, alleviating symptoms caused by disease or symptoms, or preventing and / or the syndrome that controls or stops the disease or symptoms of treatment. The anatomy of the ear shows that the outer ear is the external part of the organ and is covered by the ear (auricle), the ear canal (outer ear canal) and the tympanic membrane. Known as the tympanic membrane. This wing 'is the fleshy part of the outer ear and can be seen on the first two sides, collecting sound waves and guiding it to the ear canal. Therefore, the outer ear function part collects and directs the sound waves to the tympanic membrane and the middle ear. The ear is a chamber filled with air after the tympanic membrane, called the tympanic cavity. The tympanic membrane, also known as the tympanic membrane, is a membrane that separates the outer ear by the ear. The middle ear is located in the tibia and includes the three ear bones. In the space of the bone: the hammer bone, the stone occupying the bone and the tibia. The ossicle is joined by a tiny moving belt, which forms a bridge that crosses the raft to the space. The hammer bone is connected to the tympanic membrane at one end. Connected to the anvil, which is sequentially connected to the tibia. The tibia is joined to the oval window, one of the two windows is located in the tympanic cavity. A fibrous tissue layer, known as an annular ligament, connects the tibia to the oval window. The sound waves of the outer ear first cause the tympanic membrane to vibrate. This vibration is transmitted through the cochlea through the ossicular and ovate windows, which converts the liquid in the inner ear. Therefore, the configured ossicle provides a tympanic membrane and a machine between the liquid-filled inner ear and the oval window. a connection in which the sound is transformed and transmitted to the inner ear for further processing. The loss of hardening, rigidity or movement of the ossicle, tympanic membrane or oval window will result in hearing loss, such as otosclerosis, or hardening of the talus. The tympanic cavity is also connected via the eustachian tube The larynx. The Eustachian tube is provided between the outer space 140447.doc • 22- . The inner ear round window is the inner ear -

移动 The movement of the inner ear circle _ allows the movement of liquid in the deafness, which in turn causes the movement of hair cells in the deafness, allowing hearing signal conversion. The rigidity or movement of the inner ear circle _ causes hearing loss because the cochlear fluid lacks the ability to move. The current seminar has focused on the ability to implant mechanical transducers in the inner ear 200950787 between the gas and the middle ear cavity. The injury can also be accessed in the tympanic cavity, which opens to the inner ear. The inner ear round window is covered by a membrane consisting of three layers: an outer or mucosal layer, an intergranular or fibrous layer, and an inner membrane that is in direct fluid communication with the cochlea. Therefore, the inner ear round window communicates directly with the inner ear via the inner membrane. The movement of the oval and the inner ear round window is interconnected, that is, when the tibia is transported by the tympanic membrane to the oval window to move inward against the inner ear fluid, the inner ear circle® (more correctly the round window membrane) corresponds to the outward It is pushed out and away from the round window of the cochlear fluid, which bypasses the normal conduction path through the print window and provides an amplified input to the deafness chamber. Auditory signal conduction occurs in the inner ear. The liquid _ filling inner ear (inner ear) consists of two main components: the cochlea and the vestibular organ. The inner ear is located inside the bone or bone labyrinth, which is a complex interlaced series located within the tibia of the skull. The vestibular organ is a balanced organ and consists of a three-north tube and a vestibule. The three semicircular canals are configured to each other so that they can be moved by the motion detecting head of the liquid in three orthogonal planes and subsequently by the sensor of the semicircular canal, which is called the auditory ridge. The auditory ridge contains hair cells and supporting cells and is covered by a semi-穹 gelatin substance called a top cap. The hair cells of this hair cell are buried in the top cap. This semi-regulator detects dynamic balance, rotation or angular movement balance. When the head rotates rapidly, the semicircular canal moves with the head, but the endolymphatic fluid located in the membranous semicircular canal is still stable. The endolymphatic fluid pushes against the top cap's tendency - side. When the top cap is tilted, its f is folded over the hair on the hair cells of the ridge, which initiates a sensory pulse. Because each semi-regular is located on a different half, the corresponding audible ridge of each semi-regulator has a different response to the same movement of the head. This produces a pulsed mosaic 'which is transmitted to the central god on the vestibular branch of the vestibular sacral nerve'. The central nervous system of the system fully releases this message and initiates appropriate back to maintain balance. The central nervous system is important The sex is the cerebellum, the sense of balance and balance of the media. · The vestibule is the central part of the inner ear and contains mechanical receptors with hair cells, which determine the static equilibrium 'or the position of the head relative to gravity. Static balance in the head / Does not move or play a role in the - linear movement. This membrane in the vestibule is divided into two capsule-like structures, elliptical sacs and balloons. Each structure sequentially contains a small structure called the macula, which responds Maintenance of static balance. This macula consists of sensory hair cells embedded in a gelatinous substance (similar to the top cap) that covers the macula. Calcium carbonate particles, called the ossicles, are the surface of the embedding layer. When the head is in the up position, the hair cells are straightened along the macula. When the head is skewed 0, the gelatinous substance and the sacral corresponding to the ossicle are bent on the macular hairs of the macula. Move - pulse signals to the central nervous system, its vestibular nerve vestibular cochleafollowing into sub-branches, which are then conveyed to a motor pulse - - appropriate muscles to maintain balance I40447.doc • 24 · 200950787.

Deafness is the part of the inner ear that is related to hearing. The cochlea is a conical tube structure with a spiral-like snail-like component. The interior of the cochlea is divided into three regions, which are further defined by the position of the vestibular membrane and the basement membrane. The part on the vestibular membrane is the vestibular step, which extends from the oval window to the cochlear apex and contains peripheral lymphoid fluid, which is a low potassium but high sodium content aqueous liquid. The basement membrane defines a tympanic region that extends from the top of the cochlea to the inner ear round window and also contains peripheral lymphocytes. This brain base film contains thousands of hard fibers that extend gradually from the inner ear round window to the top of the cochlea. When activated by sound, the fibers of the bottom film vibrate. Between the vestibular step and the tympanic catheter is a cochlear catheter that terminates at the top of the cochlea as a closed capsule. The cochlear duct contains endolymph fluid, which is similar to the fluid in the cerebrospinal ridge and has a high potassium content. The τ hearing sensory organ - the Coriolis spiral is located in the basement membrane and extends upward into the deafness catheter. Coriolis loudspeakers contain hair cells that have hair-like projections that extend from a free surface and are in contact with a gelled surface, which is referred to as a coating 140447.doc -25-200950787. Although the hair cells do not have an axon, they are surrounded by sensory nerve fibers that form the vestibular cochlear nerve (brain nerve VIII) cochlear branches. As discussed, the oval window is also known as an elliptical window that communicates with the tibia to convey the sound of vibration by the tympanic membrane. The vibration transmitted to the oval window increases the pressure in the liquid-filled deaf by the peripheral lymph and vestibular steps/drums, which in turn causes the membrane on the inner ear circle 126 to expand in response. Inward of this consistent oval window

The outward expansion of the pressing/inner ear window allows the liquid within the deaf to move without changing the inner ear (four) force. "And, when the vibration travels through the periphery of the vestibular step, it produces a corresponding resonance in the vestibular membrane. These corresponding resonances travel through the endolymph of the cochlear implant and are transmitted to the basement membrane of the brain. When the brain basement vibrates M, or moves up and down, the Coriolis is expected to listen to the m-axis. In the section (4), the hair cell receptors of the tuner then move against the abdomen, causing mechanical deformation in the fortune. This mechanical deformation initiates a nerve impulse that travels through the vestibular cochlear nerve to the middle system: the mechanical transmission receives the sound wave as a signal, which is processed by the central nervous system. Symptoms of the ear, middle ear and outer ear disorders caused by, but not limited to, hearing loss, nystagmus, dizziness, swelling, infection and congestion. These disorders may have many causes, such as 2 swollen trauma, inflammation, tumors, and medication or other factors: many reasons for loss of speech and/or balance or inflammation. reaction. Hearing and / or cytokine mediators of inflammation. In A, the autoimmune disorder is adjusted to Meniere's disease. In the two cases, the ear loss hearing loss was observed in the two cases. In the implementation of the money, the money was transferred to the sensorinegic tone to autoimmune the inner ear 140447.doc •26· 200950787 Disorder (AIED). In an embodiment, the ear disorder is Meniere's disease. In still another embodiment, the ear disorder is Meniere's syndrome, vestibular neuritis, postural dizziness, Ray's syndrome (herpes zoster infection), syphilis infection, drug-induced inner ear injury, auditory nerve tumor Excessive noise hearing loss, old age deafness, otosclerosis or ankle joint disease. The diseases described herein, including those set forth hereinafter, are treated with the steroid medical compositions of the present invention. Meniere's disease Meniere's disease is a spontaneous symptom characterized by a sudden onset of dizziness, nausea, and vomiting - which can last for 3 to 24 hours and may gradually disappear. Progressive hearing loss, tinnitus, and pressure perception in the ear occur through the time of the disease. The cause of Meniere's disease may be related to a constant imbalance in the fluid in the inner ear, including an increase in fluid production in the inner ear or a decrease in fluid decomposition in the inner ear. Surgery can be used to alleviate Meniere's symptoms, including disrupting vestibular function to alleviate dizziness syndrome. The purpose of these procedures is to reduce the fluid pressure in the inner ear and/or to disrupt the inner ear balance function. An inner linba drainage surgery, relief and fluid pressure, is performed in the inner ear to alleviate vestibular dysfunction. A vestibular nerve bypass can also be used, which controls the glare and preserves the hearing force. A standard care of Meniere's disease requires the patient to follow a low-salt diet. In a special case, a low-salt diet is supplemented with an antibiotic. In a specific example, a low salt diet is supplemented with a pentamycin administration. In a specific example, the low-salt diet is supplemented with an oral solid-state fermentation. In a specific example, a low-salt diet supplemented with oral Prysone (25-50 mg PO/IM/PR q4-6h) was administered. 140447.doc -27- 200950787 In one set of embodiments, a patient treated with standard care as described above for the treatment of Meniere's disease is replaced with an acceptable formulation and method for the release of corticosteroids as described herein. In one set of embodiments, a patient treated with Meniere's disease using standard care as described above, but which is resistant or non-responsive to this treatment, is acceptable for the release of corticosteroids as described herein. Formula and method alternatives. Meniere's syndrome Meniere's syndrome, which exhibits similar symptoms to Meniere's disease, is the second cause of illness caused by other diseases, such as thyroid-infected thyroid disease or inflammation of the inner ear. Therefore, Meniere's syndrome is the second role of the pathogenesis of normal production or resorption of endolymph, including internal dissociation abnormalities, electrolyte imbalance 'autoimmune dysfunction, drug preparations, infections (eg parasitic infections) or High lipidosis. Treatment with patients suffering from Meniere's syndrome is similar to Meniere's disease. Sensorineural hearing loss, sacral nerve hearing loss is affected by the inner ear component or the accompanying nerve component and may contain a nerve, that is, when the auditory or auditory altar in the brain, the left channel is affected Occurs when 'or feelings'. Hearing loss is perceived as hereditary • or may be caused by auditory trauma (i.e., very loud noise), viral infection, drug-induced or Meniere's disease. Neurological hearing loss can be caused by brain tumors, infections, or multiple brain and nerve disorders, such as stroke. Some hereditary diseases, such as Refsum's disease (defective accumulation of branched fatty acids) can also cause neurological disorders that affect hearing loss. The auditory nerve is destroyed by the demented Zhaole disease, such as spontaneous inflammation and demyelinating diseases (including multiple 140447.doc *28- 200950787 hardening), transverse benign myelitis, Devic's disease, progressive progressive multiple leukoencephalopathy' Guniain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and anti-MAG peripheral neuropathy. The incidence of transient deafness, or sensorineural hearing loss occurs in about 1 in every 5 people and is caused by a viral or bacterial infection, such as mumps, measles, colds, chickenpox, cytomegalovirus, syphilis or infection. Physiological damage to mononuclear leukocytosis or inner ear g. In some cases, the cause of ^ was not recognized. Tinnitus and dizziness may be accompanied by an instant deafness, which gradually subsides. Oral corticosteroids are often prescribed to treat sensorineural hearing loss. In some cases, surgery is required. The formulations and methods described herein include treatment of sensorineural hearing loss, including treatment of transient sensorineural hearing loss, including spontaneous transient sensorineural hearing loss. For SSHL, current treatment options include high-dose oral steroids with methyl dehydrocorticosterol (4-10 mg/ml) or methyl-dehydrocortisol (4〇_62 5 mg/ml) for 2 weeks ( 4_7 days of treatment +7_[〇天减©量). As noted herein, high doses of oral steroids are accompanied by undesired (five) cents and adverse conditions. Thus, it is contemplated that the formulations and methods described herein for sustained release of the steroids, local delivery to the inner ear, result in significantly fewer side effects than oral/system steroid use. In one embodiment, the ISSHL is characterized by a unilateral sensorineural hearing loss during a seizure of less than 72 hours, wherein HL is defined as being at least 3 close to the test frequency > A standard care for spontaneous transient sensorineural hearing loss (ISSHL) is treatment with high dose oral steroids. In a specific example, one body is treated with a dose of oral steroid for about two weeks. In a particular example, one body is treated with oral steroids at a dose of 140447.doc • 29-200950787 for about two weeks, followed by a gradual reduction in oral steroids from about 7 to about 1 day. In a particular example, the oral steroid is methyl dehydrocorticosterol (4-10 mg/ml). In a particular example, the oral steroid is methyl-dehydrocorticin (40-62.5 111§/1111). In one set of embodiments, in a set of embodiments, a patient who is treated with standard care as described above for the treatment of ISSHL is replaced with an auris-acceptable formulation and method for controlling the release of corticosteroids as described herein. In one set of embodiments, a patient who is treated with IS S HL using the standard care described in A, but which is resistant or non-responsive to this treatment, is an auris-acceptable formulation that controls the release of corticosteroids as described herein. And method alternatives. Hearing loss due to excessive 喿 听力 Hearing loss may be caused by prolonged exposure to loud noise, such as loud sounds, heavy instruments or implements, aircraft 'snapping sounds or other human noise. This hearing loss occurs as a result of destruction of the inner ear hair cell receptor. This type of hearing loss is often accompanied by tinnitus. Permanent damage to hearing loss is usually cherished. Although currently unable to treat noise-induced hearing loss, several treatments have been experimentally developed, including treatment with insulin-growth factor therapy. (Lee et al., Otol. Neurotol. (2007) 28: 976-981). Deafness or aging in the elderly - hearing loss is part of normal aging, and because of the Coriolis spiral in the inner ear (the Corti organ receptor cells degenerate). Other causes may also constitute a reduction in several nerve fibers in the vestibular deafness and loss of elasticity in the midbrain of the cochlea. There is currently no treatment for permanent hearing loss due to deafness or excessive noise in the elderly. 140447.doc •30· 200950787 Drug-induced damage to the inner ear caused by the administration of the drug, including specific antibiotics, diuretics (such as escicolic acid (ethacrynie mail (4) and Fushimai (10) mide)), aspirin Like aspirin (such as salicylate) and quinine. Degeneration of the inner ear B can be accelerated by impaired renal function, which results in reduced clearance of the drug and its metabolites. Medicine can affect hearing and balance, but not * can affect hearing to a larger extent. 0 For example, neomycin, kenmycin, and amikacin have a greater utility in hearing ratio balance. The antibiotics ziosporin, mycotoxin and taiwansu affect both hearing and balance. Streptomycin, another commonly administered antibiotic, causes hearing loss in addition to dizziness and may cause Dandy's syndrome to be difficult to set in the dark and to trigger a sense of environmental movement at each step. Aspirin, when taken at high doses, may cause temporary hearing loss and tinnitus, which is a symptom of the sound when there is no external sound. Similarly, quetiapine, esciclamic acid, and foximab can cause temporary or permanent hearing loss. φ Autoimmune inner ear disease Autoimmune inner ear disease (AIED) is one of the few reversible causes of sensorineural hearing loss. It is two disorders that are less common in both adults and children, and it is usually a bilateral disorder of the inner ear and vestibular function. The AIED source may attack the inner ear structure with autoantibodies and/or immune cells, but with other autoimmune symptoms. In many cases, AIEDS is born without systemic autoimmune symptoms, but up to one-third of patients also suffer from systemic autoimmune diseases such as inflammation, intestinal disease, rheumatoid arthritis, ankylosing spondylitis, systemic erythema Lupus (SLE), Hugh's syndrome, Kegang's disease, ulceration 140447.doc -31 - 200950787 Colitis, Wegener's granulomatosis and scleroderma. Bessel's disease, multiple system diseases are also often heard, and there are also vestibular problems. There is some evidence that food-related allergies are the cause of autoimmune in the cochlea and vestibule, but there is currently no recognition of its importance in disease etiology. A classification of AIED has been developed (Harris and Keithley, (2002) Autoimmune inner ear disease, in Otorhinolaryngology Head and Neck Surgery. 91, 18-32). Treatment with corticosteroids relieves symptoms of AIED. Oral administration of the corticosteroid Prysson (60 mg/day for 4 weeks) showed an improvement in pure tone and speech hearing results. The regulation of corticosteroids occurs via corticosteroid receptors or salt receptors. Inflammatory disorders Inflammatory disorders of the ear include, but are not limited to, otitis media, otitis externa, mastoiditis, bullous tympanitis, Eustachian tubal catarrh, Eustachian salpingitis, vaginitis or the like. Examples include symptoms that affect otitis media (OM) in adults and children, including acute otitis media (AOM), otitis media with otitis (OME), and chronic otitis media. OM sensibility is multifactorial and complex, including the environment, microbes and host factors. An increase in cytokine production, including interleukin and TNF, has been observed in effluent mediators suffering from OM individuals. Treatment with anti-inflammatory steroids Sustained-release symptoms of inflammatory disorders in the ear (eg, otitis media, Eustachian tubal catarrh or similar). In some instances, the inflammatory disorder is a bacterial infection (e.g., OM). In some instances, a combination of an antibiotic and an anti-inflammatory corticosteroid can alleviate OM symptoms. 140447.doc -32- 200950787 Pharmacy The present invention provides corticosteroid compositions or formulations that improve or alleviate otic disorders including Meniere's disease, sensorineural hearing loss and/or inflammatory disorders and concomitant symptoms, including but Not limited to hearing loss, eye damage, * glare, tinnitus, inflammation, swelling, infection, and congestion. Ear disorders including fine or plum • Er's disease and/or inflammatory disorders are reported in response to this article. <The etiology and symptoms of a drug or other agent. Modifications that are not described herein but that are useful for φ 彳 失 或 或 或 或 或 或 或 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显 显Furthermore, 'agents which have previously been shown to be toxic, harmful or ineffective during the general or topical application of other organ systems, such as toxic metabolites formed by liver action, drugs which are toxic to specific organs, tissues or systems, Agents that require high amounts to achieve utility, are not liberated via the system pathway, or are released via ρK poor properties can also be used in certain embodiments herein. For example, side effects of methyl dehydrocorticolysis include: retention, excessive water retention, bloody heart failure in patients with susceptibility to infection, hypertension, muscle weakness, muscle atrophy, osteoporosis, sputum rupture, gastric ulcer, ulcerative Esophagitis, skin • Thinning, skin reaction, weakened wound healing, convulsions, dizziness, headache, psychological disorders, Cushing, s synd_e, delayed growth of children, diabetes, hirsutism, cataracts, f Light eyes, weight gain, increased appetite and nausea. Pharmaceutical agents with limited or no systemic release, systemic toxicity: poor ρκ properties or combinations thereof are expected to be included in the examples of the present invention. The corticosteroid formulation of the invention (iv) may optionally be in the form of an ear structure that is in need of treatment 140447.doc -33.200950787; for example, a contemplated embodiment is the direct application of the corticosteroid formulation disclosed herein to the inner ear window membrane. Or the crown of the cochlear fossa allows direct access to the inner or inner ear components and treatment. In other implementations, the corticosteroid formulations disclosed herein are applied directly to a round window. In other embodiments, direct access can be achieved by, for example, direct microinjection into the inner ear to achieve microinfusion, for example, via deafness. This embodiment can also optionally include a drug delivery device wherein the drug delivery device delivers a corticosteroid formulation via a needle and syringe, pump, microinjection device, an in situ formed sponge material, or the like. In still other embodiments, the administration of the corticosteroid formulation is directed to the middle ear via perforation of the inner eardrum and the corticosteroid formulation is applied directly to the affected middle ear structure, including the tympanic wall or ossicular bone, to the middle ear. Thus, the corticosteroid formulations disclosed herein can be limited to the target middle ear structure and are not lost by diffusion or osmosis of the tympanic membrane, for example, via the eustachian tube or perforation. Corticosteroids/Anti-inflammatory Steroids Corticosteroids are characterized by the effects of mineralocorticoids and glucocorticoids, depending on the pharmacology of the agent. The characteristic of mineralocorticoid is its similarity to aldosterone and its effect on the amount of electrolyte and water balance. Glucocorticoids, such as the endogenous glucocorticoid cortisol, which control metabolism and have anti-inflammatory properties by preventing the release of cytokines. Many agents have the degree of mineralocorticoid and glucocorticoid activity. The relative potency and activity of several synthetic glucocorticoids are shown in the table below. 140447.doc • 34- 200950787 steroid cortisol Prysone dehydrocortisol methyl dehydrocorticosterol beta cortisol prednylidene aldosterone cortisol efficacy 1 4 1.7 21 45 0.35 182 0.07 Mineralocorticoid efficacy 0.054 0,002 0.013 0.0094 0.0038 0.0002 0.0011 1.0

Systemic glucocorticoid therapy is currently used for the treatment of autoimmune hearing loss. The basic treatment line lasts for several months and has a substantial "(four) treatment side effects. For the f-based dehydrogenated cortex _ the secondary sputum m left n water retention, susceptible to septic heart failure, high blood pressure, muscle weakness, muscle Atrophy, osteoporosis, sputum rupture, gastric ulceration, ulcerative esophagitis, skin thinning, skin reaction, weakened wound healing, sputum: military glare, headache 'psychological disorder, Cushing's syndrome (Cushing, s (four) bribe Ten children with delayed growth, diabetes, hirsutism, cataract, glaucoma, weight

Increase, increase appetite and nausea. An advantage of using the formulations described herein greatly reduces systemic exposure to anti-inflammatory glucocorticoid steroids. Dehydrocortisol is a corticosteroid with a predominantly glucocorticoid and low mineralocorticoid activity. It has about 4-5 times the potency of endogenous cortisol. It is an active metabolite of oral administration of Prysone. Methyl dehydrocorticolysis is a corticosteroid with glucocorticoid activity. It has about 25-30 times the potency of endogenous cortisol. Sodium methyl dehydrocorticosterone phosphate is a water-soluble phosphate prodrug of monodecyl chlorocorticosterol. An analytical method for the determination of methyl dechlorinated cortisol phosphate in the peripheral lymphatic fluid of deafness has been disclosed (Liu et 140447.doc-35-200950787 al, J. of Chromatography B (2004), 805(2): 255 -60). Tetracortisol is a synthetic glucocorticoid that can be administered orally, by injection, by inhalation, in the form of a topical cream or ointment. Teancortidol is a more potent isoform. Teancortisol hexagram is a pivolyl ester of hexavolone. Beco Cortisol dipropionate is a very potent glucocorticoid, also known as beclomethasone (becl〇metas〇ne). Shell Cortisol S is a very potent corticosteroid for topical formulation. It has anti-inflammatory, antipruritic, tube contraction and immunomodulatory properties. In one embodiment, the active pharmaceutical ingredient of the formulation described herein is dehydrocortisol. In another embodiment, in another embodiment, the active pharmaceutical ingredient of the formulation described herein is a mercapto dehydrocorticosterol. In another embodiment, the active pharmaceutical ingredient of the formulation described herein is methyl dehydrocorticosteroid phosphate. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is becocortisol. In yet another embodiment, the active pharmaceutical ingredient of the formulation described herein is festibrol. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is steanocortisol. In yet another embodiment, the active pharmaceutical ingredient of the formulation described herein is triamcinol acetal. In yet another embodiment, the active pharmaceutical ingredient of the formulation described herein is gas shell cortisol. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is a phosphate prodrug of a glucocorticoid steroid. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is an ester prodrug of a glucocorticoid steroid. In yet another embodiment, the active pharmaceutical ingredient of the formulation described herein is selected from the group consisting of 21-B-oxygenated sterol, gas cortisol, Azeus _ (aigest〇ne), 140447.doc-36 - 200950787 Φ

Ascinoide (amcinonide, beco Cortisol, betcor Cortisol, buta Cortisol, clprepresin, spirulina cortisol, colobetasone, clocortolone, ketol ( Cloprednol), corticosterone, cortex _, cortivazol, declazacort, desonide, desoximetasone, sulfhydryl dehydrocorticosterol, difluoro Larson ester, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, fluoride Flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, flumethazone , fluperolone acetate, fluprednidene acetate, fluorodehydrocortisol, flurandonolide, fluticaginol propionate, fluococcal (formocortal) ), Haixinnuo (halcinonide), halogen Halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, lotatrol (loteprednol etabonate), mazipredone, meridone, mepredone, methyl dehydrocortisol, mometasone furoate, paramethasone, Puning Prednicarbate, dehydrocortisol, dehydrocortisol 25-diethylamino-acetate, dehydrocortisol sodium phosphate, predisin, prednival, prednylidene , rimexolone, tixocortol, triamian cortisol, acetaminophen cortisol, ban 140447.doc •37· 200950787 natalan cortisol (teanol corte benetonide), A combination of hexaacetone triamcinol and its phosphate prodrug or ester prodrug.

Clobetasol propionate In certain embodiments, the formulations described herein have an active ingredient in the formulation of between about °.〇 1°/. - between about 20%, between about 0.01% and about 10%, between about 0.01% and about 8%, between about 0.05-6°/. The concentration of active pharmaceutical ingredient is between about 0.1 and 5%, between about 0.2 and about 3%, or between about 0.1 and about 2%. In certain embodiments, the formulations described herein have a volume of the formulation of between about 70 mg/mL, between about 1 mg to about 70 mg/mL, and between about 1 mg- Between 50 mg/mL, between about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL and about 10 mg/mL, between 140447.doc -38-200950787 scoop 1 post (d) to a concentration of active pharmaceutical ingredient of between about 5 mg/mL, or between about 0.5 mg/mL and about 5 mg/mL. In certain embodiments, the formulations disclosed herein further comprise an antibiotic and can be used to treat the ear disease or condition described herein. Antibiotics include but are not limited to amikacin, mycotoxin, oxytetracycline, neomycin, refuge f, streptomycin, tambamycin, paromomycin, gelatin , in addition to Philippine, Lolacabe, ertapenem, doripenem, imipenem, imipenem, meropenem, cefotaxime, cephalosporin, cefalotin, cephalosporin Ammonia, cefotaxime, cefmenudene, cefoxitin, defprozil, cefotaxime, xifuxinmin, cefdinir, cefoperon, cefoperazone, ceftizoxime, cefpodoxime , ceftazidime, ceftibuten, ceftizoxime, ceftriaxone sodium, cefepime, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, red fluorescein, ro Erythromycin, citrillin, telithromycin, spectinomycin, nitrene, amine benzylpenicillin, ampicillin, azlocillin, carbencillin, # leucine, dithiacillin, Fluorothiacillin, mezlocillin, meticillin, ethoxypenicillin, acesulfame, penicillin , must be cillin, ticarcillan, cumin, clopidogrel, polymyxin B, cepsporin, enofloxacin, gatifloxacin, lofofloxacin , lomefloxacin, moxifloxacin, norfloxacin, oufuxixin, tlovfloxacin, mimetamine, prontosil, sulfacetamide, sulfamethoxazole , sulfanimilimde, sulfsalazine, sulfsioxazole, trimethoprim, dimecycline 140447.doc -39· 200950787 (demeclocycline), deoxygenation By tetracycline, menocycline, tetracycline, oxtetracycline, oxhenfanamine, chlorfenapyr, lincomycin, lincomycin, ethylenediamine dibutanol, Fosfomycin, fusidic acid, fulton, bismuth nicotinate, renazol, nitropyrimidine, ferromycin, nitrofurantoin, plateau, pyrazin Amine, quinupristin/dalofopine, oxymycin, AL-15469A (Alcon Research), AL-38905 (Alcon Research), etc. . General Method of Sterilization The present invention provides an ear composition to improve or alleviate the otic disorders described herein. The invention further provides a method of administering the otic composition. In some embodiments, the composition is sterilized. The apparatus and method for sterilizing a pharmaceutical composition disclosed in the embodiments disclosed herein are for use in humans. The aim is to provide a safe pharmaceutical product with relatively no infection-causing microorganisms. The US Food and Drug Administration provides a published specification manual "Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing", which can be found at: http//www.fda.gov/cder/guidance/5882fnl.htm, which is fully incorporated into the case. As a reference. Sterilization as used herein means a method of destroying or removing microorganisms present in a product or package. Any sterilizable method of the appropriate article and composition can be used. Methods of inactivating microorganisms that may be utilized include, but are not limited to, applications of superheat, lethal chemicals, or gamma radiation. In certain embodiments, a method of preparing an ear treatment formulation comprises subjecting the formulation to a sterilization process selected from the group consisting of heat sterilization, chemical sterilization, radiation sterilization, or filtration sterilization. The method used is primarily dependent on the nature of the device or composition being sterilized 140447.doc •40- 200950787. A detailed description of many of the methods of sterilization can be found in Remington: The Science and Practice of Pharmacy published by Lippincott, Chapter 40, Williams & Wilkins, incorporated herein by reference. Sterilization by heating Many methods are available for sterilization by extreme heat applications. One method is to use a saturated steam high pressure dad. In this method, at least 121 liters of saturated typhoon is allowed to come into contact with the sterilized article. In the case where the article is sterilized, the heat is directly transferred to the microorganism or indirectly to the microorganism by heating the volume of the sterilized aqueous solution. This method is widely used because it allows for flexibility, safety, and economic considerations in the sterilization process. Dry heat sterilization is used to increase the temperature to kill microorganisms and perform depyrogenation. The process comprises performing a HEPA-filtered non-microbial air for at least 13 (M8 (TC temperature for sterilization and up to at least 23 〇 25 (TC temperature for depyrogenation). Reconstituted concentrated or powdered formula water is also autoclaved. In certain embodiments, the formulations described herein comprise micronized agents (eg, corticosteroids (eg, micro-mercapto dehydrocorticosterol) The agent is sterilized by dry heat, such as at an internal powder temperature of 13 (M4 (TC heating about 7 _ Xiao Xiao, or heating at an internal temperature of H 180 C for about 1-2 hours. Chemical sterilization)

Vapor such as ethylene oxide, chlorine dioxide, 140447.doc w human (4) extreme use of bactericidal properties of chlorine, formaldehyde or ozone as anti-41-200950787 scraping agent. The bactericidal activity of ethylene bromide, for example, can be used as a reactive alkylating agent. Therefore, the sterilization requires an ethylene bromide vapor to directly contact the product to be extinguished. Radiation Sterilization - The advantage of radiation sterilization is the ability to sterilize many forms of products without thermal degradation or other damage. The general radiation used is P radiation or alternatively gamma radiation from a 6 〇 C source. The penetrating power of gamma radiation allows for sterilization of many product types, including solutions, compositions, and heterogeneous mixtures. The bactericidal effect of radiation comes from the interaction of gamma radiation with biological macromolecules. This parent interaction produces charged species and free radicals. Subsequent chemical reactions, such as recombination and cross-linking, result in the loss of normal function of these biomacromolecules. Formulations described herein may also be selected for sterilization with xenon radiation. Filtration Transition sterilization is a method for removing from a solution without destroying the microorganism. A membrane filter was used to filter the heat sensitive solution. The screen is a mixed fiber ester (MCE) having a pore size ranging from 〇.丨 to 〇22 μπι, polyvinylidene fluoride (P VF; also known as p VDF), or polytetrafluoroethylene (PTFE). Thin, strong, homogeneous polymer. Different filters can be used to selectively filter different characteristic solutions. For example, PVF and PTFE membranes are known to be suitable for filtering organic solvents' while aqueous solutions are filtered with PVF or MCE membranes. The range of webs available for use on a wide range of sizes can be achieved by a single point disposable filter on a syringe to a commercial scale for use in manufacturing plants. This membrane filter can be sterilized by high pressure dad or chemical sterilization. The effectiveness of membrane filtration systems is based on the following standard platforms (Microbiological Evaluation of Filters for U〇447d〇C -42- 200950787)

Sterilizing Liquids > Vol 4 > No. 3. Washington » D.C. · Health

Industry Manufacturers Association, 1981) and involves the challenge of membrane filters with unusual amounts of microbes in a known amount (about 107/cm2), such as with Brevendomonas diminuta (ATCC 19146) 0 pharmaceutical composition, optionally by membrane mesh Sterilize. Formulations containing nanoparticles (U.S. Patent No. 6,139,870) or multi-layered pores (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2)··144-50) are suitable for use by Ο·22 μπι The filter is filtered without damaging the sterilization of its tissue structure. In certain embodiments, the methods disclosed herein comprise sterilizing the formulation (or a component thereof) by filtration sterilization. In another embodiment, the ear-acceptable ear therapeutic formulation comprises a particle, wherein the particle formulation is suitable for filtration sterilization. In yet another embodiment, the particle formulation comprises particles having a particle size of less than 300 nm, particles less than 200 nm in size, and particles less than 100 nm. In another embodiment, the ear-acceptable ear treatment formulation comprises a particle wherein the sterility of the particle is ensured by sterile filtration of the component solution of the precursor material. In another embodiment, the ear-acceptable formulation comprises a particle formulation wherein the sterility of the particles is ensured by cryogenic sterilization. In yet another embodiment, the cryogenic sterilization filter is between 〇 and 3 (between TC temperatures or between 〇 and 2〇°C) or between 0 and i〇°c, or between 10 and Between 20 ° C, or between 20 and 30 ° C. In another embodiment is a method of preparing an ear-acceptable particle formulation comprising: filtering an aqueous solution containing a particle formulation at a low temperature via a sterile filter; Drying the sterilization solution; and reconstituting the particle formulation with sterile water prior to administration 140447.doc -43. 200950787 In another embodiment. In certain embodiments, one of the formulations described herein is a single vial containing micronization. A suspension of active pharmaceutical ingredients in a formulation. A single vial formulation is aseptically mixed with a sterile poloxamer solution and a sterile micronized active ingredient (eg, methyl dehydrocorticosterol) and delivered to the sterility Prepared in a pharmaceutical container. In certain embodiments, a single vial containing a formulation described herein is resuspended prior to dispensing and/or administration. In a particular embodiment, the filtration and/or filling steps are below this disclosure. Gel temperature of the formulation T gel) about 5. (under: the gel formulation has a viscosity of less than the theoretical value of 100 cP to allow for a reasonable time transition using a peristaltic pump. In still other embodiments, the ear - acceptable The otic therapeutic formulation comprises a nanoparticle formulation wherein the nanoparticle formulation is suitable for filter sterilization. In yet another embodiment, the nanoparticle formulation comprises a nanoparticle size of less than 300 nm 'the size is less than 200. Nm, or less than 1 〇〇 nm in size. In still other embodiments, the 'ear-acceptable formulation comprises a microsphere formulation wherein the sterility of the microspheres can be sterilized by filtration of an organic solution of the precursor material and an aqueous solution. In still other embodiments, the ear-acceptable formulation comprises a thermoreversible gel formulation wherein the sterility of the gel formulation is ensured by cryogenic sterilization filtration. In yet another embodiment, the cryostat filtration is Between 〇 and 30. (: between temperatures 'either between 〇 and 2〇〇c, or between 〇 and 10 C' or between 1〇 and 2〇. (3, or between 2〇 With 30. (: between. In other embodiments, one A preparation method for a thermoreversible gel formulation comprising: filtering an aqueous solution containing a thermoreversible gel component H0447.doc-44 - 200950787 via a sterile filter at a low temperature; lyophilizing the reversible gel formulation. Reconstitution of heat in the specific example, buffer solution) and separate, p parts are dissolved in a suitable carrier (eg, by a heat treatment, filtration, gamma irradiation) prior to administration. - separate liquid gel components) sterilized in a combined step (eg, the cooling mixture of the excipients are supplied, H or radiation). The two solutions are then separately sterilized to provide a final ear formulation. The traditionally used methods of 'bacteriolysis (eg, heat-up (eg, high) gamma radiation, filtration) in some examples result in polymer components in this formulation (eg, heat-curing, gelling, or mucoadhesive polymers) Irreversible degradation of the component and/or activator. In some instances, sterilization of the ear formulation by membrane filtration (e.g., 0.2 _ membrane) is not possible if the formulation contains a rocky visbreaking polymer that is kneeized during the passage. Accordingly, the present invention provides a method for sterilizing an ear formulation that prevents polymer, 'and injury (eg, heat curing and/or gelation and/or mucoadhesive polymer component) and/or activator at Degradation during sterilization. In certain embodiments, degradation of an activating agent (eg, any of the therapeutic ear agents described herein) can be utilized by the use of a particular range of buffer components in the formulation and a specific ratio of gelling agent in the formulation. Reduce or remove. In certain embodiments, the selection of a suitable gelling agent and/or thermoset polymer may allow for the sterilization of the formulations described herein by filtration. In certain embodiments, the use of a suitable thermoset polymer and a suitable copolymer (e.g., a gelling agent) in combination with a particular range of the formulation allows for high temperature sterilization of the formulations described herein and is substantially free of 140447.doc • 45· 200950787 Degradation of therapeutic agents or polymeric excipients. In a particular example, the present invention provides a method of sterilizing such that the formulation is subjected to final sterilization by high pressure dad without any loss of activator and/or excipients and/or polymer components during the depressing step. Substantially free of microorganisms and/or pyrogens. Microorganisms The present invention provides an oat-acceptable composition for ameliorating or ameliorating the otic disorders described herein. A method of administration comprising the otic composition is further provided. In certain embodiments, the composition is substantially free of microorganisms. The acceptable amount of sterility is a standard of administration based on a defined therapeutically acceptable ear composition, which includes, but is not limited to, the United States Pharmacopoeia Chapter 1 11 i. For example, the acceptable amount of sterility includes 10 colony forming units (cfu) per gram of formulation, 5 〇 cfu per gram of formulation, 100 c cf' per gram of formulation, 500 cfu per gram of formulation or 1 〇〇〇 cfu per gram of formulation. In addition, the amount of sterility acceptable includes the exclusion of specific adverse microbial agents. Exemplary disappointing microbial agents include, but are not limited to, Escherichia coli 'E_ coli, Salmonella sp., pseudodom〇nas aeruginosa (P. aeruginosa), and/or other specific microbial agents. The sterility of the ear-acceptable otic therapeutic formulation can be determined by the procedures of the U.S. Pharmacopoeia <61>, <62> and <71>. One of the requirements for aseptic quality control assurance, quality assurance and effective methods is the method of sterility testing. The exemplification example of the sterility test is carried out in two ways. The first is direct incubation, in which a sample of the composition to be tested is added to the medium and incubated for a period of 2 i days. The turbidity of the growth medium showed contamination. Disadvantages of this method include the small sample size reduction sensitivity of a large number of materials and the detection of microbial growth based on visual inspection. An alternative method is the membrane filtration sterility test. In the 140447.doc • 46· 200950787 method, a volume of the product passes through a small membrane mesh paper. This screen paper is then placed in the medium to promote the growth of microorganisms. This method has the advantage of greater sensitivity when sampling all quality products. A commercially available Millipore Steritest Aseptic Test System can be optionally used for the determination of the membrane sterility test. For filtration testing of creams or ointments, use the Steritest Filtration System number TLHVSL210. For filtration testing of emulsions or viscous products, use Steritest Filtration System No. TLAREM210 or TDAREM210. For filtration testing of prefilled syringes, use Steritest Filtration System No. TTHASY210. For transition tests suspended in aerosol or foam materials, use Steritest; filtration system number TTHVA210. For filtration testing of soluble powder in ampoules or vials, use the Steritest Filtration System number TTHADA210 or TTHADV210. Tests for E. coli and Salmonella include incubation with lactose broth at 30-35 ° C for 24-72 hours, including incubation in MacConkey and/or EMB wean for 18-24 hours, and / or use Rappap0rt medium. Testing for Ρ· aeruginosa includes the use of NAC agar. Chapter 62 of the US Pharmacopoeia (USP) further cites the testing procedures for specific unpleasant micro-organisms. In a particular embodiment, any of the controlled release formulations described herein have less than about 60 colony forming units (Cfu) per gram of formulation, less than about 50 colony forming units, less than about 40 colony forming units, or less than about 3 A microbial agent that forms a unit of colony colonies. In a particular embodiment, the formulated ear formulation described herein is isotonic with the endolymph and/or peripheral lymph nodes. Endotoxin 140447.doc • 47· 200950787 The present invention provides an ear composition to improve or alleviate the otic disorders described herein. A method of administering the composition of the ear is further provided. In certain embodiments the composition is substantially endotoxin free. An additional aspect of a sterilization process is the removal of by-products (hereinafter referred to as "products") derived from killing microorganisms. The method of depyrogenation removes pyrogen from the sample. The pyrogen is an endotoxin or exotoxin that will elicit an immune response. An example of an endotoxin is a lipopolysaccharide (LPS) molecule found on the cell wall of a Gram-negative bacterium. When a sterilization process such as autoclaving or treatment with ethylene oxide to kill bacteria, the LPS residue induces a pre-inflammatory response, such as septic shock. Because the molecular size of endotoxin is very broad, the presence of endotoxin is expressed as "endotoxin unit" (EU). β - EU is equivalent to 100 picograms of E. coll LPS. Humans can generate a response that is less than 5 EU/kg of body weight. This sterility is expressed in any unit that is known in the art. In a particular embodiment, the otic compositions described herein contain a lower amount of endotoxin (e.g., <4 EU/kg body weight) when compared to conventional acceptable levels of endotoxin (e.g., 5 EU/kg body weight). In certain embodiments, in certain embodiments, the auris-acceptable otic therapeutic formulation has less than about 5 EU/kg body weight of the individual. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg body weight of the individual. In additional embodiments, the ear-accommodating and otic therapeutic formulation has less than about 3 EU/kg body weight of the individual. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 2 EU/kg body weight of the individual. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg of the formulation. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 Eu/kg of the formulation. In an additional embodiment 140447.doc 200950787 the ear can be attached to the ear. The P treatment formulation has less than about 3 of the formula. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg at the time of delivery. In other embodiments, the ear-acceptable ear treatment formulation has less than about 1 EU/kg of product. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about G.2 EU/kg of the product. f In certain embodiments, the ear-acceptable otic therapeutic formulation has less than ^ 兀 or about 5 EU/kg of the product. In other embodiments, the ear-acceptable 0 sputum therapeutic formulation has less than about 4 EU/kg of the unit or product. In still other embodiments, the ear-acceptable otic therapeutic formulation has less than a unit or yields about 3 EU/kg. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 Eu/kg of the unit or product. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg of the unit or product. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 3 EU/kg of the unit or product. In a particular embodiment, the disclosed ear compositions contain from about 1 to about 5 EU/mL of the formulation. In a particular embodiment, the disclosed ear compositions comprise from about 2 to about 5 EU/mL of the formulation, from about 3 to about 5 EU/mL of the formulation, or from about 4 to about 5 EU of the formulation. mL. In a particular embodiment, the ear composition 18 described herein contains a lower endotoxin amount than a conventional acceptable amount of endotoxin (e.g., 0.5 EU/mL of the formulation) (e.g. < EU/mL). In certain embodiments, the ear-accessible ear therapeutic formulation has less than about 0.5 EU/mL of the formulation. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 0.4 EU/mL of the formulation. In additional embodiments, the ear-acceptable ear 140447.doc -49- 200950787 therapeutic formulation has less than about 0.2 EU/mL of the formulation. As an example, pyrogen detection is performed by several methods. Suitable tests for sterility include those described in the United States Pharmacopoeia (USP) Chapter 71 Asperity Test (23rd Edition, 1995). The rabbit pyrogen test and the Limulus amebocyte lysate test are described in the USP 23/151 (USP23/NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, MD, 1995). . Alternative pyrogen detection has been based on single cell activation - cytokine detection. A suitable homogeneous cell line for quality control applications has been developed and demonstrated its ability to detect exothermicity in a sample that has passed the rabbit pyrogen test and the American cockroach test method (Taktak et al. J_Pharm. Pharmacol) (1990), 43:578-82). In yet another embodiment, the ear-acceptable ear treatment formulation is an independent depyrogen. In yet another embodiment, a method of making an ear-acceptable ear treatment formulation comprises testing the fecality of the formulation. In a particular embodiment, the formulations described herein are substantially pyrogen free. pH and Volume Osmotic Concentration As used herein, "actual volume osmolality" means the volumetric osmolality of a formulation by including the active agent with all excipients but excluding gelling and/or thickening agents (eg, polyoxyethylene- Measured by polyoxypropylene copolymer, carboxymercaptocellulose or the like. The actual volumetric permeation concentration of the formulations described herein can be measured by any convenient method, such as a freezing point depressing method, as described in Viegas et al., Int. J. Pharm, 1998, 160, 157-162. The actual osmotic pressure of the ear formulations described 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 140447.doc -50 to 200950787 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 certain embodiments, the formulations described herein have an actual volumetric osmolality of from about 100 mOsm/L to about 1000 mOsm/L, from about 200 mOsm/L to about 800 mOsm/L, from about 250 mOsm/L to about 500. mOsm/L, from about 250 mOsm/L to about 350 mOsm/L, or from about 280 mOsm/L to about 320 mOsm/L. In certain embodiments, the volumetric osmolality (eg, peripheral lymph) at the site of action is about the same as the deliverable volume osmotic concentration of any of the formulations described herein (ie, the material passes through or penetrates the round window membrane) Volume osmotic concentration). In certain embodiments, the formulations described herein have a deliverable volume osmotic concentration of from about 150 mOsm/L to about 500 mOsm/L, from about 250 mOsm/L to about 500 mOsm/L, from 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 main cation present in the endolymph is potassium. In addition, the endolymph has a high concentration of a positive valency amino acid. The main cation present in the peripheral lymph is sodium. In a particular example, the ionic composition of the endolymph and peripheral lymph nodes regulates the electrochemical pulse of the hair cells. In a particular example, any change in the ionic balance of endolymph or peripheral lymphocytes results in hearing loss due to conduction changes in chemical pulses along the hair cells of the ear. In certain embodiments, the compositions disclosed herein do not interfere with the ionic balance of the peripheral lymph. In certain embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the peripheral lymph. In certain embodiments, the compositions disclosed herein do not interfere with the ionic balance of the endolymph. In certain embodiments, the 140447.doc 200950787 compositions disclosed herein have the same or substantially the same ionic balance as the endolymph. In some embodiments, the otic formulations described herein are formulated to provide an ionic balance that is compatible with the inner ear fluid (i.e., the endolymph and/or peripheral lymph). The endolymph and peripheral lymph nodes have a physiological pH close to that of the stop solution. The inner lymph has a pH range of about 7.2-7.9; the peripheral lymph has a range of about 72-74. The in situ pH of the adjacent endolymph is about 74 and is about 7.9 away from the endolymph. In certain embodiments, the pH adjustment of the compositions described herein (eg,

Use -buffer) to an endolymph-compatible range of about 55 to 9 angstroms. Q

In a particular embodiment, the cation of the compositions described herein is adjusted to a pH range of about 5.5 to U. In certain embodiments, the cation of the compositions described herein is adjusted to a pH range of about 6.0 to 7.6. In some embodiments, useful formulations also include - or - a cation or buffer. Suitable cations (iv) or buffers include, but are not limited to, lysine acetate, ammonium sulphate, citrate, sulphate, pharmaceutically acceptable salts thereof, combinations or mixtures thereof, in certain embodiments. In an embodiment, when one or more buffers are used in the formulations disclosed herein, they are combined with, for example, a pharmaceutically acceptable carrier and are present in the final I, for example, about 1%. To about 鸠, about G5% to about 1G%. In a particular embodiment of the present disclosure, the #^ included in the gel formulation is such that the pH of the gel formulation does not interfere with the body's natural buffer system. In the examples, the diluent is used to stabilize the compound because the diluent can provide a more stable environment. In this technique, a diluent (/, ', long: for pH control or maintenance) dissolved in a buffer solution is used, which includes but is not limited to 140447.doc • 52·200950787 Phosphate buffered physiological saline solution. In certain embodiments, any of the gel formulations described herein have a pH that facilitates sterilization of the gel formulation (eg, by filtration or aseptic mixing or heat treatment and/or autoclave (eg, terminal sterilization)). No drug (eg, steroid) or degradation with a gel polymer. In order to reduce the hydrolysis and/or degradation of the otic agent and/or gel polymer during sterilization, the pH of the formulation is maintained during the sterilization of the design buffer* between 7 and 8 (eg, high temperature autoclave action) ). ~ In a particular embodiment, any of the gel formulations described herein have an agent that allows for the final sterilization of the gel formulation (eg, by heat treatment and/or autoclave) without degrading the gel-containing agent (eg, , corticosteroids) or polymers. For example, to reduce hydrolysis and/or degradation of the otic agent and/or gel polymer during sterilization, the pH of the buffer is designed to maintain the pH of the formulation between 7-8 when warming. Use any suitable buffer for the ear used in this formulation. In some cases, because the pKa of the TRIS decreases as the temperature increases by approximately _〇〇3/艽❹, the increase in the enthalpy of the 当 when the temperature increases by approximately 〇〇〇3/〇c, at 250°F (12rC) The autoclave causes a significant pH shift (ie, more acidification) in the TRIS buffer, so a relatively small pH shift in the pBS buffer, thus increasing the ear agent more in the TRJS than in the pBs Hydrolysis and/or degradation. Degradation of the otic agent is reduced by the use of a suitable buffer as described herein in combination with a polymeric additive (e.g., p4 〇 7, CMC). In certain embodiments, between about 5.0 and about 9.0, between about 5.5 and about 8.5, between about 6. and about 76, between about 7 and 7 between about 7 140447.doc 53- 200950787 and about 7.6, between about 7.2 and 7.6, between about 72 and 74 are suitable for sterilization of the formulations described herein (eg by filtration or sterile tailing) Or heat treatment and / or high temperature pressure sterilization (for example, terminal sterilization). In a particular embodiment, a formulation having a pH of about 6 〇, about 65, about 7 〇, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6 is suitable for use in the description of the present invention. Sterilization of any composition (for example by filtration or aseptic mixing or heat treatment and/or high temperature pressure sterilization (eg, terminal sterilization)). In certain embodiments, the formulation has a pH as described herein and includes a thickening agent (i.e., a viscous enhancer) which is, without limitation, a cellulosic thickener as described herein. In certain instances, the addition of a second polymer (e.g., a thickener) and the pH of the formulation of the present invention allow for the sterilization of the formulations described herein without causing earrings in the ear formulation and/or Or substantial degradation of the polymer component. In certain embodiments, the ratio of thermally reversible poloxamer to thickener in a formulation having a pH as described herein is about 40:1, about 35:1, about 30:1, about 25: 1. About 20:1, about 15:1 or about 10:1. For example, 'in a particular embodiment' the sustained and/or extended release formulation described herein comprises a ratio of about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15 : 1 or about 1 〇: 1 ratio of ploxamic 4 〇 7 (pluronic F127) and carboxymethyl cellulose (CMC) combination. In certain embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 10%, about 15%, about 20%, about 25%, about 30%, or about the total weight of the formulation. 5%. In certain embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 14%, about 15%, about 16%, about 17%, about I40447.doc - of the total weight of the formulation. 54· 200950787. % about 19%, about 20%, about 21%, about 22%, about 23%, about 24% 3, / in certain embodiments, a thickening agent in any of the formulations described herein (eg ' The amount of gel dance " is about 〇, 5%, 勺1〇/° or about 15% of the total weight of the formula. In certain embodiments, the formula f of any of the formulations described herein is thick. The amount of the agent (e.g., gel) is about 5%·5%, about 1%, about h5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4% of the total weight of the formulation. %, about 4.5%, or about 5%. 'Φ In some real cases, the pharmaceuticals described herein are stable relative to pH over any of the following periods: at least about i days, 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 5 weeks, to >, 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 i months, 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, the formulations described herein are relative to at least It is stable for 1 week. Moreover, the φ side described herein is stable relative to at least about 1 month. Tension agent. Usually, the endolymph has a higher osmotic pressure than the peripheral lymph. For example, The lymph has an osmotic pressure of about 304 mOsm/kg H2, while the peripheral lymph has an osmotic pressure of about 294 mOsm/kg HW. In certain embodiments, the ear compositions described herein are formulated to provide a volumetric osmotic concentration of about 1 〇〇 to about 1000 mOsm/kg, about 200 to about 800 m〇sm/kg, about 25 〇 to about 500 mOsm/kg osmotic pressure; about 250 to about 350 m 〇sm/kg or about 28 〇 to about 320 mOsm/kg osmotic pressure. In certain embodiments, 140447.doc -55· 200950787 described herein has an actual volumetric osmotic concentration of from about 100 m〇sm/L to about 1000 mOsm/L, about 200 mOsm/L. Up to about 800 mOsm/L, from about 250 mOsm/L to about 500 mOsm/L, from about 250 mOsm/L to about 350 mOsm/L, or from about 280 mOsm/L to about 320 mOsm/L. In certain embodiments , the volume osmotic concentration of the delivered design of any of the formulations described herein is the same as the target otic structure (eg, endolymph, peripheral lymph, or the like) In particular embodiments, the ear compositions described herein are formulated to provide a volumetric osmotic concentration for delivery at a target position of from about 250 to about 320 mOsm/L (from about 250 to about 320 mOsm/kg H20). Osmotic pressure; and preferably from about 270 to about 320 mOsm/L (osmotic pressure of from about 270 to about 320 mOsm/kg H20). In a particular embodiment, the delivery volume osmotic concentration/osmotic pressure of the formulation (ie, the volume osmotic concentration/osmotic pressure of the formulation without gelling or thickening agent (eg, thermoreversible gel polymer)) is utilized, for example, by Use an appropriate salt concentration (eg, potassium or sodium salt concentration) or use an isotonic agent to adjust for endolymph-compatible and/or peripheral lymph-compatible (ie, internal) when delivered to the target location Lymphatic and / or peripheral lymphatic isotonic). The volumetric osmolality of a formulation containing a thermoreversible gel polymer is an unreliable manner because of the amount of change in monomer units accompanying water and polymer. The actual volumetric osmolality of the formulation (i.e., the volumetric osmolality of the gel-free or thickener (e.g., thermoreversible gel polymer)) is a reliable measure and can be by any convenient method (e.g., , freezing point drop method) measurement. In certain instances, the formulations described herein provide a deliverable volume osmotic concentration that causes minimal disruption to the inner ear environment and causes minimal discomfort (eg, dizziness and/or nausea) in the mammal when administered (eg, to a target) Location (eg, peripheral lymph)). 140447.doc -56- 200950787 In certain embodiments, any of the formulations described herein are isotonic with peripheral lymphocytes and/or endolymph. Isotonic formulations are provided by the addition of an isotonic agent. Suitable isotonic agents include, but are not limited to, any pharmaceutically acceptable sugar, salt or combination or mixture thereof such as, but not limited to, glucose 'glycerol, mannitol, sorbitol, gasified sodium, and other electrolytes. An effective ear composition includes one or more salts in an amount necessary to direct the osmotic pressure of the composition to an acceptable range. The salt includes sodium, potassium or ammonium cations and vapors, citrate , ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen sulfate and ammonium sulfate . In certain embodiments, the formulations described herein have a pH and grain osmotic concentration as described herein, and have a relationship between about 丨μΜ and about 丨〇, between about 1 mM and about 10 〇 mM. , between about mM and about 1 mM, between about 0.1 mM and about 1 〇〇 nM of active pharmaceutical ingredient concentration. In certain embodiments, the formulations described herein have a pH and volume osmotic concentration as described herein, and have an active pharmaceutical ingredient concentration of from about 0. 1 to about 20% by weight of the formulation. Between about 0.1 and about 10%, between about oi and about 7.5%, between about 〇·1 _5%, between about _2_about 3%, between about 0.1-about 2% Active ingredient. In certain embodiments, the formulations described herein have a pH and volume osmotic concentration as described herein, and have an active pharmaceutical ingredient concentration of between about 7 〇 mg/mL of the formulation volume, between about Between 1 mg and about 70 mg/mL, between about i „^_about 5〇mg/mL, between about 1 mg/mL and about 20 mg/mL, between about ! mg/mL to about 1 〇140447.doc • 57- 200950787 mg/mL, between about ! mg/mL to about 5 tons/can, or between about 5 mg/mL to about 5 mg/mL activator. Use reduced size to increase surface area and/or modulate formulation dissolution properties. Also used to maintain consistent average particle size distribution (PSD) for any of the formulations described herein (eg, micron size particles, nano size particles or their knives) In some instances, any of the formulations described herein comprise multiple particles, that is, a plurality of particle sizes (eg, microparticles, nano-sized particles, non-sized particles, colloidal particles); That is, the formulation is a multi-particle formulation. In some embodiments, any of the formulations described herein comprise one or more multiples. Particle (e.g., micron) therapeutic agent. Micron is a method of reducing the average diameter of particles of a solid material. The microparticles are from about micrometers in size to a diameter of about nanometers in diameter. In some embodiments, micronization The solid particles have an average diameter of from about 0.5 μϊη to about 5 μ. In certain embodiments, the micronized solid particles have an average diameter between about i μη 1 and about 100 μηι. In certain embodiments, micron. The particles of the solid solid have an average diameter of from about 2 μΐη to about 1 μμηΒ. In some embodiments, the particles of the micronized solid have an average diameter of from about 3 μηη to about 5 。. In certain embodiments The micronized solid of a particle contains a particle size of less than about 5 microns, less than about 2 microns, and/or less than about 100 microns. In certain embodiments, particles of a corticosteroid (eg, micronized) Particles) use a corticosteroid that allows any of the formulations described herein to be extended and/or sustained release relative to a formulation containing a non-multiple particle (eg, no micronized) corticosteroid ear. In some instances, The formulation of heavy particle (eg micron) corticosteroids is suitable for lmL injection of 27G needles without any clogging or agglomeration of 140447.doc -58- 200950787. In some instances, any of the particles of any of the formulations described herein are - Coating particles (eg, a coated microparticle, nanoparticle) and/or a microsphere and/or a liposome particle. Particle size reduction techniques include, for example, grinding, milling (eg, air abrasion mills) (spray mill), ball. Grinding, colloidal agglomeration, high pressure homogenization, spray drying and/or supercritical value • liquid crystallization. In some instances 'particle size is accomplished by mechanical impact φ (e.g., by a ball breaker, ball mill, and/or tip mill). In some instances, the particle size is via liquid energy (e.g., by a spiral spray mill, a loop spray mill, and/or a fluidized bed spray mill). In certain embodiments, the formulations described herein comprise crystalline particles and/or isotropic particles. In certain embodiments, the formulations described herein comprise amorphous particles and 7 or non-isotropic particles. In certain embodiments, the formulations described herein comprise a therapeutic agent particle, wherein the therapeutic agent is a free test, or a salt or prodrug of a therapeutic agent, or any combination thereof. • In certain embodiments, the formulations described herein comprise one or more pico-f steroids wherein the corticosome comprises nanoparticle. In certain embodiments, the formulations described herein comprise a corticosteroid bead coated with a controlled release excipient (e.g., methyl dehydrocorticosteroid beads), in some embodiments, The formulations described herein comprise a corticosteroid that is granulated and/or reduced in size and coated with a controlled release agent; the particulate coated corticosteroid particles are then micronized as appropriate and/or as described herein The composition is formulated. In some instances, a corticosteroid that is a free acid or a free base is used in combination with a steroidal salt of 140447.doc • 59-200950787 - a corticosteroid to prepare a pulse release ear formulation according to the process described herein: in some In the formulation, a combination of a micronized corticosteroid (and/or a salt thereof or a peony) and a coated particle (eg, a nanoparticle, a lipid globule, a microsphere) is used to prepare a pulsed release ear using any of the processes described herein. Alternatively, a pulse release profile can be obtained by cyclodextrin, surfactant (eg, poloxamer (407, 338, 188), Tween (8〇, 6〇, 2〇, Sichuan, PEG· Suihua said that oyster oil, Solvents such as N-methyl-2-guanidine or similar agents help to deliver a 20% delivery dose of corticosteroids (10), such as micronized cortical solid SI, or its free alcohol, free acid or Salt or prodrug;: a particulate corticosteroid, or a free base thereof, a free acid or a salt or a prodrug thereof, which is prepared using any of the processes described herein to prepare a pulsed release formulation. In a particular embodiment, Any of the ear compatible formulations include one or more micronized agents (eg, steroids). In some such embodiments, a micronized agent comprises micronized particles, coated (eg, Extended release coating) micronized particles or combinations thereof, etc. In some such embodiments 'a micronized particle, coated (eg, extended release Q coated) micronized particle, or the like The combined micronized agent comprises - cortex.. = sterol is a free acid, a free test, a salt, a prodrug or any other group thereof. In a particular embodiment, one of the pharmaceutical compositions described herein Containing thiol dehydrocorticosterol as a micronized powder, Dehydrocortisol or dehydrogenation = betitol. In a particular embodiment, one of the pharmaceutical compositions described herein is a thiol dehydrocorticosterol of a micromethyl dehydrocorticosteroid powder. Multiparticulate and/or micronized corticosteroids are delivered to an ear structure (eg, 'inner ear) by any matrix comprising a solid, liquid or gel matrix of the type 140447.doc-60-200950787. In some implementations The multiparticulate and/or micronized corticosteroid is delivered to an ear structure (eg, inner ear) via an in-the-ear injection by any type of matrix comprising a solid, liquid or gel matrix. " Pharmaceutical Formulation. I The pharmaceutical compositions provided include at least - steroidal steroids and pharmaceuticals. 彳 accept diluents, excipients or carriers. In certain embodiments, the pharmaceutical composition comprises other drugs or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, and salts for regulating osmotic pressure, and / or buffer. In other embodiments, the pharmaceutical composition also contains other therapeutic substances. In a specific embodiment of the auris-acceptable controlled release corticosteroid pharmaceutical formulation described herein, the corticosteroid is provided in a gel matrix and is also referred to herein as an "early acceptable gel formulation", "the inner ear is acceptable Gel Formulation, Middle Ear Acceptable Gel Formulation, Ear Acceptable Gel Formulation, Ear 9 Gel Formula, or the like. All ingredients of this gel formulation must be compatible with the standard ear structure. Furthermore, the gel formulation provides controlled release of the corticosteroid to the intended location within the target ear structure; in certain embodiments, the gel formulation also has an immediate or rapid release component to facilitate delivery of the corticosteroid to Expected location. In other embodiments, the gel formulation has a sustained release component for delivery of corticosteroids. In certain embodiments, the gel formulation comprises a multiparticulate (e.g., micronized) corticosteroid. In certain embodiments, the ear gel formulation is biodegradable. In other embodiments, the otic gel formulation includes a mucoadhesive excipient to allow adhesion to the outer mucosal layer of the 140447.doc-61 - 200950787 round window film. In still other embodiments, the otic gel formulation comprises a penetration enhancer excipient; in yet another embodiment, the otic gel formulation s has a viscous promoter which is sufficient to provide a viscous Between about 5 〇〇 to ι, οοο, οοο 泊 间 'between about 75 〇 to 1 〇〇〇〇〇〇 Μ Μ; between about 1000 and 400,000 PCT; between about 2 〇〇〇 1 〇〇〇〇〇 泊 泊; between 3,000 and 50, 〇〇〇 泊 ;; between about 4 〇〇〇 to 25 〇〇〇 ;; between 5,000 and 20, 〇〇〇 Between centipoise; or between about 6 〇〇〇 and 15 〇〇〇. In an additional or alternative embodiment, the otic gel formulation can be administered intraocularly to the round window membrane or to the round window membrane. In other embodiments, the otic gel formulation is administered through the posterior ear incision and surgically to the round window membrane or to the round window membrane or coronal fossa crown region. Alternatively, the otic gel formulation is applied with a needle and a syringe, wherein the needle is inserted into the eardrum and guided to the area of the round window media or the cochlea to write the crown. This otic gel formulation is then deposited on or near the round window membrane or the deaf crown to locally treat autoimmune ear disorders. In other embodiments, the otic gel formulation is administered by a catheter that is implanted into a patient, and in yet another embodiment, the formulation is applied to or near the round window membrane by a pump. In still the embodiment, the ear gel formulation is applied to the micro-injection device (4) to or near the round window membrane. In still other embodiments, the otic gel formulation is applied to the auricular acupoints. In still the examples, the ear gel formulation was applied to the eardrum. In still the examples, the otic gel formulation is applied to the ear canal or within the ear canal. In yet another particular embodiment, any of the pharmaceutical compositions described herein comprise a multiparticulate corticosteroid in a liquid matrix (e.g., a liquid composition for in-ear injection or ear drops). In a particular embodiment, any of the pharmaceutical compositions described herein comprise a multiparticulate cortex in a solid matrix I40447.doc • 62-200950787 Steroid. Controlled Release Formulations A 'controlled release drug formulation imparts controlled release of drug release relative to release time and release time in the body. As discussed herein, controlled release is a combination of delayed release, extended release, sustained release, and/or pulsed release (e.g., a combination of extended release and immediate release), or the like. Many advantages are provided by controlled release. First, controlled release of the pharmaceutical agent allows for less dosing frequency and thus Φ minimizes repeated treatment. Second, controlled release therapy results in more effective drug use and less compound residue. Third, controlled release provides the possibility of local drug delivery by placing a delivery device or formulation at the disease location. Further, controlled release can provide for administration and release of at least two different drugs via a single dosage unit, each having a unique release profile, or releasing the same drug at different rates or during different periods. Thus, one aspect of the embodiments described herein provides for the provision of a controlled release corticosteroid for the treatment of autoimmune disorders and/or inflammatory disorders © Accepting compositions or formulations. Controlled by the compositions and/or formulations disclosed herein (4) The metamorphic sample is conferred by a variety of agents, including but not limited to excipients, reagents or materials that are useful for internal or otic structures thereof. Ear-Acceptable Gel Gel, sometimes referred to as Kangjiao, has been defined in a number of ways. For example, the United States Pharmacopoeia defines a coagulation as a semi-solid system consisting of a small inorganic particle or a larger organic molecule consisting of a liquid-permeating suspension. Gel can be more

Phase or "* phase system. A single cypress I early phase gel is uniformly dispersed by a liquid organic macromolecule, in this way there is no obvious boundary between the dispersed knife and the liquid 140447.doc .63· 200950787 line exists. Single phase "through t is prepared from synthetic macromolecules (e.g., carbomer 8) or from natural gums (e.g., tragacanth). In certain embodiments, the single phase gel is typically aqueous <16 and can also be made using alcohols and oils. The two-phase gel is formed from a network of small dispersed particles. Kneeling can also be distinguished as hydrophobic or hydrophilic. In a particular embodiment, the hydrophobically condensed matrix is typically comprised of a fatty oil containing polyethylene or a fatty oil liquid paraffin and a gelatinized gum containing 7m zinc. Conversely, the hydrophobic conjugate matrix is typically comprised of water, glycerin, or propylene glycol with a suitable gel (eg, tragacanth, starch, cellulose derivatives, carboxyvinyl polymers, and/or aluminum magnesium silicate) Composition by gel. In a particular embodiment, the flow of the compositions disclosed herein becomes pseudoplastic, plastic, flow desorbing or bulking. In one embodiment, the viscous auris-acceptable formulations described herein are not liquid at room temperature. In certain embodiments, the viscosity enhancing formulation is characterized by a phase transition between room temperature and body temperature (including a severely feverd patient, such as south to about 42. (:). In certain embodiments, This phase transition occurs at lower than body temperature it: occurs below body temperature, below body temperature 3t>c, below body temperature 4. (: occurs, occurs below 6°c of body temperature, occurs below 8 C of body temperature, low At body temperature i (TC occurs. In some embodiments, this phase transition is at a temperature below 15 ((: occurs, occurs below body temperature 2 〇 °c, occurs below body temperature 25 ° C. In a particular embodiment) The gelatinization temperature (Tgel) of the formulations described herein is about 2 (TC, about 25 t, or about 3 Torr. In a particular embodiment, the gelatinization temperature (Tgel) of the formulations described herein is about 35 < (:, or about 40 ° C. In one embodiment, any of the formulations described herein reduces administration at about body temperature or inhibits the stun of the in-ear administration of the ear formulation. Body temperature setting 140447.doc • 64 - 200950787 Sense includes healthy body or - unhealthy body temperature, the latter includes - fever patients (up to ~ 42 ° C A polymer composed of polyoxypropylene and polyoxyethylene forms a thermoreversible gel when incorporated into an aqueous solution. These polymers have the ability to change from a liquid state to a gel state at a temperature close to body temperature' thus allowing For effective application to the target ear structure. & liquid-to-suspect colloidal phase is converted to the concentration and composition of the polymer in the solution.

Poloxamer 4〇7 (PF-127) is a nonionic surfactant composed of polyoxyethylene propylene-polyoxypropylene copolymer. Other poloxamers include 18 )), 237 (F- Level 87), 338 (F_1〇8). An aqueous solution of poloxamer in the presence of acid, test and metal ions PF_127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer having the general formula: £1〇6 p7〇ei〇6, with - The average molar mass is 13, 〇〇〇. This polymer can be further purified by a suitable method to promote gelation properties. It contains about 7 % epoxy ethene which is a hydrophilic source. It is one of a series of poloxamer aba block copolymers whose members have the chemical formula shown below. Hydrophilic Η juice O-CH, - ch2}{o-ch-ch2-){〇-ch2-ch2)-oh a CH3 hydrophobic P_F127 is special (four)' because of the concentrated solution of the copolymer (>20% w/w ) Converted from a low viscosity transparent solution to a solid gel upon heating to body temperature. Therefore, this phenomenon suggests that when placed in contact with the body, the gel formulation will form a semi-solid structure and a controlled release reservoir. Furthermore, pF_127 has a good solubility, low toxicity and is therefore considered a good drug delivery system medium. In an alternate embodiment, the thermal gel is a PEG-PGLA-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 a colloid-gel nature at a concentration of from about 5% w/w to about 40% w/w. The lactose/ethyl lactone molar ratio in the PGLA copolymer can range from about 1:1 to about 20:1, depending on the desired properties. This resulting copolymer is soluble in water and forms a free flowing liquid at room temperature, but forms a hydrogen gel at body temperature. A commercially available PEG-PGLA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Ingelheim. This material consists of a 50:50 poly(DL-lactosyl-co-caprolactone) PGLA copolymer and 10% w/w PEG and has a molecular weight of about 6,000. This material consisted of a 50:50 poly(DL-lactosyl-co-caprolactone) PGLA copolymer and was 10% w/w PEG and had a molecular weight of about 6,000. "RegelTM" is a trademark of Giant Med, which specifies a family of low molecular weight, biodegradable block copolymers having reversible thermogel properties, such as U.S. Patents 6,004,573, 6,117,949, 6,201,072 and 6,287,588. . Also included are biodegradable polymeric drug carriers disclosed in U.S. Patent Application Serial Nos. 09/906,041, 09/559,799 and 10/919,603. The biodegradable drug carrier comprises a bismuth-type or BAB-type triblock copolymer or a mixture thereof, wherein the A-block is relatively hydrophobic and comprises a biodegradable polyester or poly(orthoester) And the B-block is relatively hydrophilic and comprises polyethylene glycol (PEG) 'The copolymer has a hydrophobic content between 50.1 and 83 wt% and a hydrophilic content between 17 and 49.9 wt. And 140447.doc -66 - 200950787 The total block copolymer molecular weight is between 2000 and 8000 auricular. The drug carrier exhibits water solubility at a temperature below the body temperature of a normal mammal and undergoes a reversible thermogel action to subsequently be present as a gel at a gel temperature equivalent to the physiological body temperature of the mammal. Biodegradable, hydrophobic A polymer block • comprises a polyester or poly(orthoester) wherein the polyester is synthesized from a single body selected from the group consisting of about 600 and 3000 deaf Average molecular weight between: ·· D,L-lactoside, D-lactoside, L-lactoside, D, L_lactic acid, lactic acid, 碜L-lactic acid, ethyl lactone, glycolic acid, ε-caprolactone a copolymer of ε-hydroxycaproic acid, cadaverine lactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acid, hydroxysuccinic acid, and the like. The hydrophilic core block portion is preferably polyethylene glycol (PEG) having an average molecular weight of between about 500 and 22 ampoules. Additional biodegradable thermoplastic polyesters include AtHgelTM (supplied by AWx Laboratories) and/or disclosed in, for example, U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; ^5,990,194^; The biodegradable thermoplastic polyester is a thermoplastic polymer. Examples of suitable biodegradable thermoplastic polyesters include polylactose, polyethyl vinegar, polycaprolactone, copolymers thereof, tetrapolymers thereof, and combinations thereof, in these embodiments. Among the suitable biodegradable thermoplastic polyesters are polyglycosides, polyethyl lactones, copolymers thereof, tetrapolymers thereof, or the like. In one embodiment, the biodegradable thermoplastic polyester is 5 〇/5 〇 poly( 〇 苦 _ 共 共 共 乙 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; From wt% to about 4 〇 Wt% 'and having an average molecular weight of from about 23,000 to about 45,000. Or 140447.doc •67- 200950787, in still other embodiments, the biodegradable thermoplastic polyester is 75/25 poly(DL-lactosyl-co-lactone) having no carboxyl end group; And is present in an amount from about 40% to about 50 wt% of the composition. And having an average molecular weight of from about 15,000 to about 24,000. In still another or alternative embodiment, the terminal group of the poly(01^-lactosyl-co-lactone) is a hydroxyl group, a carboxyl group, or an ester according to a polymerization method. The polycondensation of lactic acid or glycolic acid provides a polymer having a hydroxyl group and a carboxyl group. The ring-opening polymerization of a cyclic lactose or a lactone monomer with water, lactic acid, or glycolic acid provides a polymer having the same end groups. However, the ring monomer provides a polymer having a hydroxyl group and an ester end group by ring opening of a monofunctional alcohol such as methanol, ethanol or 1-dodecanol. The ring-opening polymerization of a ring monomer with a diol such as 1,6-hexanediol or polyethylene glycol provides a polymer having only hydroxyl end groups. Since the polymer system of the thermoreversible gel dissolves more completely under cooling, the dissolution method involves adding the required amount of polymer to the amount of water used under cooling. Typically, after wetting the polymer by shaking, the mixture is capped and placed in a cold chamber or in a thermo-constant container at about 0-1 ° C to dissolve the polymer. The mixture is agitated or shaken to achieve an approximately faster thermal reversible gel polymer dissolution. Corticosteroids and various additives such as buffers, salts and preservatives are added and dissolved in order. In some instances, the corticosteroid and/or other pharmaceutically active agent is suspended in water if it is insoluble in water. This pH is modulated by the addition of a suitable buffer. The characteristics of the round window membrane mucoadhesive agent can be imparted to a thermoreversible gel by incorporating a round window membrane mucoadhesive carbomer such as Carbomo® 934P (Carbopol 934P) (Majithiya et al. AAPS PharmSciTech) (2006), 7(3), p. El; EP0551626), 140447.doc-68-200950787 both of which are incorporated herein by reference. It has been consistently practiced to accept a pharmaceutical gel formulation that does not require the addition of a viscosity enhancing agent. This gel formulation incorporates at least one pharmaceutically acceptable buffer. In one aspect, it is a gel formulation containing a corticosteroid and a pharmaceutically acceptable buffer. In another embodiment, the pharmaceutically acceptable bismuth or carrier is a gelling agent. In other embodiments, an effective corticosteroid-acceptable pharmaceutical remedy also includes one or more pH adjusting or buffering agents to provide a suitable pH for endolymph or peripheral lymph. Suitable pH adjusting or buffering agents include, but are not limited to, acetates, hydrogencarbonates, ammonium chlorides, citrates, phosphates, pharmaceutically acceptable salts thereof, and the like, or combinations or mixtures thereof. The pH adjusting or buffering agent is used in an amount to maintain a pH of the composition of between about 5 and about 9, in one embodiment, the pH is between about 6.5 and about 7.5, and in another embodiment The pH is about 6.5, 0.6, 0.7, 0.8, 0.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5. In one embodiment, when one or more buffering agents are used in the Φ formulation disclosed herein, they are combined with, for example, a pharmaceutically acceptable carrier and are present in the final formulation, for example, from about 01% to about 20〇/〇, '约〇, 5% to about! 〇%. In a particular embodiment of the invention, the amount of buffer included in the gel formulation is such that the pH of the gel formulation interferes with the natural buffer system of the middle or inner ear, or does not interfere with the natural pH of the endolymph or peripheral lymph. : Depends on the target of the steroid formulation in the cochlea. In some real palladium cases, a buffer of about 1 〇 μΜ to about 2 mM is present in the gel formulation. In a particular embodiment, a buffer is present at a concentration of from about 2 mM to about 1 mM. In one embodiment, a buffer is slightly acidic? 11 such as acetate 140447.doc • 69· 200950787 or citrate. In one embodiment, the buffer is a sodium acetate buffer having a pH of from about 4.5 to about 6.5. In one embodiment, the buffer is a sodium citrate buffer having a pH of from about 5.0 to about 8.0, or from about 5.5 to about 7.0. In one embodiment, the buffer is a tris (hydroxyindenyl) aminomethane, salt, carbonate or phosphate such as a slightly acidic pH. In one embodiment, the buffer is a sodium bicarbonate buffer having a pH of from about 6.5 to about 8.5 or from about 7% to about 8%. In one embodiment, the buffer is a disodium phosphate buffer having a pH of from about 6 Torr to about 9 Torr.

Also described herein are controlled release formulations comprising a corticosteroid and a viscosity enhancing agent. Suitable viscosifying agents include, by way of example only, exemplifying agents and bismuth. In the examples, the viscosity enhancing formulation does not include a sputum. In other embodiments, the formulation to enhance adhesion includes - the drug may be specifically buffered. Gasified sodium or other tonicity agent, and tension. * Depending on the situation _ for illustrative purposes only, the ear - can be used as an adhesive, including hydroxypropylmethyl vegan, hydroxyethyl cellulose, poly

Vinyl pyrrolidone, carboxy ketone, polyvinyl alcohol, cartilage sulphate, sodium sulphate, sodium hyaluronate. The medical group described in the article is used for I Jinle, and the adhesives of the composition include but not (gum arabic), acacia is Arab / ruined IS magnesium, alginic acid steel, hornweed, benton, Kappo ^ Sodium sulphate, Mo), Sanxian gum, fiber sound / staghorn gum, carbomer (card ^ V, microcrystalline cellulose (MCC), & - each cedar gum, glucose, rich Cold "), horny sulphate (heCt 〇rite), lactose p-degree rubber, tannin extract, sucrose, maltodextrin, sucrose, honey, corn starch, wheat, reading, mountain J wheat powder corn Powder, horse yam i I40447.doc -70- 200950787 powder, gelatin, paulownia gum, gums, polyethylene glycol (eg pEG 2〇〇_45〇〇), η蓍 gum, ethyl cellulose, hexyl hair Ethyl ethyl cellulose, ethyl methyl cellulose, methyl cellulose, transethyl ethyl cellulose, transethyl ethyl fluorenyl cellulose, hydroxypropyl cellulose, poly (hydroxyethyl urethane) ), oxy-poly-day kick, pectin, poly-gelatin, puwei, propylene carbonate, methyl ethyl maleic anhydride copolymer (PVM/MA), poly(methoxyethylamine basic acid) ·· Ester), poly(methoxyethoxyethylamino decanoate), hydroxypropyl fiber φ, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), a combination of cerium oxide, polyethyl hydrazine, ketamine (PVP: pucanone), Splenda® (glucose maltodextrin and sucralose), or the like. In a particular embodiment, the viscosity-promoting The agent is a combination of methyl cellulose (MC) and CMC. In still other embodiments, the viscosity-enhancing agent is combined with carboxymethylated polyglucamine, or chitin and alginate. The combination of chitin and alginate with the corticosteroids disclosed herein as a controlled release formulation to limit the diffusion of corticosteroids from this formulation. Furthermore, the combination of suspending φ thiolated polyglucamine and alginate Optionally used to help increase the permeability of corticosteroids to the inner ear round window membrane. • Some embodiments are a thickening formulation comprising from about 01 Mm to about 100 mM of corticosteroids, a pharmaceutically acceptable viscosity And the water used for injection, the viscosity of the adhesive is sufficient to provide the thickening formula The adhesive presently exhibits from about 100 to about 100,000 cP. In a particular embodiment, the gel viscosity ranges from about 100 to about 50,000 cP, from about 100 to about !, between 〇〇〇cP, about 5 〇〇 to Between the range of about 1,500 cP, about!, 〇〇〇 to the range of about 3,000 cp, between the range of about 2,000 to 8,000 cP 'about 4, 〇〇〇 to about 50,000 cP, 140447.doc •71· 200950787 Between 10,000 and about 500,000 cP, from about 15,000 cp to about 1,000,000 cp. In another embodiment, the biocompatible gel comprises at least about 35 wt%, at least about 45 wt%, at least about 55 wt%, at least about 65 wt% 'at least about when an even more viscous medium is desired. 70 wt%, at least about 75 wt ° / 〇, or at least about 80 wt%, etc., a corticosteroid. In a highly concentrated sample, the biocompatible extender formulation comprises at least about 25 wt%, at least about 35 wt%, at least about 45 wt% 'at least about 55 wt%, at least about 65 wt%, at least about 75 wt% At least about 85 wt%, at least about 90 wt% or at least about 95 wt% or more of the corticosteroid. In certain embodiments, the viscosity of the gel formulations described herein is measured by any of the methods described herein. For example, in some embodiments, the viscosity of the gel formulations described herein is calculated using the LVDV-II+CP Cone plate viscometer and the Cone mandrel CPE-40. In other embodiments, a Br〇〇kfield (mandrel and cup) viscometer is used to calculate the viscosity of the gel formulations described herein. In some embodiments, the viscosity range referred to herein is measured at room temperature. In other embodiments, the range of viscosity referred to herein is measured at body temperature (e.g., the average body temperature of a healthy human). In one embodiment, the pharmaceutically acceptable viscous auricular acceptable formulation comprises at least a corticosteroid and at least one gelling agent. Suitable gelling agents for formulating gel formulations with 9 include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (eg, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethyl) Cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose*, methylcellulose), cerium, sylvestre, locust bean gum, alginate (eg alginic acid), citrate, starch , tragacanth, carboxymei 140447.doc • 72· 200950787 Any dissolving or mixture of ethylene polymer, cerulein, paraffin, petrolatum and the like. In certain other embodiments, hydroxypropyl methylcellulose (Methocel®) is utilized as the gelling agent. In a particular embodiment, a thickening agent as described above is also utilized as a gelling agent for the gel formulations described herein. In certain embodiments, other gel formulations may be used depending on the particular corticosteroid, other pharmaceutical agent or excipient additive used, and are considered to be within the scope of the present disclosure. For example, other currently commercially available glycerin-based gels, glycerin-derived compounds, conjugated or crosslinked gels, matrices, gels and polymers, as well as gelatin and its derivatives, alginate, and Therapeutic acid-based gels, and even natural and synthetic hydrogen gels and hydrogen gel-derived compounds, are contemplated for use in the corticosteroid formulations described herein. In a lean embodiment, the gel acceptable for the ear includes, but is not limited to, alginate hydrogen spine # SAF®-gel (ConvaTec, Princeton, New Jersey, USA), Duoderm® Hydro active knee (ConvaTec) ), Nu-Gel® (US Circle &Johnson; Johnson Medical, Arlington); Carrasyn® (V) Acemannan Hydrogel (Carrington Laboratories, Inc.); Glycerin Gel Elta® Hydrogen gel (Swiss-American Products, Dallas, TX) and KY® Sterile (Johnson & Johnson). In yet another embodiment, the biodegradable biocompatible gel is also a compound that can be present in the acceptable formulations described and disclosed herein. In certain formulations for the formulation of compositions for mammalian administration and for human administration, the 'Ace Acceptable Gel contains substantially all of the composition weight. In other embodiments, the auris-acceptable gel comprises, for example, about 98 wt% or more than 99 wt% of the composition. This is required when a substantially non-liquid, or substantially viscous formula is required. In yet another embodiment, the biocompatible gel fraction of the formulation comprises at least about 5 wt%, at least about 60 wt when a slightly lower viscosity or slightly higher liquid ear acceptable pharmaceutical gel formulation is desired. %,at least

About 70 wt%, or even at least about 80 wt% or 90 wt% of the compound "all intermediates in this range are considered to be within the scope of the present disclosure" and in some embodiments, even more liquid. (and therefore less viscous) an auris-acceptable gel composition 'The gel or matrix component of such a mixture contains no more than about 50 wt.% of the composition. , no more than about 40 wt%, no more than about 30 wt%, or even no more than about 15 wt% or about 20 wt%. Round window film mucoadhesive

It is also contemplated in the context of the examples to incorporate a round window film mucoadhesive to the corticosteroid formulations and compositions disclosed herein. The term "mucosal binder" refers to a substance used for binding to the mucin layer of a biofilm, such as the outer membrane of a 3-layer circular window membrane. "As a circular window film mucoadhesive polymer, this The poly(n) material should have certain general physicochemical characteristics such as anionic hydrophilicity with predominantly several hydrogen bond forming groups, suitable surface properties to wet the mucus/mucosal tissue surface and sufficient elasticity to penetrate the mucosal network. Round window film mucoadhesives that can be used with acceptable ears include, but are not limited to, soluble ketone ratios of 11 ketone polymers (pvp); one water _ swellable but water-insoluble, fiber , cross-linked county · functional polymer; a cross-linked poly(acrylic acid) (such as carbomer 947P); - carbomer homopolymer; a carbomer copolymer; - hydrophilic glycan gum, malt Dextrin, a crosslinked alginate gel, a water-dispersible polycarboxylate ethylene polymer, at least two particulate components selected from the group consisting of titanium dioxide, sulphur dioxide, and clay or mixtures thereof. 140447.doc 74· 200950787 Round® Membrane Adhesives can be used in combination with an acceptable viscous excipient for use in the ear or alone to increase the interaction of the composition with the ear component of the mucosal layer. In a non-limiting embodiment, the mucoadhesive agent is maltodextrin and/or alginate gum. When used, the circular window film imparts a mucoadhesive property to the composition that is sufficient to deliver an effective amount of the corticosteroid composition to, for example, the inner ear round window mucosa or the cochlear cap crown, and the amount of which is a coatable mucosa, • and then deliver the composition to the affected area, including the example of the inner ear and/or the deaf structure as illustrated. Those skilled in the art can determine the characteristics of the mucoadhesive agent of the compositions described herein and can therefore determine the appropriate amount of use. A method of determining adequate mucoadhesiveness can include monitoring changes in the interaction of the composition with the mucosal layer, including but not limited to measuring the duration or duration of retention of the composition in the absence or presence of the excipient. In a non-limiting embodiment, the round window membrane mucoadhesive agent is maltodextrin. Maltodextrin is a carbohydrate produced by hydrolyzing starch derived from corn, potato, wheat or other plants. Maltodextrin can be used alone or in combination with other round window film mucoadhesives to impart the properties of the mucosal adhesives disclosed herein. In one embodiment, the combination of maltodextrin and carbomer polymer enhances the round window film mucoadhesive of the compositions disclosed herein. In another embodiment, the round window membrane mucoadhesive agent is an alkyl-glycoside and/or a monoalkyl ester. As used herein, an "alkyl-glycoside" refers to a compound containing any hydrophilic sugar (eg, glucose, fructose, curtain sugar, or maltose) attached to a hydrophobic alkyl group. In certain embodiments, this The round window membrane mucoadhesive agent is an interfacial activity containing an alkyl-glycoside 140447.doc • 75· 200950787 'wherein the alkyl-glycoside comprises a linkage to a hydrophobic alkyl group (eg, containing from about 6 to about 25 carbons) a sugar of an atom of an alkyl group, which is linked by a monoamine, an amine linkage, an amine citrate linkage, a hydrazine linkage, a thiol linkage, a thiol linkage, a thioester linkage, a glycosidic linkage a monothiol linkage, and/or a urethral urea linkage. In certain embodiments, the round window membrane mucoadhesive agent is hexyl-, heptyl-, octyl-, decyl-, fluorenyl-, ten Monoalkyl...dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl- and octadecyl alpha- or beta-D- Maltoside; hexyl-, heptyl-, octyl-, decyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, ten Alkyl-, hexadecyl-, heptadecyl-, and octadecanthyl-α- or β-D-glucoside; hexyl-, heptyl-, octyl-, fluorenyl-, fluorenyl- , undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-- or β-D-sucrose glycosides; hexyl-, heptyl, octyl-, dodecyl-, dodecanyl- and tetradecyl-β-D-thiomaltoside; heptyl- or octyl-丨_Sulfur_α- or β-D-gluconoside; alkyl sucrose; alkyl maltoside trisaccharide; sucrose β-amino-alkyl ether long-chain aliphatic decylamine; linked by monoamine a base chain of a sugar or is malartenine derivative and an isomalt derivative linked to a home base chain by urea; a long chain aliphatic group of sucrose β-amino-alkyl- Long-chain aliphatic guanidinium carbonate of guanidinium carbonate and sucrose β-amino-alkyl ether. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl glucoside is a combination of maltose, sucrose, glucose, or the like, linked to a single alkyl group of 9 to 16 carbon atoms with a glycoside Chains (eg, decyl-, decyl-, dodecyl-, and tetradecyl sucralose; thiol _, 140447.doc -76- 200950787 thiol-, dodecyl- and tetradecyl glucose Glycosides; and fluorenyl-, decyl-, dodecyl-, and tetradecyl maltosides. In certain embodiments, the round-window film mucoadhesive agent is a burnt-sweet It is a dodecyl maltoside, a tridecyl maltoside, and a tetradecyl maltose. In some implementations, it is acceptable to use a penetration enhancer as a thio-glycoside-containing surfactant, wherein The alkyl glycoside is tetradecyl-β-D-maltose. The round-solid film mucoadhesive agent is a hospital-sugar bitter, wherein the alkyl saccharide is a bile having at least glucose. In certain embodiments, the auris-acceptable penetration enhancer is a surfactant comprising an alpha-D-glucomannan-based peptide, η-dodecyl_4_〇_a_D _ glucopyranosyl-β-glycoside, and/or cardiac tetradecyl _4_〇_a_D_ glucopyranosyl _β- shout sugar. In some embodiments, the round window membrane mucoadhesive agent is

Φ-Alkyl-glycoside, wherein the alkyl glycoside has a critical enthalpy concentration (CMC) of less than about in pure water or aqueous solution! mMe In certain embodiments, the round window membrane mucoadhesive is an -alkyl-glycoside, and the oxygen atom in the alkyl-glycoside is replaced by a sulfur atom. In certain embodiments, the round window film mucoadhesive agent is an alkyl group-glycoside, wherein the steosyl bud is a spirulina isomer. In some embodiments, the round window film mucoadhesive agent is an alkyl-glycoside wherein the alkyl glycoside comprises 90 Å/〇, 91 〇/〇, 92 〇/. , 93〇/. , 94%, 95% ‘ 96% ‘ 97% ‘ 98% ’ 99%, 99 1%, 99 5%, or 99 9 〇 external rotation isomers. Auricularly Acceptable Cyclodextrins and Other Stabilizing Formulations In a particular embodiment, this ear acceptable formulation may alternatively comprise a cyclodextrin. This cyclodextrin is a sugar-containing unit containing 6, 7, or 8 grapes. 140447.doc •77- 200950787 Cool' respectively called 〇c- ί 糊 糊, β- 哀 糊 糊, or γ - ί Mourning. The soil dextrin has a hydrophilic outer layer which enhances the water-soluble, and hydrophobic inner layer to form a cavity. In an aqueous environment, the hydrophobic portion of other molecules typically enters the hydrophobic pockets of the cyclodextrin to form the intrinsic compound. In addition, cyclodextrins can also interact with other types of molecules that are not in hydrophobic pockets. Each glucomannan unit of the cyclodextrin has three free hydroxyl groups or 18 hydroxyl groups on the α-cyclodextrin, 21 hydroxyl groups on the β-cyclodextrin, and 24 hydroxyl groups on the γ-cyclodextrin. One of these hydroxyl groups reacts with more than one of a plurality of reagents to form a larger species of cyclodextrin derivative. Some of the more general cyclodextrin derivatives are hydroxypropyl ethers, sulfonates and sulfoalkyl ethers. The following shows the structure of β-cyclodextrin and hydroxypropyl β-cyclodextrin (HPpCD).

R = H β-cyclodextrin R = CH2CH(OH)CH3 hydroxypropyl β-cyclodextrin In certain embodiments, cyclodextrin is used in the pharmaceutical composition to improve the stability of the drug. Intrinsic compounds are associated with many examples of promoting solubility; however, interactions between other cyclodextrins and insoluble compounds can also improve solubility. Hydroxypropyl-β-cyclodextrin (HPPCD) is a commercially available pyrogen-free product. It is a moisture-proof white powder that is soluble in water. HPPCD is a heat-resistant 140447.doc -78- 200950787 in which the pH does not degrade. Therefore, the cyclodextrin improves the composition or the ... Accordingly, in certain embodiments, the inclusion of a cyclodextrin, a sputum ear, and a dissolution of a corticosteroid in a formulation described herein (4) (d), a cyclodextrin is further used as a controlled release formulation of the formulation described herein. The agent is in.

Preferred cyclodextrin derivatives which may be used include α-cyclodextrin, cyclodextrin, Y-cyclodextrin, transethylidene β-cyclodextrin, transpropyl γ-cyclodextrin, sulfation环cyclodextrin, sulfuric acid cut · ring _, sulfur (four) cyclodextrin. The concentration of the silk and the (4) cyclodextrin used in the present invention may depend on the physicochemical properties, pharmacokinetic properties, side effects or adverse conditions, formulation considerations, or concomitant effects of the therapeutic activator or its salt or prodrug. Other factors, or other excipients, vary in nature. Thus, the concentration or amount of cyclodextrin in the compositions and methods described herein can vary as desired in a particular situation. When used, the solubility of the corticosteroid and/or the amount of cyclodextrin as a controlled release excipient in any of the formulations described herein is the use of the principles, examples, and teachings described herein. (iii) Other stabilizers useful in the auris-acceptable formulations disclosed herein are selected from, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyethylene A group of ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and the like. σ ° In some embodiments ' a stabilizer decyl congener is also used. In another embodiment, the stabilizer selected is used to change the hydrophobicity of the formulation (eg, oleic acid wax), or to improve the mixing of various components of the formulation (eg, ethanol), and to compress the amount of moisture in the formulation (eg, , PVP or polyvinylpyrrolidone), the movement of the control phase 140447.doc -79- 200950787 (a substance having a melting point higher than room temperature such as a long-chain fatty acid, an alcohol, a vinegar, an ether, a guanamine or the like, or a mixture thereof; Wax, and/or improve the compatibility of formulations with encapsulated materials (eg, oleic acid, wax). In still other embodiments, certain stabilizers are used as the solvent/co-solvent (e.g., ethanol). In yet another embodiment, the stabilizer is present in an amount sufficient to inhibit degradation of the corticosteroid. Illustrative of such stabilizers include, but are not limited to, (a) from about 5% to about 2% w/v glycerol, (b) from about 0.1% to about 1% w/v aminomethyl mercaptan butyric acid, (c) from about 0.1% to about 2% w/v monothioglycerol '(d) from about i mM to about i 〇 EDTA, (e) from about 〇 '〇ι% to about 2% w/v ascorbic acid, (1) 〇〇 〇3% to about 0.〇2% w/v polysorbate 8〇, (g)〇〇〇1% to about 〇〇5% w w/v polysorbate 2〇, (h) arginine (1) heparin, (1) polyglucose sulfate, (k) cyclodextrin, (1) polypentose polysulfate and other heparinoids, (m) divalent cations such as town and zinc; or (η) combinations thereof. An additional useful corticosteroid ear-acceptable formulation includes at least one anti-agglomeration additive to promote the virginity of the corticosteroid formulation by reducing protein aggregation. The choice of anti-agglomeration additives is based on the conditional nature of the exposed corticosteroid, such as a corticosteroid antibody. For example, specific formulations for mixing and thermal stress require different anti-agglomeration additives than formulations for freeze-drying and reconstitution. Useful anti-agglomeration additives include glands, cesium chloride, simple amino acids such as glycine or arginine, sugars, polyalcohols, polysorbates, polymers such as polyethylene glycol, and poly-only for illustrative purposes. Glucose, alkyl sugars, such as alkyl glycosides, and surfactants. Other useful compositions optionally include at least one ear acceptable antioxidant to promote the desired chemical stability. Suitable antioxidants include ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite, which are not used in the 140,470. In one embodiment, the antioxidant is selected from the group consisting of metal chelating agents, thiol containing compounds, and other versatile stabilizers. Still other useful compositions include at least one ear acceptable surfactant. X promotes physical virginity or for other purposes. Suitable non-ionic interface • Active agents include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene olefin (60) hydrogenated to make sesame oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as xin Polyphenol 10, octylphenol polyether 40. In certain embodiments, an auris-acceptable pharmaceutical formulation described herein is stable on compound degradation during any of the following periods: at least about 2 days 'at least about 3 days' for at least about 4 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 (four), at least about 3 Months, at least about 4 months, at least about 5 months, at least about 6 months. In other embodiments, the formulations described herein are stable on the compound 四 (d) during at least about the old period. And, the formula described in this article is at least about! During the month, it is stable on the degradation of the compound. • In other implementations, the additional surfactant (co-interacting agent) and/or buffer is used in combination with at least the pharmaceutically acceptable carrier described above, so the surfactant and/or buffer maintains this The product is at a suitable pH for stability. Suitable co-surfactants include, but are not limited to, (4) natural and synthetic lipophilic agents, such as squamous lipids, cholesterol and cholesterol fatty acid complexes, and the like, nonionic surfactants including, for example, polyoxyethylene Fatty alcohol vinegar, sorbitol needle fatty acid brewing (Spans) 'Polyoxygen Bhd. H0447.doc -81 . 200950787 Pear fatty acid ester (for example, polyoxyethylene (20) sorbitan monooleate (Tween 80 ), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbic acid monolaurate (Tween 20) and other Tweens, sorbitol if §, glycerin For example, Myrj and triacetin (triethyl glycerol), polyethylene glycol, hexadecanol, hexadecanol, stearic acid alcohol, polysorbate 80, poloxamer, Poloxamine, polyoxyethylene sulphonic oil derivatives (eg, CMV® RH40 'Cremphor A25, Cremphor A20, CMUV® EL) and other grammore, sulfosuccinate, alkyl sulfate (SLS); PEG glyceryl fatty acid vinegar such as PEG-8 glyceryl octoate / vinegar (Labrasol), PEG -4 glyceryl caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (gelucire 444/14), PEG-6 glyceryl monooleate (Labrafil® 1944 CS), PEG -6 glyceryl linoleate (Labrafil® 2125 CS); propylene glycol mono- and di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate/caprate; Brij® 700, ascorbyl-6-palmitic acid Any combination or mixture of ester, stearic acid amine, sodium lauryl sulfate, triiricinoleate, and the like; (c) anionic surfactants including but not limited to carboxyl groups Mercapto cellulose calcium, sodium carboxymethyl cellulose, sodium sulfosuccinate, dioctyl ester, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate , any combination or mixture of bile salts and the like; and d) cationic surfactants such as quaternary acid compounds, chlorinated phenyl dihydrocarbyl bonds, hexadecyl trimethyl ammonium bromide and lauryl dimercapto Base - vaporized ammonium. In yet another embodiment, when at least one co-surfactant is used in the inventive acceptable formulation of 140447.doc-82-200950787, it is combined with, for example, a 'pharmaceutically acceptable carrier and is present in the final formulation. , for example, from about G1% to about woven, from about 0.5% to about 10%. In the examples, since the diluent can provide a more secure environment, the diluent is also used to stabilize the corticosteroid or other pharmaceutical compound. The salt dissolved in the buffer solution (which also provides pH control or maintenance) is used as a diluent, which includes, but is not limited to, an acid vinegar buffered physiological saline solution. In other embodiments Ό φ 'this radiant formula is determined by the cochlea of the peripheral lymph and/or endolymphatic isotonic: corticosteroid-based cats. An isotonic formulation is provided by the addition of an isotonic agent. Suitable isotonic agents include, but are not limited to, any combination of pharmaceuticals, sugars, or the like, such as, but not limited to, glucose and sodium chloride. The amount of tonicity agent will depend on the identity of the pharmaceutical formulation as described herein. An effective tonic composition comprising one or more salts in an amount to provide for penetration of the composition to an acceptable range of peripheral lymphoid or endolymphs. The salt comprises sodium, unloaded or recorded cations and chlorides. , citrate, ascorbate, fosphate, pot acid, bicarbonate, sulfuric acid-thiosulfate or sulfite chlorate anion; suitable salts include gasified sodium chloride, sodium carbonate, chlorine sulfate And sulfuric acid money. In certain embodiments, the auris-acceptable gels disclosed herein may alternatively or additionally contain a preservative to prevent microbial growth. Can be used as described herein = suitable for improving the viscosity of the formula _ acceptable preservatives include but not limited to benzoic acid, p- phenyl hydrazine vinegar, alcohol, quaternary compounds, stable gas, organic mercury, such as Merfen and thiomersal, the aforementioned mixtures of 140447.doc-83 - 200950787 and the like. © In still another embodiment, for illustrative purposes only, the preservative in the auris-acceptable formulations described herein is an antibacterial agent. In one embodiment, the formulation includes a preservative such as methyl p-hydroxybenzoate, sodium bisulfite, sodium thiosulfate, ascorbate, gasified butanol, and sulphur Sodium, paraben, benzyl alcohol, phenylethyl alcohol and others. In another example, the methyl paraben concentration is from about 05% to about 1.0%, from about 0.1% to about 0.2%. In still another embodiment, the gel is prepared by the combined water, methyl p-benzoic acid, transethyl cellulose, and sodium sulphate. In still another embodiment, the gel is prepared by mixing water, methyl p-hydroxybenzoate, base ethyl cellulose, and sodium acetate. In yet another embodiment, the mixture is sterilized in an autoclave at 12 Torr for about 2 minutes and tested for cation and methyl p-benzoic acid ester concentrations prior to mixing with an appropriate amount of the skin steroids disclosed herein. Sticky. The water-soluble preservative that can be used as a drug delivery carrier is hydrogen sulfite

Sodium, sodium thiosulfate, ascorbate, chlorobutanol, sodium thiomethic acid, sulfonate, benzyl alcohol, butyl (tetra) xylene (BHT), phenylethyl alcohol and others By. Such agents are typically present in amounts ranging from about wm to about 5 wt% and preferably from about 1% to about 2% by weight. In certain embodiments, the ear compatible formulation described herein is a non-preservative. Round window film penetration enhancer In another embodiment, the formulation is more advanced. The penetration of the round window film can be achieved by window film. The penetration enhancer is enhanced by the presence of one or more round window membrane penetration enhancement enhancers by the chemical entity. The circle promotes the co-administration of drug delivery. 140447.doc • 84 - 200950787 Over-window film. Window film penetration enhancers can be distinguished by chemical structure. Surfactants, both ionic and non-ionic, such as sodium lauryl sulfate, sodium laurate, polyoxyethylene -20-hexadecyl ether, Laureth_9 , sodium lauryl sulfate, sodium dioctylsulfosuccinate, polyoxyethylene _9_ lauryl ether (PLE), Tween 80, nonylphenoxy polyethylene (Npp〇E), polysorbate And similar can be used as a round window membrane penetration enhancer. Bile salts (such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurostanosporin, dihydrochloride Sodium sphaate and its similarities), fatty acids and derivatives (such as oleic acid, octanoic acid, mono- and diglycerides, lauric acid, guanidine bile , octanoic acid, thiol-based meat, octanoic acid and its similar), chelating agents (such as edta, citric acid, salicylic acid and similar), Aachen (such as dimethyl sub-milling (DMSO), 癸Methyl sulphite and its similarities), and alcohols (such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, glycerol, propylene glycol and the like) and as a round window membrane penetration Promoters. Round window membranes can penetrate liposomes. Lipid spheres or lipid particles can also be used to encapsulate corticosteroid formulations or compositions. Phospholipids gently dispersed in aqueous mediators form multilamellar vesicles with isolated lipid layers. The circle encloses the aqueous medium region. Ultrasonic waves, or vortexing of such multilamellar vesicles, result in the formation of a single layer of vesicles, typically a waxy ball of about 1 00 00 size. These lipid globules have a cortex like a cortex. A steroid or other pharmaceutical carrier-like advantage. It is biologically inert, biodegradable, non-toxic, and antigen-free. Lipid globules can be formed in different sizes and have different compositions and surface properties f. In addition, they can Enclose a variety of = molecular drugs and where the lipid globules rupture 140447.doc -85- 200950787 Suitable phospholipids for use in the auris-acceptable lipids of the present invention are, for example, phospholipid choline, ethylamine and serine, medullary myelin, cardiolipin, condensate, phospholipid Acids and cerebrosides, especially those which can be dissolved in a non-toxic, pharmaceutically acceptable organic solvent with corticosteroids. Preferred phospholipids are, for example, phospholipid choline, phospholipid ethanolamine, phospholipid serine, phospholipid cyclohexanol, Dephospholipid choline, phospholipid glycerol and the like, and mixtures thereof, especially lecithin, such as soy lecithin. The quality of the phospholipid used in the formulations of the invention may range from about i 〇 to about 30%, preferably by It is between about 15 and about 25% and especially about 2%. It may be advantageous to use a lipophilic additive to selectively modify the properties of the lipid globule. Examples of such additives include, for example, stearic acid amines, phosphatidic acid, vitamin E, cholesterol, cholesterol hemi-salicylate, and lanolin extracts. The amount of lipophilic additive used ranges from 0.5 to 8%, preferably from 5 to 4% and especially 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 especially about 1:1 Torr. The phospholipid, lipophilic additive and picosteroid and other pharmaceutical compounds are compatible with a non-toxic, pharmaceutically acceptable organic solvent system which can be used in combination with the component. The solvent system must not only completely dissolve the corticosteroid, but must also allow for the formulation of a single bilayer lipid globule. The solvent system comprises dimercaptoisosorbide and glycol (tetramethylene glycol oxime, tetrahydro π-pentanol polyethylene glycol mystery) in an amount of from about 8 to about 30%. In the solvent system, the ratio of the amount of dimethyl isosorbide to tetraethylene glycol ranges from about 2:1 to about 1:3, especially from about 1:1 to about 1:2.5. Good for about 1:2 range. Thus, the amount of tetraethylene glycol in the final composition can vary from 5 to 2%, especially from 5 to 15% and preferably about 10%. Thus, the amount of dimethyl isosorbide in the final group 140447.doc -86 - 200950787, especially from 3 to 7%, and preferably the amount of the composition, can vary from about 3 to about 10% by 5% 〇 〇 The organic component used in the text, one is a mixture containing the phospholipid, pro-monthly additives and organic solvents. Corticosteroids can be dissolved in organic, and injuring or otherwise to maintain the activity of the king of the agent. The amount of corticosteroid in the most ~ formulation is in 〇1 to . Around the room. In addition, other ingredients such as oxidizing agents can be added to the organic ingredients. Examples include vitamins, butyl

Reference to (tetra) phenyl benzene m pure base, ascorbyl palmoside acid ascorbyl oleate and the like. In other embodiments, this includes gel formulations and viscous-promoting formulations, and the acceptable formulations of the ear include excipients, other pharmaceutical or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, humidifiers or emulsifiers. A combination of a agent, a solution accelerator, a salt, a solvent, an anti-foaming agent, an antioxidant, a dispersing agent, a wetting agent, a surfactant, and the like. Suitable carriers for use in the auris-acceptable formulations described herein include, but are not limited to, any pharmaceutically acceptable solvent that is compatible with the physiological environment of the standard otic structure. In other embodiments, the base is a combination of a pharmaceutically acceptable surfactant and a solvent. In certain embodiments, other excipients include sodium stearate fumarate, monoethanolamine hexadecane sulfate, isostearate, polyethoxylated castor oil, decyloxy-l ( nonoxyM〇), octylphenol polyether 9, sodium lauryl sulfate, sorbitan ester (sorbitol monolaurate, sorbitan monooleate, saponin, single-labeled acid ester, sorbitan Monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate 140447.doc • 87 · 200950787 vinegar, sorbitan laurate, sorbitol Anhydride oleate, sorbitan palmitate, sorbitan stearate, #alcoholic dioleic acid vinegar, sorbitol xanthene-isostearate, sorbitol needles + stearate And sorbitan triisostearic acid s), and the like, or a combination or mixture thereof. In other embodiments, the carrier is polysorbate. Polysorbate vinegar is a nonionic surfactant of sorbitol (IV). Polysorbate vinegars useful in the present disclosure include, but are not limited to, polysorbate (tetra), polysorbate 40 polysorbate 4, polysorbate 8 (Tween 80), and the like or mixture. In yet another embodiment, polysorbate 8 is used as a pharmaceutically acceptable carrier. In Example +, the water-soluble glycerin-tether acceptable thickening formulation for the preparation of a pharmaceutical delivery vehicle containing at least a corticosteroid comprises at least about 0.1% water-soluble glycerin compound or more. In certain embodiments, the percentage of corticosteroids is between about 1% and about 95% of the total weight or total volume of the pharmaceutical formulation, between about 5% and about 8%, and between about 1% and about Approximately 60% or more varies. In certain embodiments, the amount of the compound in each therapeutically effective dermal steroid formulation is prepared in such a way that a particular dosage of the compound will result in a suitable dosage. Factors considered herein such as solubility, bioavailability, biological half-life, route of administration, product shelf life, and other medical considerations and preparation of this pharmaceutical formulation. If desired, the ear acceptable pharmaceutical gel also contains a cosolvent and a buffer. Suitable water soluble buffers are alkali metal or alkaline earth metal carbonates, phosphates, hydrogencarbonates, citrates, borates, acetates, salicylates and 140447.doc • 88 - 200950787 Such as steel sulphate, sodium citrate, sodium sulphate, sodium sulphate, sodium hydrogen sulphate, sodium carbonate and triclosan (TRIS). These agents are present in an amount sufficient to maintain the pH of the system at 7.4 ± 0.2 and preferably 74. Therefore, it is as much as 5% of the total composition of the weight of β Θ • However, some corticals or other pharmaceutical compounds are insoluble, ❹ co-solvent to promote corticosteroid solubility. These are typically suspended in a polymeric carrier with the aid of a colloidal suspension aid or a viscosity enhancer. Furthermore, some pharmaceutical excipients, diluents or carriers have potential ototoxicity. For example, sputum, a commonly used preservative, is expected to be ototoxic and therefore potentially harmful if applied to the vestibular or cochlear structures. In the formulation of a controlled release ear formulation, it is contemplated to avoid or combine a suitable pharmaceutical excipient, diluent or carrier to reduce or remove the potential ototoxic component of the formulation, or to reduce the excipient, diluent or carrier. the amount. A controlled release corticosteroid formulation may optionally include an ear protectant such as an antioxidant, alpha-fat, bismuth, forskolin or an iron chelator to counteract the use of a particular therapeutic agent or excipient, dilute # Potential ototoxic effects that may be caused by agents or carriers. Treatment Mode Dose Method and Pharmacy The drug delivered to the inner ear is administered orally, intravenously or subcutaneously. However, systemic administration for the pathological location of the inner ear increases systemic toxicity and adverse side effects === possibility and produces - ineffective drug distribution, which is found in serum but is found to be relatively low in the inner ear. The intra-oral injection of Chemotherapy 1 is an injection-therapeutic agent to the eardrum to enter the middle or inner ear. In the examples, the formulations described herein are administered directly to the round window membrane by intralesional injection via 140447.doc -89.200950787. In another embodiment, the corticosteroid-acceptable formulations described herein are administered to the inner ear sputum via a non-intra-injection. In additional embodiments, the formulations described herein are surgically administered to the round window membrane. It contains vortex ridge correction. In one embodiment, the delivery system is a syringe and needle device that is capable of penetrating the eardrum and directly into the round window membrane or inner ear ridge. In some embodiments, the needle is wider than the 18 gauge needle. In still other embodiments, the needle is from the 18 gauge needle to the 31 gauge needle. In yet another embodiment, the needle is a 25 gauge to a 3 gauge needle. The needle number of the syringe or hypodermic needle varies depending on the mildness or viscosity of the corticosteroid or composition formulation disclosed herein. In another embodiment, the needle is a subcutaneous needle for immediate delivery of the gel formulation. The subcutaneous/primary needle is a single use needle or a disposable needle. In a second embodiment, a syringe is a pharmaceutically acceptable gel-containing corticosteroid composition for delivering a composition comprising the present invention, wherein the syringe has a press fit (Luer) or turn on (Luer_1〇ck ) Accessories. In one embodiment, the syringe is a hypodermic syringe. In still other embodiments, the /ejector is made of plastic or glass. In still another, the hypodermic syringe is a single use syringe. In yet another embodiment, the glass syringe is capable of being sterilized. In another embodiment, the sterilization is carried out in an autoclave. In still other embodiments, the syringe comprises a cylindrical syringe body in which the gel formulation prior to use is stored. In other embodiments, the syringe comprises a cylindrical/main emitter body, wherein the corticosteroid pharmaceutically acceptable ear gel-based composition disclosed herein is stored prior to use, which is suitable for a suitable pharmaceutical acceptable buffer Liquid mixing. In other embodiments, the syringe may contain a combination of its excipients, diazepam, suspending agent, diluent, or the like, for sterilization, or may be stabilized in the eye. Among them are corticosteroids or other pharmaceutical compounds. In a certain embodiment, the syringe comprises a cylindrical syringe body, wherein the/main shot 11 body compartment' and each compartment stores at least an acne of the ear-acceptable corticosteroid formulation. In the case of the implementation of the money, this compartment with a : / main body * > the main emitter is allowed to mix before injection into the middle or inner ear

Share. In other embodiments, the delivery system comprises a plurality of syringes, each syringe of the plurality of syringes containing at least a component of the gel formulation such that each component is premixed prior to injection or mixed after subsequent injection. In still another embodiment, the syringe disclosed herein contains at least a reservoir, wherein at least the reservoir comprises a corticosteroid, or a pharmaceutically acceptable buffer, or a viscous enhancer such as a gelling agent or a combination thereof. . Alternatively, a commercially available injection device can be used in its simplest form, a plastic syringe having an injection H-tube, a needle assembly with a needle, a plunger with a plunger rod, and a gripping edge to Intrathecal injection. # In certain embodiments, the delivery device is a device designed to administer a therapeutic agent to the middle ear and/or inner ear. For illustrative purposes only: gyrus

Medi^ GmbH provides a 胄 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Etc. s incorporated into this case for reference. U.S. Patent Application Serial No. 8/874,208, the disclosure of which is incorporated herein by reference in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all A combined ear aspirator and medical dispenser for in-the-ear liquid sampling and medical applications is further disclosed in U.S. Patent Application Publication No. 2007/0167918, the disclosure of which is incorporated herein by reference. The formulations and modes of administration described herein can also be applied to direct instillation or perfusion methods in the inner ear space. Thus, the formulations described herein can also be used in surgery, and non-limiting examples include closed openings, blunt incisions, ear papillary severing, humeral pedicleectomy, endolymphatic balloon incision, or the like. . An auris-acceptable composition comprising a corticosteroid compound as described herein is for use in prophylactic and/or medical treatment. In medical applications, the corticosteroid composition is administered to a patient already suffering from a disease, condition or disorder in an amount sufficient to cure or at least partially arrest the condition, disorder or condition. The effective amount to be used in these settings will be determined by the judgment of an experienced medical professional, depending on the severity and duration of the disease, disorder or condition, prior treatment, patient health and response to the medication. In the case where the patient's symptoms have not improved, 'at the discretion of the physician, the administration of the corticosteroid compound can be administered in a long-term manner, that is, for an extended period of time, including syndromes that improve, or control or limit the disease or symptom of the patient during the life of the patient. . In the case where the patient's symptoms are indeed improved, the corticosteroid compound administration can be administered in a continuous manner at the discretion of the doctor; or, the dose can be temporarily lowered or temporarily stopped for a certain length of time (ie, a "drug holiday"). . The length of the drug holiday can vary from 2 days to 1 year, including the examples for example only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 Day, 28 days, 35 days, 50 days, 70 days, 1 day, 12〇140447.doc -92- 200950787 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days 350 days and 365 days. The doses reduced during the drug holiday are based on 丨, including examples for illustrative purposes only 1%, 15%, 2%, 25%, 30%, 35%, 4G%, 45%, 5G%, 55%, 6G%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. Once the patient's autoimmune symptoms have improved, a dose of -, maintenance is given if needed. Depending on the symptom of the syndrome T, reduce the dose or frequency of the drug, or one to maintain an improved disease, disorder or symptom. Any reproducibility of symptoms in the center of a particular case may require a treatment of the interval. The amount of corticosteroid corresponding to a particular amount of this agent will vary depending on factors such as the particular compound, the condition and severity of the disease, and will be conventionally determined in a manner known to those skilled in the art, including, for example, a particular agent. Administration, route of administration, symptoms of treatment' and the individual or subject of treatment. However, the therapeutic dose usually used to treat an adult is generally in the range of 〇2_5〇 每 per dose, preferably between 1 and 15 mg per dose. The intended dose may conveniently be administered simultaneously (or at - short time) or at intervals in a single dose or in divided doses. In certain embodiments, the initial administration is a specific corticosteroid and a different formulation or corticosteroid is administered. Pharmacokinetics of a Controlled Release Formulation In one embodiment, the formulations disclosed herein additionally provide an immediate release of a corticosteroid from the formulation 'either within 1 minute' or within 5 minutes, or within 10 minutes' or at 15 Within minutes or within 3G minutes, or within 140 minutes of 140447.doc -93.200950787 or within 90 minutes. In other embodiments, a therapeutically effective amount of at least one corticosteroid is immediately released by the formulation, or within i minutes, or within 5 minutes, or within 1 minute, or within 15 minutes, or at 30 minutes. Inside, or within 60 minutes or within 90 minutes. In a particular embodiment, the formulation comprises an o-medical acceptable gel formulation that provides immediate release of at least - cortex (tetra). Additional embodiments of this formulation may also include agents that promote the viscosity of the formulations disclosed herein. In other or additional embodiments, the formulation provides a controlled release formulation of at least a _corticosteroid. In a specific implementation, the formulation diffuses at least one corticosteroid for more than 5 minutes, or 15 minutes, or 30 minutes, or H, hour, or 4 hours, or 6 hours, or 12 hours, or i8 hours, or 1 day. , or 2 days 'or 3 days, or 4 days' or 5 days' or 6 days, or 7 days or ι〇 days, or 12 days, or days 'or 18 days, or 21 days, or 25 days or 3 weeks At least - corticosteroids are diffused from the formulation by day 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 therapeutically effective amount of at least - cortic (IV) is released by the formulation at - more than 5 minutes 'or 15 minutes' or 3 minutes, or *Temple, 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 1 () days, or 12 days, or 14 days or μ days or 21 days Or 25 days, or 3 days, or 45 days or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or leap years, the treatment of at least one corticosteroid is effective the amount. In other embodiments, this formulation provides an immediate release and extended release formulation of the skin steroid. In still another embodiment, the formulation contains 140447.doc •94-200950787 0.25:1 ratio, or a .5:1 ratio, or a 1:1 ratio, or a 丨:2 ratio, or a 1: 3 ratio 'or a 1:4 ratio, or one! : 5 ratio, or -1 · 7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:2 〇 ratio of immediate release and extended release formulations. In yet another embodiment, the formulation provides for immediate release of a first-corticosteroid and a second corticosteroid or other treatment. Extended release of the agent. In yet another embodiment, the formulation provides immediate release and an extended release formulation of at least one of the agents, with at least one therapeutic agent. In certain embodiments of φ, the formulation provides a ratio of .25", or a ratio of .5:1, or a ratio of 1·1, or a ratio of 1:2, or a ratio of 1:3, or - Bu 4 ratio, or a 1:5 ratio, or a 1:7 ratio, or a 1:1 ratio, or a 1:15 ratio, or a 1:2 ratio of the first corticosteroid and the second treatment The immediate release and extended release formulations of the agents. In yet another embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the disease site and is substantially free of systemic exposure. In yet another embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the disease site without measurable systemic exposure. In other embodiments, a therapeutically effective amount of at least an auricular agent is provided at the disease site with little or no measurable systemic exposure. Combinations of immediate, delayed, and/or extended release of a corticosteroid composition or formulation can be combined with other pharmaceutical agents disclosed herein, as well as excipients, diluents, stabilizers, tonicity agents, and other components. Thus, depending on the corticosteroid used, the desired consistency and/or viscosity, or the selected mode of delivery, another aspect of the embodiments disclosed herein can be combined with embodiments of immediate release, delayed release, and/or extended release. 140447.doc -95- 200950787 In a particular embodiment, the pharmacokinetics of the corticosteroid formulations described herein are determined by injecting this formulation into or near the inner ear round window membrane of a test animal (example scorpion or squirrel). . The pharmacokinetics of the formulation are tested at a measurement time (eg, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days for up to 1 week). Animals were euthanized and tested with 5 ml peripheral lymphatic fluid samples. Remove the inner ear and test for the presence of corticosteroids. Determine the amount of corticosteroid in other organs, if needed. In addition, the systemic amount of corticosteroids was measured by taking blood samples from the test animals. To test whether this formula interferes with hearing, test the animal's hearing to select the test for ©. The replacement is also provided for the inner ear (as removed from the test animal) and for measuring the movement of the corticosteroid. If another can suppress this IB.u force, provide an in vitro model of the inner ear window membrane and measure the movement of corticosteroids. Manufacturing Kit/Item The present invention also provides a kit for preventing, warding, numbing, or treating a disease or a symptom of a mammal. This kit

Ampoule* contains at least the composition of the steroid-controlled release oxime disclosed herein and instructions for using the kit. The present invention also contemplates the use of a corticosteroid-controlled release composition of - or a sputum for the treatment, reduction, . . . , At β ^ reduction and improvement in mammals such as human diseases, dysfunction, or genital genus f The manufacture of medical preparations for milk animals such as human i§l ancient syndromes, such as human beings, suspected of ^ ^ , , ^ X praised as the risk of inner ear disorders. In certain embodiments, the sleeve includes a carrier, a package, a compartment to accommodate one or - a garment A - the container includes - a separation element and the like for use in the methods described herein . Suitable 140447.doc • 96· 200950787 includes, for example, bottles, vials, syringes, and test tubes. In other embodiments, the container is formed from a variety of materials such as glass or plastic.

The article of manufacture provided by the present invention comprises a packaging material. A packaging material for packaging the pharmaceutical product of the present invention. See, for example, U.S. Patent 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 any suitable formulation and packaging materials for the mode of administration and treatment. . The broad sequence formulation of the corticosteroid composition provided by the present invention is intended to be a multitude of treatments for any disease, disorder, or condition, which has the advantage of being administered to the inner ear by controlled release of corticosteroids. In certain embodiments, a kit substantially comprises one or more additional containers, each having a different substance (eg, a reagent, optionally in a concentrated form, and used in the formulations described herein from a commercial and user perspective) / or device). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packs, containers, vials, and/or tube labels indicating levels and/or instructions for use, and instructions for use. The package is inserted. Basically includes a set of instructions. EXAMPLES Example 1 - Preparation of a Thermoreversible Gel Methyl Dehydrocorticosterol Formulation (Formulation mg/g) 20.0 1.0 10.0 180.0 789.0 Ingredients

Methyl dehydrocorticosterol hydroxybenzoate HPMC Poloxamer 407 TRISHC1 Buffer (0.1M) 140447.doc -97 200950787 A gel containing 2.0% methyl dehydrocorticosterol The 10-g batch of the formulation was prepared by suspending 1.80 g of poloxamer 407 (BASF) in 5.00 g TRIS HC1 buffer (0.1 Torr) and shaking at 4 °C overnight to ensure complete dissolution. Add decyl dehydrocorticosterol (200·0 mg), hydroxypropyl methylcellulose (100.0 mg), decyl paraben (10 mg) and additional TRIS HC1 buffer (0.1 M) (2_89 g) and stir again until complete dissolution was observed. This mixture was kept below room temperature until use. Example 2 - Preparation of mucoadhesive, thermoreversible gel dehydrocortisol formulation (mg/g of formula) 30 1.0 10.0 2.0 180.0 787.0 Ingredients dehydrocortisol thiol p-hydroxybenzoate HPMC Kapomo 934P Poloxamer 407 TRIS HC1 Buffer (0.1 M) A mucoadhesive containing 2.0% dehydrocortisol, a gel formulation of ΙΟ-g batch by 2.0 mg of Carbomo 934P and 1.80 g Losham 407 (BASF Corporation) was suspended in 5.00 g of TRIS HC1 buffer (0.1 M) and shaken at 4 ° C overnight to ensure complete dissolution. Add dehydrocortisol, hydroxypropyl decyl cellulose (100.0 mg), decyl p-hydroxybenzoate (10 mg) and additional TRIS HC1 buffer (0.1 M) (2_87 g) and stir until observed To completely dissolve. This mixture was kept below room temperature until use. Example 3 - Preparation of a cyclodextrin-containing thermoreversible gel 2.5% methyl dehydrocorticosterol formulation 140447.doc •98- 200950787 Amount (formulation mg/g) 500.0 1.0 180.0 317.0 Ingredient 5% CD solution Mercapto-p-hydroxybenzoate poloxamer 407 TRISHC1 buffer (0.1M) Poloxamer 407 (BASF) was suspended in TRIS HC1 buffer (0.1 Μ) and the component vibrated at 4 ° C Mix overnight to ensure complete dissolution. A cyclodextrin solution and methyl p-benzoic acid g were added and re-mixed until complete dissolution was observed. This mixture was kept below room temperature until use. Example 4 - Preparation of a cyclodextrin-containing mucoadhesive, thermoreversible gel methyl dehydrogenation Corticol formulation (mg/g of formula) 500.0 1.0 180.0 2.0 317.0

5% CD solution methyl paraben poloxamer 407 carbomer 934P TRISHC1 buffer (0.1M) Carbomo 934P and poloxamer 407 (BASF) suspended in TRIS HC1 buffer (0.1 The mixture was shaken and mixed at 4 ° C overnight to ensure complete dissolution. The cyclodextrin solution and methyl paraben were added and stirred until complete dissolution was observed. This mixture was kept below room temperature until use. Example 5 - Preparation of a Thermoreversible Gel Methyl Dehydrocorticosterol Formulation Containing Micronized Methyl Dehydrocorticosterol

Methyl dehydrogenated cortex W BHT poloxamer 407 PBS buffer (0.1 M) Amount (with mg/g of * square) 20.0 0.002 160.0 9.0 140447.doc -99· 200950787 2.0% micron of a 10-g batch Methyl dehydrocorticosterol, 13.8 mg Sodium citrate monohydrate USP (Fisher Scientific) + 3.1 mg sodium hydrate monohydrate USP (Fisher Scientific) + 74 mg sodium hydride USP (Fisher Scientific The company's gel formulation was dissolved in 8.2 g of sterile filtered DI water and the pH was adjusted to 7.4 with 1 M NaOH. This buffer solution was iced and sprinkled with 1.6 g of Poloxamer 407 (BASF, containing about 1 ppm of BHT) to this frozen PBS solution, and the solution was mixed until all the poloxamers dissolved. This poloxamer was sterilized and filtered using a 33 mm PVDF 0.22 μιη sterile syringe filter (Millipore) and transferred to a 2 ml sterilized glass vial (Wheaton) in a sterile environment. The vial was sealed with a sterile butyl rubber stopper (Kimble). It is crimped with a 13 mm A1 (Kimble). 20 mg of micronized methyl dehydrocorticochemical (Spectrum chemicals) was placed in a separate clean de-heated vial sealed with a sterilized butyl rubber stopper and crimped with a 13 mm A1 (Kimble) , the vial is at 140. The crucible was subjected to dry heat sterilization (Fisher Scientific Isotemp oven) for 7 hours. Use the 1 mL sterile syringe (Bect〇n) before performing the experimental administration described in this article.

Dickinson's 21G needle (Becton Dickinson) delivers 1 ml of cold poloxamer solution to a vial containing 20 mg of sterilized micronized sulfhydryl dehydrocorticosterol, and the suspension is thoroughly mixed by shaking to ensure the suspension Homogenization. This suspension was then withdrawn using a 21G syringe and the needle was replaced with a 27 g needle for administration. Example 6 - Preparation of micronized Prysson formulation with a thermoreversible gel containing a penetration enhancer 140447.doc • 100· 200950787 Amount (mg/g of formula) 20.0 1.0 1.0 10.0 180.0 789.0 Ingredients Presson

Mercapto-p-hydroxybenzoate dodecyl maltoside (A3) HPMC Poloxamer 407 TRISHC1 buffer (0.1M) A gel formulation containing 2.0% micronized Prysson Prepared by suspending 1.80 g of Poloxamer 407 (BASF) in 5.00 g TRIS HC1 φ buffer (0.1 Torr) and the components were shaken overnight at 4 °C to ensure complete dissolution. Adding Prysson (200.0 mg), propyl propyl decyl cellulose (100.0 mg), methyl paraben (10 mg) and dodecyl maltoside (10 mg) with additional TRIS HC1 Buffer (0.1 M) (2.89 g) and stir again until complete dissolution was observed. This mixture is kept below room temperature until use. Example 7 - pH 17% poloxamer 407 NF/2% methyl dehydrocorticosteroid phosphate (DSP) in autoclave treatment in PBS buffer Ο a 17% poloxamer 407/ 2% methyldehydrocorticosteroid phosphate (DSP). The raw material solution was dissolved by 35 1.4 mg of sodium chloride (Fisher Scientific), 302.1 mg of di-n-hydrate (Fisher Scientific), 122.1 mg of sodium silicate. Anhydrous (Fisher Scientific) and 2.062 g of methyl dehydrocorticosteroid phosphate (DSP) were prepared by sterilizing and filtering DI water with 79.3 g of an appropriate amount of ear. This solution was cooled in a freezing water bath and then sprinkled into 17.05 g of poloxamer 407 NF (Spectrum Chemicals) into a cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. The pH of this solution was measured. 140447.doc -101 - 200950787 17% poloxamer 407/2% decyl dehydrocorticosteroid phosphate (DSP) in PBS, pH 5.3. A portion (about 30 mL) of the above solution was taken and 1 M HCl was added to adjust the pH to 5.3. 17% poloxamer 407/2% decyl dehydrocorticosteroid phosphate (DSP) in PBS, pH 8.0. A portion (about 30 mL) of the above raw material solution was taken and 1 M NaOH was added to adjust the pH to 8. PBS buffer (pH 7.3) was prepared by dissolving 805. 5 mg sodium chloride (Fisher Scientific), 606 mg acid disodium anhydride anhydrate (Fisher Scientific), 247 mg sodium sulphate anhydrate (Fisher Scienti He), followed by sterilization. Prepared by converting the amount of DI water to 200 g. A 2% pH 7.3 solution of methyl dehydrocorticosteroid (DSP) in PBS by dissolving the appropriate amount of methyl dehydrocorticosterol phosphate (DSP) in PBS buffer and in PBS buffer Prepared by appropriate amount to 10 g. The 1 mL sample was placed in a 3 mL screw cap glass vial (lined with rubber) and tightly sealed. This vial was placed in a Market Forge-Sterilmatic high pressure dad (set, slow liquid) and sterilized at 250 °F for 15 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing the vial when cooled. Observe and record the appearance (eg, discoloration and/or precipitation). 2% DSP alone showed discoloration (light yellow) and partial precipitation in PBS, while samples containing poloxamer did not show discoloration. In the sample containing poloxamer, precipitation was observed only in the sample having a pH of 5.3. HPLC analysis using Agilent 1200 with Luna C18(2) 3 μιη, ΙΟΟΑ, 250 x 4.6 mm column using a 30-80 acetonitrile gradient (1-10 min) containing 140447.doc -102- 200950787 0.05% TFA The water-acetonitrile mixture was carried out for a total test time of 15 minutes. Record the main peaks as shown in the table below. The sample was diluted by taking a 30 μL sample and dissolving it in 1.5 ml of a 1:1 propionitrile water mixture. The purity of the sample was greater than 99% prior to high pressure helium treatment. Table 1 Properties observed after autoclaving of a sample containing methyl dehydrocortisol sodium phosphate (DSP). % Appearance % DSP % Dex (RRT = 1.27) 1.5% of RRT 1.68 % RRT 2% DSPpH = 7.3 Light yellow 89 6.5 1.41 17% 407/2 % DSP PBS, pH-5.3 Precipitation 53 45.9 0.48 0.56 17% 407/2% DSP PBS > pH=7.3 Clear solution/gel 88 10 0.79 17% 407/2% DSP PBS > pH = 8.0 Clear Solution / Gel 92 4.9 1.18 - The purity of all samples was 99 + % before autoclaving. Example 8 - Effect of autoclave treatment on the release profile and viscosity of 17% poloxamer 407NF / 2% methyl dehydrocorticosteroid phosphate (DSP) in PBS buffer. A component of the sample of Example 6 (autoclave treatment and no autoclave treatment) was used to evaluate the release profile and viscosity measurement to evaluate the impact of heat sterilization on the properties of the gel. Dissolution was carried out at 37 ° C in a Snap well s (6.5 mm diameter polycarbonate film having a pore size of 0.4 μηι). The 0.2 mL gel formulation was placed in Snapwell and allowed to stand until hardened, then 0.5 mL of buffer was placed in the reservoir and shaken at 70 rpm using a Labline Oscillator. The sample was taken every hour (0.1 mL was taken and replaced with warm buffer). The poloxamer concentration of the sample was analyzed using a cobalt thiocyanate method at 624 nm UV and referenced to an external calibration standard curve. Briefly, a 20 μΕ sample was mixed with 1980 pL of 15 mM cobalt thiocyanate 140447.doc • 103 · 200950787 solution and used with the Evolution 160 UV/Vis spectrometer (Thermo

Scientific) The absorbance was measured at 625 nm. Release of the ear thiol dehydrocorticosteroid phosphate (DSP) in accordance with Korsmeyer-

Peppas equation Q = ktn + b

Qx 〇 where Q is the amount of release of the ear agent at time t' Qa is the total release amount of the ear agent, k is the release constant of the nth order, η is a factorless number with respect to the dissolution mechanism and b is the axis intercept , characterized by an initial burst mechanism, where n = 1 refers specifically to an erosion control mechanism. Mean dissolution time (MDT) is the sum of the drug molecules staying in the matrix during different time periods before release, divided by the total number of molecules and calculated by the following formula: MDr = heart it + 1 viscosity measurement using a water jacket The temperature control unit (temperature increased at 15-34 ° C with a slope of 1.6 ° C / min) Brookfield viscometer RVDV-II + P at 0.08 rpm (shear rate of 0.31 s · 1) rotating CPE-51 spindle get on. Tgel is defined as the curve inflection point due to the increase in viscosity due to peptide-gel conversion. Table 2 Effect of Autoclave Treatment on 17% Poloxamer 407NF/2% Methyl Dehydrocorticophosphate Sodium Phosphate (DSP) Release Curve 舆 Viscosity in PBS Buffer. MDT(hr) TgelfC) Max Viscosity* (Pas) Not treated by high pressure dad 3.2 25 403 High pressure dad treatment. 3.2 26 341 * at a shear rate of 0.31 s·1 in gel state (up to 37 ° C) Maximum Appearance Viscosity 140447.doc •104· 200950787 This result shows the release profile after 17% poloxamer 407 NF/2% methyldehydrocorticosterone phosphate (DSP) in autoclave treated with PB S buffer. A small utility with stickiness. Example 9 - Degradation products of a second polymer added to a formulation containing 2% methyldehydrocorticosteroid phosphate (DSP) and 17% poloxamer 407 NF after heat sterilization (autoclave treatment) Viscosity utility. Solution A. — pH 7.0 in a PBS buffer containing a carboxy-mercapto cellulose nano (CMC) solution by dissolving 178.35 mg of sodium chloride (Fisher Scientific), 300.5 mg of di-nano-anhydride (Fisher Scientific), 126.6 Mg acid anhydrate (Fisher Scientific) was prepared by sterilizing and filtering DI water at 78.4 g, then sprinkling 1 g of Blanose 7M65 CMC (Hercules, viscous 5450 cP @ 2°/.) into a buffer solution and heating to help dissolve And the solution is then cooled down. 17% poloxamer 407 NF/1% CMC/2% decyl dehydrocorticosterone sodium phosphate (DSP) at pH 7.0 to PBS by cooling 8.1 g of solution A in a chilled water bath followed by 205 mg Methyl dehydrocortisol sodium phosphate (DSP) is then prepared by mixing. 1.74 g of poloxamer 407 NF (Spectrum Chemicals) was sprinkled into a cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved. 2 ml of the previous sample was placed in a 3 mL screw-cap glass vial (lined with rubber) and tightly sealed. This vial was placed in a Market Forge-Sterilmatic high pressure dad (set in slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing as the vial was cooled. 140447.doc -105- 200950787 No precipitation or discoloration was observed after autoclaving. HPLC analysis as described in Example 6 was carried out. Less than 1% degradation product was detected due to hydrolysis of the sulfhydryl dehydrocorticosteroid product, i.e., the formulation was stabilized after autoclaving. Viscosity measurements were made as described in Example 7. The results show that the autoclave treatment has a slight effect on the viscosity of the gel or the Tgel temperature. Less overall impurities were observed in the formulation containing the poloxamer compared to the control (2% DSP in PBS). The dissolution test was carried out as described in Example 7. The results show that the MDT of 11.9 hr is compared to the MDT of 3.2 without the CMC formulation. The addition of CMC or a primary polymer is a diffusion barrier that introduces a release rate that reduces the thiol-dehydrocorticosterol (i.e., increases MDT). Example 10 Buffer type The utility of the degradation product of the formulation containing poloxamer 407NF after heat sterilization (autoclave treatment). A TRIS buffer was adjusted to 7.4 with 1 M HCl by dissolving 377.8 mg of sodium hydride (Fisher Scientific) and 602.9 mg of tributanol (Tromethamine, Sigma Chemical) followed by sterilizing the transition of DI water to 100 g. Stock solution containing 25% solution of TRIS buffer poloxamer 407: Weigh 45 g of TRIS buffer, freeze in a freezer bath, then sprinkle 15 g of poloxamer 407 NF (Spectrum Chemicals) into buffer while mixing. This mixture is further mixed until the poloxamer is completely dissolved. Stock solution containing 25% poloxamer 407 solution in PBS buffer (pH 7.3): dissolve 704 mg sodium chloride (Fisher Scientific), 601.2 mg fill 140447.doc •106- 200950787 acid dihydrate anhydrate (Fisher Scientific ), 242.7 mg of sodium phosphate anhydrate (Fisher Scientific) was sterilized in 140.4 g of DI water. The bath was cooled in a freezer bath and then sprinkled with 50 g of poloxamer 407 NF (SPECTRUM CHEMICALS) into a cold solution while mixing. The mixture was further mixed until the poloxamer was completely dissolved, and a clear and transparent solution was obtained. The pH of the obtained solution was measured to be 7.3. / Prepare a series of formulations with the above stock solution. The DNA dehydrocorticosteroid vinegar (DSP) and the micronized dehydrocorticosteroid USP from Spectrum chemicals were used in the experiments used. The 1 ml sample was placed in a 3 mL screw cap glass vial (lined with rubber) and tightly sealed. This vial was placed in a Market Forge-Sterilmatic high pressure dad (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing as the vial was cooled. HPLC analysis as described in Example 6 was carried out. Compare the stability in TRIS with PBS buffer. Table 3 Buffer type in the formulation containing methyl dehydrocorticosterol and methyl dehydrocorticosteroid phosphate in the degradation of the utility sample number appearance 1% DSP % Dex (RRT = 1.27) 1.54% RRT 1.68 %RRT 1%DSP/TRIS Light Yellow & Precipitation 41 54 2.68 0.97 2% DSP/TRIS Light Yellow & Shen Dang 41 55 2.4 0.57 4% DSP/TRIS Light Yellow & Precipitation 58 36 2.4 0.23 16%P407/2DSP /TRIS Precipitation 54 41 0.79 0.62 18% P407/2DSP/TRIS Precipitation 52 45 1.21 0.51 140447.doc -107- 200950787 20% P407/2DSP/TRIS Precipitation 55 43 0.86 0.49 18% P407/2DEX/TRIS Suspension - 99 0.22 0.55 2% DEX/TRIS suspension - 99 - 0.28 2% DSP/PBS Light yellow & precipitate 85.6 9.8 2.09 - 16% P407/2DSP/PBS Clear solution 78 17.5 1.86 - 18% P407/2DSP/PBS Clear solution 81.2 16.2 1.14 - 20% P407/2DSP/PBS Clear Solution 81.5 16.1 1.04 - 18% P407/2DEX/PBS Suspension - 97 1.06 0.45 2% DEX/PBS Suspension - 94.7 1.34 - Viscosity Measurement According to Example 7 get on. The results show that in order to reduce the hydrolysis during the autoclave treatment, the buffer needs to maintain a pH between 7 and 8 when warming up. An increased drug hydrolyzability was observed in TRIS buffer than in PBS (Table 3). The occurrence of other degradation products can be reduced by using the polymeric additives (e.g., P407) described herein. A reduction in degradation products was observed by comparison of the formulation containing 20% poloxamer 407 with the formulation without poloxamer 407 (Table 7). Formulations containing suspended micronized sulfhydryl dehydrocorticosteroids have greater stability in autoclave treatment than their solution counterparts. Example 11: Pulsed release otic formulations using sulfhydryl dehydrocorticosterol and sulfhydryl groups A combination of dehydrocorticosterol sodium phosphate (DSP) (1:1 ratio) was prepared as described herein for a pulse release agent formulation. 20% of the deliverable dose of methyldehydrocorticosterol was dissolved in the 17% poloxamer solution of Example 7 with the aid of beta cyclodextrin. The remaining 80% of the deliverable methyl dehydrocorticosterol dose is then added to the mixture and the final formulation is prepared according to any of the processes described herein. A pulse release formulation containing sulfhydryl dehydrocorticosteroid was prepared according to the procedure of the examples described herein and tested using the procedure described herein to determine the pulse 140447.doc -108 - 200950787 release profile. Example 12: Preparation of 17% poloxamer 407/2% DSP agent / 78 ppm Evans blue in PBS Stock solution of Ivans blue (5.9 mg/mL) in PBS buffer by dissolving 5_9 mg Ivans Blue (Sigma Chemical) was prepared with 1 mL PBS buffer (from Example 61). - A stock solution containing 25% poloxamer 407 solution in PBS buffer from Example 8 was used in this study. An appropriate amount of DSP was added to the stock solution of Example 8 to prepare a formulation containing 2% DSP (Table 4). Table 4 contains a stock solution of 25% poloxamer 407 solution in PBS buffer from Example 9. Sample ID 25% P407 in PBS (g) DSP (mg) PBS buffer (g) Evans blue solution (4) _ 17% P407/2DSP/EB 13.6 405.6 6 265 20% P407/2DSP/EB 16.019 407 3.62 265^ 25% P407/2DSP/EB 19.63 407 - 265~~ The above formulation was dosed to the middle ear of guinea pigs according to the procedure described herein and the gel of the formula was contacted at the dose administered and 24 hours after the dose was administered. Chemical ability and location of the gel. Example 13: Final sterilization of a poloxamer 407 formulation with a visible dye and no visible dye. 17% poloxamer 407/2% DSP/in phosphate buffer, pH 7.3: Dissolve 709 mg gasification sodium (Fisher Scientific), 742 mg acid dihydrate anhydrate USP (Fisher Scientific), 251.1 mg Sodium phosphate monohydrate USP (Fisher Scientific) and an appropriate amount of ear and 158.1 g of sterile filtered DI water. This solution was cooled in an ice water bath and then sprayed with 34.13 g of poloxamer 140447.doc-109-200950787 NF NF (Spectrum chemicals) to the cooled solution and mixed at the same time. This mixture is further mixed until the poloxamer is completely dissolved and a clear transparent solution is obtained. The pH of this solution was 7.3. 17. / 〇 poloxamer 407/2% DSP / 59ppm Evans blue in maleic acid buffer: take 2 mL 17% poloxamer 407 / 2% ear / in sulphate buffer solution and add 2 A solution of 5.9 mg/mL of Ivan's Blue (sigma-Aldrich chemical) in PBS buffer. 25% poloxamer 407/2% DSP/phosphate buffer: solvent 330.5 rng gasification nano (Fisher Scientific), 334.5 mg diammonium dihydrate USP (Fisher Scientific), 125.9 mg sodium sulphate monohydrate USP (Fisher Scientific) and an appropriate amount of ear are sterilized in 70.5 g of DI water. This solution was cooled in an ice water bath and then sprayed with 2 5.1 g of poloxamer 407 NF (Spectrum chemicals) to the cooled solution while mixing. This mixture is further mixed until the poloxamer is completely dissolved and a clear and transparent solution is obtained. The pH of this solution was 7.3. 25% poloxamer 407/2% DSP/59ppm Evans blue in phosphate buffer: Take 2 mL 25% poloxamer 407/2% DSP/phosphate buffer solution and add 2 mL of 5.9 A solution of mg/mL Ivan's Blue (Sigma-Aldrich Chemical) in PBS buffer. A 2 ml formulation was placed in a 2 mL glass vial (Wheaton serum glass vial) sealed with a 13 mm Butylstr (kimble plug) and sealed at 13 mm. This vial was placed in a Market Forge-Sterilmatic high pressure setting (slow, liquid state) and sterilized at 250 °F for 25 minutes. After the action of the high pressure dad, the sample 140447.doc -110- 200950787 was allowed to cool to room temperature and then placed in a refrigerator. This vial was placed in a refrigerator and mixed while cooling to homogenize the sample. The sample was decolorized or precipitated after autoclaving. HPLC analysis was performed as described in Example 6. Table 5 Effect of autoclave treatment on formulations containing visible dyes and sodium-containing dehydrocorticosterone phosphate without visible dyes. Sample ID 0.68%RRT % DSP % Dex (RRT-1.28) 1.41%RRT 1.76%RRT 17%P407 1.1 84.5 12.0 0.7 0.09 17% P407/Ivan Blue 1.1 84.4 11.7 0.8 0.09 25% P407 0.8 80.9 16.0 0.7 0.10 25% P407/Ivan Blue 0.9 80.9 15.3 0.7 0.12 Viscosity measurement was carried out as described in Example 7. The results show that the dye-containing formulation treated with high pressure ruthenium is ineffective for product degradation and viscosity of the formulation. Determine 25 ° /. The average dissolution time of the poloxamer 407 formulation (measured as described in Example 7, the amount of sulfhydryl dehydrocorticosteroid citrate released by UV @ 245 nm) was 5.6 hr and 17% Polo The sam 407 formulation is shown as _ 3.2 hr ° Example 14: Comparison of in vitro release profiles in Snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm) at 37 ° C, 0.2 mL The gel formulation described herein was placed in Snapwell and allowed to stand until hardened, then 0.5 mL of buffer was placed in the reservoir and shaken at 70 rpm using a Labline orbital shaker. The sample was taken every hour (0.1 mL was taken and replaced with warm buffer). An external calibrated standard curve was compared with the concentration of the ear of the sample analyzed by UV at 245 nm. Pluronic® 140447.doc • 111 - 200950787 Concentration was analyzed at 624 nm using a thiocyanate drilling method. The relative rank sequence of the mean dissolution time (MDT) of the function of %p4〇7 was determined. A linear relationship between the mean dissolution time (MDT) and the P407 concentration of this formulation showed that this methyldehydrocorticosterol release was attributed to the erosion of the polymer gel (poloxamer) but did not spread. A none-linear relationship shows a combination of otic release via diffusion and/or polymer gel degradation. - Alternatively, the sample was analyzed using the method described in Li Xin-Yu [Acta Pharmaceutica Sini Technology 2008, 43(2): 208-203] and determined as a function of % P407 as the average dissolution time (MDT) grade sequence. . © 'Figure 1 illustrates the in vitro release profile of a methyl dehydrocorticosteroid formulation with different concentrations of poloxamer 407. Figure 2 illustrates the near linear relationship (1:1 correlation) between the mean dissolution time (MDT) and the P407 concentration of the formulation. This result indicates that the methyldehydrocorticosterol release is attributed to the erosion of the polymer gel (poloxamer) but not to diffusion. Example 15: Comparison of gelation temperature in vitro. Evaluation of poloxamer 1 88 and methyldehydroquinone cortisol at gelation temperature with poloxamer 407 formulation for the purpose of gelation temperature Viscosity effect. - A 25% poloxamer 407 stock solution in PBS buffer (Example 9) was used with the PBS solution from Example 6. Poloxamer 188 NF from BASF was used. 140447.doc •112- 200950787 Table 6 Preparation of samples containing poloxamer 407/poloxamer 188 25% P407 stock solution (8) Poloxamer 188 (mg) PBS system s (g 16%P407/10%P188 3.207 501 1.303?^-- 17%P407/10%P188 3.4089 500 1.1056 ~~~ 18%P407/10%P188 3.6156 502 09072~~~~ 19% P407/10% PI 88 3.8183 500 0.7050-— 20% P407/10% PI 88 4.008 501 05032^ - 20% P407/5% PI 88 4.01 256 0770 20% poloxamer 407/10% rossam 188 average dissolution time (in implementation The method described in Example 7 was determined to be 2.2 hr and 20% poloxamer 407/5% poloxamer 18 8 was shown to be 2 · 6 hr. The viscosity was measured using the method described in Example 7. Autoclave treatment is not effective on the viscosity or Tgel of formulations containing poloxamer 188. An equation suitable for the data obtained and which can be used to estimate the gelation temperature of the F127/F68 mixture (for 171-2% F127 and 0-10% F68) is as follows. T»»=-1.8 (%F127)+1.3 (% F68)+53 One suitable for the data obtained and can be used to estimate a gel based on F127/F68 mixture (for 17-25% F127 and 0-10% F68) The equation for the average dissolution (hr) of the temperature was used for the results obtained in Examples 12 and 14. MDT = -0.2 (T-gel) + 8 Example 16: Determination of the temperature range for sterilization transitions The viscosity at low temperatures is measured to help guide the temperature range that is required for sterilization filtration to reduce the likelihood of blockage. Use a Brookfield viscometer RVDV-II+P with a water jacketed temperature control unit (temperature increase at 1 〇 -25 ° C with a slope of 1.6 ° C / min) at 1, 5 and 10 rpm (shear rate 7.5) , 37.5 and 75 s-1) Rotating CPE-40 heart 140447.doc -113- 200950787 Viscosity measurement under the shaft. A 17% Pluronic P407 Tgel oxime agent was tested for increasing concentration function. The Tgel increased by 1 7% Pluronic formula is estimated by the following equation: △ T condensate = 0.93 [〇 / 〇 ear &> 1] Table 7 Viscosity of potential formulations under manufacturing/filtration conditions.

Sample Appearance Viscosity * \ia (cP) Temperature @ lOOcP Below Tgel5°C 20°C Placebo 52cP@ 17°C 120 cP 19°C 17% P407/2% DSP 90cP@ 18°C 147 cP 18.5〇C 17% P407/6% DSP 142 cP@ 22〇C 105 cP 19.7 V Viscosity measured at a shear rate of 3 7.5 s·1 This result shows that the sterilization filtration of the formulation described in this article can be performed at approximately 19 ° C get on. Example 17: Determination of manufacturing conditions A 7 liter batch of 17% P407 placebo was prepared to evaluate manufacturing/filtration conditions. Placebo was prepared by placing 6_4 liters of DI water in a 3 gallon SS pressure vessel and allowed to stand in the freezer for overnight cooling. Remove the container in the next morning and add (water temperature 5 ° C, RT 18 ° C) and 48 g sodium chloride, 29.6 g disodium phosphate anhydrous and 10 g sodium phosphate monohydrate and use a top mixer (IKA RW20 @ 1720 rpm) dissolved. After half an hour, once the buffer was dissolved (solution temperature 8 ° C, RT 18 ° C), 1.36 kg of poloxamer 407 NF (Spectrum Chemicals) was slowly sprinkled into the buffer solution at a 15 minute interval (solution temperature 12 ° C, RT 1 8 ° C), then increase the speed to 2430 rpm. After mixing for another hour, the mixing speed was reduced to 1062 rpm (completely dissolved). . The room temperature was maintained below 25 ° C to keep the temperature of the solution below 19 °C. The solution temperature 140447.doc -114- 200950787 degrees was maintained below 19 °C for 3 hours of initial manufacture without the need for a freeze/cool container. Estimating three different Sartoscale (Sartorius Stedim) sites with a surface area of 17.3 cm2 at 20 psi and 14 °C

Sartopore 2, 0.2 μm 5445307HS-FF (PES), flow rate 16 mL/min

Sartobran P, 0·2 μπι 5235307HS-FF (cellulose ester), flow rate 12 mL/min

Sartopore 2 XLI, 0.2 μm 5445307IS-FF (PES), flow rate 15 mL/min using Sartopore 2 filter 5441307H4-SS, using a 0.45, 0·2 μη Sartopore 2 150 sterilized capsule with a surface area of 0.015 m2 at the solution temperature (Sartorius Stedim) was simmered at a pressure of 16 psi. The flow rate was measured at 16 psi at approximately 100 mL/min and the rate was unchanged when the temperature was maintained at 6.5-14 °C. The reduced pressure of the solution and the increased temperature cause a decrease in flow rate due to the increased viscosity of the solution. The discoloration of the solution was monitored during the process. Table 8 Predicted filtration time of a 17% poloxamer 407 placebo using a Sartopore 2, 0.2 μιη filter at a pressure of 16 psi at a solution temperature of 6.5-14 °C. Filter size (m2) Estimated flow rate (mL/min) Filter 8 L time (estimated) Sartopore 2, size 4 0.015 lOOmL/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 140447.doc -115- 200950787 Viscosity, Tgel and UV/Vis absorbance were measured prior to filtration evaluation. Pluronic UV/Vis spectra were obtained by Evolution 160 UV/Vis (Thermo Scientific). The peak in the 250-300 nm range is derived from the BHT stabilizer present in the raw material (poloxamer). The foregoing process can be used to make 17% P407 formulations and includes temperature analysis in ambient conditions. The temperature of 19 ° C reduces the cost of the cooling vessel during manufacturing. In some instances, a jacketed container is used to further control the temperature of the solution to alleviate manufacturing concerns. Example 18 Methyl dehydrocorticosterol In vitro release of 17% poloxamer 407/1.5% otic agent in TRIS buffer by autoclave-treated micronized sample: 250.8 mg sodium chloride (Fisher ScientiHc And 302.4 mg of tributanol (Sigma Chemical) were dissolved in 39.3 g of sterilized transition DI water and the pH was adjusted to 7.4 with 1 M HCl. 4.9 g of the foregoing solution was used and an appropriate amount of micronized deuterated dehydrocorticosterol USP (Spectrum Scientific) was suspended and well dispersed. 2 mL of this formulation was transferred to a 2 mL glass vial (Wheaton serum glass vial) sealed with a 13 mm butyl styrene S (kimble plug) and sealed with a 13 mm|S seal. This vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the high pressure dad, the sample was allowed to cool to room temperature. This vial was placed in a refrigerator and mixed while cooling to homogenize the sample. The sample was precipitated or decolored after the autoclave was applied. Dissolution in Snapwells (6.5 mm diameter polycarbonate film with a pore size of 0.4 μηη) at 37 ° C, 0.2 mL gel formulation placed at 140447.doc -116- 200950787

The Snapwell was allowed to stand until it hardened, then 5 mL of PBS buffer was placed in the reservoir and the Labline was used to vibrate at 70 rpm. The sample was taken every hour [0.1 mL was taken out and replaced with 2% PEG-40 hydrogenated castor oil (B ASF) warm PBS buffer to promote methyl dehydrocorticosteroid solubility]. The thiol-dehydrocorticosteroid concentration of the sample was analyzed using a 245 nm UV reference-external calibration standard curve. The release rate is compared to other formulations disclosed herein. Calculate the MDT time for each sample. The solubility of sulfhydryl dehydrocorticosteroid in the 17% poloxamer system was assessed by the concentration of methyl dehydrocorticosterol in the supernatant of the sample centrifuged at 15,000 rpm for 10 minutes in an Eppendorf centrifuge 5424. The methyl dehydrocorticosterol concentration in the supernatant was determined using a 245 nm UV reference-external calibration standard curve. Figure 3 illustrates the release profile of different steroids containing 17% P407. Table 9 describes the solubility of sulfhydryl dehydrocorticosteroid in TRIS buffer and 17% P407 solution. Table 9 Methyl dehydrocorticosteroid concentration in the solubility sample of TRES buffer and 17% P407 solution _ WmL) ___ 17% P407/1.5% DEX/TRIS 580 2% DES of TRIS Buffer (Example 4) 86 2% DEX of TRIS Buffer Treated by Autoclave (Example 4) 153 Example 19 Release Rate or MDT of Formulation Containing Sodium Carboxymethyl Cellulose With stickiness. 17% poloxamer 407/2% DSP/1% CMC (Hercules Blanose 7M): carboxymethylcellulose sodium (CMC) solution (pH 7.0) in PBS buffer. 140447.doc -117- 200950787

The DI water was sterilized by dissolving 205. 6 mg of sodium chloride (Fisher Scientific), 372_1 mg of di-nanohydrate dihydrate (Fisher Scientific), and 106.2 mg of sodium sulphate monohydrate (Fisher Scientific) at 78.1 g. preparation. Then sprinkle 1 g of Blanose 7M CMC (Hercules, viscous 533 cP @ 2%) to the buffer solution and heat to aid dissolution, and the solution was then cooled 'and sprinkled into 17.08 g of Poloxamer 407NF (Spectrum Chemicals) to Mix in a cold solution at the same time. Prepare a formulation containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer, add/dissolve an appropriate amount of thiol dehydrocorticosterol to 9.8 g of the above solution, and Mix until the ear is completely dissolved. The pH of this solution was 7.0.

17% poloxamer 407/2% DSP/0.5% CMC (Blanose 7M65): Solvent 257 mg sodium chloride in carboxy buffered sodium methacrylate (CMC) solution (pH 7.2) in PBS buffer (Fisher Scientific ), 375 mg of di-nanohydrate dihydrate (Fisher Scientific), 108 mg of sodium carbonate monohydrate (Fisher Scientific) were prepared by sterilizing and filtering DI water at 78.7 g. Sprinkle 0.502 g of Blanose 7M65 CMC (Hercules, viscous of 5450 cP @ 2%) to the buffer solution and heat to aid dissolution, and then cool the solution and sprinkle with 17.06 g of Poloxamer 407 NF (Spectrum Chemicals) Mix simultaneously into the cold solution. A solution containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer was prepared, and 201 mg DSP was added/dissolved to 9.8 g of the above solution and mixed until the DSP was completely dissolved. The pH of this solution was 7.2. 170/〇泊洛沙姆407/2% DSP/0.5% CMC (Blanose 7H9): a solution of sodium carboxymethyl cellulose (CMC) in PBS buffer (pH 7.3) by 140447.doc -118- 200950787 Prepared by dissolving 256.5 mg of sodium chloride (Fisher Scientific), 374 mg of di-nanohydrate dihydrate (Fisher Scientific), and 107 mg of sodium citrate monohydrate (Fisher Scientific) in 78.6 g of sterile filtered DI water, followed by sprinkling 0·502 g Blanose 7H9 CMC (Hercules, viscous of 5600 cP @ 1%) to a buffer solution and heated to aid dissolution, and this solution was then cooled and poured into 17.03 g of Poloxamer 407 NF (Spectrum Chemicals) Mix simultaneously into the cold solution. A solution containing Π% poloxamer 407 NF/l°/〇 CMC/2% DSP in PBS buffer was prepared, added/dissolved 203 mg DSP to 9.8 g of the above solution, and mixed until the DSP was completely dissolved. The pH of this solution was 7.3. Viscosity measurements were performed as described in Example 7. Dissolution was carried out as described in Example 7. Figure 4 illustrates the correlation between the mean dissolution time (MDT) of the formulation and the apparent viscosity of the formulation. The rate of release is modulated by the incorporation of a secondary polymer. The grade and concentration of the primary and secondary polymers can be selected by promoting the use of one of the generally available water soluble polymerizations shown in Figures 5 and 6, Example 20 - Micro-methyl dehydrogenation Dry Sterilization of Corticosteroid Powder 10 mg of micronized methyl dehydrocorticosterol powder (Spectrum lot XD0385) was filled into a 2 ml glass vial and sealed with a 13 mm butyl rubber stopper (Kimble) and placed in an oven at different temperatures In 7-11 hours. HPLC analysis using Agilent 1200 with Luna C18(2) 3 μιη, 100A, 250 x 4.6 mm column using 30-95 solution B (solvent A 35% methanol: 35 ° / hydrazine: 30% acetate) Buffer, solvent B 70% methanol: 30% B 140447.doc • 119- 200950787 Acid buffer pH 4) Gradient (1-6 min) followed by isocratic (95% solvent B) ll minutes, total test 22 minutes . The sample was dissolved in ethanol and analyzed. Dry heat sterilization of micro-degraded methyl dehydrocorticosterol at temperatures up to 13 8 °C does not affect the particle size distribution of micronized sulfhydryl dehydrocorticosteroids. HPLC analysis showed 99% purity of the micronized methyl dehydrocorticosteroid sterilized by dry heat. Example 21 - Adhesive corticosteroid formulation for inner ear round window film Formulation was prepared as in Example 1 and loaded into a gas-filled disposable 5 ml deuterated glass syringe with a 15 gauge needle. Lidocaine is topically applied to the tympanic membrane and a small incision for viewing the middle ear chamber is made. The needle tip is guided to the position on the inner round window membrane and the anti-inflammatory corticosteroid formulation is applied directly to the round window membrane. Example 22 - In-the-ear test for intra-oral injection of a corticosteroid formulation of the day of the mole. A 21-day-old mole (Charles River, female weighing 2〇〇_3〇〇§) of the same attribute group was injected intratracheally with 2% of the 20% DSP formula. Figure 7 shows the results of gelation after 5 days of intrathecal injection of guinea pig ears. Increased injection volume increased by up to 90 μιη injection volume of gel retention. However, the 12-injected injection volume showed a lower gel retention. The 2nd-day-old squirrel of the same attribute group (Charles River, weighing 2〇〇3〇〇§ although ‘!·生) is 50 L 之 冬 冬 η 乂 乂 乂 。 η.

DSP distribution;

process. Degree of DS 140447.doc 200950787 solution time (MDT)). Furthermore, when the P407 concentration for the 6% DSP formulation (6% Dex-P(*)) was increased from 17% to 19%, a faster gel removal was observed, as shown in Figure 8. Therefore, the injection volume and concentration of corticosteroids in the formulations described herein are tested to determine the optimal parameters for preclinical and clinical trials. It has been observed that an in-ear formula with a high concentration of DSP has a release profile that is different from an in-ear formula with a lower concentration of DSP. Example 23 - 21-day-old zigzag (Charles River, 200-300 g female) with a release kinetic energy in vivo and in vivo was buffered at 50 pL 17% at 280 mOsm/kg and had a formulation of 1.5 wt% Intra-injection of Pluronic F-127 formulation to 4.5 wt% thiol dehydrocorticosteroid. Animals were dosed on day 1. Figure 9 shows the release profile of the formulation based on the peripheral lymphatic analysis. In the 1.5% thiol dehydrocorticosterol treatment, the exposure on days 7-10 was about 10% of the Cmax with an average residence time of about 3.5 days. In the 4.5% methyl dehydrocorticosterol treatment, the exposure was maintained at a similar or higher than the amount observed on Day 1 for at least 10 days, and a predicted average residence time was over 18 days. Example 24 - Evaluation of corticosteroid formulations in animal models of AIED Methods and substances Induction of immune response

Female white Swiss mice (Swiss rats) weighing 20 to 24 g from the National Institutes of Health (Harlan Sprague-Dawley, Inc., Indianapolis, Indiana) were used. Keyhole limpet hemocyanin (KLH; Pacific Biomarine Supply, Vic, Canada) was suspended in phosphate-buffered saline (PBS) IpH 140447.doc -121 - 200950787 6.4, sterile dialysis against PBS And centrifuged twice. The pellet (attached to KLH) was dissolved in PBS and injected subcutaneously into the back of the animal (0.2 mg emulsified in Freund's complete adjuvant). Animals were given a supplement (0.2 mg KLH in Freund incomplete adjuvant) and then injected into the micropores through the cochlear sac with 0.1 mg KLH in 5 μM PBS (pH 6.4) after 10 weeks. Use the operating microscope and sterilization technology to access the cochlea. The incision is made after one ear and a hole is drilled into the bubble to allow visibility of the cochlear gyrus, the radial artery and the rounded window of the inner ear. Cauterize the iliac artery and remove it, and drill a 25 μπι hole through the ear sac to the basal back of the basal ganglia. The KLH or PBS control group was slow to use a Hamilton syringe coupled to a plastic tube to inject a glass microtiter filled with antigen or control. This well is sealed with bone soil after injection and excess liquid is removed. Only one deafness per animal was treated with KLH. Treatment KLH and control mice were divided into two groups (n=10 per group). The corticosteroid formulation of Example 1 containing methyl dehydrocorticosteroid was applied to the inner ear window membrane of a group of animals. A control formulation containing no methyldehydrocorticosterol was administered to the second group. This methyl dehydrocorticosterol and control formulation was administered three days after the initial administration. The animals were killed after 7 days of treatment. Analysis of Results Electrophysiological Testing The hearing floor of the auditory brainstem response bottom (ABR) was measured by tapping each ear of each animal initially and after 1 week of the experimental procedure. The animals were placed in a single walled environmental chamber (Industrial Acoustics, Brooks, NY, USA) on a heating mat. Subcutaneous electrode (Astro-140447.doc -122- 200950787, Siva Walk, Rhode Island, USA)

Med's Grass Instrument branch) inserts the cranial (active electrode), mastoid (reference electrode) and hind leg (grounding wire). The tapping stimulus (0.1 ms) was generated by the brain and transmitted to a Beyer DT 48, 200 Ohm amplifier with an ear speculum placed in the external auditory canal. Amplify the recorded ABR and digitize it with a battery operated preamplifier and enter a Tucker-Davis Technologies ABR recording system that provides computer control for stimulation, recording, and averaging (Tucker Davis Technology, Inc., Ghana, Florida, USA) ). The amplitude-stimulated stimulation was successively reduced to the animals in a 5-dB step, and the stimuli-activity was recorded on average (n = 5 12) and was shown. The bottom limit is defined as the amount of stimulus that is invisible and can be used to detect responses and to clearly distinguish between responses. Histochemical analysis Anesthetized animals were sacrificed by intracardiac perfusion of heparinized warm saline and then fixed with approximately 40 ml of periodic acid- lysine-trimaldehyde (4% final concentration of paraformaldehyde). The right tibia was removed immediately and decalcified with buffered 5% ethylenediamine tetra-acetate (pH 7.2) for 14 days (4 °C). After decalcification, the tibia is then impregnated with increasing concentrations (50%, 75%, 100%) of frozen embedding agent (〇ct) compound (Tissue-Tek, Miles, Inc., Ihart, USA), fast Freeze (_7〇 °C) and freeze the sections (4 μιη) in parallel with the bone axis. The harvested sections were stained with hematoxylin and eosin (Η & Ε) and immunohistochemically analyzed. The severity of inflammation was assessed by cytosolic diafiltration and each cochlea was given an unbiased estimator. A score of 0 indicates no inflammation, while a score of 5 indicates that all of the deafness has severe inflammatory cell percolation. Example 25 - Evaluation of Corticosteroid Formulations in Animal Models of Otitis Media 140447.doc • 123- 200950787 Induction of Otitis Media In these studies, 400 to 600 g of weight were used with normal middle ear and examined with otoscope and tympanogram Healthy into a rat. The Eustachian tube barrier was performed for 24 hours prior to inoculation to prevent the inoculum from flowing out of the Eustachian tube. 1 ml of type 3 S. pneumoniae strain was placed directly on the low tympanic membrane of the middle ear of the long-tailed chinchilla in a 4-h-log phase (containing approximately 40 colony forming units (CFU)). Control rats were incubated with 1 ml of sterile PBS. Treatment S. pneumoniae culture and control mice were divided into two groups (n=l 0 in each group). The dehydrocortisol formulation containing Example 2 was applied to the tympanic wall of a group of animals. A control formulation containing no dehydrocortisol was administered to the second group. This dehydrocortisol and control formulation were re-administered three days after the initial administration. The animals were killed after 7 days of treatment. Analysis of Results Middle ear fluid (MEF) was sampled at 1, 2, 6, 12, 24, 48 and 72 hours after streptococcal inoculation. Quantitative MEF medium was performed on amniotic fluid, and the quantitative limit was set at 50 CFU/ml. Inflammatory cells were measured by a hemocytometer and the number of differentiated cells was stained by Wright's stain. Example 26 - AIDD Clinical Trial Using Methyl Dehydrocorticosterol Formulation 10 adult patients were selected who had previously responded to the system of thiol dehydrocorticosteroid treatment, but currently discontinued treatment due to adverse events. The thiol dehydrocorticosteroid hot reversible gel formulation of Example 1 was administered via a puncture tympanic membrane to the round window membrane of each patient. A gel formulation of thiol dehydrocorticosterol was administered again 7 days after the initial administration and re-administered at 2 and 3 weeks of treatment. 140447.doc -124- 200950787 A hearing assessment consisting of a pure tone audio test (250-8,000 Hz) and a speech test using a French two-syllable word list was performed for each patient. The tests were performed prior to the administration of the thiol dehydrocorticosterol formulation and at 1, 2, 3 and 4 weeks after the initial treatment. Example 27 - Assessment of dehydrocortisol in a rat model of hearing impairment Methods and materials '' Induction of ototoxicity Twelve mice weighing 20 to 24 grams (Harlan Sprague-Dawley gas) were used. The baseline of the auditory brainstem evoked response (ABR) at 4-20 mHz was determined. The rats were anesthetized and exposed to a continuous pure tone of 6 kHz with a loudness of 120 dB for 30 minutes. Treatment The control group (n=10) was given saline after hearing loss. The experimental group was given dehydrocortisol (2.0 mg/kg body weight) prepared in Example 2 after hearing loss. Electrophysiological testing φ The hearing deficit of the auditory brainstem evoked response low (ABR) was measured by tapping each ear of each animal initially and 1 week after the experimental procedure. The animals were placed in a single wall environmental chamber (Industrial Acoustics, Bryan, NY, USA) on a heating mat. The subcutaneous electrode (Grass Instrument Branch, Astro-Med, Siva Walk, Rhode Island, USA) was inserted into the top (acting electrode), the mastoid (reference electrode), and the hind leg (grounding wire). The tap stimulus (0.1 ms) was generated by a computer and transmitted to a Beyer DT 48, 200 Ohm amplifier with an ear spectrometer placed in the external auditory canal. Amplify the recorded ABR and digitize it with a battery operated preamplifier and enter a Tucker-Davis Technologies ABR record 140447.doc -125- 200950787 recording system that provides computer control for stimulation, recording and averaging (Gani, Florida, USA) Tucker Davis Techn〇l〇a, Foer). The amplitude-stimulated stimuli of the f dB step were successively reduced to the animals, and the activity was observed (n=512). The bottom limit is defined as the amount of stimulus between (4) response and clearly identifiable response. . Example 28 - Experimental study of methyl dehydrocorticosteroids in patients with Meniere's disease Objectives The main objective of this study was to evaluate thiol dehydrocorticosteroids in the placebo group - improvement in human subjects The safety and efficacy of tinnitus symptoms in patients suffering from Meniere's disease. Study Design This was a 3-phase, multicenter, double-blind, randomized, placebo-controlled, 3-arm parallel study to compare the treatment of tinnitus in the JB004/A versus placebo groups. Joel. Patients were enrolled in this study and were randomized (1:1) into 3 treatment groups in a random order prepared by the sponsor. Each group received 3 mg of methyl dehydrocorticosterol, which was reversely delivered by a thermogel, or a controlled release placebo formulation. The release of methyl dehydrogenated cortisol was controlled release and occurred within 30 days. Medication route - for intra-ear injection. & · Major Outcome Indicators. Visual Analog Scale (VA s ) to measure changes in tinnitus loudness (or relative pre-dose baseline at any other time point) measured after 2 hours of dosing. Alternatively, a hearing test is used in a healthy ear to match the tinnitus tone in the affected ear. β 140447.doc •126- 200950787 Secondary Outcome Indicators VAS measures the frequency, pain and anxiety of tinnitus. Pure tone hearing test Divine hearing assessment. Sleep Test & Fine Tinnitus Questionnaire Safety, Tolerance Dynamics. [Time frame 靼.+ sex and music in any other _ point (four) pre. (four) baseline). ^ Principles of Selection ... If any of the following principles are used, then: - Have a male or female individual with a diagnosis of tinnitus. - Individuals are willing to limit alcohol intake. _ Women who have the possibility to give birth but agree to give up sexual intercourse or consent to birth control. • Women without fertility. Exclusion Principles Patients selected if they have any of the following principles are excluded: - Intermittent or pulsed tinnitus - Individuals with pathological grade anxiety or depression. ❹ - The individual has no hearing impairment and has normal hearing. - The individual does not respond to the lidocaine injection test or shows a large variation in the pre-injection value. - There are any surgical or medical symptoms that may interfere with the pK of the drug. _ Individuals with a history of liver disability or abnormal liver function. - Individual with kidney disability. - Individuals with HIV, hepatitis C or sputum hepatitis positive. - The individual has an abnormal laboratory, ECG or physical examination decision. - The individual has no thyroid. 140447.doc -127· 200950787 - Individual with liver, heart, kidney, nerve, cerebrovascular, metabolic or pulmonary disease. - The individual has a myocardial infarction. - Individuals with a history of epilepsy disorders. - Individuals with a history of cancer. - Individuals with medication or other allergies. · Individuals are positive for drug use and/or substance abuse or dependence history. _ - Individuals take a psychotropic or antidepressant at a specific time frame. ^ - Agents or foods known to interfere with liver enzymes (eg grapefruit or grapefruit ©* juice). - Individual non-mental abnormalities with serotonergic mechanism of action. - The individual has currently used a study medication or recent participation - clinical trials. - Females have a positive pregnancy test. _ Pregnant women or men who will be fathers within 4 weeks after the last study of this study. - Individuals donated blood in the first few months with a donation of one unit of blood or more or one month after completing the study. Example 29 - Evaluation of methyl dehydrocorticosterol formulation in endolymphatic water animals (IV) This step is the efficacy of the thiol dehydrocorticosteroid formulation prepared in the Example 测定. MATERIALS AND METHODS A 35-day-old Hartley guinea pig was used with positive forward sounding of 140447.doc -128-200950787 (positive Preyer's reflex) and weighing approximately 3 〇〇 g. Five of them were used as control group (normal ear group) for 5 weeks without or without treatment, while the other 3 groups were only used as experimental animals. All experimental animals received an electrocauterized endolymphatic sac (Ere et al., Acta Otolaryngol. (1992) 112: 658-666; Takeda et al., Equilib. Res. (1993) 9: 139-143). Four weeks after the operation, the animals were divided into three groups: no-perfusion edema ear, carrier _ treatment of edema ear and methyl dehydrocorticosteroid-treated edema ear, one group of animals per group. No perfusion edema ear ❹ group did not receive treatment, in addition to electric cauterization of the endolymphatic sac. In the vehicle-treated edema ear and methyl dehydrocorticosteroid-treated edema ear group, the liposome formulation was applied to a round window membrane. One week after the composition was administered, the animals used were sacrificed to assess changes in endolymphatic space. All animals were undisturbed and free to move in their respective cages in a quiet room, except during the entire experimental period. In the assessment of changes in the endolymphatic space, all animals were perfused with a saline solution under deep anesthesia with pentobarbital in the abdomen and fixed in 1% F. Marlin. Remove the left tibia and set it at 10°/. The formalin solution is fixed for 1 〇 • days or longer. Next, it was decalcified by 5% trichloroacetic acid for 12 days and dehydrated in a grade ethanol series. It is embedded in paraffin and fire cotton glue. The prepared block was sliced in a horizontal direction of 6 μm. Sections were stained with hematoxylin and eosin and observed under a light microscope. Endolymphatic space change assessment was performed according to the Takeda method (Takeda et al., Hearing Res. (2003) 182: 9-18). Example 30 - Assessment of Spontaneous Instantaneous Sensorineural Hearing Loss (ISSHL) in Methyl Dehydrocorticosteroids 140148.doc -129- 200950787 The main purpose of this study is to do oral steroid therapy or ear Safety and efficacy of endogenous (it) steroid therapy. The primary outcome measures were plain tone hearing (PTA) and vocabulary recognition as endpoints of equal weight; for speech discrimination scores, a 50-word monosyllabic system was used; improvements in ρτΑ or all or part of the frequencies greater than 20 dB were The frequency loss is greater than 30 dB, and/or a 20% or more improvement in WDS; in addition to the absolute change, the recovery of the contralateral ear is also determined. Full recovery - restores to 5% of the opposite side speech discrimination score, or within 5 dB9 of the opposite side PTA. Study Design This was a multicenter, double-blind, randomized, placebo-controlled, parallel group study comparing ISShl treatment with methyldehydrocorticosterol and placebo. Approximately 1 40 individuals were enrolled in this study and were randomized into 3 treatment groups in random order (丨··丨). • Individuals in group I received oral Prysson (administered 1 mg/kg/day of prednisone for 14 days followed by daily dose reduction of 1 〇mg until no longer administered steroids) - Individuals in group II received IT thiol Dehydrocorticosterone sodium phosphate (administered with 0.3-0.5 mL of methyl dehydrocorticosterol per month/one injection per mL of carrier until up to 3 injections) and oral Prysson (1 mg administered) /kg/day Pleisson for 14 days, followed by a daily dose reduction of 1 〇mg until steroids are no longer administered) • Individuals in group III receive placebo IT injection (to a monthly dose of 0·3-〇·5 mL vehicle) One injection up to 3 injections) and oral Pryson hearing assessment 140447, doc -130- 200950787 Hearing assessment includes: - Average pure tone hearing (500 Hz, 1 & 2 kHz; 4, 6 & 8 kHz). The two PTA values were determined: a low frequency value (500 Hz-2 kHz) and a high frequency value (4-8 kHz). - Tibial muscle reflexes • Tympanogram examination & loudness attenuation check - - Speech recognition threshold ❿ Measure the hearing loss of each individual before the start of treatment (two times before the study is assigned and before the random assignment). Hearing was assessed at 1, 2, 4 & 8 weeks, 4 & 6 months after the start of treatment. The main selection principle - male or female patients between the ages of 18 and 75 - unilateral SHL (sensorineural hearing loss) progresses within 72 hours - the individual has a hearing loss exclusion principle at any frequency not exceeding 70 dB φ - In the previous 30 days for more than 10 days for any reason _ steroid treatment - in the previous 14 days due to ISSHL for 5 or more days of oral steroid treatment - hearing in either ear Change History Example 31 - Assessment of the administration of methyl dehydrocorticosteroids in the treatment of Meniere's disease The purpose of this study was to evaluate the improvement of the in vivo (IT) thiol-dehydrocorticosteroids in human individuals. The safety and efficacy of Niel's disease. 140447.doc -131 - 200950787 The main efficacy indicators are dizzy with the following system of self-description system - no dizziness days; - days with mild invasion -1; - moderate severe attacks lasting more than 20 minutes -2; - severe attack Sustained for 1 hour or more or accompanied by nausea or convulsions, U; - to the present worst attack attack to date-4;

- The monthly dizziness score is defined as 50 or more than 50 consecutive months for treatment failure. Principles of selection According to the 1995 AAO-HNS principle of MD clinical diagnosis: • At least two decisive dizziness attacks. · - A decisive long time to maintain a spontaneous (rotating) dizziness of at least 20 minutes 0 Elimination principle

- using an aminoglycoside or macrolide antibiotic; - treating with an anticancer drug - starting compound, - difluorodecylguanine. Study Design This was a multi-center, double-blind, randomized, placebo-controlled: comparison of urinary dehydrogenated skin sterols with placebo (10) fox treatment. Approximately 140 individuals were enrolled in this study and were 3 treatment groups. Randomized randomized (five) 140447.doc -132- 200950787 Individuals in group 1 received standard care (nmt 1500 mg/day sodium diet 'without two-base sputum absorption and/or diuretic) - accepted in group 11 IT methyl dehydrocorticosterone sodium phosphate (administered with 0.3-0.5 mL of methyl dehydrocorticosterol per month / 1 carrier per injection. Injection up to 3 injections) and standard care - at Individuals in group 111 received a placebo IT injection (up to 3 injections with 0.3-0.5 mL of vehicle per month for up to 3 injections) and standard care • Assessment ― - Measurement of each individual's Meni before treatment begins The severity of the disease (second time before the study was assigned and before the randomization). Meniere's assessment hearing assessment was performed at 1, 2, 4 & 8 weeks, 4 & 6 months after the start of treatment - Dizziness and tinnitus occurrence cycle, frequency, time and severity; - reduction of ear pressure perception, using standard VAS questionnaire and effective rating agreement φ - serum vasopressin measurement although the present invention has been presented and described herein Preferred embodiments, such provided embodiments are merely examples A variety of variations of the embodiments described herein may be employed to implement the present invention. The method and structure of the present invention, and thus the scope of the scope of the patent application, and the like [Ease of the diagram] Figure 1 illustrates the in vitro release profile of thiol dehydrocorticosterol formulations with different concentrations of poloxamer 4〇7 (p〇i〇xamer 407). -133· 200950787 Figure 2 illustrates the correlation between the average dissolution time of the formulation (]V1DT) and the concentration of P4〇7. Figure 3 illustrates the release profile of different steroids containing 17% P407. Cortisol 0 Figure 4 illustrates The correlation between the average dissolution time (MDT) of the formulation and the apparent viscosity of the formulation. Figure 5 illustrates the effect of the concentration on the viscosity of the aqueous solution of BMC that is refined by Blanose. Figure 6 illustrates the concentration of the aqueous solution in Methocel. Viscosity effect. Figure 7 shows the results of gelation after 5 days of intrathecal injection of guinea pig ears. Figure 8 shows the gel elimination time course of the formulations described herein. Figure 9 shows the Release of formula Curve. 140447.doc 134-

Claims (1)

200950787 VII. Scope of Application: 1. A pharmaceutical composition for treating an ear disease or condition modulated to provide a therapeutically effective amount of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrogenation Cortisol' The composition comprises a substantially low degradation product of methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol, and the composition further comprises two or more properties selected from the group consisting of: (1) Methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof, between about 1 %% 〇Wt%; (ii) A polyoxyethylene-polyoxypropylene triadlocene copolymer having a formula of E106 P70 E106 of about 16 wt% and about 21 wt% per day; (iii) sterilized water, suitably buffered to provide between about 5 5 and about 8 (iv) multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol; (v) - a gel between about 19 ° C and about 40 ° C (VI) less than about 5 colony forming units (cfu) per g of formula, and (VII) - less than 0.5 kg per kg of body weight 5 endotoxin units. 2. The pharmaceutical composition according to claim 1, wherein the composition comprises: (1) methyl dehydrocorticosterol, mercapto dehydrocortisol, between about 1 wt% and about 10 wt% Or dehydrocorticulin, or a pharmaceutically acceptable prodrug or salt thereof; (11) between about 16 wt% and about 21 wt% of a polyoxyethylene having a formula ei〇6 P70 140447.doc 200950787 E106 An oxypropylene tri-embedded copolymer; and (a multiparticulate methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol. 3. The pharmaceutical composition according to claim 1, wherein The composition comprises: (1) between about 0.1 wt% and about 1% by weight of decyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof; 11) a polyoxyethylene-polyoxypropylene trimeric copolymer having a formula of E106 P70 E106 between about 16 wt% and about 21 wt%; (out) multiparticulate sulfhydryl dehydrocorticosterol, fluorenyl Dehydrocortisol or dehydrocortisol (iv) - a pharmaceutical composition according to any one of items 1 to 3, wherein the pharmaceutical composition of any one of items 1 to 3, Where the composition The osmotic concentration of the delivery volume of between about 250 and 320 mOsm/L. The pharmaceutical composition according to any one of claims 4 to 4, wherein the thiol de-corticosteroid, sulfhydryl dehydrogenation The pharmaceutical composition of any one of the above items 1 to 4, wherein the methyl dehydrocorticosterol, sulfhydryl dehydrogenation, is released from the formulation for at least 3 days. The medicinal composition of any one of items 1 to 4, wherein the thiol dehydrocorticosterol, thiol Hydrogen cortisol or dehydrocortisol is released from the formulation for at least 10 days. 140447.doc 200950787. The pharmaceutical composition of any one of clauses, wherein the pharmaceutical formulation is acceptable for one ear. The medicinal composition according to any one of the preceding claims, wherein the polyoxyethylene-polyoxypropylene triblock copolymer is a claw as described in the item (1) The medical group also contains mucoadhesives. Furthermore, it further comprises 11. The pharmaceutical composition according to any one of claims 1 to 10, a penetration enhancer. 12. If request item 1 to! A pharmaceutical composition according to any one of the preceding claims, a thickening agent. 13. A dye according to any one of claims 1 to 12. The pharmaceutical composition according to any one of claims 1 to 13, further comprising a drug delivery system selected from the group consisting of a needle and a syringe, a chestnut, and a microinjection The second set, and the original place to form a sponge substance or a combination thereof. The pharmaceutical composition according to any one of claims 1 to 14, wherein the methyl dehydrocortex (tetra), methyl dehydrocortisol or dehydrocortisol pharmaceutically acceptable salt is limited or absent System release, system toxicity, bad sag characteristics, or a combination thereof. 16. The pharmaceutical composition according to any one of the preceding claims, wherein the methyl dehydrocortex (tetra), methyl dehydrogenated furanol or dehydrogenated skin (tetra) is a free alcohol, a salt, or the like The form of the drug, or a combination thereof. 17. The pharmaceutical composition according to claim 16, wherein the methyl dehydrocorticosterol, decyl dehydrocortisol or dehydrocorticolysis is administered as a phosphate ester prodrug 140447.doc 200950787. 18. 19. 20. 21. 22. 23. 24. 25. The pharmaceutical composition according to Item 17, wherein the steroid is sulfhydryl corticosteroid or sulfhydryl dehydrocorticosterol acetate. The pharmaceutical composition according to any one of claims 1 to 18, which further comprises a mercapto dehydrocorticosteroid, a mercapto dehydrocortisol dehydrocortisol, or a medically acceptable salt thereof, The drug or a combination thereof is an immediate release agent. The pharmaceutical composition according to any one of items 1 to 19, wherein the methyl dehydrocorticosterol, sulfhydryl dehydrocorticolysis or dehydrocortisol comprises a plurality of particles. The pharmaceutical composition according to claim 20, wherein the sulfhydryl dehydrocorticosteroid, decyl dehydrocortisol or dehydrogenated skin (IV) is substantially in the form of micronized particles. The pharmaceutical composition according to any one of claims 1 to 2, wherein the methyl dehydrocorticosterol is in the form of a micro-mercapto dehydrocorticosteroid powder. The pharmaceutical composition according to any one of items 1 to 22, which further comprises an additional therapeutic agent. The pharmaceutical composition according to claim 23, wherein the additional therapeutic agent is - Na/K ATPase modulator, - chemotherapeutic agent, a collagen, a globulin, an interferon, an antimicrobial agent, an antibiotic, a Topical anesthetic, a platelet activating factor antagonist, an ear protectant, a nitric oxide synthase inhibitor, an anti-stun agent, a vasopressin antagonist, an antiviral agent, an anti-emetic agent, or the like combination. The pharmaceutical composition according to any one of the preceding claims, wherein the pH of the composition is from about 6.〇 to about 76. The pharmaceutical composition according to any one of claims 1 to 25, wherein the polyoxyethylene-polyoxypropylene triblock=polymer and a thickener having the formula E106 P70 E106 The ratio is from about 4 〇: 丨 to about 5 · 1. 27. The pharmaceutical composition of claim 26, wherein the thickening agent is carboxymethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. 28. The pharmaceutical composition according to claim 1, wherein the ear disease or symptom is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging-related hearing loss Autoimmune ear disease or tinnitus. 29. A method of treating an ear disease or condition comprising administering to a subject in need of an in-ear composition comprising a therapeutically effective amount of methyl dehydrocorticosterol, methyl dehydrocortisol or Dehydrocortisol, the composition comprising a low degradation product of substantially methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, the composition further comprising two or two selected from the group consisting of: (1) thiol-dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.1% by weight and about 10% by weight; (8) between about 16 wt% of about 21 wt0 / day of polyoxyethylene _ polyoxypropylene tri-embedded copolymer of formula E106 P70 E106; (in) sterilized water 'moderate buffer to provide between about 5 5 to about 8. (iv) multiparticulate thiol dehydrocorticosterol, sulfhydryl dehydrocortisol or dehydrocortisol; 140447.doc 200950787 (V) less than about 5 colonies per microgram of microbial formulation Units (cfu), and (Vi) - the individual has less than about 5 endotoxin units per kilogram of body weight. 30. The method of claim 29, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition for at least 3 days. 31. The method of claim 29, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition for at least 5 days. 32. The method of claim 29, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition by at least one day. 33. The method of claim 29 wherein the composition is administered throughout a round window. 34. The method of claim 29, wherein the ear disease or symptom is Meniere, sudden sensorineural hearing loss, noise-induced I loss, aging-related hearing loss, autoimmune ear disease or ear. 140447.doc