Gelling solutions for administering compounds to the inner ear

Abstract

To provide polymer compositions and extended-release otic agents.SOLUTION: In one aspect, provided herein is a polymer composition including: a functional polymer which is contained in an amount of about 5 wt.% to about 15 wt.% of the polymer composition, and which includes a first functional group; a crosslinker which is contained in an amount of about 0.05 wt.% to about 0.6 wt.% of the polymer composition, and which includes a second functional group; and water. A crosslinking reaction can be induced between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 024,232, filed May 13, 2020, which is incorporated herein by reference in its entirety.

[0002] Description of electronically submitted text files The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety, and a computer-readable format copy of the Sequence Listing

number

[0003] The present disclosure relates to formulations for the treatment of inner ear conditions or diseases, particularly solutions that form stable hydrogels at body temperature to provide controlled delivery of therapeutic, prophylactic and / or diagnostic agents over a period of time. [Background technology]

[0004] The inner ear can be difficult to treat effectively. For example, it accounts for only 0.004% of the average circulating blood volume and is encapsulated in one of the densest bones in the body. These, combined with the presence of the blood-labyrinth barrier (BLB), limit access of most therapeutic compounds to the inner ear. Oral, intravenous, and intramuscular routes of administration can be inefficient, require high doses, and carry the risk of systemic side effects. Summary of the Invention

[0005] This document is based, at least in part, on compositions that can be used to deliver active agents to the middle and / or inner ear of a subject.

[0006] Provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C.

[0007] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first and second functional groups to form a gel, the gel having a residence time of at least 5 days when formed in the middle ear.

[0008] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the gel has a gel duration of at least 5 days at 37°C.

[0009] Further provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein the polymer composition has a pH of about 5.5 to about 8.5, and wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0010] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first and second functional groups to form a gel, wherein the gel swells less than 100% after equilibration in phosphate buffered saline (PBS) for 2 days.

[0011] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, wherein the gel is elastic.

[0012] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the gel is mucoadhesive.

[0013] Also provided herein is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; and water, wherein the polymer composition has a viscosity of about 1 mPa·s to about 1000 mPa·s, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0014] In some embodiments of any of the polymer compositions herein, the polymer composition may have a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C. In some embodiments of any of the polymer compositions herein, the gel, when formed in the middle ear, may have a residence time of at least 5 days. In some embodiments of any of the polymer compositions herein, the gel may have a gel duration of at least 5 days at 37°C. In some embodiments of any of the polymer compositions herein, the polymer composition may have a pH of about 5.5 to about 8.5. In some embodiments of any of the polymer compositions herein, the gel swells less than 100% after equilibration in phosphate buffered saline (PBS) for 2 days. In some embodiments of any of the polymer compositions herein, the gel may be elastic. In some embodiments of any of the polymer compositions herein, the gel may be mucoadhesive. In some embodiments of any of the polymer compositions herein, the polymer composition may have a viscosity of about 1 mPa·s to about 1000 mPa·s.

[0015] In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 8% to about 12% by weight of the functional polymer. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 10% by weight of the functional polymer. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 0.3% to about 0.5% by weight of the crosslinker. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 0.4% to about 0.6% by weight of the crosslinker.

[0016] In some embodiments of any of the polymer compositions herein, the polymer composition can have a gelation time of about 5 minutes to about 20 minutes at a temperature of about 20° C. In some embodiments of any of the polymer compositions herein, the polymer composition can have a gelation time of about 8 minutes to about 12 minutes at a temperature of about 20° C. In some embodiments of any of the polymer compositions herein, the polymer composition can have a gelation time of about 10 seconds to about 30 minutes at a temperature of about 37° C. In some embodiments of any of the polymer compositions herein, the polymer composition can have a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37° C. In some embodiments of any of the polymer compositions herein, the gel, when formed in the middle ear, can have a residence time of at least 1 week. In some embodiments of any of the polymer compositions herein, the gel, when formed in the middle ear, can have a residence time of at least 2 weeks. In some embodiments of any of the polymer compositions herein, the gel, when formed in the middle ear, can have a residence time of at least 1 month. In some embodiments of any of the polymer compositions herein, the gel, when formed in the middle ear, can have a residence time of at least 2 months. In some embodiments of any of the polymer compositions herein, the polymer composition can have a pH of about 6.4 to about 7.4. In some embodiments of any of the polymer compositions herein, the polymer composition can have a pH of about 6.0 and 7.0. In some embodiments of any of the polymer compositions herein, the gel swells less than 80% after equilibration in phosphate buffered saline (PBS) for 2 days. In some embodiments of any of the polymer compositions herein, the gel swells less than 60% after equilibration in phosphate buffered saline (PBS) for 2 days. In some embodiments of any of the polymer compositions herein, the polymer composition can have a viscosity of about 1 mPa·s to about 100 mPa·s. In some embodiments of any of the polymer compositions herein, the polymer composition can have a viscosity of about 1 mPa·s to about 50 mPa·s.In some embodiments of any of the polymer compositions herein, the gel can be hypotonic with respect to the endolymph or perilymph. In some embodiments of any of the polymer compositions herein, the gel can be isotonic with respect to the endolymph or perilymph. In some embodiments of any of the polymer compositions herein, the gel can be hypertonic with respect to the endolymph or perilymph. In some embodiments of any of the polymer compositions herein, the gel can have a pH of about 6.0 to about 7.7. In some embodiments of any of the polymer compositions herein, the gel can have a pH of about 6.6 to about 6.8.

[0017] In some embodiments of any of the polymer compositions herein, the ratio of the first functional group to the second functional group can be about 0.9:1 to about 1:0.9. In some embodiments of any of the polymer compositions herein, the ratio of the first functional group to the second functional group can be about 1:1. In some embodiments of any of the polymer compositions herein, the functional polymer can be a modified PEG.

[0018] In some embodiments of any of the polymer compositions herein, the first functional group comprises an electrophile and the second functional group comprises a nucleophile. In some embodiments of any of the polymer compositions herein, the first functional group comprises a succinimidyl ester. In some embodiments of any of the polymer compositions herein, the second functional group comprises a primary amine. In some embodiments of any of the polymer compositions herein, the functional polymer can be pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. In some embodiments of any of the polymer compositions herein, the crosslinker comprises polylysine. In some embodiments of any of the polymer compositions herein, the crosslinker comprises trilysine.

[0019] In some embodiments of any of the polymer compositions herein, the first functional group comprises a nucleophile and the second functional group comprises an electrophile. In some embodiments of any of the polymer compositions herein, the first functional group comprises a primary amine. In some embodiments of any of the polymer compositions herein, the second functional group comprises a succinimidyl ester.

[0020] Also described herein are sustained release otic compositions comprising any one or more of the polymer compositions described herein and an active agent.

[0021] In some embodiments, the active agent can be selected from the group consisting of a therapeutic agent, a prophylactic agent, a diagnostic or visualization agent, and combinations thereof. In some embodiments, the therapeutic or prophylactic agent can be selected from the group consisting of a protein, a carbohydrate, a nucleic acid, a small molecule, and combinations thereof. In some embodiments, the protein can be selected from the group consisting of an enzyme, a growth factor, an antibody or antigen-binding fragment thereof, and combinations thereof. In some embodiments, the carbohydrate can be a glycosaminoglycan. In some embodiments, the nucleic acid can be selected from the group consisting of an antisense oligonucleotide, an aptamer, a microRNA, a short interfering RNA, a ribozyme, and combinations thereof. In some embodiments, the small molecule can be selected from the group consisting of an antibiotic, an anti-tumor agent, a local anesthetic, a steroid, a hormone, an anti-apoptotic agent, an angiogenic agent, an anti-angiogenic agent, a neurotransmitter, a psychotropic agent, an anti-inflammatory agent, and combinations thereof. In some embodiments, the small molecule can be an inhibitor of Apaf-1.

[0022] In some embodiments, the active agent can be a tyrosine kinase inhibitor. In some embodiments, the active agent can be a VEGF inhibitor. In some embodiments, the VEGF inhibitor can be selected from the group consisting of agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, revastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, vandetanib, and combinations thereof. In some embodiments, the VEGF inhibitor comprises an antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof can be selected from the group consisting of alacizumab, bevacizumab, icrucumab, ramucirumab, ranibizumab, and combinations thereof. In some embodiments, the VEGF inhibitor comprises a decoy receptor. In some embodiments, the decoy receptor can be aflibercept. In some embodiments, the VEGF inhibitor comprises an allosteric modulator of a VEGFR. In some embodiments, the allosteric modulator can be cyclotraxin B. In some embodiments, the VEGF inhibitor can be at least 10-fold selective for VEGFR2 over another VEGFR. In some embodiments, the VEGF inhibitor can be at least 20-fold selective for VEGFR2 over another VEGFR. In some embodiments, the VEGF inhibitor can be at least 50-fold selective for VEGFR2 over another VEGFR.

[0023] In some embodiments, the tyrosine kinase inhibitor or VEGF inhibitor can be present in an amount sufficient to reduce edema and lymphatic dysfunction in the affected ear. In some embodiments, the active agent comprises an anti-inflammatory agent. In some embodiments, the active agent comprises a steroid. In some embodiments, the active agent does not comprise a steroid.

[0024] In some embodiments, the active agent comprises a diagnostic or visualization agent, which may be selected from the group consisting of a dye, a fluorophore, an MRI contrast agent, and combinations thereof.

[0025] In some embodiments, the active agent can be present in the sustained release otic composition in the form of microparticles, hi some embodiments, the active agent can be present in the sustained release otic composition in the form of nanoparticles.

[0026] In some embodiments, the active agent may be present in an amount of about 0.01% to about 40% by weight of the polymer composition. In some embodiments, the active agent may be present in an amount of about 0.1% to about 20% by weight of the polymer composition. In some embodiments, the active agent may be present in an amount of about 1% to about 10% by weight of the polymer composition.

[0027] In some embodiments, the sustained release otic composition can further comprise an excipient, which can be selected from the group consisting of a buffer, a tonicity agent, a mucoadhesive agent, a stabilizer, a preservative, a carrier, a penetration enhancer, a diluent, a dispersant, a viscosity modifier, a solubilizer, an osmolality modifier, and combinations thereof.

[0028] Also provided herein are gels formed from any one or more of the polymer compositions described herein. Also provided herein are gels formed from any one or more of the sustained release otic compositions described herein.

[0029] Also provided herein is a medicament for the treatment of an otic disease or disorder, the medicament comprising any one or more of the sustained release otic compositions described herein.

[0030] Provided herein is a method of preparing a sustained release otic composition, comprising combining a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group, a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group, and an active agent to form the sustained release otic composition, whereby the functional polymer can be present in an amount of about 5% to about 15% by weight of the sustained release otic composition, the crosslinker can be present in the sustained release otic composition in an amount of about 0.2% to about 0.6% by weight of the sustained release otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0031] Provided herein is a method of preparing a sustained release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group; (b) forming a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group; and (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker to form the sustained release otic composition, whereby the functional polymer can be present in an amount of about 5% to about 15% by weight of the sustained release otic composition, the crosslinker can be present in the sustained release otic composition in an amount of about 0.2% to about 0.6% by weight of the sustained release otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0032] Provided herein is a method of preparing a sustained release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group; and (b) combining the solution or suspension of the functional polymer with a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group, whereby the functional polymer can be present in an amount of about 5% to about 15% by weight of the sustained release otic composition, the crosslinker can be present in the sustained release otic composition in an amount of about 0.2% to about 0.6% by weight of the sustained release otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0033] Also provided herein is a method of preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group; (b) altering the pH of a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group; and (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0034] Also provided herein is a method of preparing a sustained release otic composition, comprising: (a) forming a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group; and (b) combining the solution or suspension of the crosslinker with a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group, whereby the functional polymer can be present in an amount of about 5% to about 15% by weight of the sustained release otic composition, the crosslinker can be present in the sustained release otic composition in an amount of about 0.2% to about 0.6% by weight of the sustained release otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0035] Provided herein is a method for preparing a sustained-release otic composition, the method comprising: (a) forming a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group; (b) altering the pH of a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group; and (c) combining the solution or suspension of the functional polymer with a solution or suspension of the crosslinker, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0036] In some embodiments of any of the preparation methods provided herein, the active agent can be present in a solution or suspension of the functionalized polymer. In some embodiments of any of the preparation methods provided herein, the active agent can be combined with the functionalized polymer before forming the solution or suspension of the functionalized polymer. In some embodiments of any of the preparation methods provided herein, the active agent can be combined with the solution or suspension of the functionalized polymer. In some embodiments of any of the preparation methods provided herein, combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker comprises combining the solution or suspension of the functionalized polymer, the solution or suspension of the crosslinker, and the active agent. In some embodiments of any of the preparation methods provided herein, the active agent can be provided as a solid. In some embodiments of any of the preparation methods provided herein, the active agent can be provided as a solution or suspension. In some embodiments of any of the preparation methods provided herein, the sustained-release otic composition can be any one or more of the sustained-release otic compositions provided herein.

[0037] Provided herein are methods of treating an otic disease or disorder in a subject, comprising identifying the subject as having an otic disease or disorder and administering a therapeutically effective amount of any one or more of the sustained release otic compositions provided herein to the affected ear of the subject.

[0038] Provided herein are methods of treating an otic disease or disorder in a subject, comprising administering a therapeutically effective amount of any one or more of the sustained release otic compositions provided herein to the ear of a subject in need thereof.

[0039] Also provided herein are methods of treating an otic disease or disorder in a subject, comprising: (i) preparing a sustained-release otic composition by any one or more of the methods provided herein; and (ii) administering a therapeutically effective amount of the sustained-release otic composition to the ear of a subject in need thereof.

[0040] Also provided herein are methods of treating an otic disease or disorder in a subject, comprising: (i) identifying the subject as having an otic disease or disorder; (ii) preparing a sustained-release otic composition by any one or more of the methods described herein; and (iii) administering a therapeutically effective amount of the sustained-release otic composition to the affected ear of the subject.

[0041] In some embodiments of any of the methods of treatment provided herein, the ear disease or disorder can be selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. In some embodiments of any of the methods of treatment provided herein, the sensorineural hearing loss can be sudden sensorineural hearing loss. In some embodiments of any of the methods of treatment provided herein, the sensorineural hearing loss can be associated with diabetes.

[0042] Provided herein are methods of treating Meniere's disease in a subject, comprising administering a therapeutically effective amount of any one or more of the sustained release otic compositions described herein to the ear of a subject in need thereof.

[0043] Provided herein are methods of treating Meniere's disease in a subject, comprising: (i) identifying the subject as having Meniere's disease; and (ii) administering to the affected ear of the subject a therapeutically effective amount of any one or more of the sustained-release otic compositions described herein.

[0044] Also provided herein are methods of treating Meniere's disease in a subject, comprising: (i) preparing a sustained-release otic composition by any one or more of the methods described herein; and (ii) administering a therapeutically effective amount of the sustained-release otic composition to the ear of a subject in need thereof.

[0045] Also provided herein are methods of treating Meniere's disease in a subject, comprising: (i) identifying the subject as having Meniere's disease; (ii) preparing an extended-release otic composition by any one or more of the methods described herein; and (iii) administering a therapeutically effective amount of the extended-release otic composition to the affected ear of the subject.

[0046] In any one or more of the methods of treatment provided herein, the administering may occur within 10 minutes after combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. In any one or more of the methods of treatment provided herein, the administering may occur within 5 minutes after combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. In any one or more of the methods of treatment provided herein, the administering may comprise administering about 5 μL to about 500 μL of the sustained-release otic composition. In any one or more of the methods of treatment provided herein, the administering may comprise administering about 50 μL to about 200 μL of the sustained-release otic composition. In any one or more of the methods of treatment provided herein, the administering may comprise injecting through the tympanic membrane.

[0047] Provided herein is a method of treating an ear disease or disorder in a subject, the method comprising identifying the subject as having an ear disease or disorder and administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor.

[0048] In some embodiments, the ear disease or disorder can be selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. In some embodiments, the sensorineural hearing loss can be sudden sensorineural hearing loss. In some embodiments, the sensorineural hearing loss can be associated with diabetes.

[0049] Also provided herein is a method of treating Meniere's disease in a subject, the method comprising: (i) identifying the subject as having Meniere's disease; and (ii) administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor.

[0050] Provided herein is a method of treating Meniere's disease in a subject, comprising administering a therapeutically effective amount of a tyrosine kinase inhibitor to a subject in need thereof.

[0051] In some embodiments, administering can include systemic administration. In some embodiments, administering can include administering to the affected ear of the subject. In some embodiments, the tyrosine kinase inhibitor can include a VEGF inhibitor. In some embodiments, the VEGF inhibitor can be selected from the group consisting of agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, rebastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, vandetanib, and combinations thereof. In some embodiments, the VEGF inhibitor comprises an antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof can be selected from the group consisting of alacizumab, bevacizumab, icrucumab, ramucirumab, ranibizumab, and combinations thereof. In some embodiments, the VEGF inhibitor comprises a decoy receptor. In some embodiments, the decoy receptor can be aflibercept. In some embodiments, the VEGF inhibitor comprises an allosteric modulator of a VEGFR. In some embodiments, the allosteric modulator of a VEGFR can be cyclotraxin B. In some embodiments, the VEGF inhibitor can be at least 10-fold selective for VEGFR2 over another VEGFR. In some embodiments, the VEGF inhibitor can be at least 20-fold selective for VEGFR2 over another VEGFR. In some embodiments, the VEGF inhibitor can be at least 50-fold selective for VEGFR2 over another VEGFR. In some embodiments, the tyrosine kinase inhibitor can be present in an amount sufficient to reduce edema and lymphatic dysfunction in the affected ear. In some embodiments, the tyrosine kinase inhibitor can be provided in the form of any one or more of the sustained release otic compositions described herein.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although the present invention can be practiced using methods and materials similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0053] The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the present disclosure will become apparent from the description and drawings, and from the claims. The word "comprising" in the claims may be replaced with "consisting essentially of" or "consisting of," in accordance with standard practice in patent law. In certain embodiments, for example, the following are provided: (Item 1) 1. A polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A polymer composition, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and wherein the polymer composition has a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C. (Item 2) 1. A polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A polymer composition, wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and wherein the polymer composition has a gelation time of about 10 seconds to about 30 minutes at a temperature of about 37°C. (Item 3) 3. The polymer composition according to claim 1 or 2, wherein the gel, when formed in the middle ear, has a residence time of at least 5 days. (Item 4) 4. The polymer composition according to any one of items 1 to 3, wherein the gel has a gel duration at 37° C. of at least 5 days. (Item 5) 5. The polymer composition according to any one of items 1 to 4, wherein the polymer composition has a pH of about 5.5 to about 8.5. (Item 6) 6. The polymer composition according to any one of items 1 to 5, wherein the gel swells less than 100% after equilibration in phosphate buffered saline (PBS) for 1 day. (Item 7) 7. The polymer composition according to any one of items 1 to 6, wherein the gel is elastic. (Item 8) 8. The polymer composition according to any one of items 1 to 7, wherein the gel is mucoadhesive. (Item 9) 9. The polymer composition according to any one of items 1 to 8, wherein the polymer composition has a viscosity of about 1 mPa·s to about 1000 mPa·s. (Item 10) 10. The polymer composition of any one of items 1 to 9, wherein the polymer composition comprises about 6% to about 12% by weight of the polymer composition of the functional polymer. (Item 11) 11. The polymer composition according to any one of items 1 to 10, wherein the polymer composition comprises about 0.1% to about 0.3% by weight of the polymer composition of the crosslinking agent. (Item 12) 12. The polymer composition according to any one of items 1 to 11, wherein the polymer composition has a gelation time of about 8 minutes to about 12 minutes at a temperature of about 20°C. (Item 13) 13. The polymer composition according to any one of items 1 to 12, wherein the gel has an osmotic pressure of about 300 mOsmol / kg to about 600 mOsmol / kg. (Item 14) 14. The polymer composition according to any one of items 1 to 13, wherein the gel has a pH of about 6.0 to about 6.5. (Item 15) 15. The polymer composition according to any one of items 1 to 14, wherein the ratio of the first functional group to the second functional group is from about 0.8:1.2 to about 1.2:0.8. (Item 16) 16. The polymer composition according to any one of items 1 to 15, wherein the ratio of the first functional group to the second functional group is about 1:1. (Item 17) 17. The polymer composition of any one of items 1 to 16, wherein the first functional group comprises a succinimidyl ester. (Item 18) 18. The polymer composition of any one of items 1 to 17, wherein the functional group is selected from the group consisting of succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl gluraramide, succinimidyl carbonate, succinimidyl carboxymethyl ester, or a combination thereof. (Item 19) 19. The polymer composition of any one of items 1 to 18, wherein the second functional group comprises a primary amine. (Item 20) 20. The polymer composition according to any one of items 1 to 19, wherein the functional polymer is pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. (Item 21) 21. The polymer composition according to any one of items 1 to 20, wherein the crosslinking agent comprises polylysine or a salt thereof. (Item 22) 22. The polymer composition according to any one of items 1 to 21, wherein the crosslinking agent comprises trilysine or a salt thereof. (Item 23) 1. A sustained release otic composition comprising: The polymer composition according to any one of items 1 to 22, and an active agent. (Item 24) 24. The sustained release otic composition of claim 23, wherein the active agent is selected from the group consisting of a therapeutic agent, a prophylactic agent, a diagnostic or visualization agent, and combinations thereof. (Item 25) 25. The sustained release otic composition of claim 24, wherein the therapeutic or prophylactic agent is selected from the group consisting of proteins, carbohydrates, nucleic acids, small molecules, and combinations thereof. (Item 26) 26. The sustained release otic composition of any one of items 23 to 25, wherein the active agent is a tyrosine kinase inhibitor. (Item 27) 27. The sustained release otic composition of any one of items 23 to 26, wherein the active agent comprises a glucocorticoid. (Item 28) 28. The sustained release otic composition of claim 27, wherein the active agent comprises dexamethasone. (Item 29) 29. The sustained release otic composition of any one of items 23 to 28, wherein the active agent is present in an amount of about 1% to about 15% by weight of the polymer composition. (Item 30) 1. A sustained release otic composition comprising: about 5% to about 15% pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; about 0.05% by weight to about 0.6% by weight of trilysine or a salt thereof; about 0.01% to about 40% by weight of dexamethasone; and water. (Item 31) 1. A sustained release otic composition comprising: about 8.3% pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; About 0.2% by weight of trilysine or a salt thereof; about 6% by weight of dexamethasone; and water. (Item 32) about 0.01% by weight to about 3.0% by weight of sodium borate decahydrate; about 0.01% by weight to about 3.0% by weight of sodium phosphate; about 0.01% by weight to about 3.0% by weight of phosphoric acid; Approximately 0% to 0.5% of FD&C Blue #1 and 32. The sustained-release otic composition of item 30 or 31, further comprising about 0% to about 0.01% by weight of butylated hydroxytoluene. (Item 33) about 1.2% by weight of sodium borate decahydrate; about 1.1% to about 3.0% by weight of sodium phosphate; about 0.9% by weight to about 3.0% by weight of phosphoric acid; Approximately 0.01% of FD&C Blue #1 and 32. The sustained-release otic composition of claim 30 or 31, further comprising about 0.002% by weight of butylated hydroxytoluene. (Item 34) A gel formed from the polymer composition according to any one of items 1 to 22 or the sustained release ear composition according to any one of items 23 to 33. (Item 35) Manufacture of a medicament comprising the sustained release otic composition according to any one of items 23 to 33 for the treatment of an ear disease or disorder. (Item 36) 1. A method of treating an ear disease or disorder in a subject, comprising: Identifying a subject as having an ear disease or disorder; and administering a therapeutically effective amount of the sustained release otic composition of any one of items 23 to 33 to the affected ear of the subject. (Item 37) 1. A method of treating an ear disease or disorder in a subject in need thereof, comprising: A method comprising administering a therapeutically effective amount of the sustained release otic composition of any one of items 23 to 33 to the ear of the subject. (Item 38) 38. The method of item 36 or 37, wherein the ear disease or disorder is selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. (Item 39) 1. A method of treating Meniere's disease in a subject, comprising: A method comprising administering a therapeutically effective amount of the sustained release otic composition of any one of items 23 to 33 to the ear of a subject in need thereof. (Item 40) 1. A method of treating Meniere's disease in a subject, comprising: (i) identifying a subject as having Meniere's disease; (ii) administering a therapeutically effective amount of the sustained release otic composition of any one of items 80 to 124 to the affected ear of the subject. (Item 41) 41. The method of any one of items 36 to 40, wherein the administering comprises administering about 40 μL to about 60 μL of the sustained release otic composition. (Item 42) 41. The method of any one of items 36 to 40, wherein the administering comprises administering the sustained-release otic composition so that it contacts the round window membrane. [Brief explanation of the drawings]

[0054] [Figure 1A] Structure of pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. [Figure 1B] This is the structure of trilysine. [Figure 2A]1 is a graph of the swelling profile (percent) over time (days) of pH-adjusted PEG-trilysine polymer samples (n=3) containing 0% (filled squares), 1% (open squares), 3% (diamonds), and 6% (triangles) dexamethasone (Dex). [Figure 2B] 1 is a graph of cumulative drug release (μg) of pH-adjusted PEG-trilysine polymer samples (n=3) containing 6% (triangles), 3% (diamonds), or 1% (squares) dexamethasone. [Figure 3] 1 is a graph of the swelling profile (percent swelling) over time (days) of pH-adjusted PEG-trilysine polymer samples (n=6) containing 6 wt% dexamethasone with a pot life of 67 minutes (circles), 26 minutes (squares), or 16 minutes (triangles). [Figure 4] 1 is a graph of drug release (μg) over time (days) for pH-adjusted PEG-trilysine polymer samples (n=6) containing 6 wt% dexamethasone (n=6), with a pot life of 67 minutes (circles), 26 minutes (squares), or 16 minutes (triangles). [Figure 5A] FIG. 1 is a graph of drug release (μg) over time (days) of 6 wt % dexamethasone gel in pH-adjusted PEG-trilysine polymer (circles) and poloxamer 407 (triangles) (n=5) in PBS solution. [Figure 5B] FIG. 1 is a graph of membrane permeation (drug release (μg)) over time (days) for 6 wt % dexamethasone gels in pH-adjusted PEG-trilysine polymer (circles) and poloxamer 407 (triangles) (n=3). [Figure 6A] 1 is a graph of plasma dexamethasone concentration versus time in an in vivo study. Open symbols are from subjects receiving the PEG-trilysine polymer formulation, and closed symbols are from subjects receiving the P407 formulation. [Figure 6B]1 is a graph of dexamethasone concentration in perilymph over time in an in vivo study. The dots represent the left ear (L, circle, square, hexagon) and right ear (R, triangle, and diamond) of individual subjects. Open symbols are from subjects administered the PEG-trilysine polymer formulation, and closed symbols are from animals administered the P407 formulation. The arrow symbol represents subject A843, who received the P407 formulation, and whose dexamethasone level is above the detection level (limit: 9500 ng / mL). [Figure 6C] The same data as in Figure 6B is plotted for both the left and right ears. [Figure 7] 1 is a graph of gel time (min) versus pH for various pH-adjusted PEG-trilysine polymer compositions. [Figure 8] 1 is a graph of gel time (minutes) versus years from expiration date for PEG-trilysine kits for otic compositions prepared with a 0.23 M 50:50 dilution (circles) and a 0.25 M 50:50 dilution (triangles). [Figure 9] 1 is a graph of cumulative release of dexamethasone (mg) versus time (days) for sustained release otic compositions D1 (circles), D2 (triangles), D3 (squares), and D4 (diamonds). [Figure 10A] 1 is a graph of threshold shift (dB) from baseline versus days after treatment in an in vivo study. [Figure 10B] 1 is a graph of threshold shift (dB) from baseline versus ABR stimulation frequency for an in vivo study. [Figure 10C] 1 is a graph of threshold shift (dB) from baseline versus ABR stimulation frequency in an in vivo study 8 weeks after treatment. [Figure 11A] 1 is a graph of dexamethasone concentration (ng / mL) versus time in plasma for the subject population in an in vivo study. [Figure 11B] 1 is a graph of dexamethasone concentration (ng / mL) versus time in plasma for individual subjects in an in vivo study. DETAILED DESCRIPTION OF THE INVENTION

[0055] Potential side effects of systemic therapy and complications associated with prolonged, high-dose therapy can be avoided with topical therapy. Inner ear therapeutic agents (e.g., drugs formulated as biocompatible gels) can be delivered via intratympanic injection into the middle ear through the tympanic membrane (TM). Passive diffusion of drugs from the middle ear to the inner ear after intratympanic injection into the inner ear can vary in efficacy due to anatomical variations, such as the presence of a pseudomembrane overlying the round window membrane, the lack of contact of the injected formulation with the round window membrane, and the limited permeability of the round window and oval window membranes. This can lead to poor patient outcomes. Furthermore, there is a high risk of surgical complications. Furthermore, rapid clearance of drugs from the perilymph of the inner ear can result in the need for repeated intratympanic injections, which is undesirable for patients and is associated with the risk of poor compliance as well as the cumulative risk of infection, inflammation, and long-term damage to the tympanic membrane.

[0056] Local delivery of therapeutic agents to the inner ear typically results in higher concentrations in the inner ear fluid than systemic application. Locally applied substances (e.g., at lower doses than those used for systemic administration) can be administered even when there are significant limitations or even contraindications associated with systemic application. See, e.g., Salt, et al., Drug Discov Today. 2005 Oct 1;10(19):1299-1306. Substances are applied intratympanically, e.g., injected through the tympanic membrane into the middle ear cavity. Without being bound by any theory, this procedure is based on the premise that the drug contacts the round window membrane (RWM) of the cochlea, enters the scala tympani (ST), and spreads throughout the ear. Target tissues for such treatment include sensory hair cells, afferent nerve fibers, and supporting cells in the cochlear (hearing) or vestibular (balance) portions of the inner ear.

[0057] Anesthetics, glucocorticoids, and aminoglycosides have been used to treat inner ear disorders. Currently, the most widely used form of intratympanic therapy is the injection of glucocorticoids into the middle ear of subjects with Meniere's disease or sudden sensorineural hearing loss. There have also been clinical reports of topical application of gentamicin for the treatment of Meniere's disease. Gentamicin is toxic to sensory cells in the balance system, and partial ablation of the vestibular system suppresses vertigo in some subjects. Other substances tested in humans include local anesthetics, neurotransmitters, and neurotransmitter antagonists. There has also been interest in the administration of growth factors, antioxidants, apoptosis inhibitors, and antisense oligonucleotides. Animal studies have shown promising results using topically applied drugs to protect the ear from noise and drug toxicity. One extension of such research is topical viral and non-viral gene transfer for the sustained treatment of inner ear disorders.

[0058] Meniere's disease (MD) is a chronic disorder of the inner ear typically characterized by recurrent episodes of spontaneous vertigo, fluctuating hearing loss, tinnitus, and a sensation of ear fullness or blockage. These clinical symptoms can have a significant negative impact on an individual's quality of life. There is no cure for MD, and there are currently no approved pharmacological treatments for the condition.

[0059] Current treatments for MD primarily focus on reducing the frequency and severity of vertigo attacks, reducing tinnitus and aural fullness, and maintaining or improving hearing and quality of life. Various treatments are prescribed, including a low-salt diet, diuretics, betahistine, oral steroids, antivirals, benzodiazepines, and intratympanic (IT) injections of gentamicin or corticosteroids. In addition, destructive surgical ablation of the cochlea or auditory nerve can be performed in some cases.

[0060] The use of corticosteroids as a promising treatment option for patients with MD stems from the established clinical benefits of using corticosteroids to treat other hearing disorders, such as autoimmune inner ear disease and sudden sensorineural hearing loss (SNHL), combined with the role of inflammatory and immune mechanisms in the pathophysiology of MD. In addition to their anti-inflammatory and immunosuppressive effects in the cochlea, the mechanism of action of corticosteroids in MD also indicates that they improve inner ear function through increased labyrinthine circulation and ion or water transport mechanisms that affect cochlear fluid homeostasis. The corticosteroid dexamethasone has been shown to suppress inflammation by inhibiting multiple proinflammatory cytokines, reducing edema, fibrin deposition, capillary leakage, and inflammatory cell migration.

[0061] Direct drug injection into the middle ear for symptomatic management of MD may have significant advantages: the tight blood-labyrinth barrier allows therapeutic drug levels to be achieved in the inner ear after IT administration, while minimizing systemic exposure and the side effects often associated with systemic administration.

[0062] The clinical use of corticosteroids to treat patients with MD and tinnitus via the IT route of administration began over 30 years ago. Clinical benefits have been reported in both patient populations, with no adverse effects to treatment. Topical administration of dexamethasone, which is believed to enter the inner ear by diffusion through the round and oval window membranes, has been shown to play a role in improving hearing outcomes in patients with MD.

[0063] The AAO 2020 Clinical Practice Guideline for MD describes IT steroid therapy as a treatment option for patients with active MD who do not respond to non-invasive treatments (e.g., dietary and lifestyle modifications) and as an alternative to IT gentamicin therapy. Topical treatment with dexamethasone sodium phosphate has been established as an option in clinical practice as a result of systematic reviews and randomized controlled trials. The conclusion is that IT steroid therapy provides more benefits than harms.

[0064] Meniere's disease is a chronic disorder of the inner ear characterized by recurrent episodes of spontaneous dizziness (vertigo), fluctuating hearing loss, tinnitus (ringing in the ears), and a sensation of fullness or blockage in the ears (aural fullness). These symptoms can be debilitating and significantly impact quality of life. Meniere's disease typically manifests as unilateral (affecting only one ear), with no difference in the ratio of right to left ears. However, in 25–40% of cases (bilateral MD), the opposite ear is eventually affected. Bilateral MD is associated with increased vestibular symptoms and a negative impact on health-related quality of life (Espinosa-Sanchez JM and JA Lopez-Escamez. Meniere's disease. Handbook of Clinical Neurology 2016;137:257–77. nidcd.nih.gov / health / menieres-disease).

[0065] The prevalence of MD is approximately 50-200 per 100,000 adults in the United States (US) (Basura et al. Clinical Practice Guideline: Meniere's Disease. Otolaryngology-Head and Neck Surgery 2020, Vol. 162(2S)S1-S55), with a lower proportion of women (Lopez-Escamez JA, Carey J, Chung WH et al. (2015). Diagnostic criteria for Meniere's disease. J Vestib Res 25:1-7). MD can occur at any age, but adults in their 40s to 60s are more likely to be affected. Consequently, children are rarely affected (Espinosa-Sanchez JM and JA Lopez-Escamez. Meniere's Disease disease.Handbook of Clinical Neurology 2016;137:257-77).

[0066] There is no cure for MD, and currently no approved pharmacological treatments are indicated for its treatment. The natural history of MD is typically characterized by fluctuations in hearing and vestibular vision accompanied by periodic attacks of severe vertigo and a long-term, progressive decline in hearing and vestibular function (Basura et al., 2020). Some patients with MD suffer from other diseases and comorbidities, including allergies and autoimmune disorders (Espinosa-Sanchez JM and JA Lopez-Escamez. Meniere's disease. Handbook of Clinical Neurology 2016;137:257-77), and the causal relationship between MD and these comorbidities has not been fully established (Gurkov R, Pyyko I, Zou J, Kentala E. What is Meniere's disease? A contemporary re-evaluation of endolymphatic hydrops. J Neurol. 2016;263(Suppl 1):S71-81).

[0067] In 1861, Prosper Meniere pointed out that the symptoms of dizziness, balance problems, and hearing loss associated with MD were the result of lesions in the inner ear ( Basura et al., 2020 ).

[0068] The underlying pathogenesis of MD is not entirely clear, but it is associated with an increase in the volume of inner ear fluid (endolymph) (hydrops), which ultimately leads to temporary ear symptoms (dizziness, fluctuating hearing loss, tinnitus, and aural fullness) ( Basura et al., 2020 ).

[0069] The diagnostic criteria for MD were jointly developed by the Classification Committee of the Barany Society, the Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS), and the Korean Balance Society.

[0070] The classification has two categories: definite MD and probable MD (see Table B1). [Table B1]

[0071] Management of MD generally aims to reduce the frequency and severity of vertigo attacks, reduce tinnitus and aural fullness, and maintain or improve hearing and quality of life. A variety of treatments are prescribed, including a low-salt diet, diuretics, betahistine, oral steroids, antivirals, benzodiazepines, and IT injections of gentamicin or corticosteroids. In refractory cases, destructive surgical ablation of the cochlea or auditory nerve can be performed (Albu S, Chirtes F, Trombitas V et al. (2015). Intratympanic dexamethasone versus high dosage of betahistine in the treatment of intractable unilateral Meniere's disease. Am J Otolaryngol 36:205-209; Coelho DH, Lalwani AK. Medical management of Meniere's disease. Laryngoscope 2008;118:1099-108; Alarcon AV, Hidalgo LO, Arevalo RJ, Diaz MP. Labyrinthectomy and Vestibular Neurectomy for Intractable Vertiginous Symptoms. Int Arch Otorhinolaryngol.2017 Apr;21(2) 184-190.doi:10.1055 / s-0037-1599242.PMID:28382129;PMCID:PMC5375706).

[0072] The established clinical benefits of using corticosteroids to treat autoimmune inner ear diseases and other hearing disorders such as sudden SNHL (Li H, Feng G, Wang H, Feng Y (2015). Intratympanic steroid therapy as a salvage treatment for sudden sensorineural hearing loss after failure of conventional therapy: a meta-analysis of randomized, controlled trials. Clin Ther 37:178-187), combined with the role of inflammation and immune mechanisms in the pathophysiology of MD, have led to corticosteroids being considered as a promising treatment option in MD (Espinosa-Sanchez JM and JA Lopez-Escamez. Meniere's disease. Handbook of Clinical Neurology 2016;137:257-77, Lopez-Escamez JA, Vilchez JR, Soto-Varela A et al. al. (2007). The HLA-DRB1*1101 allele may be associated with bilateral Meniere's disease in a Southern European population.Otol Neurotol 28:891-895;Lopez-Escamez JA,Saenz-Lopez P,Acosta L et al.(2010).Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere's disease.Laryngoscope 120:103-107;Hamid M,Trune D(2008).Issues,indications,and controversies regarding intratympanic steroid perfusion.Curr Opin Otolaryngol Head Neck Surg 16:434-440, Hu A,Parnes LS.Intratympanic steroids for inner ear disorders:a review.Audiol Neurootol.2009;14(6):373-82).

[0073] The corticosteroid dexamethasone has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines, reducing edema, fibrin deposition, capillary leakage, and inflammatory cell migration. In addition to its anti-inflammatory and immunosuppressive effects in the cochlea, the mechanism of action of corticosteroids in MD also indicates that they improve inner ear function through ion or water transport mechanisms that increase labyrinthine circulation and affect cochlear fluid homeostasis (Espinosa-Sanchez, 2016, Nevoux J, Viengchareun S, Lema I et al. (2015). Glucocorticoids stimulate endolymphatic water reabsorption in inner ear through aquaporin 3 regulation. Pflugers Arch 467:1931-1943).

[0074] Direct middle ear drug injection for symptomatic management of MD has significant advantages: the tight blood-labyrinth barrier allows therapeutic drug levels to be achieved in the inner ear after IT administration while minimizing systemic exposure.

[0075] Animal studies have shown that IT delivery of corticosteroids significantly increases steroid levels in the inner ear compared to systemic administration, avoiding many of the adverse effects associated with systemic administration, such as osteoporosis, diabetes mellitus, hypertension, peptic ulcer disease, cataracts, and endocrine disorders (Espinosa-Sanchez, 2016).

[0076] From a historical perspective, the clinical use of corticosteroids via the IT route began with Sakata et al. (1986) and 10 years later with Shea et al. (Shea JJ Jr, Ge X. Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Meniere's disease. Otolaryngol Clin North Am 1996;29:353-358) has been used to treat patients with MD and tinnitus. Clinical benefits have been reported in both patient groups, with no adverse effects from treatment. Topical administration of dexamethasone is believed to enter the inner ear by diffusion through the round and oval window membranes and has been shown to play a role in improving hearing in patients with MD. Dexamethasone is thought to target the endolymphatic sac and act on the stria vascularis and spiral ligament, known targets of the immune response in the inner ear. As a result, a reduction in endolymphatic hydrops (EH) is observed, and endolymphatic fluid dynamics are restored (Shea et al., 1996). After IT injection, steroid concentrations in the perilymph are estimated to be 260-fold higher than with oral administration (Devantier L, Djurhuus BD, Hougaard DD, et al. Intratympanic steroids for Meniere's Disease: A Systematic Review. Otol Neurotol. 2019;40(6):806-812; Bird PA, Murray DP, Zhang M, Begg EJ. Intratympanic versus intravenous delivery of dexamethasone and dexamethasone sodium phosphate to cochlear perilymph. Otol Neurotol 2011;32:933-6).

[0077] IT-delivered steroid therapy appears to have a lower risk of treatment-related hearing loss than IT gentamicin therapy, 0%-8% vs. 12.5%-15.4%, respectively (Basura et al., 2020; Casani AP, Piaggi P, Cerchiai N, Seccia V, Franceschini SS, Dallan I. Intratympanic treatment of intractable unilateral Meniere's disease: gentamicin or dexamethasone?A randomized controlled trial.Otolaryngol Head Neck Surg.2012;146(3):430-437, ElBeltagy Y, Shafik A, Mahmoud A,Hazaa N.Intratympanic injection in Meniere's disease;symptomatic and audiovestibular;comparative, prospective randomized 1-year control study.Egypt J Otolaryngol.2012;28(3):171-183;Sarafraz M,Saki N,Nikakhlagh S,Mashali L,Arad A.Comparison the efficacy of intratympanic injections of methylprednisolone and gentamicin to control vertigo in unilateral Meniere's disease.Biomed Pharmacol J.2015;8:705-709, Syed MI,Ilan O,Nassar J,Rutka JA.Intratympanic therapy in Meniere's syndrome or disease:up to date evidence for clinical practice.Clin Otolaryngol.2015;40(6):682-690). One study found that both IT steroid therapy (38%) and IT gentamicin therapy (31%) resulted in similar improvement in ear fullness.

[0078] Similar to sudden sensorineural hearing loss, two systematic reviews suggest that intrathecal steroid therapy may play a role in restoring hearing secondary to MD flares (Basura et al., 2020; Lavigne P, Lavigne F, Saliba I. Intratympanic corticosteroid injections: a systematic review of literature. Eur Arch Otorhinolaryngol. 2016;273(9):2271-2278; Patel M. Intratympanic corticosteroids in Meniere's disease: a mini-review. J Otol. 2017;12(3):117-124), although one randomized controlled trial found no benefit in terms of hearing restoration (Basura et al., 2020; Silverstein H, Isaacson JE, Olds MJ, Rowan PT, Rosenberg S. Dexamethasone inner ear perfusion for the treatment of Meniere's disease: a prospective, randomized, double-blind, crossover trial. Am J Otol. 1998;19(2):196-201).

[0079] One randomized controlled trial (Basura et al., 2020; Paragache G, Panda NK, Ragunathan M, Sridhara. Intratympanic dexamethasone application in Meniere's disease - is it superior to conventional therapy? Indian J Otolaryngol Head Neck Surg. 2005;57(1):21-23) and three systematic reviews (Lavigne et al., 2016; Patel, 2017; Phillips JS, Westerberg B. Intratympanic steroids for Meniere's disease or syndrome. Cochrane Database Syst Rev. 2011;(7):CD008514) have shown that intratympanic steroid therapy generally results in greater improvement of dizziness symptoms (85%-90% vs. 57%-80%) when compared with placebo or conventional medical therapy. Variable benefit has been seen in associated symptoms of tinnitus and ear fullness, with one randomized controlled trial comparing intrathecal steroids with placebo (Garduno-Anaya MA, Couthino De Toledo H, Hinojosa-Gonzalez R, Pane-Pianese C, Rios-Castaneda LC. Dexamethasone inner ear perfusion by intratympanic injection in unilateral Meniere's disease: a two-year prospective, placebo-controlled, double-blind, randomized trial. Otolaryngol Head Neck Surg 2005;33:285-94) showing improvement in tinnitus (48% vs. 20%), hearing loss (35% vs. 10%), and ear fullness (48% vs. 20%).

[0080] Early studies using a sustained-release form of dexamethasone documented a reduction in the frequency of dizziness (56% and 73%, respectively) at 3 mg and 12 mg doses compared to placebo (42%), as well as a similar reduction in tinnitus (Basura et al., 2020; Lambert PR, Nguyen S, Maxwell KS, et al. A randomized, double-blind, placebo-controlled clinical study to assess the safety and clinical activity of OTO-104 given as a single intratympanic injection in patients. with unilateral Meniere's disease. Otol Neurotol. 2012;33(7):1257-1265). Subsequent studies reported a statistically insignificant reduction in dizziness severity compared to placebo, with no difference in tinnitus perception (Basura et al., 2020, Lambert et al., 2016). Statistically significant reductions in the mean number of daily dizziness attacks and number of dizziness days per month were observed (Basura et al., 2020, Lambert et al., 2016). Overall, IT steroid therapy is well tolerated, with few side effects and / or complications. The most frequently cited complications were postoperative otitis media (7%) (Basura et al., 2020, Patel et al., 2016) and persistent tympanic membrane perforation (3%-38%) (Basura et al., 2020, Lambert et al., 2012, Lambert PR, Carey J, Mikulec AA, LeBel C. Intratympanic sustained-exposure dexamethasone thermosensitive gel for symptoms of Meniere's disease: randomized phase 2b safety and efficacy trial. Otol Neurotol. 2016;37(10):1669-1676).

[0081] As Basura et al. (2020) pointed out, the effectiveness of intrathyroid steroid therapy has been difficult to assess due to the variability of treatment protocols, including the number of doses, the interval between doses, the duration of follow-up, and the effect on dizziness control, tinnitus, and aural fullness (Syed MI, Ilan O, Nassar J, Rutka JA. Intratympanic therapy in Meniere's syndrome or disease: up to date evidence for clinical practice. Clin Otolaryngol. 2015;40(6):682-690).

[0082] IT-delivered steroid therapy is more effective than oral steroid therapy (Basura et al., 2020; Morales-Luckie E, Cornejo-Suarez A, Zaragoza-Contreras MA, Gonzalez-Perez O. Oral administration of prednisone to control refractory vertigo in Meniere's disease: a pilot study. Otol Neurotol. 2005;26(5):1022-1026; Phillips et al., 2011; Doyle KJ, Bauch C, Battista R, et al. Intratympanic steroid treatment: a review. Otol Neurotol. 2004;25(6):1034-1039; Morgan AE, Ismail EI,Ashraf B.Intratympanic injections of dexamethasone in delayed endolymphatic hydrops: a prospective clinical study.ORL J Otorhinolaryngol Relat Spec.2018;80(1):19-27) and IT gentamicin therapy (Basura et al.,2020;Casani AP, Piaggi P, Cerchiai N, Seccia V, Franceschini SS, Dallan I. randomized controlled trial.Otolaryngol Head Neck Surg.2012;146(3):430-437; ElBeltagy et al.,2012; Patel et al.,2016; Sarafraz et al.,2015).

[0083] Oral steroids carry a significant risk of side effects (Basura et al., 2020; Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg. 2012;146(3):S1-S35; Doyle et al., 2004). Patients with usable hearing may be hesitant to undergo ablative cochlear therapies, such as IT gentamicin, which are known to cause hearing loss. Therefore, patient preference plays an important role when offering IT steroid therapy (Basura et al., 2020; Radtke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Neuhauser H. Migraine and Meniere's disease: is there a link? Neurology. 2002;59(11):1700-1704). Intratympanic delivery may be a minimally invasive injection performed in an office setting that offers a potential direct route of administration (Piu F, Wang X, Fernandez R, Dellamary L, Harrop A, Ye Q, Sweet J, Tapp R, Dolan DF, Altschuler RA, Lichter J, LeBel C. OTO-104: a sustained-release dexamethasone hydrogel for the treatment of otic disorders.Otol Neurotol.2011 Jan;32(1):171-9).

[0084] Over the years, several clinical investigations have been conducted to evaluate the safety and efficacy of IT administration of corticosteroids in patients with MD. The safety, tolerability, and clinical activity of a single IT injection of 12 mg of dexamethasone (n = 93) were evaluated in two recent clinical studies in patients with unilateral MD. The results demonstrated that dexamethasone (formulated in a buffered solution containing the glycol polymer, poloxamer 407) was safe, well-tolerated, and showed promising improvements in dizziness endpoints, supporting the program's progression to the currently ongoing phase 3 study. (Lambert PR, Nguyen S, Maxwell KS, et al. A randomized, double-blind, placebo-controlled clinical study to assess safety and clinical activity of OTO-104 given as a single intratympanic injection in patients with unilateral Meniere's disease. Otol Neurotol. 2012;33(7):1257-1265, Lambert PR, Carey J, Mikulec AA, LeBel C. Intratympanic sustained-exposure dexamethasone thermosensitive gel for symptoms of Meniere's disease:randomized phase 2b safety and efficacy trial.Otol Neurotol.2016;37(10):1669-1676).

[0085] In a phase 1b study, 16 patients received a single IT injection of 12 mg dexamethasone, 14 patients received 3 mg dexamethasone, and 14 patients received placebo. There were no deaths, serious adverse events (SAEs), or adverse events (AEs) leading to withdrawal from the study. There were also no adverse findings on laboratory measurements, physical examination, vital signs, or electrocardiogram (ECG) (Lambert et al., 2012).

[0086] In this study, most patients experienced at least one treatment-emergent adverse event (TEAE). The only pre-specified AE of interest observed in more than one patient was tympanic membrane (TM) perforation. At the end of the study, the incidence of TM perforation was 3% in patients receiving dexamethasone (3 mg or 12 mg). TM perforation has been observed in other studies using IT injections (Lambert et al., 2012; Rauch SD, Halpin CF, Antonelli PJ, et al. Oral vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: a randomized trial. JAMA 2011;305:2071-79, Herraiz C, Plaza G, Aparicio JM, et al. Transtympanic steroids for Meniere's disease. Otol Neurotol 2010;31:162-7), most perforations resolved spontaneously (Lambert et al., 2012, Muehlmeier G, Biesinger E, Maier H. Safety of intratympanic injection of AM-101 in patients with acute inner ear tinnitus.Audiol Neurotol 2011;16:388-97).

[0087] In a phase 2b study, 77 patients received a single IT injection of 12 mg dexamethasone and 77 patients received a placebo. Most AEs were mild or moderate in severity, and no TEAEs led to patient discontinuation in this study. The results of safety assessments in this study (otoscopy, audiometry, tympanometry, vital signs, clinical laboratory assessments, word recognition, and the Columbia-Suicide Rating Scale (C-SSRS)) support continued evaluation of IT corticosteroid injections, as they were well tolerated and no new risks were identified.At the end of this study, persistent TM perforation was observed in two patients treated with dexamethasone, consistent with perforations observed after IT administration of corticosteroids (Lambert et al., 2016; Garduno-Anaya MA, Couthino De Toledo H, Hinojosa-Gonzalez R, Pane-Pianese C, Rios-Castaneda LC. Dexamethasone inner ear perfusion by intratympanic injection in unilateral Meniere's disease: a two-year prospective, placebo-controlled, double-blind, randomized trial. Otolaryngol Head Neck Surg 2005;33:285-94; Silverstein H, Farrugia M, Van Ess M. Dexamethasone inner ear perfusion for subclinical endolymphatic hydrops. Ear Nose Throat J 2009;88:778-85, Kitahara T, Kubo T, Okumura S, Kitahara M. Effects of endolymphatic sac drainage with steroids for intractable Meniere's disease: a long-term follow-up and randomized controlled study. Laryngoscope 2008;118:854-61, Herraiz C, Plaza G, Aparicio JM, et al. Transtympanic steroids for Meniere's disease. Otol Neurotol 2010;31:162-7, Rauch SD, Halpin CF, Antonelli PJ, et al. Oral. vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: a randomized trial.JAMA 2011;305:2071-79).

[0088] Although the etiology of the disease remains unknown, EH is generally accepted as a pathological feature of MD.

[0089] In 2010, Naganawa et al. (Naganawa, S. et al. Visualization of endolymphatic hydrops in Meniere's disease with single-dose intravenous gadolinium-based contrast media using heavily T(2)-weighted 3D-FLAIR. Magn Reson Med Sci 9, 237-242 (2010)) developed intravenous gadolinium (Gd)-enhanced inner ear MRI to visualize EH in MD patients. IV-Gd-enhanced inner ear MRI is minimally invasive, has a relatively short waiting time (4 hours), and can visualize both inner ears simultaneously, allowing for the identification of asymptomatic EH in the contralateral ear. Cho YS et al. (Cho YS, Ahn JM, Choi JE, et al. Usefulness of Intravenous Gadolinium Inner Ear MR Imaging in Diagnosis of Meniere's Disease. Sci Rep. 2018;8(1):17562. Published 2018 Dec 3. doi:10.1038 / s41598-018-35709-5) conducted a clinical study aimed at investigating the usefulness of IV-Gd-enhanced cochlear MRI in the diagnosis of MD and found a correlation between the degree of EH and hearing tests. The results demonstrated adequate correlation with auditory-vestibular function tests, indicating the usefulness of IV-Gd cochlear MRI as a diagnostic method for visualizing EH in MD. Despite these findings, EH is not currently part of the diagnostic criteria for definite MD cases.

[0090] To improve diagnostic accuracy in patients suspected of having MD based on imaging, recent studies have introduced perilymphatic enhancement (PE) as an additional MD discrimination parameter. However, what remains unclear is the presence and value of PE in other vertigo-associated inner ear pathologies (VAIEPs).

[0091] In February 2020, JM van Steekelenburg et al. published a retrospective analysis of 220 patients (median age, 55.8) with inner ear lesions suspected to be MD. The aim of this study was to evaluate the added value of the presence of EH and PE in the diagnosis of patients with MD and other VAIEP patients not due to MD (Van Steekelenburg JM, van Weijnen A, de Pont LMH, Vijlbrief OD, Bommelje CC, Koopman JP, Verbist BM, Blom HM, Hammer S. Value of Endolymphatic Hydrops and Perilymph Signal Intensity in Suspected Meniere Disease. AJNR Am J Neuroradiol. 2020 Mar;41(3):529-534. doi:10.3174 / ajnr.A6410. Epub 2020 Feb 6). Results showed that increased PE was more common in definite and probable MD ears compared with other VAIEP ears (p<0.001 and p=0.003, respectively) and asymptomatic ears (both p<0.001). This study highlights the relevance of EH as a feature of definite MD, as vestibular or cochlear EH or both were present in 91.9% of definite MD ears. Compared with asymptomatic ears, definite MD ears showed increased PE by both visual and quantitative measurements.

[0092] This study also demonstrated the value of delayed Gd-enhanced 3D-FLAIR MRI in diagnosing MD in a cohort with widespread VAIEP, indicating that the combination of EH and increased PE is not common in other patients with VAIEP. These findings may be useful in differentiating patients with dizziness due to MD (van Steekelenburg et al., 2020).

[0093] Off-label intravenous steroid injections are often administered to patients with MD. However, therapeutic benefit is limited, at least in part, by the rapid clearance of solution formulations from the middle ear, the uncertainty of drug placement within the middle ear due to the "blind" nature of the injection, and the presence of membrane barriers and air pockets in the middle ear. Current MD treatment guidelines (Basura, 2020) suggest administering a compound dexamethasone sodium phosphate or methylprednisolone sodium succinate solution every 3–7 days for 3–4 sessions. Dexamethasone suspension gel formulations have shown promise in improving dizziness symptoms in patients with MD (Lambert 2012, 2016), but even such thermoresponsive gel formulations have been shown to be cleared from the middle ear within a few days of administration (Piu 2011). Pseudomembranes (false membranes) are present in 42% of ears (Sahin B, Orhan KS, Asliyuksek H, Kara E, Buyuk Y, Guldiken Y. Endoscopic evaluation of middle ear anatomic variations in autopsy series: analyses of 204 years.Braz J Otorhinolaryngol.2020 Jan-Feb;86(1):74-82), which is rapidly cleared and limits contact of randomly placed formulations with the round window membrane.

[0094] However, currently available formulations for intratympanic delivery have short middle ear residence times and typically require multiple administrations to achieve the desired effect in the inner ear. The short residence times of these formulations can result in inconsistent drug distribution and release, leading to poor pharmacokinetics.

[0095] It is therefore an object to provide a beneficial formulation that can be administered for sustained intratympanic delivery of therapeutic, prophylactic, or diagnostic agents to the inner ear over several days, providing controlled release and pharmacokinetics while minimizing the risk of systemic exposure and reducing the need for repeat administration.

[0096] I. Definition "Active agent" and "active pharmaceutical ingredient" are used interchangeably and refer to a physiologically and / or pharmacologically active substance that acts locally and / or systemically in the body. An active agent is a substance administered to a subject for the treatment (e.g., glucocorticoids or anti-angiogenesis), prevention (e.g., anti-apoptosis), or diagnosis (egadolinium) of a disease or disorder.

[0097] The term "AUC" or "area under the curve" in the field of pharmacokinetics is the definite integral in a plot of plasma active agent concentration versus time. In practice, the active agent concentration is usually measured at specific discrete time points, and the trapezoidal rule is used to estimate the AUC. The AUC of an active agent is typically used to assess a subject's exposure to the active agent over time.

[0098] The term "auditory brainstem response" or "ABR" refers to auditory evoked potentials (AEPs) extracted from ongoing electrical activity in the brain and recorded, for example, via electrodes placed on the scalp. Because ABRs depend on external factors, they are considered exogenous responses.

[0099] The term "blood-labyrinth barrier" or "BLB" refers to the barrier between the vasculature and the inner ear fluid, either endolymph or perilymph. The BLB is involved in maintaining the ionic homeostasis of the inner ear fluid.

[0100] The term "BLLQ" is an abbreviation for "below limit of quantitation" and is defined as below the lowest standard of the calibration curve.

[0101] "C max The term "maximum (or peak) serum concentration" refers to the maximum (or peak) serum concentration achieved by an active agent after the active agent is administered (e.g., systemically or in a particular compartment or test area of ​​a subject). In some embodiments, C max is measured before the second dose of active agent.

[0102] "C min The term "C" refers to the minimum (or trough) serum concentration that an active agent achieves after it is administered (e.g., systemically or in a particular compartment or test area of ​​a subject). In some embodiments, C min is measured before the second dose of active agent.

[0103] The term "cytochoreogram" refers to a graphic representation of the anatomy of hair cells along the entire width and length of the organ of Corti.

[0104] The abbreviation "DDI" refers to drug-drug interactions.

[0105] The term "degree of functionalization," when referring to a polymer capable of participating in crosslinking, is the number of functional groups per suitable polymer unit (e.g., polymer chain, branch, or monomer) that is suitable for crosslinking using a given crosslinking agent. For example, if a polymer has one or more functional groups per monomer, then a suitable polymer unit is a monomer. As another example, if a polymer has one or more functional groups per branch end, then a suitable polymer unit is a branch. It will be further understood that in some cases, the degree of functionalization may be less than 1, for example, if a subpopulation of functional groups has degraded.

[0106] The term "drug absorption" or "absorption" typically refers to the process of movement of an active agent from a site of local administration to a site of therapeutic effect. In some cases, drug absorption may occur through the round window niche of the cochlea and across a barrier (such as the round window membrane) into one or more inner ear structures. As used herein, the term "co-administration" is generally meant to encompass the administration of two or more active agents to a single subject and is intended to include prophylactic regimens in which the active agents are administered by the same or different routes of administration or at the same or different times.

[0107] The term "elastic" as used herein with respect to gels may mean that the gel exhibits elasticity, e.g., resists a distorting force and returns to its original size and shape when the force is removed. Elastic modulus may also be measured by oscillatory rheology.

[0108] The phrase "effective amount" or "effective concentration" refers to an amount of an active agent, when present at the site of action, sufficient to (i) treat a disease or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of an active agent that would correspond to such an amount will vary depending on factors such as the particular active agent, the condition and its severity, and the identity (e.g., age and / or weight) of the patient requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art. As used herein, the term "effective amount" or "therapeutically effective amount" may refer to a sufficient amount of an active agent at the site of action that would be expected to alleviate to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, an effective amount of an active agent is the amount necessary to produce the desired anti-inflammatory result in a prophylactically effective amount. The term "therapeutically effective amount" includes, for example, an "effective amount" of an active agent to achieve a desired pharmacological effect without undue adverse side effects.

[0109] The phrase "effective dose" refers to an amount of an active agent that, when administered to a patient in need of such treatment, is sufficient to (i) treat a disease or disorder, (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In some embodiments, an "effective dose" is an amount of an active agent that, when administered to a patient in need of such treatment, achieves a concentration at the site of action sufficient to (i) treat a disease or disorder, (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The dose of an active agent that would correspond to such an amount will vary depending on factors such as the particular active agent, the condition and its severity, and the identity (e.g., age and / or weight) of the patient requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art. As used herein, the term "effective dose" or "therapeutically effective dose" may refer to a sufficient administration of an active agent that would be expected to relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, an effective dose of an active agent is the amount necessary to produce the desired anti-inflammatory result. The term "therapeutically effective dose" includes, for example, an "effective dose" of an active agent to achieve a desired pharmacological effect without undue adverse side effects. It will also be understood that an "effective dose" in a sustained-release dosage format may differ from an "effective dose" in an immediate-release dosage format based on pharmacokinetic and / or pharmacodynamic considerations.

[0110] The terms "enhance" or "enhancing" can refer to an increase in efficacy or a prolongation of a desired effect. In some cases, "enhance" or "enhancing" can also refer to a reduction in one or more side effects associated with an active agent. For example, with respect to enhancing the effect of an active agent disclosed herein, the term "enhancing" can refer to the ability of an anti-inflammatory agent to increase the efficacy or prolong the duration of the effect of the active agent. As used herein, an "enhancing-effective amount" refers to that amount of agent sufficient to enhance the effect of the active agent in a desired system. The amount of the agent that would correspond to such an amount will vary depending on factors such as the particular active agent, the condition and its severity, and the identity (e.g., age and / or weight) of the patient requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0111] The term "gel" refers to a semi-solid composition. In some embodiments, gels can be distinguished from liquids by assessing their flow under gravity, e.g., by performing a gelation reaction in a vial and then inverting the vial. Some assessments can be performed by visual inspection to determine whether the composition still flows. In some cases, gravimetric assessments can be performed after inverting the vial and wiping the liquid from the sample in the insert. In some cases, gels can be distinguished from liquids by the composition's ability to prevent a stir bar from rotating (e.g., a 7 x 2 mm PTFE stir bar containing about 0.2 to about 1 mL of composition in a 2 mL vial). In some embodiments, gels can be distinguished from liquids by their elastic modulus. In some embodiments, gel formation can be determined by a rapid change in the ordinate value when plotting the ratio of storage modulus to loss modulus (G" / G') versus time (t). In some embodiments, gels can be distinguished from liquids by analyzing their cohesive strength, for example, by drop weight or compressive force (see Edsman, Katarina LM, et al. "Is there a method that can measure cohesion? Cohesion by sensory evaluation compared with other test methods." Dermatologic Surgery 41 (2015):S365-S372, and Edsman, Katarina LM, and Ake Ohrlund. "Cohesion of hyaluronic acid fillers: correlation between cohesion and other physicochemical properties." Dermatologic Surgery 44.4 (2018):557, both of which are incorporated herein by reference in their entireties).

[0112] The term "gelling" refers to the formation of a gel. Typically, a gel is formed by the gelation of a liquid composition.

[0113] The term "gel duration" refers to the time it takes for a gel to break down, dissolve, or return to solution. In some cases, gel duration is measured by placing the gel in a vial and storing it at room temperature, 37°C, or accelerated conditions at 50°C. In some cases, gel duration is measured by placing the gel (e.g., at least 1 mL) in receptor solution (e.g., PBS at pH 7.4) at 37°C (or accelerated conditions at 50°C) and periodically replacing the receptor solution as needed.

[0114] The term "gelation time" refers to the time it takes for a composition to form a gel after combining all appropriate components. In some cases, gelation time can be determined by measuring the time it takes to achieve one or more of the gel characteristics defined herein. In some embodiments, gelation time can be determined by measuring the time it takes for a stir bar to stop rotating in a container in which gelation occurs.

[0115] The term "GLP" refers to "Good Laboratory Practice," a set of principles intended to ensure the quality and integrity of non-clinical laboratory research.

[0116] The term "hERG" can refer to the human ether-a-go-go-related gene, which encodes a protein that is the alpha subunit of a potassium ion channel. In some cases, ion channels containing this subunit are also called hERG.

[0117] "I C 50 The term "" refers to the concentration of inhibitor at which the assay result is reduced by 50%.

[0118] The term "inhibit" can mean to reduce or decrease an activity (e.g., signaling activity) or expression (e.g., of a gene or gene product). The term can also include preventing, delaying, or reversing the onset of a disease or condition or the progression of a disease or condition in a subject. In some cases, inhibition can be partial. In some cases, inhibition can be complete. In some embodiments, the level of inhibition can be determined based on comparison to a control or standard level.

[0119] The term "macromolecule" generally refers to a molecule greater than 1500 g / mol, greater than about 2000 g / mol, or greater than about 2500 g / mol. In some embodiments, a macromolecule can be a polymer and / or an oligomer.

[0120] The term "MRSD" or "maximum recommended starting dose" refers to the largest amount of a drug that can be administered safely and without complications while maintaining its effectiveness.

[0121] The term "MTD" or "maximum tolerated dose" refers to the highest dose of a drug or prevention that does not cause unacceptable side effects.

[0122] As used herein, the term "mucoadhesion" may refer to adhesion between two substances, one of which is a mucosal surface.

[0123] The term "NOAEL" refers to "no observed adverse effect level" and can be an important part of nonclinical risk assessment.

[0124] The terms "otic" and "auris" refer to anything relating to the ear. For example, an otic composition may be a composition intended for administration to the ear.

[0125] The term "pharmaceutically acceptable" indicates that a compound, or a salt or composition thereof, is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated therewith. In some embodiments, a pharmaceutically acceptable salt may be a salt that preserves the efficacy and / or biological properties of the free base or free acid. In some embodiments, a pharmaceutically acceptable salt may alter the efficacy and / or biological properties of the free base or free acid. For example, a pharmaceutically acceptable salt may improve the bioavailability of the free base or free acid.

[0126] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical treatment resulting from the mixing or combination of multiple active agents, and includes both fixed and non-fixed combinations of active agents. The term "fixed combination" means that a first active agent, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional active agent are both administered to a patient simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a first active agent, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional active agent are formulated as separate compositions or dosages that can be administered simultaneously or sequentially to a subject in need thereof, using the same or different routes of administration with variable intervening time limits, such that such administration provides effective levels of the two or more compounds in the subject's body. In one embodiment, the first and second active agents are formulated as separate unit dosage forms, which are suitable for either sequential or simultaneous administration. These terms also apply to cocktail therapy, e.g., the administration of three or more active ingredients.

[0127] The term "pot life," as used herein when referring to a solution or suspension containing a moiety that includes an electrophile (e.g., succinimidyl ester-functionalized PEG) that can form crosslinks with a nucleophile, refers to the time after the moiety has gone into solution or suspension (e.g., from a powder or solid).

[0128] The term "VEGF inhibitor" includes any agent (e.g., a small molecule, antibody, or antigen-binding fragment thereof) that exhibits inhibition of vascular endothelial growth factor (VEGF) signaling. In some embodiments, the VEGF inhibitor is capable of binding to a vascular endothelial growth factor receptor (VEGFR). In some embodiments, the VEGF inhibitor is capable of binding to a vascular endothelial growth factor (e.g., a ligand for VEGFR).

[0129] The term "ear-acceptable penetration enhancer" or "penetration enhancer" refers to an agent that reduces barrier resistance (e.g., the barrier resistance of the round window membrane).

[0130] The term "prophylactically effective amount" refers to an amount of an active agent sufficient, when administered to a site of action in a patient in need of such treatment, to (i) prevent a disease or disorder, or (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder before it occurs. In some cases, a "prophylactically effective amount" refers to the amount of a composition at a site of action administered to a subject susceptible to or otherwise at risk of a particular disease, disorder, or condition; for example, a prophylactically effective amount of an active agent can be an amount effective to prevent or reduce ototoxicity at the site of action.

[0131] The term "prophylactically effective dose" refers to an amount of an active agent that, when administered to a patient in need of such treatment, is sufficient to (i) prevent a disease or disorder, or (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder before it occurs. In some cases, a "prophylactically effective dose" refers to the amount of a composition administered to a subject susceptible to or otherwise at risk of a particular disease, disorder, or condition; for example, a prophylactically effective amount of an active agent can be an amount effective to prevent or reduce ototoxicity. For example, an apoptosis-inhibiting formulation can be administered to an individual prior to chemotherapy to prevent hearing loss caused by the subsequently administered chemotherapy agent.

[0132] As used herein, the term "dwell time" can refer to the time a formulation remains at the administration site. In some embodiments, the dwell time can be the time when there is no visualized gel on the round window membrane area, for example, the time after collecting the gel at some point after injection.

[0133] The term "room temperature" refers to a temperature of about 15°C to less than about 27°C, preferably about 20°C.

[0134] The term "body temperature" refers to a temperature between about 36.5°C and about 37.5°C, preferably about 37°C.

[0135] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0136] A "small molecule" generally refers to a molecule that is less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is non-polymeric and / or non-oligomeric. In some embodiments, a small molecule can be organic. In some embodiments, a small molecule can be inorganic. In some embodiments, a small molecule can contain both organic and inorganic atoms.

[0137] "Steady state" can refer to when the amount of drug administered (e.g., to the middle ear and / or inner ear) equals the amount of drug eliminated within a single dosing interval, resulting in a plateau or constant level of drug exposure within the target structure.

[0138] As used herein, "stable" may refer to chemical and / or physical stability over a period of time under defined conditions. In some embodiments, a stable solution can retain a high percentage or all of what was originally dissolved in solution. In some embodiments, a solution can retain more than 60, 70, 80, 90, 95, 98, 99, or 100% of the initially dissolved solutes at room temperature (about 15-25°C, most preferably 25°C).

[0139] As used herein, "sustained release" refers to the release of a substance over an extended period of time. In some embodiments, this can be contrasted with bolus-type administration, where the entire amount of the substance becomes bioavailable at once.

[0140] As used herein, "swelling" of a gel may refer to the percent increase in gel weight after equilibration with phosphate-buffered saline (PBS). Gel swelling can be measured, for example, by preparing a gel in an insert, recording the initial gel weight, allowing the gel to form at room temperature for approximately 20-60 minutes, immersing the insert in PBS (the PBS volume is at least five times the volume of the gel) (e.g., pH 7.4), storing the insert at 37°C, removing the gel-filled insert after 1-3 days, wiping off the surface fluid, and recording the weight. Then, calculate the increase in gel weight normalized by the initial gel weight.

[0141] "T max The term "concentration" refers to the maximum concentration of a drug or other substance at which max It refers to the time it takes to reach

[0142] The term "transtympanic" or "intral" administration refers to administration of an active agent through the tympanic cavity, in some cases through a hypodermic needle that accesses the tympanic cavity (middle ear) by piercing the tympanic membrane (eardrum).

[0143] As used herein, the terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, a stable (i.e., not worsening) state of the disease, a delay or slowing of the progression of the disease, an improvement or alleviation of the condition (e.g., one or more symptoms of the disease), and remission (whether partial or total).

[0144] The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other patients, each unit containing a predetermined quantity of active material (i.e., an active agent described herein) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0145] As used herein, the terms "prevent," "preventing," or "prevention" refer to the prevention, in whole or in part, of the onset, recurrence, or spread of a disease or condition described herein, or a symptom thereof.

[0146] II. Sustained-release otic composition Provided herein are otic compositions (e.g., sustained-release otic compositions) comprising the polymer compositions provided herein and an active agent. Otic (sometimes referred to as aural) compositions are developed to sustainedly release therapeutic, prophylactic, and / or diagnostic agents in the ear, either continuously or pulsatilely, or both. In some embodiments, the sustained-release otic compositions described herein can increase the area under the curve (AUC) of the delivered agent in ear fluids (e.g., endolymph and / or perilymph) by about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to compositions that are not sustained-release otic compositions. Sustained-release compositions can, in some cases, increase the C in ear fluids (e.g., endolymph and / or perilymph) compared to compositions that are not sustained-release otic compositions. max The C may also be reduced by about 40%, about 30%, about 20%, or about 10% compared to a composition that is not a sustained release otic composition.max and C min The ratio of C to C can be reduced. Thus, in some embodiments, the sustained release otic composition can provide a more consistent release of the active agent. In certain implementations, C max and C min The ratio of C to C can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. min The length of time that the sustained release composition exceeds C may be increased by about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to a composition that is not a sustained release otic composition. max Delay the time until the drug concentration reaches C min In some embodiments, the sustained-release auris compositions extend the residence time of the drug in the inner ear.

[0147] In some cases, sustained-release otic compositions are provided in gel form, thereby achieving sustained delivery to the middle and / or inner ear. In some such embodiments, the gel can remain intact in a preferred location, such as the round window membrane, for an extended period of time. In some embodiments, a sustained-release otic composition in gel form can provide at least about a 2-fold, 4-fold, 10-fold, or 20-fold increase in residence time, which can result in about a 2-fold, 4-fold, 10-fold, or 20-fold increase in AUC, compared to a composition that is not a sustained-release otic composition.

[0148] In some embodiments, once the concentration of drug in the endolymph or perilymph reaches steady state, the concentration of active agent in the endolymph or perilymph remains at or near an effective concentration for an extended period of time (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months).

[0149] In some embodiments, the sustained release otic composition can have at least two components: an active agent (e.g., a therapeutic, prophylactic, and / or diagnostic agent), a gel-forming polymer composition (e.g., comprising a functional polymer, a crosslinker, and water), and optionally one or more excipients that together form the sustained release otic composition.

[0150] A. Therapeutic, preventive and diagnostic agents In some embodiments, the sustained release otic compositions are useful for local therapy, prevention, and / or diagnosis. A therapeutically active agent, a prophylactically active agent, a diagnostic or visualization agent, or a combination thereof, can be delivered from the sustained release otic composition, for example, from a crosslinked polymer or gel formed after administration of the sustained release otic composition.

[0151] The active agent can be any suitable active agent. In some embodiments, the active agent can be a therapeutic agent. In some embodiments, the active agent can be a prophylactic agent. In some embodiments, the active agent can be a diagnostic or visualization agent. In some embodiments, the active agent can include a diagnostic or visualization agent and a therapeutic agent. In some embodiments, the active agent can include a diagnostic or visualization agent and a prophylactic agent. The active agent can include, for example, a protein (e.g., an enzyme, a growth factor, an antibody or antigen-binding fragment thereof), a carbohydrate (e.g., a glycosaminoglycan), a nucleic acid (e.g., an antisense oligonucleotide, an aptamer, a microRNA, a short interfering RNA, or a ribozyme), a small molecule, or a combination thereof. In some embodiments, the small molecule can comprise an antibiotic, an anti-tumor agent (e.g., doxorubicin), a local anesthetic, a steroid, a hormone, an apoptosis inhibitor (e.g., an inhibitor of Apaf-1, see, e.g., U.S. Pat. No. 9,040,701, incorporated herein by reference in its entirety), an angiogenic agent, an anti-angiogenic agent (e.g., a VEGF inhibitor), a neurotransmitter, a psychotropic agent, an anti-inflammatory agent, and combinations thereof. In some embodiments, the active agent can comprise an anti-angiogenic agent. In some embodiments, the active agent can comprise an anti-angiogenic agent and a steroid. In some embodiments, the active agent comprises dexamethasone. In some embodiments, the active agent is dexamethasone.

[0152] In some embodiments, the diagnostic or visualization agent may include a dye, a fluorophore, an MRI contrast agent (e.g., a gadolinium-containing agent), or other agent detectable by ultrasound, MRI, or X-ray. In some embodiments, the visualization agent may improve the visibility of the polymer composition or sustained-release otic composition during surgery. Non-limiting examples of visualization agents include coloring substances suitable for use in medical implantable devices, such as FD&C dyes 1, 3, and 6, eosin, methylene blue, indocyanine green, or colored dyes commonly found in synthetic surgical sutures. In some embodiments, the visualization agent may include FD&C Blue #1. In some embodiments, the visualization agent can be present in the polymer composition or sustained-release otic composition in an amount of about 0% to about 0.5% by weight (e.g., about 0% to about 0.02%, about 0% to about 0.05%, about 0% to about 0.1%, about 0% to about 0.2%, about 0.02% to about 0.5%, about 0.05% to about 0.5%, about 0.1% to about 0.5%, or about 0.2% to about 0.5% by weight). In some embodiments, the visualization agent can be present in the polymer composition or sustained-release otic composition in an amount of about 0% to about 0.05% by weight (e.g., about 0.005% to about 0.02%, about 0.005% to about 0.0015%, about 0.009%, or about 0.1% by weight). In some embodiments, the visualization agent is green or blue. Without being bound to any particular theory, it is possible that green or blue is more visible in the presence of blood or against a pink or white tissue background.

[0153] In some embodiments, the active agent can be in substantially microparticle or nanoparticle form. Without being bound by theory, it is believed that in some cases, the microparticle form can aid in the controlled release of the active agent from the sustained release otic compositions described herein. In some cases, the nanoparticle form can increase the dissolution rate and deliver the active agent at a higher controlled release rate from the microparticle. In some embodiments, the microparticle can be a particle having a diameter of about 0.1 μm to about 100 μm (e.g., about 0.1 μm to about 1 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 50 μm, about 1 μm to about 100 μm, about 10 μm to about 100 μm, about 50 μm to about 100 μm, about 1 μm to about 50 μm, or about 1 μm to 10 μm), as measured, for example, by optical microscopy. In some embodiments, the nanoparticles can be particles having a diameter of about 1 nm to about 100 nm (e.g., about 1 nm to about 10 nm, about 1 nm to about 50 nm, about 10 nm to about 100 nm, or about 50 nm to about 100 nm), for example, as measured by electron microscopy.

[0154] In some embodiments, the active agent can include an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent can be a VEGF inhibitor. In some cases, the VEGF inhibitor can be an antibody or antigen-binding fragment thereof, a decoy receptor, a VEGFR kinase inhibitor, an allosteric modulator of VEGFR, or a combination thereof. In some cases, the VEGF inhibitor can be an antibody or antigen-binding fragment thereof. For example, in some embodiments, the VEGF inhibitor can be alacizumab, bevacizumab (AVASTIN®), icrucumab (IMC-18F1), ramucirumab (LY3009806, IMC-1121B, CYRAMZA®), or ranibizumab (LUCENTIS®). In some embodiments, the VEGF inhibitor can be a decoy receptor (e.g., aflibercept). In some embodiments, the VEGF inhibitor can be a VEGFR kinase inhibitor such as agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, rebastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, or vandetanib. Other examples of VEGF inhibitors may be known in the art. In some embodiments, the VEGFR inhibitor can be an allosteric modulator of VEGFR (e.g., cyclotraxin B).

[0155] In some embodiments, a VEGF inhibitor may be selective for VEGFR2 over other VEGFRs. In some embodiments, a VEGF inhibitor may exhibit at least 10-fold selectivity for VEGFR2 over another VEGFR. For example, a VEGF inhibitor may exhibit at least 20-fold selectivity, at least 30-fold selectivity, at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity, at least 100-fold selectivity, at least 200-fold selectivity, at least 300-fold selectivity, at least 400-fold selectivity, at least 500-fold selectivity, at least 600-fold selectivity, at least 700-fold selectivity, at least 800-fold selectivity, at least 900-fold selectivity, or at least 1000-fold selectivity for VEGFR2 over another VEGFR. In some embodiments, selectivity for VEGFR2 over another VEGFR is measured by an enzymatic assay. In some embodiments, the additional VEGFR can be selected from the group consisting of VEGFR1, VEGFR3, and both VEGFR1 and VEGFR3.

[0156] The vascular endothelial growth factor (VEGF) signaling pathway is associated with many diseases and disorders, including cancer, rheumatoid arthritis, and age-related macular degeneration. In general, activation of the VEGF signaling pathway normally leads to tissue angiogenesis. The VEGF signaling pathway signals through its four component receptors: VEGFR1 (also called Flt-1; an exemplary human VEGFR1 sequence is set forth in SEQ ID NO:1), VEGFR2 (also called KDR or Flk-1; an exemplary human VEGFR2 sequence is set forth in SEQ ID NO:2), and VEGFR3 (also called Flt4; an exemplary human VEGFR3 sequence is set forth in SEQ ID NO:3), and its five growth factors: VEGF-A (an exemplary human VEGF-A sequence is set forth in SEQ ID NO:4), VEGF-B (an exemplary human VEGF-B sequence is set forth in SEQ ID NO:5), VEGF-C (an exemplary human VEGF-C sequence is set forth in SEQ ID NO:6), VEGF-D (an exemplary human VEGF-D sequence is set forth in SEQ ID NO:7), and PlGF (placental growth factor; an exemplary human PlGF sequence is set forth in SEQ ID NO:8). VEGF has different affinities for various VEGFRs. See, e.g., Shibuya, Masabumi. "VEGF-VEGFR signals in health and disease." Biomolecules & Therapeutics 22.1 (2014):1, doi:10.4062 / biomolther.2013.113 (incorporated herein by reference in its entirety). Both VEGF and VEGFR have variant isoforms and / or may be processed to a mature form compared to the sequences set forth herein. VEGF-A, in particular, has several isoforms in humans. VEGFR can usually be spliced ​​as a soluble or membrane-bound form. Some accounts group VEGFR with platelet-derived growth factor receptors (PDGFRs) as a superfamily of tyrosine kinase receptors. SEQ ID NO: 1, human VEGFR1 sequence from Uniparc ID UPI000013DCDD MVSYWDTGVL LCALLSCLLL TGSSSGSKLK DPELSLKGTQ HIMQAGQTLH LQCRGEAAHK WSLPEMVSKE SERLSITKSA CGRNGKQFCS TLTLNTAQAN HTGFYSCKYL AVPTSKKKET ESAIYIFISD TGRPFVEMYS EIPEIIHMTE GRELVIPCRV TSPNITVTLK KFPLDTLIPD GKRIIWDSRK GFIISNATYK EIGLLTCEAT VNGHLYKTNY LTHRQTNTII DVQISTPRPV KLLRGHTLVL NCTATTPLNT RVQMTWSYPD EKNKRASVRR RIDQSNSHAN IFYSVLTIDK MQNKDKGLYT CRVRSGPSFK SVNTSVHIYD KAFITVKHRK QQVLETVAGK RSYRLSMKVK AFPSPEVVWL KDGLPATEX ARYLTRGYSL IIKDVTEEDA GNYTILLSIK QSNVFKNLTA TLIVNVKPQI YEKAVSSFPD PALYPLGSRQ ILTCTAYGIP QPTIKWFWHP CNHNHSEARC DFCSNNEESF ILDADSNMGN RIESITQRMA IIEGKNKMAS TLVVADSRIS GIYICIASNK VGTVGRNISF YITDVPNGFH VNLEKMPTEG EDLKLSCTVN KFLYRDVTWI LLRTVNNR™ HYSISKQKMA ITKEHSITLN LTIMNVSLQD SGTYACRARN VYTGEEILQK KEITIRDQEA PYLLRNLSDH TVAISSSTTL DCHANGVPEP QITWFKNNHK IQQEPGIILG PGSSTLFIER VTEEDEGVYH CKATNQKGSV ESSAYLTVQG TSDKSNLELI TLTCTCVAAT LFWLLLLFI RKMKRSSSEI KTDYLSIIMD PDEVPLDEQC ERLPYDASKW EFARERLKLG KSLGRGAFGK VVQASAFGIK KSPTCRTVAV KMLKEGATAS EYKALMTELK ILTHIGHHLN VVNLLGACTK QGGPLMVIVE YCKYGNLSNY LKSKRDLFFL NKDAALHMEP KKEKMEPGLE QGKKPRLDSV TSSESFASSG FQEDKSLSDV EEEEDSDGFY KEPITMEDLI SYSFQVARGM EFLSSRKCIH RDLAARNILL SENNVVKICD FGLARDIYKN PDYVRKGDTR LPLKWMAPES IFDKIYSTKS DVWSYGVLLW EIFSLGGSPY PGVQMDEDFC SRLREGMRMR APEYSTPEIY QIMLDCWHRD PKERPRFAEL VEKLGDLLQA NVQQDGKDYI PINAILTGNS GFTYSTPAFS EDFFKESISA PKFNSGSSDD VRYVNAFKFM SLERIKTFEE LLPNATSMFD DYQGDSSTLL ASPMLKRFTW TDSKPKASLK IDLRVTSKSK ESGLSDVSRP SFCHSSCGHV SEGKRRFTYD HAELERKIAC CSPPPDYNSV VLYSTPPI SEQ ID NO:2, human VEGFR2 sequence from Uniparc entry UPI000003AE04 MQSKVLLAVA LWLCVETRAA SVGLPSVSLD LPRLSIQKDI LTIKANTTLQ ITCRGQRDLD WLWPNNQSGS EQRVEVTECS DGLFCKTLTI PKVIGNDTGA YKCFYRETDL ASVIYVYVQD YRSPFIASVS DQHGVVYITE NKNKTVVIPC LGSISNLNVS LCARYPEKRF VPDGNRISWD SKKGFTIPSY MISYAGMVFC EAKINDESYQ SIMYIVVVVG YRIYDVVLSP SHGIELSVGE KLVNLCTART ELNVGIDFNW EYPSSKHQHK KLVNRDLKTQ SGSEMKKFLS TLTIDGVTRS DQGLYTCAAS SGLMTKKNST FVRVHEKPFV AFGSGMESLV EATVGERVRI PAKYLBYPPP EIKWYKNGIP LESNHTIKAG HVLTIMEVSE RDTGNYTVIL TNPISKEKQS HVVSLVVYVP PQIGEKSLIS PVDSYQYGTT QTLTCTVYAI PPPHHIHWYW QLEEECANEP SQAVSVTNPY PCEEWRSVED FQGGNKIEVN KNQFALIEGK NKTVSTLVIQ AANVSALYKC EAVNKVGRGE RVISFHVTRG PEITLQPDMQ PTEQESVSLW CTADRSTFEN LTWYKLGPQP LPIHVGELPT PVCKNLDTLW KLNATMFSNS TNDILIMELK NASLQDQGDY VCLAQDRKTK KRHCVVRQLT VLERVAPTIT GNLENQTTSI GESIEVSCTA SGNPPPQIMW FKDNETLVED SGIVLKDGNR NLTIRRVRKE DEGLYTCQAC SVLGCAKVEA FFIIEGAQEK TNLEIIILVG TAVIAMFFWL LLVIILRTVK RANGGELKTG YLSIVMDPDE LPLDEHCERL PYDASKWEFP RDRLKLGKPL GRGAFGQVIE ADAFGIDKTA TCRTVAVKML KEGATHSEHR ALMSELKILI HIGHHLNVVN LLGACTKPGG PLMVIVEFCK FGNLSTYLRS KRNEFVPYKT KGARFRQGKD YVGAIPVDLK RRLDSITSSQ SSASSGFVEE KSLSDVEEEE APEDLYKDFL TLEHLICYSF QVAKGMEFLA SRKCIHRDLA ARNILLSEKN VVKICDFGLA RDIYKDPDYV RKGDARLPLK WMAPETIFDR VYTIQSDVWS FGVLLWEIFS LGASPYPGVK IDEEFCRRLK EGTRMRAPDY TTPEMYQTML DCWHGEPSQR PTFSELVEHL GNLLQANAQQ DGKDYIVLPI SETLSMEEDS GLSLPTSPVS CMEEEEVCDP KFHYDNTAGI SQYLQNSKRK SRPVSVKTFE DIPLEEPEVK VIPDDNQTDS GMVLASEELK TLEDRTKLSP SFGGMVPSKS RESVASEGSN QTSGYQSGYH SDDTDTTVYS SEEAELLKLI EIGVQTGSTA QILQPDSGTT LSSPPV SEQ ID NO: 3, human VEGFR3 sequence from Uniparc entry UPI00001488E7 MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA WPGAQEAPAT GDKDSEDTGV VRDCEGTDAR PYCKVLLLHE VHANDTGSYV CYYKYIKARI EGTTAASSYV FVRDFEQPFI NKPDTLLVNR KDAMWVPCLV SIPGLNVTLR SQSSVLWPDG QEVVWDDRRG MLVSTPLLHD ALYLQCETTW GDQDFLSNPF LVHITGNELY DIQLLPRKSL ELLVGEKLVL NCTVWAEFNS GVTFDWDYPG KQAERGKWVP ERRSQQTHTE LSSILTIHNV SQHDLGSYVC KANNGIQRFR ESTEVIVHEN PFISVEWLKG PILEATAGDE LVKLPVKLAA YPPPEFQWYK DGKALSGRHS PHALVLKEVT EASTGTYTLA LWNSAAGLRR NISLELVVNV PPQIHEKEAS SPSIYSRHSR QALTCTAYGV PLPLSIQWHW RPWTPCKMFA QRSLRRRQQQ DLMPQCRDWR AVTTQDAVNP IESLDTWTEF VEGKNKTVSK LVIQNANVSA MYKCVVSNKV GQDERLIYFY VTTIPDGFTI ESKPSEELLE GQPVLLSCQA DSYKYEHLRW YRLNLSTLHD AHGNPLLLDC KNVHLFATPL AASLEEVPG ARHATLSLSI PRVAPEHEGH YVCEVQDRRS HDKHCHKKYL SVQALEAPRL TQNLDTLLVN VSDSLEMQCL VAGAHAPSIV WYKDERLLEE KSGVDLADSN QKLSIQRVRE EDAGRYLCSV CNAKGCVNSS ASVAVEGSED KGSMEIVILV GTGVIAVFFW VLLLLIFCNM RRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQ WEF PRERLHLGRV LGYGAFGKVV EASAFGIHKG SCSDTVAVKM LKEGATASEH RALMSELKIL IHIGNHLNVV NLLGACTKPQ GPLMVIVEFC KYGNLSNFLR AKRDAFSPCA EKSPEQRGRF RAMVELARLD RRRPGSSDRV LFARFSKTEG GARRASPDQE AEDLWLSPLT MEDLVCYSFQ VARGMEFLAS RKCIHRDLAA RNILLSESDV VKICDFGLAR DIYKDPDYVR KGSARLPLKW MAPESIFDKV YTTQSDVWSF GVLLWEIFSL GASPYPGVQI NEEFCQRLRD GTRMRAPELA TPAIRRIMLN CWSGDPKARP AFSELVEILG DLLQGRGLQE EEEVCMAPRS SQSSEEGSFS QVSTMALHIA QADAEDSPPS LQRHSLAARY YNWVSFPGCL ARGAETRGSS RMKTFEEFPM TPTTYKGSVD NQTDSGMVLA SEEFEQIESR HRQESGFSCK GPGQNVAVTR AHPDSQGRRR RPERGARGGQ VFYNSEYGEL SEPSEEDHCS PSARVTFFTD NSY SEQ ID NO: 4, human VEGF-A sequence from Uniparc entry UPI0000030866 MNFLLSWVHW SLALLLYLHH AKWSQAAPMA EGGGQNHHEV VKFMDVYQRS YCHPIETLVD IFQEYPDEIE YIFKPSCVPL MRCGGCCNDE GLECVPTEES NITMQIMRIK PHQGQHIGEM SFLQHNKCEC RPKKDRARQE KKSVRGKGKG QKRKRKKSRY KSWSVYVGAR CCLMPWSLPG PHPCGPCSER RKHLFVQDPQ TCKCSCKNTD SRCKARQLEL NERTCRCDKP RR SEQ ID NO: 5, human VEGF-B sequence from Uniparc entry UPI0000001047 MSPLLRRLLL AALLQLAPAQ APVSQPDAPG HQRKVVSWID VYTRATCQPR EVVVPLTVEL MGTVAKQLVP SCVTVQRCGG CCPDDGLECV PTGQHQVRMQ ILMIRYPSSQ LGEMSLEEHS QCECRPKKKD SAVKPDRAAT PHHRPQPRSV PGWDSAPGAP SPADITHPTP APGPSAHAAP STTSALTPGP AAAAADAAAS SVAKGGA SEQ ID NO: 6, human VEGF-C sequence from Uniparc entry UPI0000001C2A MHLLGFFSVA CSLLAAALLP GPREAPAAAA AFESGLDLSD AEPDAGEATA YASKDLEEQL RSVSSVDELM TVLYPEYWKM YKCQLRKGGW QHNREQANLN SRTEETIKFA AAHYNTEILK SIDNEWRKTQ CMPREVCIDV GKEFGVATNT FFKPPCVSVY RCGGCCNSEG LQCMNTSTSY LSKTLFEITV PLSQGPKPVT ISFANHTSCR CMSKLDVYRQ VHSIIRRSLP ATLPQCQAAN KTCPTNYMWN NHICRCLAQE DFMFSSDAGD DSTDGFHDIC GPNKELDEET CQCVCRAGLR PASCGPHKEL DRNSCQCVCK NKLFPSQCGA NREFDENTCQ CVCKRTCPRN QPLNPGKCAC ECTESPQKCL LKGKKFHHQT CSCYRRPCTN RQKACEPGFS YSEEVCRCVP SYWKRPQMS SEQ ID NO: 7, human VEGF-D sequence from Uniparc entry UPI00000012B2 MYREWVVVNV FMMLYVQLVQ GSSNEHGPVK RSSQSTLERS EQQIRAASSL EELLRITHSE DWKLWRCRLR LKSFTSMDSR SASHRSTRFA ATFYDIETLK VIDEEWQRTQ CSPRETCVEV ASELGKSTNT FFKPPCVNVF RCGGCCNEES LICMNTSTSY ISKQLFEISV PLTSVPELVP VKVANHTGCK CLPTAPRHPY SIIRRSIQIP EEDRCSHSKK LCPIDMLWDS NKCKCVLQEE NPLAGTEDHS HLQEPALCGP HMMFDEDRCE CVCKTPCPKD LIQHPKNCSC FECKESLETC CQKHKLFHPD TCSCEDRCPF HTRPCASGKT ACAKHCRFPK EKRAAQGPHS RKNP SEQ ID NO:8, human PlGF precursor sequence from Uniparc entry UPI0000131BEF MPVMRLFPCF LQLLAGLALP AVPPQQWALS AGNGSSEVEV VPFQEVWGRS YCRALERLVD VVSEYPSEVE HMFSPSCVSL LRCTGCCGDE NLHCVPVETA NVTMQLLKIR SGDRPSYVEL TFSQHVRCEC RHSPGRQSPD MPGDFRADAP SFLPPRRSLP MLFRMEWGCA LTGSQSAVWP SSPVPEEIPR MHPGRNGKKQ QRKPLREKMK PERCGDAVPR R

[0157] B. Polymer Composition Also provided herein are polymer compositions. Typically, the polymer compositions described herein comprise a functionalized polymer, a crosslinker, and water. In some embodiments, the polymer compositions described herein are injectable into the middle and / or inner ear, where the functionalized polymer ionically and / or covalently crosslinks to produce a crosslinked polymer composition in the form of a gel (e.g., a hydrogel). Crosslinking can occur during mixing and injection of the polymer composition, by altering the pH, by exposure to ions, and / or by exposure to a photocrosslinker.

[0158] In some embodiments, the polymer compositions described herein can have one or more organoleptic properties that are advantageous for administration to a subject (e.g., to the middle and / or inner ear of a subject).

[0159] In some cases, polymer compositions can be characterized by their ability to crosslink and form durable gels (e.g., hydrogels), e.g., in situ. The transition phenomenon from solution to gel is commonly referred to as the sol-gel transition. The sol-gel transition of a polymer composition can be experimentally verified by a number of techniques, including vial inversion, spectroscopy, differential scanning calorimetry (DSC), and rheology.

[0160] In some embodiments, gels formed from the polymer compositions described herein can have a gel duration of at least 20 days (e.g., at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 80 days, at least 90 days, at least 100 days, or more) when stored in an inverted vial at room temperature (e.g., 20°C). In some embodiments, gels formed from the polymer compositions described herein can have a gel duration of at least 5 days (e.g., at least 7 days, at least 10 days, at least 14 days, at least 18 days, at least 21 days, at least 25 days, at least 28 days, or more) when stored at body temperature (e.g., 37°C) as measured by disposing the gel (e.g., 200 μL) in receptor solution (e.g., PBS at pH 7.4). In situ degradation of gels (e.g., hydrogels) formed from the polymer compositions described herein can depend on the identity of the components of the polymer composition (e.g., functional polymer and / or crosslinker), as well as the accuracy of administration and the subject's metabolism. In some embodiments, a gel formed from a polymer composition described herein, when administered to the middle ear of a subject, can have a residence time of at least 5 days (e.g., at least 7 days, at least 10 days, at least 14 days, at least 18 days, at least 21 days, at least 25 days, at least 28 days, at least 42 days, at least 56 days, or more).

[0161] In some cases, polymer compositions can be characterized by their ability to crosslink and form shape-conforming gels (e.g., hydrogels), e.g., in situ. In some embodiments, a gel (e.g., 200 μL of gel) formed from a polymer composition described herein can retain its shape for at least 20 days (e.g., at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 80 days, at least 90 days, at least 100 days, or more) when stored in an upright vial containing 1 mL of PBS at 37°C. Inversion of the vial can be used to determine whether the polymer composition is still a gel.

[0162] In some embodiments, the polymer compositions described herein can form gels that are significantly elastic rather than significantly viscoelastic. Without being bound by any particular theory, it is believed that elastic gels have a longer residence time at the administration site than viscoelastic gels, which may run off. For example, in some embodiments, a gel formed from a polymer composition described herein can have an elastic modulus of about 0.01 to about 100 kPa (e.g., about 0.1 to about 100 kPa, about 1 to about 100 kPa, about 5 to about 100 kPa, about 10 to about 100 kPa, about 25 to about 100 kPa, about 50 to about 100 kPa, about 75 to about 100 kPa, about 0.01 to about 0.1 kPa, about 0.01 to about 1 kPa, about 0.01 to about 5 kPa, about 0.01 to about 10 kPa, about 0.01 to about 25 kPa, about 0.01 to about 50 kPa, or about 0.01 to about 75 kPa).

[0163] In some embodiments, the polymer composition can have a wide viscosity transition; for example, some polymer compositions described herein can flow (e.g., as a solution or suspension) to a target site and form a gel (e.g., a hydrogel) in situ. In some embodiments, the polymer composition can be injected in solution or suspension form and flow by gravity throughout the middle ear or to one or more sites within the middle ear, then form a gel (e.g., a hydrogel). In some such embodiments, the polymer composition wets (e.g., completely wets) the round window membrane. In some embodiments, delivery of the polymer composition can be achieved without air bubbles, e.g., air bubbles in the gel and / or air bubbles trapped between the gel and the round window membrane. In some embodiments, the viscosity of the polymer composition (e.g., immediately after combining the functional polymer, crosslinker, and water) is about 1 to about 100 mPa*s (e.g., about 2 to about 100 mPa*s, about 5 to about 100 mPa*s, about 10 to about 100 mPa*s, about 25 to about 100 mPa*s, about 50 to about 100 mPa*s, about 75 to about 100 mPa*s, about 1 to about 2 mPa*s, about 1 to about 5 mPa*s, about 1 to about 10 mPa*s, about 1 to about 25 mPa*s, about 1 to about 50 mPa*s, or about 1 to about 75 mPa*s). In some cases, the polymer compositions described herein can be injected using, for example, a 23-gauge (23G) needle or a higher-gauge (smaller diameter) needle without significant needle clogging.

[0164] In some cases, the polymer composition can be characterized by its ability to crosslink and form a gel (e.g., a hydrogel), e.g., in situ, with a gelation time suitable for administration to a site (e.g., the middle ear and / or inner ear). Some polymer compositions, such as DURASEAL®, can form a gel in 3 seconds or less, which may be undesirable for delivery of the sustained-release otic compositions disclosed herein.

[0165] In some embodiments, the polymer compositions described herein are cured at a temperature of about 20° C. for about 45 seconds to about 60 minutes (e.g., about 1 minute to about 60 minutes, about 45 seconds to about 45 minutes, about 45 seconds to about 30 minutes, about 45 seconds to about 20 minutes, about 45 seconds to about 10 minutes, about 45 seconds to about 8 minutes, about 45 seconds to about 5 minutes, about 45 seconds to about 3 minutes, about 45 seconds to about 2 minutes, about 45 seconds to about 1 minute, The polymer compositions described herein may have a gelation time of about 1 minute to about 60 minutes, about 2 minutes to about 60 minutes, about 3 minutes to about 60 minutes, about 4 minutes to about 60 minutes, about 5 minutes to about 60 minutes, about 8 minutes to about 60 minutes, about 10 minutes to about 60 minutes, about 20 minutes to about 60 minutes, about 30 minutes to about 60 minutes, about 45 minutes to about 60 minutes, about 1 minute to about 5 minutes, about 5 minutes to about 20 minutes, about 8 minutes to about 12 minutes, about 4 minutes to about 12 minutes, or about 1 minute to about 8 minutes. In some embodiments, the polymer compositions described herein may have a gelation time of about 8 minutes to about 16 minutes (e.g., about 9 minutes to about 15 minutes, about 10 minutes to about 14 minutes, or about 11 minutes to about 13 minutes) at a temperature of about 20°C. In some embodiments, the polymer compositions described herein may have a gelation time of about 9 minutes to about 11 minutes at a temperature of about 20°C. In some embodiments, the polymer compositions described herein can have a gel time of at least about 45 seconds (e.g., at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 5 minutes, or at least about 10 minutes) at a temperature of about 20° C. In some embodiments, the polymer compositions described herein can have a gel time of about 8 minutes, 9 minutes, 10 minutes, 11 minutes, or 12 minutes at a temperature of about 20° C.

[0166] In some embodiments, the polymer compositions described herein can be cured at about 37° C. for about 10 seconds to about 30 minutes (e.g., about 10 seconds to about 30 seconds, about 10 seconds to about 1 minute, about 10 seconds to about 2 minutes, about 10 seconds to about 3 minutes, about 10 seconds to about 4 minutes, about 10 seconds to about 5 minutes, about 10 seconds to about 8 minutes, about 30 seconds to about 10 minutes, about 30 seconds to about 15 minutes, about 30 seconds to about 20 minutes, about 1 minute to about 30 minutes, about 2 minutes). In some embodiments, the polymer compositions described herein may have a gelation time of about 30 seconds to about 2 minutes (e.g., about 45 seconds to about 1 minute) at about 37°C. In some embodiments, the polymer compositions described herein can have a gelation time of at least about 10 seconds (e.g., at least about 30 seconds, at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 8 minutes, or at least about 10 minutes), and optionally less than 30 minutes (e.g., less than 15 minutes), at about 37° C. In some embodiments, the polymer compositions described herein can have a gelation time of about 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, or 8 minutes at a temperature of about 37° C.

[0167] Without being bound by theory, it is believed that the gelation time of a polymer composition or sustained-release otic composition may affect its usefulness in a clinical setting, as a rapidly gelling composition may shorten the time period during which the composition can be administered to a subject's ear (e.g., via transtympanic injection). In some embodiments, the polymer compositions or sustained-release otic compositions provided herein are injectable through a 27-gauge (or larger diameter) needle for at least 10 minutes after combining the functional polymer and crosslinker. In some embodiments, the polymer compositions or sustained-release otic compositions provided herein are injectable through a 27-gauge (or larger diameter) needle for at least 2 minutes (e.g., 2-4 minutes, 2-6 minutes, 2-8 minutes, 2-10 minutes) after combining the functional polymer and crosslinker.

[0168] The rate of the crosslinking reaction can be influenced by the selection of properties of the polymer composition. For example, pH, amount of crosslinker and functionalized polymer, and choice of buffer can affect gelation time. Mixing the components under cooling slows the crosslinking reaction, allowing time for injection. In some cases, the polymer composition or sustained-release otic composition can form a sufficiently crosslinked gel that will adhere to the tissue of the middle ear and remain in the middle ear for an extended period of time before breaking down into a liquid.

[0169] Controlled rates of active agent delivery can also be achieved with this system due to the degradable covalent attachment of molecules to the crosslinked hydrogel network. The nature of the covalent attachment can be controlled to allow for control of the release rate over a period of hours to weeks or longer. By using composites made from attachments with a range of hydrolysis times, the controlled release profile can be extended for longer periods of time.

[0170] In some cases, gels formed from the polymer compositions or sustained-release otic compositions described herein can exhibit swelling of less than about 150% (e.g., less than about 140%, less than about 120%, less than about 100%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, or less than about 40%) when incubated in excess phosphate buffered saline (PBS) at 37° C. (e.g., for about 1 day or about 2 days). In some cases, gels formed from the polymer compositions or sustained-release otic compositions described herein can exhibit swelling of about 25% to about 45% (e.g., about 30% to about 40%) when incubated in excess phosphate buffered saline (PBS) at 37° C. after, for example, 1 day. In some cases, a gel formed from a polymer composition or sustained-release otic composition described herein can exhibit, for example, about 40% to about 80% (e.g., about 50% to about 70%) swelling when incubated in excess phosphate-buffered saline (PBS) at 37° C. after 7 days. In some embodiments, a gel formed from a polymer composition or sustained-release otic composition can have a resorption time (e.g., the time it takes for the mass of a gel incubated in excess PBS at 50° C. to become less than the starting mass of the gel) of about 5 to about 30 days (e.g., about 5 to about 10 days, about 5 to about 15 days, about 5 to about 20 days, about 5 to about 25 days, about 10 to about 30 days, about 15 to about 30 days, about 20 to about 30 days, about 25 to about 30 days, about 7 to about 9 days, or about 7 to about 15 days). In some embodiments, gels formed from the polymer compositions or sustained-release otic compositions described herein can be characterized by exhibiting adhesion to surfaces that come into contact with the polymer composition during gelation. In some embodiments, adhesion can be mechanical, gel, chemical, mucoadhesion, or a combination thereof. In some cases, the polymer composition can exhibit adhesion to tissues within the ear (e.g., the round window membrane). This can be achieved, for example, by crosslinking one or more components of the polymer formulation, which can include components that form covalent crosslinks with the tissue. As an example, the polymer composition can include amine-reactive and / or thiol-reactive groups that can bind to tissue.In some embodiments, gels formed from the polymer compositions described herein can be characterized by exhibiting mucoadhesion to mucosal surfaces (e.g., round window membranes) that come into contact with the polymer composition during gelation. In some embodiments, adhesion can be achieved by the formation of covalent bonds between amine groups of proteins in the tissue and activated esters of the functional polymer.

[0171] An active agent (e.g., a therapeutic agent, a prophylactic agent, and / or a visualization or diagnostic agent), such as any one or more of the active agents described herein, can be included in any of the polymer compositions described herein. Typically, when an active agent is present in a polymer composition described herein, such a composition is referred to as a sustained release otic composition.

[0172] The active agent can be present in any suitable amount or concentration in the polymer compositions described herein. In some embodiments, the active agent can be present in the polymer composition in an amount sufficient to deliver a therapeutically effective concentration to the site of action (e.g., through the round window membrane) for a period of time. In some embodiments, the period of time can be equal to or less than the residence time of the sustained-release otic composition at the administration site. For example, in some embodiments, the period of time can be from about 5 days to about 6 months (e.g., from about 5 days to about 1 week, from about 5 days to about 2 weeks, from about 5 days to about 3 weeks, from about 5 days to about 1 month, from about 5 days to about 2 months, from about 5 days to about 3 months, from about 5 days to about 4 months, from about 5 days to about 5 months, from about 1 week to about 6 months, from about 2 weeks to about 6 months, from about 3 weeks to about 6 months, from about 1 month to about 6 months, from about 2 months to about 6 months, from about 3 months to about 6 months, from about 4 months to about 6 months, from about 5 months to about 6 months, from about 2 weeks to about 2 months, or from about 1 month to about 3 months). In some embodiments, for example, the active agent is present in an amount of from about 0.01% to about 40% by weight of the polymer composition (e.g., from about 0.01% to about 0.1% by weight, from about 0.01% to about 1% by weight, from about 0.01% to about 2% by weight, from about 0.01% to about 3% by weight, from about 0.01% to about 5% by weight, from about 0.01% to about 8% by weight, from about 0.01% to about 10% by weight, from about 0.01% to about 12% by weight, from about 0.01% to about 10 ... The active agent can be present in an amount of about 1% to about 15%, about 0.01% to about 20%, about 0.01% to about 20%, about 0.01% to about 40%, about 0.1% to about 40%, about 1% to about 40%, about 2% to about 40%, about 3% to about 40%, about 5% to about 40%, about 8% to about 40%, about 10% to about 40%, or about 12% to about 40% by weight of the polymer composition. In some embodiments, the active agent can be present in an amount of about 1% to about 10% by weight (e.g., about 2% to about 9%, about 3% to about 8%, or about 4% to about 6% by weight) of the polymer composition. In some embodiments, the active agent can be present in an amount of about 4%, 5%, 6%, 7%, or 8% by weight of the polymer composition.In some embodiments, the active agent can be present in an amount of about 8% to about 18% by weight of the polymer composition (e.g., about 8% to about 10%, about 8% to about 12%, about 8% to about 14%, about 8% to about 16%, about 10% to about 18%, about 12% to about 18%, about 14% to about 18%, about 16% to about 18%, about 9% to about 16%, or about 10% to about 15% by weight). In some embodiments, the active agent can be present in an amount of about 10%, 11%, 12%, 13%, 14%, or 15% by weight of the polymer composition.

[0173] The active agent can be present in the polymer composition in any suitable form. In some embodiments, the active agent can be present in the polymer composition as a solution or suspension. In some embodiments, the active agent can be present in the polymer composition in the form of microparticles or nanoparticles. In some embodiments, the active agent can change from a solution to a suspension, or from one form of microparticles or nanoparticles to another form of microparticles or nanoparticles, after the components of the sustained-release otic composition are combined.

[0174] A generally desirable feature of a drug suspension composition is the ability to administer a uniform dose. This is easily achieved with a composition that does not form a dense precipitate during storage and that can be easily redispersed by manually agitating the container. In some embodiments, the sustained-release otic composition can contain particles of an active agent that disperse easily with manual agitation and have a low viscosity for ease of injection. This can optionally be achieved by adding a flocculating agent that promotes aggregation of the drug particles into loose aggregates. Flocculation efficiency can be defined as the ratio of the final sediment volume (e.g., as a percentage of the total volume) to the particle concentration. The final sediment volume cannot exceed 100%, thereby limiting the upper limit of flocculation efficiency. In some embodiments, the flocculation efficiency of the sustained-release otic compositions described herein is greater than about 3 (e.g., greater than about 4 or greater than about 5). In some embodiments, the selection of a functional polymer and / or crosslinker can affect the flocculation efficiency of a given active agent in solution. For example, in some embodiments, the use of polylysine (e.g., trilysine or tetralysine) or its salts as a crosslinker can provide a high degree of aggregation without the addition of other dispersing agents. To minimize the number of excipients in a sustained-release formulation, it may be desirable for the crosslinker to also function as an aggregating agent. Other amphiphilic crosslinkers, such as tetralysine, can also be used for the dual purpose of crosslinking and aggregating drug particles.

[0175] In some embodiments, the active agent is stored as a dry powder until combined with other components of the sustained-release otic composition (e.g., at or near the time of use). For example, microparticles and nanoparticles prepared by spray drying and / or supercritical fluid processing can form loose agglomerates that have good flow and handling properties and are easily dispersed into primary particles with low energy input. Upon combining the components of the sustained-release otic composition, the agglomerates can be separated into primary particles by shear caused by the introduction of air and / or other components of the sustained-release otic composition.

[0176] As noted above, the polymer compositions described herein typically include a functional polymer, a crosslinker, and water. Gels (e.g., hydrogels) can be formed from the reaction of a functional polymer having functional groups, such as electrophilic or nucleophilic functional groups, with a crosslinker.

[0177] As used herein, a "functional polymer" can be a polymer that includes one or more functional groups that can react with one or more functional groups on a crosslinker to form a bond (e.g., a covalent bond).

[0178] As used herein, a "crosslinker" can be a molecule containing one or more functional groups that can react with one or more functional groups on a functional polymer to form a bond (e.g., a covalent bond). In some cases, the crosslinker is a polymer (e.g., trilysine or tetralysine, or a salt thereof). In some cases, the crosslinker is not a polymer.

[0179] Generally, the functional polymer and crosslinker are water-soluble, non-toxic, and biologically acceptable. In some embodiments, the crosslinker is a small molecule. In some embodiments, the crosslinker has a solubility of at least 1 g / 100 mL in aqueous solution. In some embodiments, the functional polymer is a macromolecule. Exemplary classes of functional polymers and crosslinkers are described in U.S. Patent Nos. 6,566,406, 6,887,974, 7,332,566, and 8,535,705, each of which is incorporated herein by reference in its entirety.

[0180] In some embodiments, the functional polymer or crosslinker can be multifunctional, meaning that it contains two or more functional groups. In some embodiments, a multifunctional polymer or crosslinker has only one type of functional group (e.g., all nucleophilic or all electrophilic functional groups). In some cases, the functional polymer or crosslinker can contain at least three (e.g., at least four, at least five, or more) functional groups, such that the functional polymer and crosslinker combine to form a crosslinked gel (e.g., a hydrogel) as a result of a reaction (e.g., an electrophilic-nucleophilic reaction). Such a reaction is typically referred to as a "crosslinking reaction."

[0181] The functional polymer can include a plurality of first functional groups. The crosslinker can include a plurality of second functional groups. In some such embodiments, the first functional group of the polymer can form a covalent bond with the second functional group of the crosslinker, thereby producing a gel (e.g., a hydrogel). The distribution of the functional groups can be any suitable distribution. In some embodiments, the functional polymer is a branched polymer, with each branch end functionalized with a first functional group. In some embodiments, the functional polymer can include a first type of monomer, where the functional polymer is a homopolymer of the first type of monomer. In some embodiments, the functional polymer can include a first type of monomer, where each of the first type of monomers includes a first functional group. In some cases, the first type of monomer can be randomly distributed in the functional polymer. In some cases, the first type of monomer can be regularly distributed in the functional polymer (e.g., as a block copolymer or an alternating copolymer). In some cases, the first type of monomer can be part of a grafted copolymer in the functional polymer (e.g., as the backbone or as a branch). The functional polymer can be of any suitable size. In some embodiments, the functional polymer is a large molecule, e.g., an M of 5,000, 10,000, 20,000, 30,000, or more. n It is a large molecule having the following structure.

[0182] In some embodiments, the crosslinker can include a second type of monomer, and the functional polymer is a homopolymer of the second type of monomer. In some embodiments, the crosslinker is a branched polymer, and the end of each branch is functionalized with a second functional group. In some embodiments, the crosslinker can include a second type of monomer, and each of the second type of monomers includes a second functional group. In some embodiments, the second type of monomer can be randomly distributed in the crosslinker. In some embodiments, the second type of monomer can be regularly distributed in the crosslinker (e.g., as a block copolymer or as an alternating copolymer). In some embodiments, the second type of monomer can be part of a grafted copolymer in the crosslinker (e.g., as the backbone or as a branch). The crosslinker can be of any suitable size. In some embodiments, the crosslinker is a small molecule. In some embodiments, the crosslinker is an oligomer, such as a dimer, trimer, tetramer, or pentamer.

[0183] It is understood that the first functional group (e.g., on the functional polymer) and the second functional group (e.g., on the crosslinker) should be such that a crosslinking reaction can occur. Thus, the selection of the functional polymer can be based on the selection of the crosslinker, or vice versa. In some embodiments, the first functional group can be an NHS group and the second functional group can be an amine (e.g., a primary amine), or vice versa.

[0184] In some cases, the functional polymer contains only electrophilic or nucleophilic functional groups, and the crosslinker contains only nucleophilic or electrophilic functional groups, respectively. Thus, for example, if the crosslinker has nucleophilic functional groups such as amines (e.g., primary amines), the functional polymer may, in some cases, contain only electrophilic functional groups, such as N-hydroxysuccinimide. For example, if the crosslinker has electrophilic functional groups such as sulfosuccinimide, the functional polymer may, in some cases, contain nucleophilic functional groups such as amines (e.g., primary amines).

[0185] The functionalized polymer can be present in any suitable concentration in the polymer compositions described herein. In some embodiments, the functionalized polymer can be present at a concentration of about 5% to about 15% by weight of the polymer composition (e.g., about 5% to about 7%, about 5% to about 9%, about 5% to about 11%, about 5% to about 13%, about 7% to about 15%, about 9% to about 15%, about 11% to about 15%, about 13% to about 15%, about 7% to about 13%, about 8% to about 11%, about 6% to about 12%, or about 7% to about 10% by weight). In some embodiments, the functionalized polymer can be present at a concentration of about 6%, about 7%, about 8%, about 9%, about 10%, or about 11% by weight of the polymer composition. In some embodiments, the functional polymer can be present in a concentration of about 8.3% by weight of the polymer composition. In some embodiments, the functional polymer can be present in the sustained release otic composition, such as in the polymer compositions described herein.

[0186] The crosslinking agent can be present in any suitable concentration in the polymer compositions described herein. In some embodiments, the crosslinking agent can be present at a concentration of about 0.2% to about 0.6% by weight of the polymer composition (e.g., about 0.2% to about 0.4% by weight, about 0.4% to about 0.6% by weight, or about 0.3% to about 0.5% by weight). In some embodiments, the crosslinking agent can be present at a concentration of about 0.05% to about 0.6% by weight of the polymer composition (e.g., about 0.05% to about 0.2% by weight, about 0.05% to about 0.4% by weight, about 0.05% to about 0.5% by weight, about 0.1% to about 0.6% by weight, about 0.2% to about 0.6% by weight, about 0.4% to about 0.6% by weight, or about 0.1% to about 0.3% by weight). In some embodiments, the crosslinking agent can be present at a concentration of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% by weight of the polymer composition. For example, it can be present at a concentration of about 0.05% to about 10% by weight of the polymer composition (e.g., about 0.05% to about 0.5%, about 0.05% to about 1%, about 0.05% to about 2%, about 0.05% to about 3%, about 0.05% to about 5%, about 0.05% to about 7%, about 0.05% to about 9%, about 0.5% to about 10%, about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 5% to about 10%, about 7% to about 10%, about 9% to about 10%, or about 0.5% to about 2% by weight). In some embodiments, a crosslinker can be present in a sustained release otic composition, as in the polymer compositions described herein.

[0187] In some embodiments, the crosslinker can include an amine (e.g., primary amine) group, or a salt thereof (e.g., acetate). In some embodiments, the crosslinker can be polylysine, such as trilysine, or a salt thereof (e.g., acetate). It will be understood that the weight percentage of the crosslinker when in salt form corresponds to the smaller weight percentage of the crosslinker when not in salt form (e.g., as the free base). As an illustrative example, if the crosslinker is trilysine acetate, the weight percentage of crosslinker in the polymer composition or sustained-release otic composition for trilysine free base is about 69% of the weight percentage of trilysine acetate, all else being equal.

[0188] The functional groups can be present in any suitable ratio. In some embodiments, when a first functional group and a second functional group (e.g., an electrophilic functional group, a nucleophilic functional group) are used, the ratio of the first functional group to the second functional group can be from about 1.2 equivalents of the first functional group to 0.8 equivalents of the second functional group to about 0.8 equivalents of the first functional group to 1.2 equivalents of the second functional group. In some embodiments, the ratio of the first functional group to the second functional group can be from about 1 equivalent of the first functional group to 0.9 equivalents of the second functional group to about 0.9 equivalents of the first functional group to 1 equivalent of the second functional group. In some embodiments, the ratio of the first functional group to the second functional group is about 1:1. It is understood that the molar or weight ratio of the functional polymer and the crosslinker is based on the relative number of functional groups per functional polymer or crosslinker, respectively.

[0189] In some embodiments, the functional polymer can be a modified polyethylene glycol (PEG) polymer. Exemplary modified PEG polymers include linear, branched, or multi-armed water-soluble polymers containing multiple polyethylene glycol units and two or more examples of functional groups (e.g., succinimidyl esters (e.g., N-hydroxysuccinimide esters (NHS)), sulfo-succinimidyl esters, epoxides, or similar reactive groups) (e.g., as part of the monomers or as end caps). Multi-armed functional polymers can include a water-soluble core, such as a sugar (xylitol, erythritol), glycerol, or trimethylolpropane. Optionally, the water-soluble core can be extended by at least one biodegradable bond between each end group, which can optionally be a functional group. The biodegradable bond can optionally be a single bond or a copolymer or homopolymer of an absorbable polymer, such as a polyhydroxy acid or polylactone.

[0190] In some embodiments, functional polymers can include enzymatically and / or hydrolytically cleavable linkages. For example, molecules that are cleaved by enzymes such as collagenase can be synthesized and inserted into polymers using methods known to those skilled in the art of peptide synthesis. In some embodiments, carboxyl-, amine-, or hydroxyl-terminated polyethylene glycol can be used as a starting material to construct a peptide sequence suitable for enzymatic cleavage, and the termini of the peptide sequence can be converted to carboxylic acids by reacting succinic anhydride with the appropriate amino acid. The resulting acid groups can then be converted to NHS esters by reaction with N-hydroxysuccinimide.

[0191] In some cases, functional polymers can be purchased commercially or prepared using a variety of synthetic methods.

[0192] The functional groups on the functional polymer or crosslinker can, in some embodiments, be reactive functional groups that are also water-soluble, such as succinimidyl ester groups further functionalized with PEG or sulfonate groups. Ionic groups, such as metal salts (e.g., sodium salts) of sulfonic acids, or nonionic groups, such as polyethylene oxide on succinimide rings, improve water solubility, while NHS esters provide chemical reactivity toward amines.

[0193] Functional polymers such as polyethylene glycol functionalized with reactive functional groups such as succinimidyl ester groups are commercially available, for example, from MilliporeSigma (Milwaukee, WI) and Creative PEGWorks (Chapel Hill, NC). Functional polymers such as polyethylene glycol functionalized with reactive functional groups such as primary amines and thiols are commercially available, for example, from MilliporeSigma (Milwaukee, WI) and JenKem (Plano, Texas). In some embodiments, commercially available polymers with terminal hydroxyl groups can be converted to functional polymers with amine groups by methods known in the art. Similarly, crosslinkers complementary to functional polymers are typically commercially available from companies such as MilliporeSigma.

[0194] In some embodiments, the functional polymer is a multi-arm (e.g., 3-arm, 4-arm, 6-arm, or 8-arm) polyethylene glycol (PEG) comprising multiple (e.g., two or more) succinimidyl functional groups (e.g., succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl glulamide, succinimidyl carbonate, or succinimidyl carboxymethyl ester) or sulfo-succinimidyl ester functional groups, and the crosslinker comprises multiple amine (e.g., primary amine) functional groups. In some embodiments, the functional polymer is a 4-arm PEG having a pentaerythritol core. In some embodiments, the functional polymer is an 8-arm PEG having a hexaglycerol core. In some embodiments, the functional polymer is an 8-arm PEG having a tripentaerythritol core. In some embodiments, the multi-arm PEG can have two or more arms terminating in succinimidyl functional groups. In some embodiments, one or more monomers of the multi-arm PEG can comprise a succinimidyl functional group. In some embodiments, the crosslinker can be polylysine (e.g., epsilon-polylysine) (e.g., trilysine, tetralysine, or pentalysine), or a salt thereof (e.g., acetate). For example, in some embodiments, the functional polymer can be pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, and the crosslinker can be trilysine or a salt thereof (shown in Figures 1A and 1B, respectively). In some embodiments, the functional polymer (e.g., pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate) has a molecular weight (M) of about 10 kDa to about 25 kDa (e.g., about 10 kDa to about 15 kDa, about 10 kDa to about 20 kDa, about 15 kDa to about 25 kDa, or about 20 kDa to about 25 kDa). NIn some embodiments, the functional polymer (e.g., pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate) can have a molecular weight (M) of about 10 kDa to about 25 kDa (e.g., about 10 kDa to about 15 kDa, about 10 kDa to about 20 kDa, about 15 kDa to about 25 kDa, or about 20 kDa to about 25 kDa). W ). Molecular weight can be determined, for example, by gas phase chromatography or matrix-assisted laser desorption chromatography. In some embodiments, the functional polymer (e.g., pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate) can have a polydispersity (PD) of 1.5±0.5.

[0195] In some embodiments, the functional polymer is a multi-arm (e.g., 3-arm, 4-arm, 6-arm, or 8-arm) polyethylene glycol containing two or more amine (e.g., primary amine) functional groups, and the crosslinker contains multiple succinimidyl ester (e.g., succinimidyl succinate or succinimidyl glutarate) or sulfo-succinimidyl ester functional groups. In some embodiments, the multi-arm PEG can have two or more arms terminating in amine (e.g., primary amine) functional groups. In some embodiments, one or more monomers of the multi-arm PEG can contain an amine (e.g., primary amine) functional group. In some embodiments, the crosslinker can be disuccinimidyl glutarate, disuccinimidyl suberate, bis(sulfosuccinimidyl) suberate, or disuccinimidyl succinate.

[0196] Crosslinking reaction Typically, the cross-linking reaction can occur under physiological conditions. In some embodiments, the cross-linking reaction can occur "in situ," meaning that it occurs at a localized site, such as an organ or tissue in a living animal or human body. In some embodiments, the cross-linking reaction does not release heat of polymerization.

[0197] Crosslinking between the functional polymer and the crosslinker can be initiated under any suitable conditions. In some embodiments, crosslinking between the functional polymer and the crosslinker is initiated by the addition of a catalyst (e.g., an initiator molecule). In some embodiments, crosslinking is initiated by a stimulus, such as a change in pH, temperature, or irradiation (e.g., using photoinitiation). The crosslinking rate and gel time can be affected by factors such as pH, temperature, excipients, the ratio of functional groups, the degree of functionalization of the functional polymer, and the concentrations of the functional polymer and crosslinker.

[0198] In some embodiments, crosslinking between the functional polymer and the crosslinker is initiated upon mixing the functional polymer and the crosslinker. In some such embodiments, the gelation time is sufficient to allow the polymer composition or sustained-release otic composition to be administered to the administration site (e.g., the middle and / or inner ear region) in a fairly fluid form (e.g., by injection with a 23G needle). In some embodiments, crosslinking can be initiated before or during administration, but the polymer composition does not significantly gel before flowing into the administration site (e.g., the middle and / or inner ear region). Because viscosity typically increases with crosslinking, it is generally desirable to administer the polymer composition or sustained-release otic composition before significant crosslinking has occurred. Thus, in some embodiments, the polymer composition or sustained-release otic composition can have a viscosity of less than about 1000 mPa·s (e.g., less than about 800 mPa·s, 500 mPa·s, 300 mPa·s, 100 mPa·s, 75 mPa·s, 50 mPa·s, or 25 mPa·s) at a temperature of about 20°C. In some embodiments, the polymer composition or sustained-release otic composition can have a viscosity of about 1 mPa·s to about 100 mPa·s (e.g., about 1 mPa·s to about 80 mPa·s, about 1 mPa·s to about 60 mPa·s, about 1 mPa·s to about 50 mPa·s, about 1 mPa·s to about 40 mPa·s, about 1 mPa·s to about 20 mPa·s, about 1 mPa·s to about 10 mPa·s, about 10 mPa·s to about 100 mPa·s, about 20 to about 100, about 40 to about 100, about 50 to about 100 mPa·s, about 60 mPa·s to about 100 mPa·s, or about 80 mPa·s to about 100 mPa·s) at a temperature of about 20° C.

[0199] In some embodiments, pH is used to affect gelation time. DURASEAL®, a reference product marketed as a spinal sealant, contains pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate and trilysine. DURASEAL®, prepared according to the manufacturer's instructions, has a pH of approximately 10, and crosslinking typically occurs rapidly; the product can form a gel in 3 seconds or less (see, e.g., Example 1). As described herein, adjusting the trilysine component to about 5.5 to about 8.5 (e.g., about 5.5 to 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.5 to about 7.0, about 6.5 to about 7.5, about 6.5 to about 8.0, about 7.0 to about 8.5, about 7.5 to about 8.5, or about 8.0 to about 8.5) can result in longer gelation times, such as those described above in this specification. In some embodiments, the polymer composition or sustained-release otic composition can have a pH of about 5.5 to about 8.5 (e.g., about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.5 to about 7.0, about 6.5 to about 7.5, about 6.5 to about 8.0, about 7.0 to about 8.5, about 7.5 to about 8.5, or about 8.0 to about 8.5). In some embodiments, the polymer composition or sustained-release otic composition can have a pH of about 5.0 to about 7.7 (e.g., about 5.0 to about 5.5, about 5.0 to about 6.0, about 5.0 to about 6.5, about 5.0 to about 7.0, about 5.0 to about 7.5, about 5.5 to about 7.7, about 6.0 to about 7.7, about 6.5 to about 7.7, about 7.0 to about 7.7, about 6.0 to about 7.0, about 6.6 to about 7.7, about 6.8 and about 7.7, about 6.6 to about 6.8). In some embodiments, the polymer composition or sustained-release otic composition can have a pH of about 7.2. In some embodiments, the polymer composition or sustained-release otic composition can have a pH of about 5.5 to about 6.5 (e.g., about 5.7 to about 6.2, or about 6.0).The pH of the polymer composition or sustained-release otic composition can be adjusted by adding an acid (e.g., HCl, phosphoric acid), a base (e.g., NaOH, KOH), and / or a buffer (e.g., a phosphate salt (e.g., a phosphate salt form (e.g., sodium phosphate (e.g., monobasic and / or dibasic), phosphoric acid, or a combination thereof), a borate salt (e.g., sodium borate (e.g., decahydrate)), or a combination thereof), as appropriate. In some embodiments, the pH of the polymer composition or sustained-release otic composition, when gelled, can be measured indirectly by equilibrating with purified distilled water. In some embodiments, the gel formed from the polymer composition or sustained-release otic composition described herein has a pH of about In some embodiments, the polymer compositions described herein may have a pH of 5.5 to about 8.5 (e.g., about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.5, about 5.5 to about 6.0, about 6.5 to about 7.0, about 6.5 to about 7.5, about 6.5 to about 8.0, about 7.0 to about 8.5, about 7.5 to about 8.5, or about 8.0 to about 8.5). The gel formed from the gelling polymer composition or sustained-release otic composition can have a pH of about 6.0 to about 7.7 (e.g., about 6.0 to about 7.0, about 6.6 to about 7.7, about 6.8 to about 7.7, about 6.6, and about 6.8). In some such embodiments, the pH of the gelling polymer composition or sustained-release otic composition can be about 6.0 to about 6.5 (e.g., about 6.1 to about 6.4).

[0200] In some embodiments, temperature is used to affect gel time, and in some such embodiments, the polymer composition can be prepared as a chilled composition and / or from one or more chilled components.

[0201] The crosslink density of a gel can be affected by the overall molecular weight of the crosslinker and functional polymer, as well as the number of available functional groups per molecule. Functional polymers with lower molecular weights, such as about 600 Da, typically result in higher crosslink densities compared to higher molecular weights, such as 10,000 Da. Crosslink density can also be affected by the overall percent solids of the crosslinker and functional polymer solution. Increasing the percent solids increases the likelihood that electrophilic groups will combine with nucleophilic groups before hydrolytic deactivation. Another way to influence crosslink density is by adjusting the stoichiometry of nucleophilic groups to electrophilic groups. Generally, a 1:1 ratio maximizes crosslink density.

[0202] excipients The sustained release otic compositions or polymer compositions described herein can include excipients such as pH buffers, tonicity agents, mucoadhesives, stabilizers, preservatives, carriers, and penetration enhancers. In some embodiments, excipients that can be incorporated into the polymer compositions or sustained release otic compositions include diluents, buffers, dispersants or viscosity modifiers, solubilizers, stabilizers, and osmolality adjusters.

[0203] The term "diluent" refers to a compound that can be used to dilute (e.g., prior to delivery) the components of the polymer composition or sustained-release otic composition (e.g., functional polymer, crosslinker, and / or active agent). In some embodiments, the diluent is in the middle ear and / or inner ear.

[0204] The terms "dispersing agent" and / or "viscosity modifier" and / or "thickener" refer to a material that enhances the dispersion of particulate matter in a solution or modifies the viscosity of a solution or suspension. Examples of dispersing agents / materials include, but are not limited to, hydrophilic polymers, electrolytes, TWEEN® 60 or TWEEN® 80, PEG, polyvinylpyrrolidone (PVP; also known as povidone, commercially known as Kollidon® and PLASDONE®), and carbohydrate-based dispersing agents, such as hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100). Examples of thickeners include modified celluloses such as modified celluloses (e.g., modified celluloses such as modified celluloses like K100M), carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer containing ethylene oxide and formaldehyde (also known as tyloxapol), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), and polyethylene glycols having a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400. In some embodiments, the amount of thickener is about 1%, 5%, 10%, or 15% by weight of the total composition. In some cases, dispersing agents improve the physical stability of the composition by inhibiting crystallization of the drug.

[0205] The term "solubilizer" refers to auris-acceptable compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin and other cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, TRANSCUTOL®, propylene glycol, and dimethyl isosorbide, ethanol, and other organic solvents. Amphiphilic molecules such as poloxamers and Tween® can also function as solubilizers. In some embodiments, when these solubilizers are present at concentrations above their critical micelle concentration (CMC) or their solubility (e.g., bile salts), a sustained reservoir of solubilizer can be achieved. In some embodiments, the solubilizer comprises propylene glycol, PEG300, ethanol, and one or more of cyclodextrin, poloxamer 407, and poloxamer 188.

[0206] Various physical or viscosity modifiers can be used to enhance the mechanical strength and stability of the polymer composition or sustained-release otic composition. In some embodiments, particles (e.g., microparticles or nanoparticles) of the active agent can be used to enhance the mechanical stability of the hydrogel. The particles can be suspended in the hydrogel, covalently bonded, or attached to the polymer through ionic or hydrophobic interactions.

[0207] In some embodiments, other viscosity modifiers, stabilizers, and / or penetration enhancers can be included in the polymer composition or sustained-release otic composition. Non-limiting examples of viscosity modifiers include polymers such as dextran or other polysaccharides, PLURONIC® (also known as poloxamers, a class of synthetic block copolymers consisting of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) arranged in an ABA triblock structure to give PEO-PPO-PEO), emulsifiers, and micelles. Micelles of penetration enhancers and / or solubilizers can be used in some embodiments to achieve sustained concentrations in the formulation. In some embodiments, micelles of poloxamer 407 and / or poloxamer 188 can be used as solubilizers, for example, at a concentration of about 1% to about 10% by weight of the polymer composition or sustained-release otic composition (e.g., about 1% to about 2%, about 1% to about 3%, about 1% to about 5%, about 1% to about 8%, about 2% to about 10%, about 3% to about 10%, about 5% to about 10%, or about 8% to about 10%). In some embodiments, the concentration of poloxamer does not contribute to gel formation or cause high viscosity. In some embodiments, the polymer compositions or sustained-release otic compositions described herein do not comprise a poloxamer.

[0208] In some cases, the active agent may exist in a metastable solid form, such as an amorphous particle, a polymorph, or a salt form in which a different solid form has lower solubility, e.g., a free base crystalline form. In some embodiments, excipients such as polyvinylpyrrolidone and poloxamer 407 may function as solubilizers and dispersants to inhibit drug crystallization.

[0209] The term "stabilizer" refers to compounds such as antioxidants, buffers, acids, and preservatives that are typically compatible with the environment of the middle and / or inner ear. Stabilizers can include, for example, agents that improve the stability of components of a sustained-release otic composition or polymer composition to avoid phase changes, or that improve the compatibility of an excipient with a container or delivery system, including a syringe or vial, that improves the stability of the composition.

[0210] To achieve a specific isotonicity, in some embodiments, an isotonicity agent can be included. Generally, endolymph has a higher osmotic pressure than perilymph. For example, the osmotic pressure of endolymph is approximately 304 mOsm / kg HO, while the osmotic pressure of perilymph is approximately 294 mOsm / kg HO.

[0211] In some embodiments, the polymer compositions or sustained release otic compositions described herein have a pH of from about 100 mOsm / kg to about 1000 mOsm / kg (e.g., from about 200 mOsm / kg to about 400 mOsm / kg, from about 240 mOsm / kg to about 350 mOsm / kg, from about 250 mOsm / kg to about 350 mOsm / kg, from about 270 mOsm / kg to about 320 mOsm / kg, from about 280 mOsm / kg to about 320 mOsm / kg, from about 100 mOsm / kg to about 200 mOsm / kg, from about 100 mOsm / kg to about 300 mOsm / kg). The present invention provides an osmolality of about 100 to about 500 mOsm / kg, about 100 to about 700 mOsm / kg, about 100 to about 900 mOsm / kg, about 200 to about 1000 mOsm / kg, about 300 to about 1000 mOsm / kg, about 500 to about 1000 mOsm / kg, about 700 to about 1000 mOsm / kg, about 900 to about 1000 mOsm / kg, or about 300 to about 600 mOsmol / kg. In some embodiments, the polymer compositions or sustained-release otic compositions described herein provide an osmolality of about 550 mOsm / kg to about 600 mOsm / kg (e.g., about 560 to about 590 mOsm / kg). In some embodiments, the polymer compositions or sustained-release otic compositions described herein have an osmolality of about 280 mOsm / kg.In some embodiments, the polymer compositions or sustained release otic compositions described herein have a pH of about 100 mOsm / L to about 1000 mOsm / L (e.g., about 200 mOsm / L to about 400 mOsm / L, about 240 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 270 mOsm / L to about 320 mOsm / L, about 280 mOsm / L to about 320 mOsm / L, about 100 mOsm / L to about 20 ... The composition has an osmolality of about 100 mOsm / L to about 300 mOsm / L, about 100 mOsm / L to about 500 mOsm / L, about 100 mOsm / L to about 700 mOsm / L, about 100 mOsm / L to about 900 mOsm / L, about 200 mOsm / L to about 1000 mOsm / L, about 300 mOsm / L to about 1000 mOsm / L, about 500 mOsm / L to about 1000 mOsm / L, about 700 mOsm / L to about 1000 mOsm / L, or about 900 mOsm / L to about 1000 mOsm / L. In some embodiments, the osmolality of the composition is designed so that the gel is hypotonic with the target ear structures (e.g., endolymph, perilymph, etc.). In some forms, the osmolality of the composition is designed so that the gel is isotonic with the target ear structure (e.g., endolymph, perilymph, etc.). In some forms, the osmolality of the composition is designed so that the gel is hypertonic with the target ear structure (e.g., endolymph, perilymph, etc.).

[0212] Osmolality / osmolarity can be adjusted, for example, by using an appropriate salt concentration (e.g., potassium salt concentration) or by using a tonicity agent, which makes the composition endolymph- and / or perilymph-compatible (e.g., a gel is isotonic with the endolymph and / or perilymph). In some cases, an endolymph- and / or perilymph-compatible sustained-release otic composition or polymer composition can minimize disturbance to the inner ear environment and minimize discomfort (e.g., dizziness and / or nausea) to a subject (e.g., a mammal) upon administration.

[0213] In some embodiments, the gel formed by the sustained-release otic composition or polymer composition may be isotonic with the perilymph. An isotonic composition can optionally be formed by including an isotonicity agent in the sustained-release otic composition or polymer composition. Suitable isotonicity agents include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. Sodium chloride or other isotonicity agents can optionally be used to adjust isotonicity as needed. Representative salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. It will be understood that in the case of phosphate buffers, monobasic sodium phosphate and dibasic sodium phosphate are typically used in combination to achieve a particular pH and can be collectively referred to as "sodium phosphate." In some cases, for example, when borate is also used, phosphoric acid can be used to further modify the pH. In some embodiments, the tonicity agent can be sodium chloride.

[0214] In some embodiments, the sustained-release otic composition or gel formed by the polymer composition may be slightly hypotonic so that water is drawn from the formulation into the tissue, increasing contact and adhesion with the tissue.

[0215] In some embodiments, the sustained-release otic composition or polymer composition can include one or more pH adjusters or buffers. Non-limiting examples of pH adjusters or buffers include acetate, bicarbonate, ammonium chloride, citrate, phosphate, borate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. Non-limiting examples of water-soluble buffers include alkali or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates, and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate, and HEPES. In some embodiments, tromethamine (TRIS) is not used in polymer compositions or sustained-release otic compositions in which a primary amine is the functional group.

[0216] In some embodiments, the polymer composition or sustained-release otic composition can include sodium borate decahydrate in an amount of about 0.01% to about 3.0% by weight (e.g., about 0.01% to about 0.1% by weight, about 0.01% to about 0.5% by weight, about 0.01% to about 1.0% by weight, about 0.01% to about 2.0% by weight, about 0.1% to about 3.0% by weight, about 0.5% to about 3.0% by weight, about 1.0% to about 3.0% by weight, about 2.0% to about 3.0% by weight, about 0.05% to about 2.0% by weight, or about 0.5% to about 1.5% by weight). In some embodiments, the sustained-release otic composition or polymer composition can include sodium borate decahydrate in an amount of about 0.05% to about 2.0% by weight (e.g., about 0.5% to about 1.5% by weight, or about 1.2% by weight).

[0217] In some embodiments, the polymer composition or sustained-release otic composition can include sodium borate in an amount of about 0.01% to about 3.0% by weight (e.g., about 0.01% to about 0.1% by weight, about 0.01% to about 0.5% by weight, about 0.01% to about 1.0% by weight, about 0.01% to about 2.0% by weight, about 0.1% to about 3.0% by weight, about 0.5% to about 3.0% by weight, about 1.0% to about 3.0% by weight, about 2.0% to about 3.0% by weight, about 0.05% to about 2.0% by weight, or about 0.5% to about 1.5% by weight). In some embodiments, the sustained-release otic composition or polymer composition can include sodium phosphate in an amount of about 0.05% to about 2.0% by weight (e.g., about 0.5% to about 1.5% by weight, or about 1.1% by weight).

[0218] In some embodiments, the sustained-release otic composition or polymeric composition can include phosphoric acid in an amount of about 0.01% to about 3.0% by weight (e.g., about 0.01% to about 0.1%, about 0.01% to about 0.5%, about 0.01% to about 1.0%, about 0.01% to about 2.0%, about 0.1% to about 3.0%, about 0.5% to about 3.0%, about 1.0% to about 3.0%, about 2.0% to about 3.0%, about 0.05% to about 2.0%, or about 0.5% to about 1.5%). In some embodiments, the sustained-release otic composition or polymeric composition can include phosphoric acid in an amount of about 0.05% to about 2.0% (e.g., about 0.5% to about 1.5%, or about 0.9%).

[0219] In some embodiments, the composition includes a mucoadhesive. In some cases, the mucoadhesive facilitates adhesion to parts of the ear, such as the round window membrane. Mucoadhesives include, but are not limited to, carbomers, such as CARBOPOL® 934P, polyvinylpyrrolidone polymers (PVP); water-swellable but water-insoluble cross-linked carboxy-functional polymers; cross-linked poly(acrylic acid) (e.g., CARBOPOL® 947P); carbomer homopolymers; carbomer copolymers; hydrophilic polysaccharide gums; maltodextrin; cross-linked alginate gum gel, hydroxypropyl methylcellulose, and water-dispersible polycarboxylated vinyl polymers. Mucoadhesives are described in U.S. Patent No. 8,828,980 to Lichter et al., incorporated herein by reference in its entirety.

[0220] Examples of surfactants include, but are not limited to, sodium lauryl sulfate, sodium decussate, TWEEN® 60 (polyethylene glycol sorbitan monostearate) or TWEEN® 80 (polyethylene glycol sorbitan monooleate), triacetin, D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS), phospholipids, lecithin, phosphatidylcholine (c8-c18), phosphatidylethanolamine (c8-c18), phosphatidylglycerol (c8-c18), sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, bile salts, and glyceryl monostearate.

[0221] In some embodiments, sustained-release otic compositions or polymeric compositions can include a penetration enhancer that allows delivery of the active agent across a barrier, such as the oval or round window of the ear. Typically, the penetration enhancer is ear-compatible. Penetration enhancers include sodium lauryl sulfate, sodium octyl sulfate, sodium dodecyl sulfate, octyl-trimethyl-ammonium bromide, dodecyl-trimethylammonium bromide, sodium laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecyl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene-9-lauryl ether (PLE), TWEEN® 20, TWEEN® 80, nonylphenoxy polyethylene (NP-POE), polysorbates, bile salts, fatty acids and derivatives, chelating agents (such as EDTA, citric acid, and salicylic acid), sulfoxides (such as dimethyl sulfoxide (DMSO) and decylmethyl sulfoxide), and alcohols (such as ethanol, isopropanol, glycerol, and propanediol). In some cases, the penetration enhancer is a partially soluble fatty acid, such as oleic acid, that is present in a high enough concentration to form a suspension, thus providing a microreservoir for the sustained presence of the penetration enhancer. In some embodiments, the sustained release composition includes a penetration enhancer that provides an initial higher release of the active agent and then is depleted.

[0222] In some embodiments, the sustained-release otic composition or polymer composition can include a preservative. Exemplary preservatives are also described in U.S. Patent No. 8,828,980 to Richter et al., which is incorporated herein by reference in its entirety. Suitable preservatives include, but are not limited to, benzoic acid, boric acid, p-hydroxybenzoates, alcohols, quaternary compounds, stabilized chlorine dioxide, mercurials such as merphen and thiomersal, or combinations thereof. In some embodiments, the preservative can include butylated hydroxytoluene (BHT). In some embodiments, the sustained-release otic composition or polymer composition can include BHT in an amount of about 0% to about 0.01% (e.g., about 0.0005% to about 0.01%, about 0.001% to about 0.01%, or about 0.005% to about 0.01%). In some embodiments, the preservative can include butylated hydroxytoluene (BHT). In some embodiments, the sustained-release otic composition or polymeric composition can include BHT in an amount of about 0% to about 0.01% (e.g., about 0.0005% to about 0.01%, about 0.001% to about 0.01%, or about 0.005% to about 0.01%). In some embodiments, the sustained-release otic composition or polymeric composition can include BHT in an amount of about 0% to about 0.005% (e.g., about 0.001% to about 0.003%, or about 0.002%).

[0223] III. Polymer Administration and Crosslinking The polymer composition or sustained release otic composition can be administered using any suitable method.

[0224] Also provided herein are methods for preparing polymer compositions or sustained-release otic compositions. In some embodiments, the polymer compositions or sustained-release otic compositions can be prepared by combining a solution or suspension of a functionalized polymer with a solution or suspension of a crosslinker. In some embodiments, the solution or suspension of the functionalized polymer and the solution or suspension of the crosslinker are combined during administration of the polymer composition or sustained-release otic composition (e.g., when using a dual syringe device). In some embodiments, the polymer compositions or sustained-release otic compositions can be prepared by combining a solution or suspension of a functionalized polymer with a solution or suspension of a crosslinker such that the combination has a pH of about 5.5 to about 8.5.

[0225] In some embodiments, the functionalized polymer is a solid (e.g., a lyophilized powder) and is reconstituted at or near the time of use. Thus, in some embodiments, the polymer composition or sustained-release otic composition can be prepared by (a) creating a solution or suspension of the functionalized polymer, (b) creating a solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker. In some embodiments, the crosslinker is provided as a solution. Thus, in some embodiments, the polymer composition or sustained-release otic composition can be prepared by (a) creating a solution or suspension of the functionalized polymer, and (b) combining the solution or suspension of the functionalized polymer with a solution or suspension of the crosslinker. In some embodiments, the polymer composition or sustained-release otic composition can be prepared by (a) creating a solution or suspension of the functionalized polymer, (b) altering the pH of the solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker. In some embodiments, preparing a solution or suspension of the functionalized polymer or crosslinker can include adjusting the pH of the solution or suspension. In some embodiments, adjusting the pH of the functionalized polymer solution or suspension can include adjusting the pH to about 1.6 to about 4.0. In some embodiments, adjusting the pH of the crosslinker solution or suspension can include adjusting the pH to about 5.5 to about 8.5. In some embodiments, the functionalized polymer solution or suspension and the crosslinker solution or suspension are combined during administration of the polymer composition or sustained-release otic composition (e.g., when using a dual syringe device).

[0226] In some embodiments, the functionalized polymer is provided as a solution or suspension. Thus, in some embodiments, the polymer composition or sustained-release otic composition can be prepared by (a) forming a solution or suspension of the crosslinker and (b) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker. In some embodiments, the crosslinker is provided as a solution. In some embodiments, the polymer composition or sustained-release otic composition can be prepared by combining a solution or suspension of the functionalized polymer with a solution or suspension of the crosslinker. In some embodiments, the polymer composition or sustained-release otic composition can be prepared by (a) forming a solution or suspension of the crosslinker, (b) altering the pH of the solution or suspension of the functionalized polymer, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker. In some embodiments, forming the solution or suspension of the functionalized polymer or crosslinker can include adjusting the pH of the solution or suspension. In some embodiments, adjusting the pH of the solution or suspension of the functionalized polymer can include adjusting the pH to about 1.6 to about 4.0. In some embodiments, adjusting the pH of the crosslinker solution or suspension can include adjusting the pH to about 5.5 to about 8.5. In some embodiments, the functionalized polymer solution or suspension and the crosslinker solution or suspension are combined during administration of the polymer composition or sustained-release otic composition (e.g., when using a dual syringe device).

[0227] In some embodiments, a sustained-release otic composition can be prepared from the components: (i) a solid form (e.g., powder) of an active agent (e.g., dexamethasone), (ii) a diluent solution, (iii) a solid form (e.g., powder) of a functional polymer (e.g., NHS-PEG), and (iv) a solution of a crosslinker (e.g., trilysine). In some embodiments, a sustained-release otic composition can be prepared by (a) combining the active agent (e.g., dexamethasone) with a solution of the crosslinker (e.g., trilysine) to form a first mixture, (b) combining the functional polymer with a diluent solution to form a second mixture, and (c) combining the first mixture with the second mixture.

[0228] In some embodiments, the active agent can be included in the solution or suspension of the functionalized polymer, the solution or suspension of the crosslinker, provided in a separate solution or suspension, provided as a separate solid (e.g., a dry powder), provided as a solid (e.g., a dry powder) and combined with the functionalized polymer (e.g., prior to forming a solution or suspension of the functionalized polymer), provided as a solid (e.g., a dry powder) and combined with the crosslinker (e.g., prior to forming a solution or suspension of the crosslinker), or a combination thereof. In some embodiments in which the active agent is provided as a separate solution, suspension, or solid (e.g., a dry powder), combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker can further include combining a solution, suspension, or solid form (e.g., a dry powder) of the active agent.

[0229] In some embodiments, combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker occurs less than 60 minutes (e.g., less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or within 10 minutes) after making the solution or suspension of the functional polymer.

[0230] Also provided herein are methods of administering a polymer composition or sustained release otic composition. In some embodiments, a polymer composition or sustained release otic composition can be administered by (i) preparing a polymer composition or sustained release composition, e.g., by any of the methods described herein, and (ii) administering the polymer composition or sustained release otic composition to a subject.

[0231] In some embodiments, the polymer composition or sustained-release otic composition can be administered by (i) preparing the polymer composition or sustained-release otic composition by combining a solution or suspension of the functionalized polymer with a solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained-release otic composition to a subject. In some embodiments, the polymer composition or sustained-release otic composition can be administered by (i) preparing the polymer composition or sustained-release composition by combining a solution or suspension of the functionalized polymer with a solution or suspension of the crosslinker, such that the combination has a pH of about 5.5 to about 8.5, and (ii) administering the polymer composition or sustained-release otic composition to a subject. In some embodiments, the preparation of the polymer composition or sustained-release otic composition can be accomplished during administration, for example, using a dual syringe device containing separate reservoirs of the functionalized polymer and the crosslinker.

[0232] In some embodiments, the polymer composition or sustained release otic composition can be administered by (i) preparing the polymer composition or sustained release otic composition by (a) forming a solution or suspension of the functionalized polymer, (b) forming a solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained release otic composition to a subject. In some embodiments, the polymer composition or sustained release otic composition can be administered by (i) preparing the polymer composition or sustained release composition by (a) forming a solution or suspension of the functionalized polymer, and (b) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained release otic composition to a subject. In some embodiments, the polymer composition or sustained release otic composition can be administered by (i) preparing the polymer composition or sustained release composition by (a) creating a solution or suspension of the functionalized polymer, (b) altering the pH of the solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained release otic composition to a subject.

[0233] In some embodiments, the polymer composition or sustained release otic composition can be administered by (i) preparing the polymer composition or sustained release composition by (a) forming a solution or suspension of the crosslinker, (b) combining the solution or suspension of the crosslinker with a solution or suspension of the functionalized polymer, and (ii) administering the polymer composition or sustained release composition to a subject. In some embodiments, the polymer composition or sustained release otic composition can be administered by (i) preparing the polymer composition or sustained release composition by (a) forming a solution or suspension of the crosslinker, (b) altering the pH of the solution or suspension of the functionalized polymer, and (c) combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained release composition to a subject.

[0234] In some embodiments of administering a polymer composition or sustained-release otic composition, the active agent can be included in the solution or suspension of the functionalized polymer, the solution or suspension of the crosslinker, provided in a separate solution or suspension, provided as a separate solid (e.g., a dry powder), provided as a solid (e.g., a dry powder) and combined with the functionalized polymer (e.g., prior to forming the solution or suspension of the functionalized polymer), or a combination thereof. In some embodiments in which the active agent is provided as a separate solution, suspension, or solid (e.g., a dry powder), combining the solution or suspension of the functionalized polymer with the solution or suspension of the crosslinker can further comprise combining a solution, suspension, or solid form (e.g., a dry powder) of the active agent.

[0235] In some embodiments, combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker occurs less than 60 minutes (e.g., less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes) after making the solution or suspension of the functional polymer. In some embodiments, step (ii) occurs less than 10 minutes (e.g., less than 9 minutes, less than 8 minutes, less than 7 minutes, less than 6 minutes, less than 5 minutes, less than 4 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute) after combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker.

[0236] In the case of inherent gelation due to the presence of a crosslinking agent, it may be important to control the timing of chemical crosslinking and administration. It will be understood that the timing of step (ii) is related to the gelation time of the sustained-release otic composition or polymer composition. Typically, the timing of step (ii) is such that administration of the sustained-release otic composition or polymer composition is not yet a gel.

[0237] In some embodiments, gelation can be initiated by application of an external factor, such as light or other external energy, before, during, or after administration. In some embodiments, the polymer composition or sustained-release otic composition can be administered to a subject, followed by initiation of the crosslinking reaction.

[0238] The sustained-release otic composition can be administered to the middle ear of a subject in need thereof, for example, by transtympanic injection. In some embodiments, the sustained-release otic composition is administered on or near the round window membrane by transtympanic injection. In some embodiments, the sustained-release otic composition can also be administered on or near the round window or crista fenestrae cochleae through a postauricular incision and surgical access to or near the round window or fenestra cochleae region. In some embodiments, the sustained-release otic composition does not involve any of the ossicles when administered to a subject's ear. In some embodiments, the sustained-release otic composition does not contact any of the ossicles when administered to a subject's ear.

[0239] In some cases, administering can involve using a syringe and a small diameter needle (e.g., 23G to 30G, or smaller), which is inserted through the tympanic membrane and guided to the area of ​​the round window or crista fenestrae. The composition is then deposited on or near the round window or crista fenestrae. In some embodiments, the sustained release otic composition is a liquid when administered. In some embodiments, prior to administration, the sustained release otic composition is not exposed to a temperature above about 26°C. In some embodiments, during administration, the sustained release otic composition has a temperature of about 20°C to about 25°C.

[0240] In some embodiments, the sustained release auris compositions can also be administered intratympanically or applied onto the tympanic membrane or onto or into the ear canal by injection, direct infusion or perfusion of the inner ear compartment, or in surgical procedures including cochleotomy, labyrinthotomy, mastectomy, stapedectomy, or endolymphatic sacotomy.

[0241] In some embodiments, administering can include administering a therapeutically effective dose. In some embodiments, administering can include administering a prophylactically effective dose. In some embodiments, administering can include administering a prophylactically effective dose. In some embodiments, administering can include administering a prophylactically effective dose of about 5 to about 500 microliters (e.g., about 5 μL to about 400 μL, about 5 μL to about 300 μL, about 5 μL to about 200 μL, about 5 μL to about 100 μL, 5 μL to about 50 μL, about 5 μL to about 25 μL, about 5 μL to about 10 μL, about 10 μL to about 500 μL, about 25 μL to about 50 In some embodiments, administering can include administering about 50 μL, about 100 μL, about 50 μL to about 500 μL, about 100 μL to about 500 μL, about 200 μL to about 500 μL, about 300 μL to about 500 μL, about 400 μL to about 500 μL, about 25 μL to about 300 μL, about 50 μL to about 200 μL, about 30 μL to about 70 μL, or about 40 μL to about 60 μL. In some embodiments, administering can include administering about 50 μL, about 100 μL, or about 200 μL.

[0242] In some embodiments, administering can include administering 3 mg of dexamethasone in a volume of 50 μL of a sustained release otic composition comprising 6% dexamethasone by weight.

[0243] In some cases, a gel formed from the polymeric compositions or sustained-release otic compositions described herein may exhibit less than about 100% swelling (e.g., less than about 80%, less than about 70%, less than about 60%, less than about 50%, or less than about 40%) within one day of administration to the ear of a subject.

[0244] In some embodiments, administering can optionally include the use of specific equipment, such as an in-line mixer (sometimes called a static mixer) downstream of a dual syringe injector, which can mix the components and minimize the time between initial mixing and administration to the target site. In some embodiments, methodologies and devices for performing in situ gelation developed for other adhesive or sealant systems, such as fibrin glue or sealant applications, can be used with the polymer compositions or sustained-release otic compositions described herein. See, e.g., U.S. Patent Nos. 4,874,368, 4,631,055, 4,735,616, 4,359,049, 4,978,336, 5,116,315, 4,902,281, 4,932,942, PCT WO 91 / 09641, and RATange, "Fibrin Sealant" in Operative Medicine: Otolaryngology, volume 1 (1986), each of which is incorporated herein by reference in its entirety.

[0245] In some embodiments, an anesthetic can be applied to the subject's tympanic membrane and / or ear canal prior to administration of the polymer compositions or sustained-release otic compositions provided herein. For example, prior to administration, an anesthetic (e.g., EMLA® Cream) can be applied to the subject's tympanic membrane and / or ear canal about 5 minutes to about 1 hour (e.g., about 5 minutes to about 50 minutes, about 5 minutes to about 40 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 20 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 40 minutes to about 1 hour, or about 50 minutes to about 1 hour) prior to administration. In some embodiments, prior to administration, an anesthetic (e.g., EMLA® Cream) can be applied to the subject's tympanic membrane and / or ear canal immediately prior to administration.

[0246] In some embodiments, administration can be visualized, for example, using an endoscope. Without being bound to any particular theory, it is believed that visualization aids in placing the sustained-release otic composition in a desired location (e.g., on the round window membrane) and / or helps avoid placing the sustained-release otic composition in an undesirable location (e.g., involving one or more ossicles).

[0247] In some embodiments, the sustained-release otic composition can be administered in a single dose or multiple doses. Certain factors can affect the dosage required to effectively treat or prevent a disorder, including, but not limited to, the severity of the disease or disorder, previous prevention, the general health and / or age of the subject, and other diseases present. It will also be understood that the effective dosage of a sustained-release otic composition used for prevention may increase or decrease over the course of a particular prevention. Dosage variations may occur and will be evident from the results of assays.

[0248] Before, during, or after administration, the polymer composition or sustained-release otic composition undergoes a transition from a liquid state to a gel state. In some embodiments, the gel provides a therapeutically effective concentration of the active agent for a period of about 5 days to about 6 months (e.g., about 5 days to about 1 week, about 5 days to about 2 weeks, about 5 days to about 3 weeks, about 5 days to about 1 month, about 5 days to about 2 months, about 5 days to about 3 months, about 5 days to about 4 months, about 5 days to about 5 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, about 2 weeks to about 2 months, or about 1 month to about 3 months). In some embodiments, the gel provides a therapeutically effective concentration of the active agent for at least 1 week (e.g., at least about 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months).

[0249] In some cases, the subject being treated is an adult or child undergoing treatment that may cause hearing loss, such as chemotherapy, age-related hearing loss, hearing loss due to repeated exposure to loud noise, and other disorders that damage the cilia in the inner ear (such as autoimmune disorders, infections, excess fluid or pressure, etc.).

[0250] In some embodiments, the subject being treated is an adult. In some embodiments, the subject being treated has a diagnosis of definite unilateral Meniere's disease as defined by the Classification Committee of the Barany Society or the American Academy of Otolaryngology (AAO-HNS). In some embodiments, the subject being treated has reported two or more episodes of definite vertigo (lasting 20 minutes or more) in the month prior to screening for administration of the sustained-release otic composition. In some embodiments, the subject has documented acquired asymmetric sensorineural hearing loss, as reported by the patient or documented by audiology. In some embodiments, the subject is not administered the sustained-release otic composition provided herein if the subject has an ongoing chronic inflammatory or infectious middle ear disease. In some embodiments, the subject is not administered the sustained-release otic composition provided herein if the subject has an active infection of the ear, sinuses, or upper respiratory system. In some embodiments, if the subject has a current tympanic membrane perforation, the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has active symptoms of benign paroxysmal positional vertigo (BPPV), the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has a history of superior semicircular canal dehiscence, the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has a history of fall attacks (Tumarkin's otolith crisis), the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has a history of vestibular migraine, the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has a history of endolymphatic sac surgery, the subject is not administered a sustained release otic composition provided herein. In some embodiments, if the subject has a history of middle ear surgery (other than tympanostomy tubes), the subject is not administered the sustained-release otic compositions provided herein.In some embodiments, a subject is not administered a sustained release otic composition provided herein if the subject has a retrolabyrinthine pathology affecting the hearing or vestibular system (e.g., acoustic neuroma, multiple sclerosis). In some embodiments, a subject is not administered a sustained release otic composition provided herein if the subject has a significant abnormality in the ear canal or tympanic membrane that prevents IT injection. In some embodiments, a subject is not administered a sustained release otic composition provided herein if the subject has a history of an immunodeficiency or autoimmune disease.

[0251] Thus, provided herein are methods of treating a subject having an otic disease or disorder. In some embodiments, provided herein are methods of treating a subject having an otic disease or disorder, comprising administering a therapeutically effective dose of a sustained-release otic composition described herein. In some embodiments, provided herein are methods of treating a subject having an otic disease or disorder, comprising administering a therapeutically effective dose of a sustained-release otic composition described herein to the ear of a subject in need thereof. In some embodiments, provided herein are methods of treating a subject having an otic disease or disorder, comprising (i) identifying the subject as having an otic disease or disorder, and (ii) administering a therapeutically effective dose of a sustained-release otic composition described herein to the affected ear of the subject. In some embodiments, the ear disease or disorder can be selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof.

[0252] Further provided herein are methods of treating Meniere's disease, comprising administering a therapeutically effective dose of a sustained-release otic composition described herein to the ear of a subject in need thereof. Also provided herein are methods of treating Meniere's disease, comprising (i) identifying a subject as having Meniere's disease, and (ii) administering a therapeutically effective dose of a sustained-release otic composition described herein to the affected ear of the subject.

[0253] In some embodiments, the subject is evaluated prior to administering the sustained-release otic composition. For example, the subject may be evaluated prior to administering the sustained-release otic composition, for example, by delayed intravenous gadolinium contrast 3T. The subject may be evaluated for baseline levels of endolymphatic hydrops, perilymphatic augmentation, or both, as assessed by MRI. Optionally, the subject is evaluated for baseline levels of endolymphatic hydrops. In some embodiments, the subject is evaluated for baseline levels of perilymphatic augmentation. In some embodiments, the subject is evaluated for baseline levels of both endolymphatic hydrops and perilymphatic augmentation. In some embodiments, the subject may be evaluated for baseline levels of severity and / or frequency of dizziness episodes prior to administration of the sustained-release otic composition. In some embodiments, the subject's hearing may be evaluated for a baseline (e.g., using a hearing assessment) prior to administration of the sustained-release otic composition. In some embodiments, the subject may be evaluated for a baseline Dizziness Handicap Inventory (DHI) score and / or Tinnitus Handicap Inventory (THI) score prior to administration of the sustained-release otic composition. Optionally, the subject is evaluated on the same day that the sustained-release otic composition is administered. In some cases, the subject is evaluated about 1 day to about 6 weeks (e.g., about 1 day to about 1 week, about 1 day to about 2 weeks, about 1 day to about 3 weeks, about 1 day to about 4 weeks, about 1 day to about 5 weeks, about 1 week to about 6 weeks, about 3 weeks to about 6 weeks, about 4 weeks to about 6 weeks, about 5 weeks to about 6 weeks, or about 3 weeks to about 5 weeks) before administration of the sustained-release otic composition.

[0254] In some embodiments, the subject is evaluated after administering the sustained-release otic composition. For example, after administering the sustained-release otic composition, the subject can be evaluated for levels of endolymphatic hydrops, perilymphatic enhancement, or both, as assessed, for example, by delayed intravenous gadolinium-enhanced 3T MRI. In some cases, the subject is evaluated for levels of endolymphatic hydrops. In some embodiments, the subject is evaluated for levels of perilymphatic enhancement. In some embodiments, the subject is evaluated for levels of both endolymphatic hydrops and perilymphatic enhancement. In some embodiments, the subject can be evaluated for the severity and / or frequency of vertigo attacks. In some embodiments, the subject's hearing can be evaluated (e.g., using a hearing assessment). In some embodiments, the subject can be evaluated for a Dizziness Handicap Inventory (DHI) score and / or a Tinnitus Handicap Inventory (THI) score. In some cases, the subject is evaluated about 1 week to about 4 weeks (e.g., about 1 week to about 2 weeks, about 1 week to about 3 weeks, about 2 weeks to about 4 weeks, or about 3 weeks to about 4 weeks) after administration of the sustained-release otic composition. In some cases, the subject is evaluated about 2 weeks after administration of the sustained-release otic composition.

[0255] In some embodiments, a subject exhibits improvement in one or more assessments after administration of a sustained-release otic composition provided herein. For example, in some embodiments, a subject may exhibit improved levels of endolymphatic hydrops, perilymphatic enhancement, or both, as assessed, for example, by delayed intravenous gadolinium-enhanced 3T MRI. In some cases, a subject may exhibit improved levels of endolymphatic hydrops, e.g., compared to baseline levels. In some embodiments, a subject may exhibit improved levels of perilymphatic enhancement, e.g., compared to baseline levels. In some embodiments, a subject may exhibit improved levels of both endolymphatic hydrops and perilymphatic enhancement, e.g., compared to baseline levels. In some embodiments, a subject may exhibit improved levels of severity and / or frequency of dizziness episodes, e.g., compared to baseline levels. In some embodiments, a subject may exhibit improved hearing (e.g., using a hearing assessment), e.g., compared to baseline levels. In some embodiments, a subject may exhibit improved Dizziness Handicap Inventory (DHI) scores and / or Tinnitus Handicap Inventory (THI) scores, e.g., compared to baseline scores.

[0256] In some embodiments, dizziness episodes can be assessed by having the subject keep a daily dizziness diary of the severity and frequency of dizziness episodes. In some embodiments, the mean dizziness severity and frequency after administration (e.g., average over the past four weeks) can be compared to the baseline dizziness severity and frequency (e.g., average over the four weeks before administration).

[0257] In some embodiments, hearing may be assessed by audiometry. In some embodiments, hearing may be assessed using pure-tone audiometry at 125, 250, 500, 1000, 2000, 4000, and 8000 Hz and / or word recognition scores. In some embodiments, change from baseline in hearing from pure-tone audiometry at 125, 250, 500, 1000, 2000, 4000, and 8000 Hz and word recognition scores may be characterized using descriptive statistics.

[0258] In some embodiments, the change in a patient's DHI and THI scores from baseline to post-administration assessment (e.g., about day 29 and / or about day 85) can be assessed and characterized using descriptive statistics.

[0259] For subjects undergoing MRI, changes from baseline in endolymphatic hydrops and perilymphatic enhancement as assessed by delayed intravenous gadolinium-enhanced 3T MRI scan can be assessed post-administration (e.g., about day 15).

[0260] The amount and extent of distribution of the polymer composition or sustained-release otic composition in the middle ear of the subject after administration (e.g., about day 15) can also be assessed.

[0261] IV. Ear Diseases and Disorders Ear disorders with an underlying microvascular etiology, including Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and similar ear disorders, have no treatment and no cure except for some symptoms.

[0262] Meniere's disease is a chronic, incurable inner ear disorder that causes recurring, debilitating symptoms that affect hearing and balance. It is named after French physician Prosper Meniere, who first identified and described the condition's symptoms in 1861. Researchers do not know the cause of fluid accumulation in the inner ear that causes MD. Some believe it is related to vascular dysfunction, while others say the disease may result from an autoimmune condition, a viral infection, an allergic reaction, or may develop from trauma. MD appears to have a genetic component, and gene mutations may be related to the regulation of inner ear fluid.

[0263] Autoimmune inner ear disease is a rare disorder that manifests in both adults and children and is caused by an immune system response. The inner ear can be a direct target of the immune response, but it can also be further damaged by the deposition of circulating immune complexes or systemic immune-mediated diseases. The clinical manifestation of immune-mediated inner ear disease shows a progressive bilateral and asymmetric SNHL profile. Cochlear symptoms are often associated with vestibular disorders. In approximately 50% of patients with AIED, hearing loss is also associated with vestibular symptoms, such as imbalance and motion intolerance, ataxia, and positional or episodic vertigo.

[0264] Sensorineural hearing loss is due to the inability of the cochlea to effectively convert pressure waves into nerve signals. SNHL is commonly associated with exposure to loud noise, aging, head trauma, exposure to ototoxic drugs, infections, autoimmune disorders, Meniere's disease, genetic mutations, and tumors of the auditory nerve.

[0265] Noise-induced hearing loss is caused by exposure to loud and / or prolonged noise. Hearing loss can occur after prolonged exposure to loud noises such as heavy machinery, loud music, airplanes, or gunfire. Prolonged, repetitive, or impulsive exposure to sounds above 85 decibels can cause hearing loss. NIHL damages hair cells and / or the auditory nerve.

[0266] Symptoms of MD, AIED, SNHL, NIHL, and other ear disorders include dizziness, hearing loss, ear ringing (tinnitus), and ear pressure. Dizziness can cause severe nausea and imbalance. Hearing loss can be permanent.

[0267] There is no treatment or cure for all but a few symptoms. Medications for motion sickness or nausea may help manage symptoms.

[0268] The present disclosure also provides methods of treating otic diseases and disorders using tyrosine kinase inhibitors (e.g., VEGF inhibitors). Accordingly, provided herein is a method of treating an otic disease or disorder in a subject, comprising identifying the subject as having an otic disease or disorder and administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor.

[0269] Non-limiting examples of ear diseases and disorders include Meniere's disease, autoimmune inner ear disease (AIED), sensorineural hearing loss (e.g., sudden sensorineural hearing loss or sensorineural hearing loss associated with diabetes), noise-induced hearing loss (NIHL), age-related hearing loss, tinnitus, damage to cilia due to autoimmune disorders, damage to cilia due to infection, damage to cilia due to excess fluid or pressure, and chemotherapy-induced hearing loss.

[0270] In some cases, the tyrosine kinase inhibitor can be a VEGF inhibitor (e.g., any of the VEGF inhibitors described herein. In some embodiments, the tyrosine kinase inhibitor is administered in an amount sufficient to reduce edema and lymphatic dysfunction of the affected ear.

[0271] The tyrosine kinase inhibitor can be administered in any suitable form or by any suitable route. In some embodiments, the tyrosine kinase inhibitor can be administered systemically. In some embodiments, the tyrosine kinase inhibitor can be administered locally (e.g., via transtympanic injection, e.g., into the middle or inner ear). In some cases, the tyrosine kinase inhibitor can be provided in the form of a hydrogel. Non-limiting examples of hydrogels are provided in U.S. Patent Nos. 9,066,865 and 10,561,736, each of which is incorporated herein by reference in its entirety. As another example, the tyrosine kinase inhibitor can be provided in the form of any of the sustained-release otic compositions described herein.

[0272] Illustrative Embodiments Embodiment 1 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C. Embodiment 2 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 10 seconds to about 30 minutes at a temperature of about 37°C. Embodiment 3 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A polymer composition in which a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, the gel having a residence time of at least 5 days when formed in the middle ear. Embodiment 4 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, The polymer composition is capable of undergoing a crosslinking reaction between the first functional group and the second functional group to form a gel, the gel having a gel duration of at least 5 days at 37°C. Embodiment 5 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, The polymer composition has a pH of about 5.5 to about 8.5, and is a polymer composition in which a crosslinking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 6 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A polymer composition in which a cross-linking reaction can occur between first and second functional groups to form a gel, the gel swelling less than 100% after equilibration in phosphate buffered saline (PBS) for 1 day. Embodiment 7 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, The polymer composition is capable of undergoing a crosslinking reaction between the first functional group and the second functional group to form a gel, the gel being elastic. Embodiment 8 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, A polymeric composition in which a cross-linking reaction can occur between the first and second functional groups to form a gel, the gel being mucoadhesive. Embodiment 9 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 0.6% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, The polymer composition has a viscosity of about 1 mPa·s to about 1000 mPa·s, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 10 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 45 seconds to about 60 minutes at a temperature of about 20°C. Embodiment 11 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A crosslinking reaction can occur between the first functional group and the second functional group to form a gel, and the polymer composition has a gelation time of about 10 seconds to about 30 minutes at a temperature of about 37°C. Embodiment 12 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A polymer composition in which a crosslinking reaction can occur between the first functional group and the second functional group to form a gel, the gel having a residence time of at least 5 days when formed in the middle ear. Embodiment 13 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; The polymer composition is capable of undergoing a crosslinking reaction between the first functional group and the second functional group to form a gel, the gel having a gel duration of at least 5 days at 37°C. Embodiment 14 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; The polymer composition has a pH of about 5.5 to about 8.5, and is a polymer composition in which a crosslinking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 15 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A polymer composition in which a cross-linking reaction can occur between first and second functional groups to form a gel, the gel swelling less than 100% after equilibration in phosphate buffered saline (PBS) for 1 day. Embodiment 16 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A polymer composition in which a cross-linking reaction can occur between the first and second functional groups to form a gel, the gel being elastic. Embodiment 17 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; A polymeric composition in which a cross-linking reaction can occur between the first and second functional groups to form a gel, the gel being mucoadhesive. Embodiment 18 is a polymer composition comprising: about 5% to about 15% by weight of the polymer composition of a functional polymer, the functional polymer comprising a first functional group; about 0.05% to about 10% by weight of the polymer composition of a crosslinker, the crosslinker comprising a second functional group; water, the first functional group and the second functional group are present in a ratio of about 1.2:0.8 to about 0.8:1.2; The polymer composition has a viscosity of about 1 mPa·s to about 1000 mPa·s, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 19 is the polymer composition of any one of embodiments 9-16, wherein the polymer composition comprises from about 1% to about 10% crosslinker by weight of the polymer composition. Embodiment 20 is the polymer composition of any one of embodiments 9-16, wherein the polymer composition comprises from about 1% to about 5% crosslinker by weight of the polymer composition. Embodiment 21 is the polymer composition of any one of embodiments 2-9 or 11-20, wherein the polymer composition has a gel time of from about 45 seconds to about 60 minutes at a temperature of about 20°C. Embodiment 22 is the polymer composition of any one of embodiments 1, 2, 4-11, or 13-21, wherein the gel, when formed in the middle ear, has a residence time of at least 5 days. Embodiment 23 is the polymer composition of any one of embodiments 1-3, 5-12, or 14-22, wherein the gel has a gel duration at 37° C. of at least 5 days. Embodiment 24 is the polymer composition of any one of embodiments 1-4, 6-13, or 15-23, wherein the polymer composition has a pH of about 5.5 to about 8.5. Embodiment 25 is the polymer composition of any one of embodiments 1-5, 7-14, or 15-24, wherein the gel swells less than 100% after equilibration in phosphate buffered saline (PBS) for 1 day. Embodiment 26 is the polymer composition of any one of embodiments 1-6, 8-15, or 17-25, wherein the gel is elastic. Embodiment 27 is the polymer composition of any one of embodiments 1-7, 9-16, or 18-26, wherein the gel is mucoadhesive. Embodiment 28 is the polymer composition of any one of embodiments 1-8, 10-17, or 19-27, wherein the polymer composition has a viscosity of from about 1 mPa·s to about 1000 mPa·s. Embodiment 29 is the polymer composition of any one of embodiments 1 to 28, wherein the polymer composition comprises from about 6% to about 12% of the functional polymer by weight of the polymer composition. Embodiment 30 is the polymer composition of any one of embodiments 1 to 28, wherein the polymer composition comprises from about 7% to about 10% of the functional polymer by weight of the polymer composition. Embodiment 31 is the polymer composition of any one of embodiments 1 to 28, wherein the polymer composition comprises about 8.3% of the functional polymer by weight of the polymer composition. Embodiment 32 is the polymer composition of any one of embodiments 1 to 28, wherein the polymer composition comprises from about 8% to about 12% of the functional polymer by weight of the polymer composition. Embodiment 33 is the polymer composition of any one of embodiments 1 to 28, wherein the polymer composition comprises about 10% of the functional polymer by weight of the polymer composition. Embodiment 34 is the polymer composition of any one of embodiments 1 to 33, wherein the polymer composition comprises from about 0.05% to about 0.5% of a crosslinker by weight of the polymer composition. Embodiment 35 is the polymer composition of any one of embodiments 1 to 33, wherein the polymer composition comprises from about 0.1% to about 0.3% of a crosslinker by weight of the polymer composition. Embodiment 36 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises about 0.2% crosslinker by weight of the polymer composition. Embodiment 37 is the polymer composition of any one of embodiments 1 to 33, wherein the polymer composition comprises from about 0.2% to about 0.6% of a crosslinker by weight of the polymer composition. Embodiment 38 is the polymer composition of any one of embodiments 1 to 33, wherein the polymer composition comprises from about 0.3% to about 0.5% of a crosslinker by weight of the polymer composition. Embodiment 39 is the polymer composition of any one of embodiments 1 to 33, wherein the polymer composition comprises from about 0.4% to about 0.6% of a crosslinker by weight of the polymer composition. Embodiment 40 is the polymer composition of any one of embodiments 1-39, wherein the polymer composition has a gel time of about 5 minutes to about 20 minutes at a temperature of about 20°C. Embodiment 41 is the polymer composition of any one of embodiments 1-40, wherein the polymer composition has a gel time of about 4 minutes to about 12 minutes at a temperature of about 20°C. Embodiment 42 is the polymer composition of any one of embodiments 1-41, wherein the polymer composition has a gel time of about 8 minutes to about 12 minutes at a temperature of about 20°C. Embodiment 43 is the polymer composition of any one of embodiments 1, 2-11, or 13-42, wherein the polymer composition has a gel time of from about 10 seconds to about 30 minutes at a temperature of about 37°C. Embodiment 44 is the polymer composition of any one of embodiments 1-43, wherein the polymer composition has a gel time of about 1 minute to about 4 minutes at a temperature of about 37°C. Embodiment 45 is the polymer composition of any one of embodiments 1 to 44, wherein the polymer composition has a gel time of about 2 minutes to about 8 minutes at a temperature of about 37°C. Embodiment 46 is the polymer composition of any one of embodiments 1 to 45, wherein the gel, when formed in the middle ear, has a residence time of at least one week. Embodiment 47 is the polymer composition of any one of embodiments 1 to 46, wherein the gel, when formed in the middle ear, has a residence time of at least two weeks. Embodiment 48 is the polymer composition of any one of embodiments 1 to 47, wherein the gel, when formed in the middle ear, has a residence time of at least one month. Embodiment 49 is the polymer composition of any one of embodiments 1 to 48, wherein the gel, when formed in the middle ear, has a residence time of at least 2 months. Embodiment 50 is the polymer composition of any one of embodiments 1 to 49, wherein the gel has a resorption time in PBS at 50° C. of about 5 days to about 30 days. Embodiment 51 is the polymer composition of any one of embodiments 1-50, wherein the gel has a resorption time of about 7 days to about 15 days at 50° C. in PBS. Embodiment 52 is the polymer composition of any one of embodiments 1 to 51, wherein the polymer composition has a pH of about 6.4 to about 7.4. Embodiment 53 is the polymer composition of any one of embodiments 1 to 52, wherein the polymer composition has a pH of about 6.0 and 7.0. Embodiment 54 is the polymer composition of any one of embodiments 1 to 53, wherein the polymer composition has a pH of from about 5.5 to about 8.0. Embodiment 55 is the polymer composition of any one of embodiments 1 to 54, wherein the gel swells less than 80% after equilibration in phosphate buffered saline (PBS) for 1 day. Embodiment 56 is the polymer composition of any one of embodiments 1 to 55, wherein the gel swells less than 60% after equilibration in phosphate buffered saline (PBS) for 1 day. Embodiment 57 is the polymer composition of any one of embodiments 1 to 56, wherein the polymer composition has a viscosity of from about 1 mPa·s to about 100 mPa·s. Embodiment 58 is the polymer composition of any one of embodiments 1 to 57, wherein the polymer composition has a viscosity of about 1 mPa·s to about 50 mPa·s. Embodiment 59 is the polymer composition of any one of embodiments 1 to 58, wherein the gel is hypotonic with respect to the endolymph or perilymph. Embodiment 60 is the polymer composition of any one of embodiments 1 to 58, wherein the gel is isotonic with respect to the endolymph or perilymph. Embodiment 61 is the polymer composition of any one of embodiments 1 to 58, wherein the gel is hypertonic with respect to the endolymph or perilymph. Embodiment 62 is the polymer composition of any one of embodiments 1 to 61, wherein the gel has an osmolality of about 300 mOsmol / kg to about 600 mOsmol / kg. Embodiment 63 is the polymer composition of any one of embodiments 1 to 62, wherein the gel has a pH of about 6.0 to about 7.7. Embodiment 64 is the polymer composition of any one of embodiments 1 to 63, wherein the gel has a pH of about 6.6 to about 6.8. Embodiment 65 is the polymer composition of any one of embodiments 1 to 64, wherein the gel has a pH of about 6.0 to about 6.5. Embodiment 66 is the polymer composition of any one of embodiments 1-9 or 21-65, wherein the ratio of the first functional group to the second functional group is from about 0.8:1.2 to about 1.2:0.8. Embodiment 67 is the polymer composition of any one of embodiments 1 to 66, wherein the ratio of the first functional group to the second functional group is from about 0.9:1 to about 1:0.9. Embodiment 68 is the polymer composition of any one of embodiments 1-67, wherein the ratio of first functional groups to second functional groups is about 1:1. Embodiment 69 is the polymer composition of any one of embodiments 1 to 68, wherein the functional polymer is a modified PEG. Embodiment 70 is the polymer composition of any one of embodiments 1-69, wherein the first functional group comprises an electrophile and the second functional group comprises a nucleophile. Embodiment 71 is the polymer composition of any one of embodiments 1 to 70, wherein the first functional group comprises a succinimidyl ester. Embodiment 72 is the polymer composition of any one of embodiments 1 to 70, wherein the functional group is selected from the group consisting of succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl gluraramide, succinimidyl carbonate, succinimidyl carboxymethyl ester, or a combination thereof. Embodiment 73 is the polymer composition of any one of embodiments 1 to 72, wherein the second functional group comprises a primary amine. Embodiment 74 is the polymer composition of any one of embodiments 1 to 73, wherein the functional polymer is pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. Embodiment 75 is the polymer composition of any one of embodiments 1 to 74, wherein the crosslinker comprises polylysine or a salt thereof. Embodiment 76 is the polymer composition of any one of embodiments 1 to 75, wherein the crosslinker comprises trilysine or a salt thereof. Embodiment 77 is the polymer composition of any one of embodiments 1-76, wherein the first functional group comprises a nucleophile and the second functional group comprises an electrophile. Embodiment 78 is the polymer composition of embodiment 77, wherein the first functional group comprises a primary amine. Embodiment 79 is the polymer composition of embodiment 77 or embodiment 78, wherein the second functional group comprises a succinimidyl ester. Embodiment 80 is a sustained release otic composition comprising: The polymer composition of any one of embodiments 1 to 79; and and an active agent. Embodiment 81 is the sustained release otic composition of embodiment 80, wherein the active agent is selected from the group consisting of a therapeutic agent, a prophylactic agent, a diagnostic or visualization agent, and combinations thereof. Embodiment 82 is the sustained release otic composition of embodiment 81, wherein the therapeutic or prophylactic agent is selected from the group consisting of proteins, carbohydrates, nucleic acids, small molecules, and combinations thereof. Embodiment 83 is the sustained-release otic composition of embodiment 82, wherein the protein is selected from the group consisting of an enzyme, a growth factor, an antibody or an antigen-binding fragment thereof, and combinations thereof. Embodiment 84 is the sustained-release otic composition of embodiment 82 or embodiment 83, wherein the carbohydrate is a glycosaminoglycan. Embodiment 85 is the sustained release otic composition of any one of embodiments 82 to 84, wherein the nucleic acid is selected from the group consisting of an antisense oligonucleotide, an aptamer, a microRNA, a short interfering RNA, a ribozyme, and combinations thereof. Embodiment 86 is the sustained release otic composition of any one of embodiments 82 to 85, wherein the small molecule is selected from the group consisting of antibiotics, antitumor agents, local anesthetics, steroids, hormones, antiapoptotic agents, angiogenic agents, antiangiogenic agents, neurotransmitters, psychotropic agents, anti-inflammatory agents, and combinations thereof. Embodiment 84 is the sustained-release otic composition of any one of embodiments 82 to 86, wherein the small molecule is an inhibitor of Apaf-1. Embodiment 88 is the sustained release otic composition of any one of embodiments 82-84, wherein the active agent is a tyrosine kinase inhibitor. Embodiment 89 is the sustained release otic composition of any one of embodiments 80-88, wherein the active agent is a VEGF inhibitor. Embodiment 90 is the sustained release otic composition of embodiment 89, wherein the VEGF inhibitor is selected from the group consisting of agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, rebastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, vandetanib, and combinations thereof. Embodiment 91 is the sustained-release otic composition of embodiment 89 or embodiment 90, wherein the VEGF inhibitor comprises an antibody or antigen-binding fragment thereof. Embodiment 92 is the sustained-release otic composition of embodiment 91, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of alacizumab, bevacizumab, icrucumab, ramucirumab, ranibizumab, and combinations thereof. Embodiment 93 is the sustained release otic composition of any one of embodiments 89 to 92, wherein the VEGF inhibitor comprises a decoy receptor. Embodiment 94 is the sustained release otic composition of embodiment 92, wherein the decoy receptor is aflibercept. Embodiment 95 is the sustained release otic composition of any one of embodiments 89 to 94, wherein the VEGF inhibitor comprises an allosteric modulator of a VEGFR. Embodiment 96 is the sustained release otic composition of embodiment 95, wherein the allosteric modulator is cyclotraxin B. Embodiment 97 is the sustained release otic composition of any one of embodiments 89 to 96, wherein the VEGF inhibitor is at least 10-fold selective for VEGFR2 over another VEGFR. Embodiment 98 is the sustained release otic composition of any one of embodiments 89 to 97, wherein the VEGF inhibitor is at least 20-fold selective for VEGFR2 over another VEGFR. Embodiment 99 is the sustained-release otic composition of any one of embodiments 89 to 98, wherein the VEGF inhibitor is at least 50-fold selective for VEGFR2 over another VEGFR. Embodiment 100 is the sustained release otic composition of any one of embodiments 88 to 99, wherein the tyrosine kinase inhibitor or VEGF inhibitor is present in an amount sufficient to reduce edema and lymphatic dysfunction of the affected ear. Embodiment 101 is the sustained release otic composition of any one of embodiments 82-100, wherein the active agent comprises an anti-inflammatory agent. Embodiment 102 is the sustained release otic composition of any one of embodiments 82-101, wherein the active agent comprises a steroid. Embodiment 103 is the sustained-release otic composition of embodiment 102, wherein the active agent comprises a glucocorticoid. Embodiment 104 is the sustained-release otic composition of embodiment 103, wherein the active agent comprises dexamethasone. Embodiment 105 is the sustained release otic composition of any one of embodiments 80-101, wherein the active agent does not include a steroid. Embodiment 106 is the sustained release otic composition of any one of embodiments 80 to 105, wherein the active agent comprises a diagnostic or visualization agent. Embodiment 107 is the sustained release otic composition of embodiment 106, wherein the diagnostic or visualization agent is selected from the group consisting of a dye, a fluorophore, an MRI contrast agent, and combinations thereof. Embodiment 108 is the sustained release otic composition of any one of embodiments 80-107, wherein the active agent is present in the sustained release otic composition in the form of microparticles. Embodiment 109 is the sustained release otic composition of any one of embodiments 80 to 108, wherein the active agent is present in the sustained release otic composition in the form of nanoparticles. Embodiment 110 is the sustained release otic composition of any one of embodiments 80 to 109, wherein the active agent is present in an amount of about 0.01% to about 40% by weight of the polymer composition. Embodiment 111 is the sustained-release otic composition of any one of Embodiments 80-110, wherein the active agent is present in an amount of about 0.1% to about 20% by weight of the polymer composition. Embodiment 112 is the sustained release otic composition of any one of embodiments 80 to 111, wherein the active agent is present in an amount of about 1% to about 15% by weight of the polymer composition. Embodiment 113 is the sustained-release otic composition of any one of embodiments 80 to 112, wherein the sustained-release otic composition has a cumulative release of about 30% to about 50% of the active agent in about 3 weeks when equilibrated against excess PBS at 37°C. Embodiment 114 is the sustained release otic composition of any one of embodiments 80 to 113, further comprising an excipient. Embodiment 115 is the sustained-release auris composition of embodiment 114, wherein the excipient is selected from the group consisting of a buffer, a tonicity agent, a mucoadhesive agent, a stabilizer, a preservative, a carrier, a penetration enhancer, a diluent, a dispersant, a viscosity modifier, a solubilizer, an osmolality modifier, and combinations thereof. Embodiment 116 is a sustained release otic composition, comprising: about 5% to about 15% pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; about 0.05% by weight to about 0.6% by weight of trilysine or a salt thereof; about 0.01% to about 40% by weight of dexamethasone; and water. Embodiment 117 is a sustained release otic composition, comprising: about 7% to about 9% pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; about 0.1% by weight to about 0.3% by weight of trilysine; about 1% to about 10% by weight of dexamethasone; and water. Embodiment 118 is a sustained release otic composition comprising: about 8.3% pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; About 0.2% by weight of trilysine or a salt thereof; about 6% by weight of dexamethasone; and water. Embodiment 119 is about 0.01% by weight to about 3.0% by weight of sodium borate decahydrate; about 0.01% by weight to about 3.0% by weight of sodium phosphate; about 0.01% by weight to about 3.0% by weight of phosphoric acid; Approximately 0% to 0.5% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0% to about 0.01% by weight of butylated hydroxytoluene. Embodiment 120 is about 0.05% to about 2.0% by weight of sodium borate decahydrate; about 0.05% to about 2.0% by weight of sodium phosphate; about 0.05% by weight to about 2.0% by weight of phosphoric acid; Approximately 0% to 0.05% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0% to about 0.005% by weight of butylated hydroxytoluene. Embodiment 121 is about 1.2% by weight of sodium borate decahydrate; about 1.1% to about 3.0% by weight of sodium phosphate; about 0.9% by weight to about 3.0% by weight of phosphoric acid; Approximately 0.01% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0.002% by weight of butylated hydroxytoluene. Embodiment 122 is about 0.01% by weight to about 6.0% by weight of sodium phosphate; Approximately 0% to 0.5% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0% to about 0.01% by weight of butylated hydroxytoluene. Embodiment 123 is about 0.05% to about 6.0% by weight of sodium phosphate; Approximately 0% to 0.05% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0% to about 0.005% by weight of butylated hydroxytoluene. Embodiment 124 is about 2.0% to about 6.0% by weight of sodium phosphate; Approximately 0.01% of FD&C Blue #1 and 119. The sustained-release otic composition of any one of embodiments 116-118, further comprising about 0.002% by weight of butylated hydroxytoluene. Embodiment 125 is a gel formed from the polymer composition of any one of embodiments 1-79 or the sustained release otic composition of any one of embodiments 80-124. Embodiment 126 is the manufacture of a medicament comprising the sustained-release otic composition of any one of Embodiments 80 to 124 for the treatment of an ear disease or disorder. Embodiment 127 is a method for preparing a sustained-release otic composition, comprising: The method includes combining a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group, a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group, and an active agent to form an otic composition, whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the otic composition, the crosslinker is present in the otic composition in an amount of about 0.05% to about 0.6% by weight of the otic composition, and a crosslinking reaction can occur between the first and second functional groups to form a gel. Embodiment 128 is a method for preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group; (b) preparing a solution or suspension of a crosslinker, the crosslinker comprising a second functional group; (c) combining a solution or suspension of the functional polymer with a solution or suspension of the crosslinker to form the sustained release otic composition, whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the sustained release otic composition and the crosslinker is present in the sustained release otic composition in an amount of about 0.05% to about 0.6% by weight of the sustained release otic composition; A method in which a cross-linking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 129 is a method for preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group; (b) combining a solution or suspension of the functional polymer with a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group, whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the otic composition and the crosslinker is present in the otic composition in an amount of about 0.05% to about 0.6% by weight of the otic composition; A method in which a cross-linking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 130 is a method for preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group; (b) altering the pH of a solution or suspension of the crosslinker, wherein the crosslinker comprises a second functional group; (c) combining a solution or suspension of the functionalized polymer with a solution or suspension of a crosslinker; A method in which a cross-linking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 131 is a method for preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a crosslinker, the crosslinker comprising a second functional group; (b) combining a solution or suspension of a crosslinker with a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group, whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the otic composition and the crosslinker is present in the otic composition in an amount of about 0.05% to about 0.6% by weight of the otic composition; A method in which a cross-linking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 132 is a method for preparing a sustained-release otic composition, comprising: (a) forming a solution or suspension of a crosslinker, the crosslinker comprising a second functional group; (b) altering the pH of a solution or suspension of the functionalized polymer, wherein the functionalized polymer comprises a first functional group; (c) combining a solution or suspension of the functionalized polymer with a solution or suspension of a crosslinker; A method in which a cross-linking reaction can occur between the first functional group and the second functional group to form a gel. Embodiment 133 is the method of any one of embodiments 127-132, wherein the active agent is present in a solution or suspension of the functional polymer. Embodiment 134 is the method of embodiment 133, wherein the active agent is combined with the functional polymer prior to forming the solution or suspension of the functional polymer. Embodiment 135 is the method of embodiment 133, wherein the active agent is combined with the solution or suspension of the functional polymer. Embodiment 136 is the method of any one of embodiments 127-135, wherein combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker comprises combining the solution or suspension of the functional polymer and the solution or suspension of the crosslinker with an activator. Embodiment 137 is the method of embodiment 136, wherein the active agent is provided as a solid. Embodiment 138 is the method of embodiment 136, wherein the active agent is provided as a solution or suspension. Embodiment 139 is the method of any one of Embodiments 127-138, wherein the sustained release otic composition is the sustained release otic composition of any one of Embodiments 80-124. Embodiment 140 is a method of treating an ear disease or disorder in a subject, comprising: Identifying a subject as having an ear disease or disorder; administering a therapeutically effective amount of the sustained release otic composition of any one of embodiments 80-124 to the affected ear of the subject. Embodiment 141 is a method of treating an ear disease or disorder in a subject in need thereof, comprising: A method comprising administering a therapeutically effective amount of the sustained release otic composition of any one of embodiments 80-124 to the ear of a subject. Embodiment 142 is a method of treating an ear disease or disorder in a subject, comprising: (i) preparing a sustained-release otic composition by the method of any one of embodiments 127-139; (ii) administering a therapeutically effective amount of a sustained-release otic composition to the ear of a subject in need thereof. Embodiment 143 is a method of treating an ear disease or disorder in a subject, comprising: (i) identifying a subject as having an ear disease or disorder; (ii) preparing a sustained-release otic composition by the method of any one of embodiments 127 to 139; (iii) administering a therapeutically effective amount of a sustained release otic composition to the affected ear of the subject. Embodiment 144 is the method of any one of embodiments 140 to 125, wherein the ear disease or disorder is selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. Embodiment 145 is the method of embodiment 126, in which the sensorineural hearing loss is sudden sensorineural hearing loss. Embodiment 146 is the method of embodiment 126, wherein the sensorineural hearing loss is associated with diabetes. Embodiment 147 is a method of treating Meniere's disease in a subject, comprising: A method comprising administering a therapeutically effective amount of the sustained release otic composition of any one of embodiments 80-124 to the ear of a subject in need thereof. Embodiment 148 is a method of treating Meniere's disease in a subject, comprising: (i) identifying a subject as having Meniere's disease; (ii) administering a therapeutically effective amount of the sustained release otic composition of any one of embodiments 80-124 to the affected ear of the subject. Embodiment 149 is a method of treating Meniere's disease in a subject, comprising: (i) preparing a sustained-release otic composition by the method of any one of embodiments 127-139; (ii) administering a therapeutically effective amount of a sustained-release otic composition to the ear of a subject in need thereof. Embodiment 150 is a method of treating Meniere's disease in a subject, comprising: (i) identifying a subject as having Meniere's disease; (ii) preparing a sustained-release otic composition by the method of any one of embodiments 127 to 139; (iii) administering a therapeutically effective amount of a sustained release otic composition to the affected ear of the subject. Embodiment 151 is the method of any one of embodiments 140-150, wherein the administering occurs within 10 minutes after combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. Embodiment 152 is the method of any one of embodiments 140-151, wherein the administering occurs within 5 minutes of combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. Embodiment 153 is the method of any one of embodiments 140-152, wherein administering comprises administering about 5 μL to about 500 μL of the sustained-release otic composition. Embodiment 154 is the method of any one of embodiments 140 to 153, wherein administering comprises administering about 50 μL to about 200 μL of the sustained-release otic composition. Embodiment 155 is the method of any one of embodiments 140-153, wherein administering comprises administering about 40 μL to about 60 μL of the sustained-release otic composition. Embodiment 156 is the method of any one of embodiments 140-153, wherein administering comprises administering about 50 μL of the sustained-release otic composition. Embodiment 157 is the method of any one of embodiments 140-156, wherein administering comprises administering the sustained-release otic composition such that it contacts the round window membrane. Embodiment 158 ​​is the method of any one of embodiments 140-157, wherein administering comprises administering the sustained-release otic composition such that it does not involve any of the ossicles. Embodiment 159 is the method of any one of embodiments 140-158, wherein administering comprises administering the sustained-release otic composition such that it does not contact any of the ossicles. Embodiment 160 is the method of any one of embodiments 140-159, wherein the sustained-release otic composition is a liquid during administration. Embodiment 161 is the method of any one of embodiments 140-160, wherein the sustained-release otic composition is not exposed to a temperature above about 26° C. prior to administration. Embodiment 162 is the method of any one of Embodiments 140-161, wherein the sustained-release otic composition has a temperature of about 20°C to about 25°C during administration. Embodiment 163 is the method of any one of embodiments 140 to 162, wherein administering comprises injecting through the tympanic membrane. Embodiment 164 is a method of treating an ear disease or disorder in a subject, comprising: Identifying a subject as having an ear disease or disorder; administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor. Embodiment 165 is the method of embodiment 164, wherein the ear disease or disorder is selected from the group consisting of Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, cilia damage due to autoimmune disorders, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. Embodiment 166 is the method of embodiment 165, wherein the sensorineural hearing loss is sudden sensorineural hearing loss. Embodiment 167 is the method of embodiment 165, wherein the sensorineural hearing loss is associated with diabetes. Embodiment 168 is a method of treating Meniere's disease in a subject, comprising: (i) identifying a subject as having Meniere's disease; (ii) administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor. Embodiment 169 is a method of treating Meniere's disease in a subject, comprising: administering a therapeutically effective amount of a tyrosine kinase inhibitor to a subject in need thereof. Embodiment 170 is the method of embodiment 168 or 169, wherein the administering comprises systemic administration. Embodiment 171 is the method of embodiment 168 or 169, wherein administering comprises administering to the affected ear of the subject. Embodiment 172 is the method of any one of embodiments 168 to 171, wherein the tyrosine kinase inhibitor comprises a VEGF inhibitor. Embodiment 173 is the method of embodiment 172, wherein the VEGF inhibitor is selected from the group consisting of agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, rebastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, vandetanib, and combinations thereof. Embodiment 174 is the method of embodiment 172 or embodiment 173, wherein the VEGF inhibitor comprises an antibody or an antigen-binding fragment thereof. Embodiment 175 is the method of embodiment 174, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of alacizumab, bevacizumab, icrucumab, ramucirumab, ranibizumab, and combinations thereof. Embodiment 176 is the method of any one of embodiments 172 to 175, wherein the VEGF inhibitor comprises a decoy receptor. Embodiment 177 is the method of embodiment 176, wherein the decoy receptor is aflibercept. Embodiment 178 is the method of any one of embodiments 172 to 177, wherein the VEGF inhibitor comprises an allosteric modulator of a VEGFR. Embodiment 179 is the method of embodiment 178, wherein the allosteric modulator of VEGFR is cyclotraxin B. Embodiment 180 is the method of any one of embodiments 172 to 179, wherein the VEGF inhibitor is at least 10-fold selective for VEGFR2 over another VEGFR. Embodiment 181 is the method of any one of embodiments 172 to 180, wherein the VEGF inhibitor is at least 20-fold selective for VEGFR2 over another VEGFR. Embodiment 182 is the sustained-release otic composition of any one of embodiments 172 to 181, wherein the VEGF inhibitor is at least 50-fold selective for VEGFR2 over another VEGFR. Embodiment 183 is the method of any one of embodiments 168 to 182, wherein the amount of the tyrosine kinase inhibitor is sufficient to reduce edema and lymphatic dysfunction of the affected ear. Embodiment 184 is the method of any one of embodiments 168-169 or 171-183, wherein the tyrosine kinase inhibitor is provided in the form of a sustained release otic composition of any one of embodiments 80-124.

[0273] The present invention will be further understood by reference to the following non-limiting examples. [Example]

[0274] Example 1: Effect of pH on the gelation time of PEG-trilysine polymers Materials and Methods The commercially available PEG-trilysine polymer system (COVIDIEN Ref. DS-D-5005) forms a gel in approximately 3 seconds after mixing equal volumes of trilysine amine solution and PEG ester solution. To slow the crosslinking reaction and allow for injection time into the middle ear, the pH of the trilysine solution was altered as described in Table 1 by adding HCl (1N HCl, Millipore). The PEG ester solution was prepared according to the package insert and used within 1 hour of reconstitution. The gelation time was measured at room temperature by monitoring the time when the stir bar stopped rotating.

[0275] result As shown in Table 1, adjusting the pH of the PEG-trilysine polymer trilysine solution from pH 10 to pH 8.4 successfully delayed the gelation time from 3 seconds to approximately 1 minute. In a previous screening study, samples prepared with a trilysine solution further adjusted to pH 6.8 did not form gels after 25 minutes of observation. [Table 1]

[0276] Example 2: Effect of pH on gel duration of PEG-trilysine polymer Materials and Methods The vials from the gel time measurements in Example 1 were monitored to observe when the gel broke down into a liquid. The vials with the stir bar were stored inverted at room temperature, and the time at which the sample was found to be liquid was recorded as shown in Table 1.

[0277] result Unmodified PEG-trilysine polymer (i.e., trilysine, pH 10) was liquid after 1.5 days of storage at room temperature in a sealed glass vial, whereas samples prepared with trilysine adjusted to pH 8.4 remained gels even after more than 3 months.

[0278] In addition to affecting the cross-linking reaction, pH also affects hydrolysis. The pH of the trilysine solution is preferably 6 to 8.4, more preferably 6.5 to 8, for injection into the middle ear. These pH values ​​are also advantageous from the viewpoint of tissue biocompatibility.

[0279] Example 3: Effect of drug particle concentration on gelation time Materials and Methods The PEG-trilysine polymer trilysine solution was pH adjusted with 1N HCl as described in Example 1. Micronized dexamethasone (Dex, Spectrum Chemical DE121) was then added to the pH-adjusted trilysine solution and vortexed. 100 microliters of the pH-adjusted trilysine drug suspension was then added to 100 microliters of the PEG-trilysine polymer PEG solution in a glass vial for the gelation time stir bar test. The time after addition when the stir bar stopped rotating was recorded.

[0280] result Adding HCl to the trilysine polymer solution dilutes the trilysine, and when added to the PEG-trilysine polymer PEG solution, a stoichiometry of less than 1:1 is obtained, but adding drug particles further dilutes it, resulting in a lower stoichiometry. [Table 2]

[0281] As shown in Table 2, the fraction of the original trilysine solution in the trilysine modified to pH 8.4 contains 85% of the original trilysine solution, and the addition of 12 wt% dexamethasone reduces the amount of the original trilysine solution to 75%.

[0282] As also shown in Table 2, the addition of up to 12 wt % dexamethasone to trilysine solutions at pH 8.4 did not substantially affect the gelation time measured in the stir bar test.

[0283] Example 4: Drug release and erosion studies for 0-6 wt% dexamethasone in pH-modified PEG-trilysine polymers Materials and Methods In vitro drug release and gel erosion tests were performed using 200 μL of gel sample in an insert (CORNING TRANSWELL® 3414 insert with a 0.4 μm pore size polycarbonate membrane). To simulate drug delivery to potential fluids within the middle ear, the insert was immersed in 45 mL of receptor solution (PBS, pH 7.4, SIGMA-ALDRICH® P5368) in a 37°C incubator. A large receptor volume was chosen to keep the drug concentration low (i.e., sink conditions) so that saturation of the receptor solution would not limit the drug release rate. This test was performed in the test configuration (0.33 cm directly exposed to PBS). 2 The maximum drug release rate into PBS and the area of ​​0.33 cm 2 The drug release through a membrane with an area of ​​0.05 mm was measured. Furthermore, the swelling and erosion were monitored gravimetrically.

[0284] PEG-trilysine polymer samples were prepared in triplicate using pH-adjusted trilysine solution and 0, 1, 3, and 6 wt% dexamethasone, as described in Example 3. The two components were combined in a microcentrifuge tube and vortex-mixed, after which aliquots were dispensed into each insert. At the start of the study, samples were immersed in the receptor solution and stored at 37°C. Periodically, samples of the receptor solution were removed and analyzed for drug concentration to determine drug release. At intervals not exceeding 9 days, samples were also transferred to new vials of receptor solution. Before sampling or transferring inserts, the receptor vial was manually inverted several times to ensure homogeneity of the receptor solution.

[0285] After removing excess fluid with laboratory tissue, sample weights were recorded periodically. Percent swelling was calculated as the change in sample weight divided by the initial sample weight, which reflects the degree of swelling and initial cross-linking.

[0286] result As the study progressed, sample weight was subject to changes due to hydrolytic degradation. Sample weight initially increased as the initial 90% water-containing gel absorbed water due to contact with the receptor fluid. As the gel degraded and swelled due to reduced cross-linking, sample weight continued to increase, with gel erosion contributing to weight loss. Eventually, the gel completely eroded and dissolved in the receptor fluid. As the gel eroded, the remaining solid drug particles tended to settle and flow out of the insert when it was placed on its side and during the manual mixing process before transferring the insert to a new vial.

[0287] The results in Figure 2A show that the day 4 samples had 64–95% initial swelling, and these values ​​were not strongly dependent on the amount of dexamethasone. All 12 inserts contained gel for at least 15 days. By day 19, four samples showed significant erosion-related weight loss. Further evaluation revealed that samples with shorter gel duration appeared to correlate with the pot life of the PEG solution (time from PEG reconstitution) rather than dexamethasone content. For example, samples with longer time since PEG reconstitution exhibited less cross-linking and degraded more readily (see, e.g., Example 7).

[0288] Drug release from dexamethasone-containing samples is shown in Figure 2B. The 1% Dex sample was completely depleted of drug by day 15, while the 3% and 6% gels showed cumulative release of 48% and 30%, respectively. As the gel disintegrated to a liquid consistency, the remaining drug particles settled and spread from the insert into the receptor fluid. This increased the amount of drug released into the receptor fluid, as demonstrated by the increased drug release of one of the 6% Dex samples at day 19.

[0289] The observation of clear and cloudy gels was consistent with the measured amount of drug released. The 1% Dex samples initially had clear gel primarily on the surface directly exposed to PBS and less on the membrane surface. Ultimately, these samples had no cloudy gel areas. At the other extreme, only a small amount of clear gel was observed on the PBS-exposed surface of the 6% Dex samples.

[0290] Example 5: Tissue adhesion of 0-6 wt% dexamethasone in pH-modified PEG-trilysine polymer Materials and Methods Qualitative assessment of tissue adhesion was performed by applying the samples to raw turkey breast. Parallel to the sample preparation in Example 4, the remaining material was pipetted onto the surface of the turkey and a small wooden stick was applied to it. After a few minutes of gelation time, adhesion was assessed by pulling the wooden stick.

[0291] The test was performed in triplicate using samples with final contents of 0, 1, 3, and 6 wt. % dexamethasone in the PEG-trilysine polymer trilysine adjusted to pH 8.4.

[0292] result Better adhesion was observed in the 3 and 6 wt% Dex samples compared to the 0 and 1 wt% Dex samples. Furthermore, gels with higher drug content exhibited greater cohesion, demonstrating that drug particles can improve the mechanical properties of gels, similar to filler particles that can reinforce viscoelastic materials.

[0293] Example 6: Gelation time of PEG-trilysine polymers with higher dexamethasone content Materials and Methods PEG-trilysine polymer samples prepared from 20% dexamethasone in PEG-trilysine polymer trilysine adjusted to pH 8.4 were tested for gel time by the stir bar test. Sample preparation and testing procedures were similar to those described in Example 1.

[0294] result As shown in Table 3, the gelation time was slightly longer for the 10% Dex sample than for the 6% Dex sample. [Table 3]

[0295] Dilution of the PEG-trilysine polymer trilysine by the addition of 1 N HCl and dexamethasone corresponds to approximately 68% of the original trilysine in the pH-adjusted trilysine-drug suspension. The corresponding deviation from the 1:1 stoichiometry may be approaching a level insufficient for robust gel formation.

[0296] Example 7: Drug release and erosion studies of 6 wt% dexamethasone in pH-modified PEG-trilysine polymer Materials and Methods In vitro drug release and gel erosion studies were performed as described in Example 4. Samples were prepared from PEG-trilysine polymer trilysine adjusted to pH 8.4 with 12% by weight dexamethasone, with the final sample containing 6% by weight dexamethasone. The pH-modified trilysine drug suspension was combined with the PEG-trilysine polymer PEG solution using a blending connector equipped with a static mixer (Nordson FibriJet® SA-3678). Six inserts were filled with sample using each blending connector.

[0297] result Each of the six groups of data is designated by the pot life of the PEG solution at the time of use, ie, the time since the PEG was reconstituted.

[0298] As shown in Figure 3, the 67-minute pot life group exhibited higher initial swelling and shorter gel duration than the groups with a pot life of less than 30 minutes. The cumulative drug release, shown in Figure 4, was highly reproducible regardless of pot life until the gel eroded in the 67-minute pot life group on day 17. The PEG-trilysine polymer package insert specifies that the PEG solution be used before the 60-minute pot life to allow crosslinking to occur before a portion of the PEG degrades. These results demonstrate that the test was able to distinguish between samples with various degrees of crosslinking.

[0299] All samples prepared from PEG with a pot life of less than 30 minutes had a gel duration of at least 24 days and were completely eroded after being submerged in PBS receptor solution during storage at 37°C. Aliquots of the formulations were stored at 37°C without PBS in sealed microcentrifuge tubes in a humid chamber to avoid dehydration. Two samples prepared with a 30-minute PEG pot life had gel durations of over 60 and 80 days when the samples were not in contact with PBS.

[0300] Example 8: In vitro comparison of 6 wt% dexamethasone in POLOXAMER® 407 thermosensitive gel versus pH-modulated PEG trilysine polymer chemically crosslinked gel Materials and Methods A larger batch of 12 wt% dexamethasone in PEG-trilysine polymer trilysine adjusted to pH 8.4 was prepared by pooling five PEG-trilysine polymer syringes of trilysine solution. The volume of the trilysine solution was calculated from the weight of the solution and its density of 1.02 g / mL. The volume of the trilysine solution was multiplied by 0.08 to calculate the volume of 2N HCl to be added. After the addition of the acid, the pH of the aliquot was confirmed. Dexamethasone was then added, and the vial was vortexed to obtain a 12 wt% drug suspension in pH-adjusted trilysine.

[0301] The pH-adjusted PEG-trilysine polymer trilysine was combined with a PEG solution with a pot life of 30 minutes or less. The final formulation had 6% by weight dexamethasone.

[0302] A POLOXAMER® 407 gel containing 6 wt% dexamethasone was prepared to serve as a comparator. A 0.01 M PBS buffer solution was prepared from PBS pH 7.4 (Sigma-Aldrich) and water for injection (CalbioChem). A 16 wt% POLOXAMER® 407 stock solution (BASF) was prepared by slowly adding POLOXAMER® 407 (BASF) to cold phosphate buffer solution with stirring.

[0303] Dexamethasone was added to an aliquot of the POLOXAMER® 407 stock solution to obtain 6% by weight dexamethasone in 15% by weight POLOXAMER® 407. This final formulation is designated POLOXAMER® 407-Dex. A vial inversion test was performed to confirm that POLOXAMER® 407-Dex would gel when placed in a 30° C. incubator.

[0304] result Visualization of erosion of PEG-trilysine polymer-Dex versus POLOXAMER® 407-Dex Gel erosion was observed in UV-cured disposable microcuvettes that were partially filled with sample and then filled with PBS. Two sets of cuvettes were filled with 250 μL of sample. For the PEG-trilysine polymer, the two portions were first combined, vortexed in a microcentrifuge tube, and transferred to the cuvette. The cuvettes were placed in a 37°C incubator for 10 minutes for gelation before adding 2 mL of PBS preheated to 37°C. The cuvettes were sealed with parafilm and stored horizontally at 37°C.

[0305] The surface of the POLOXAMER® 407-Dex sample began to erode immediately after the addition of PBS. As the POLOXAMER® 407 dissolved, the drug particles settled and flowed to the bottom of the cuvette. The POLOXAMER® 407-Dex sample was completely eroded within 2 hours.

[0306] In contrast, after 1 day, the appearance of the PEG-trilysine polymer-Dex sample prepared in the pH-modified PEG-trilysine polymer remained almost unchanged. Even at 14 days, the majority of the gel remained intact.

[0307] Drug release of PEG-trilysine polymer-Dex versus POLOXAMER® 407-Dex Drug release was measured for 6 wt% dexamethasone in pH 8.4 modified PEG-trilysine polymer (PEG-trilysine polymer-Dex) versus POLOXAMER® 407 (407-Dex). Inserts were submerged in 50 mL of PBS receptor solution as described in Example 4. The two portions of PEG-trilysine polymer-Dex were first combined, vortexed in a microcentrifuge tube, and then transferred to the insert. The sample was placed at 37°C for 45 minutes to form a gel before adding preheated PBS.

[0308] Within the first day, all 407-Dex samples were completely eroded, and the remaining drug particles dispersed from the insert into the receptor vial (Figure 5A). The 50 mL of receptor fluid was allowed to equilibrate with the drug solids within one day; therefore, the amount of drug released depended on the volume of receptor fluid (50 mL). Variable amounts of free solid drug were transferred with the insert to the next vial of receptor fluid, until the insert was free of drug particles.

[0309] In contrast, the chemically crosslinked PEG-trilysine polymer-Dex sample delivered the drug to the receptor fluid at a constant rate for 11 days, after which the sample degraded and eroded, dispersing the drug particles into the receptor fluid and allowing faster delivery to the receptor fluid.

[0310] Permeation of PEG-trilysine polymer-Dex versus 407-Dex through biomimetic membranes In vitro drug permeation of the two formulations was evaluated using a biomimetic membrane (PermeaPad Barrier Membrane) with a lipid layer between two cellulose layers. This method utilizes an equilibrium dialysis cell (Harvard Apparatus) to create a 500 μL PTFE chamber in contact with the membrane. Donor cells loaded with 480 μL of formulation were heated to 37°C for 45 minutes to gel. The cells were then submerged in a bottle containing 75 mL of PBS acceptor solution and stored at 37°C. The acceptor side of the equilibrium dialysis cell was left open, exposing the membrane to a large volume of acceptor solution. To measure the cumulative amount of drug delivered, the acceptor solution was periodically sampled after manual mixing. In this test configuration, all drug delivery occurred via permeation through the biomimetic membrane. This differs from previous drug release configurations in inserts, which could release drug directly into the PBS as well as through the insert's porous membrane. Drug permeation through the biomimetic membrane aims to more closely simulate drug permeation through biological tissues such as the round window membrane.

[0311] The drug delivery rate of dexamethasone was slightly higher from the poloxamer gel (Figure 5B). Without being bound by any particular theory, it is believed that the micellar structure of the poloxamer gel aids in the solubilization of drugs such as dexamethasone and aids in the transport of the drug from the particle to the membrane.

[0312] Gel integrity during the permeation study was also monitored by looking for the appearance of settled drug particles. Evidence of this liquid donor was seen in the 407-Dex and PEG-trilysine polymer-Dex samples on days 4 and 14, respectively. As in the erosion and drug release studies, the permeation setup and nonporous membrane prevented direct contact with PBS, but water was able to pass through the biomimetic membrane, as suggested by the swollen membrane. This water uptake was sufficient to cause dissolution of the thermosensitive gel by day 4.

[0313] Gel duration of isolated PEG-trilysine polymer-Dex versus 407-Dex at 37 °C Aliquots of these formulations were stored at 37°C in sealed microcentrifuge tubes in a humid chamber to prevent dehydration. This configuration assessed gel integrity when stored isolated from liquid at body temperature. Both formulations demonstrated long gel duration of over 21 days.

[0314] A chemically crosslinked formulation, PEG-trilysine polymer-Dex, was compared with a thermosensitive poloxamer formulation, 407-Dex, in multiple in vitro studies. The combined results indicate expected differences in erosion and gel integrity when these two formulations are injected into the middle ear. Both are expected to achieve zero-order drug delivery across the round window membrane if the formulations remain in contact with the membrane. Poloxamer gels with physical crosslinks begin to erode immediately upon contact with fluids, such as mucus, or upon absorption of water from contact with tissue. Once the gel becomes liquid, it may flow and be expelled from the round window, resulting in a short and variable gel duration in the target tissue. On the other hand, the in situ chemically crosslinked formulation should provide more durable drug delivery performance due to its longer, reproducible retention time in the target tissue.

[0315] Example 9: Dual role of cross-linking agent and flocculating agent A generally desirable feature of drug suspension products is the ability to deliver a uniform dose. This is easily achieved with formulations that do not form dense precipitates during storage and that are easily redispersible upon manual agitation of the vial. Settling of drug particles in the pH-modified trilysine drug suspension and poloxamer formulations described in Example 8 was assessed by visual inspection.

[0316] After more than 14 days, the pH-adjusted trilysine drug suspension had a clear top layer of less than 40% of its volume, corresponding to an aggregation efficiency of 60 / 12 or greater than 5. In addition to playing a key role in cross-linking when this component was combined with the PEG solution, trilysine provided loose, easily dispersible agglomerates of dexamethasone.

[0317] Within a few hours, the dexamethasone particles in Dex-407 settle to a clear supernatant of greater than 90%, which corresponds to an agglutination efficiency of <10 / 6 or 1.7.

[0318] Example 10: In vivo testing of PEG-trilysine polymer-Dex versus 407-Dex Chemically crosslinked gels prepared from pH-modified PEG-trilysine polymers and thermosensitive gels prepared from poloxamer 407 (P407) were tested in vivo in a green monkey model. Formulations containing 6% by weight dexamethasone were prepared as described in Example 8. The formulations were administered until visible in the TM perforation, with final injection volumes ranging from 30 to 100 μL.

[0319] The results showing the residence times of these formulations are shown in Table 4A. [Table 4A]

[0320] Information regarding the absorption, distribution, and pharmacokinetics of PEG-trilysine polymer formulations administered to the ear was obtained from pharmacokinetic (PK) and tolerability studies conducted in African green monkeys (Chlorocebus sabaeus).

[0321] Perilymph and plasma concentrations of the PEG-trilysine polymer formulation were assessed after a single IT injection. Perilymph and plasma levels of the test and control products were measured after 1, 10, and 22 days. Given the small study size (N=9 enrolled) and total number of ears treated, PK data are presented only as descriptive statistics.

[0322] Auditory brainstem response thresholds were assessed before and after dosing, and cochleae were collected at necropsy for analysis of cochlear hair cell histology. ABR testing measures whether an animal's cochlea, cochlear nerve, and brainstem respond to each sound stimulus and is often used as a measure of ear health. This same basic test is commonly used in hospitals to test the hearing of newborns and is the standard hearing test used in laboratory animals.

[0323] ABR was performed using a compact audio-electrodiagnostic system for stimulus generation, and neural responses were amplified 100,000 times and band-pass filtered between 300 and 3,000 hertz (Hz) using an additional 60 Hz notch filter. The amplified and filtered signals were averaged over 10 millisecond (ms) epochs with 512 artifact-free averages before plotting on the screen. An initial subjective estimate of threshold was determined at the time of testing. Threshold was defined as the lowest intensity of each stimulus frequency that the subject's brainstem could reliably process.

[0324] In this study, a total of 9 animals received bilateral intratympanic injections of the formulations at follow-up intervals of 1, 10, and 22 days. Of the 18 treated ears, 12 received the PEG-trilysine polymer formulation and 6 received the P407 formulation.

[0325] Table 4B provides a summary of the treatment groups and study procedures. [Table 4B]

[0326] Overall, both formulations were well tolerated, as assessed by electrophysiological audiometry, cochlear histology, and behavioral observations. Baseline ABR thresholds were similar to or better than those seen in other nonhuman primate ABR studies. Shifts in auditory brainstem response thresholds were generally minimal and consistent with increased thresholds in both groups at higher frequencies. Furthermore, hair cell analysis by 6A and immunofluorescence staining demonstrated few missing hair cells, at levels consistent with normal aging and unlikely to be related to treatment.

[0327] No apparent changes in the health and well-being of the subjects were observed during the study. The majority of the PEG-trilysine polymer formulation was retained in the middle ear by Day 10, with residual formulation detected by Day 22. The formulation delivered sustained concentrations of dexamethasone to the perilymph through Day 22 with relatively low systemic exposure.

[0328] The results of this study establish the African green monkey as a model for delivering long-lasting depot formulations of PEG-trilysine polymer to the inner ear using IT injection. Furthermore, this study successfully established the African green monkey model for use in PK and tolerability studies of novel otic therapeutics.

[0329] The absorption and distribution of dexamethasone was also investigated in African green monkeys. Dexamethasone concentrations were assessed in plasma, perilymph, and the cochlea.

[0330] Over time, dexamethasone plasma levels decreased but remained within detectable ranges until day 22, the final time point of the study. Levels appeared to be more sustained in animals treated with the PEG-trilysine polymer formulation, consistent with the observation of delayed gel clearance from the middle ear compared with P407. Figure 6A shows the total amount of dexamethasone observed in plasma. In Figure 6A, the vertical axis is the concentration of dexamethasone (ng / mL). The horizontal axis is time since dosing. Dots represent individual subjects. Open symbols are from subjects receiving the PEG-trilysine polymer formulation, and closed symbols are from subjects receiving the P407 formulation.

[0331] Perilymphatic dexamethasone concentrations remained well above plasma levels throughout the study, consistent with sustained release from the depot formulation. While variability in dexamethasone levels was evident between subjects at each time point (Figures 6B and 6C), an overall gradual decrease in perilymphatic concentrations was observed over the course of the 22-day study. In Figures 6B and 6C, the vertical axis represents dexamethasone concentration (ng / mL). The horizontal axis represents time since dosing. Figure 6B: Dots represent the left ear (L, circle, square, hexagon) and right ear (R, triangle, and diamond) of individual subjects. Open symbols are from subjects administered the PEG-trilysine polymer formulation, while closed symbols are from animals administered the P407 formulation. The arrow symbol represents subject A843, who received the P407 formulation, whose dexamethasone level exceeds the detection level (limit: 9500 ng / mL). Figure 6C: The same data pooled for both ears. Same symbols as in Figure 6B.

[0332] Fluctuations in dexamethasone levels were evident in the cochlea at each time point, and although there was some variability, the concentration over time was consistent with sustained release from the depot formulation, particularly in the PEG-trilysine polymer formulation.

[0333] Sustained exposure of dexamethasone was observed in the targeted perilymphatic compartment, as evidenced by higher dexamethasone levels in the perilymph and cochlea than in plasma, with relatively low systemic exposure.

[0334] Dexamethasone concentrations throughout the cochlear preparations were generally lower than those in the perilymph. Variation in dexamethasone levels between ears was evident at each time point. Despite some variability, group mean concentrations over time were also consistent with sustained release from the depot formulation.

[0335] Example 11: PEG buffer composition for extending gelation time Instead of lowering the pH of the trilysine solution in Example 1 with hydrochloric acid, the gelation time was reduced by changing the composition of the solution used to reconstitute the PEG, i.e., the PEG diluent.

[0336] Materials and Methods Diluents were prepared containing 0.13, 0.14, 0.15, and 0.16 M phosphoric acid (Spectrum Chemical) in water for injection. 2.6 mL of each diluent was added to a PEG ester powder vial and manually stirred until reconstitution was achieved.

[0337] For the gel time stir bar test, 100 microliters of PEG ester solution was combined with 100 microliters of trilysine solution. Additionally, the pH of an equal mixture of fresh diluent and trilysine was measured. To avoid gel formation during pH measurement, the pH was measured without the presence of PEG ester. To measure the pH of the final otic composition, the pH of water (e.g., distilled water or low impedance) can be measured after equilibration with the final otic composition.

[0338] result Increasing the concentration of phosphoric acid in the diluent solution from 0.13 to 0.16 M decreased the pH from 7.44 to 6.78 when mixed in equal amounts with trilysine. As shown in Figure 7, gelation times of 3 to 11 min were achieved by varying the phosphoric acid concentration in the diluent and the pH of the resulting mixture.

[0339] The 1-10 minute gelation time required for intratympanic injection can be achieved by modifying the trilysine or PEG ester solution with components that lower the pH.

[0340] A further embodiment of intratympanic injection is envisioned, which involves reconstituting the PEG ester powder with a single solution containing trilysine and all pH adjusting ingredients.

[0341] Example 12: Effect of PEG functionality on gelation time and gel duration Gel properties such as gel time and gel duration can be affected by changes in functionality, e.g., a decrease from near 4 NHS per multi-arm PEG to near 3 NHS per PEG. PEG functionality can decrease during storage, and in this study, this was tracked by time since expiration.

[0342] Materials and Methods Samples were prepared as in Example 11, except that aliquots of PEG were reconstituted with a scaled-down amount of diluent based on the weight of the PEG aliquot. Kits were tested with expiration dates ranging from 1.1 years to 3.6 years prior to the test date. PEG diluents containing monobasic sodium phosphate (Millipore) and phosphoric acid (Spectrum Chemical) in water for injection were prepared in ratios of 0:100, 50:50, and 100:0. The pH was measured for the diluent alone, the PEG ester reconstituted with the diluent, and an equal volume mixture of the diluent and trilysine.

[0343] Gel time was measured by the stir bar test at room temperature (approximately 20°C) by combining 100 microliters of PEG ester solution with 100 microliters of trilysine solution. Gel duration was assessed by preparing 0.2 mL of otic composition gel in the bottom of a 2 mL glass vial, adding 1 mL of PBS, and storing at 37°C or 50°C. Samples were inspected by periodically inverting the vial and noting when the gel became liquid. Additionally, gel volume was qualitatively assessed as a measure of crosslink density.

[0344] result The 50:50 diluents were tested at strengths ranging from 0.20 to 0.27 M. The pH of these diluents was approximately 2.0, which increased to approximately 2.3 with PEG reconstituted in these diluents and to approximately 6.5 to 7.1 with diluents added to trilysine solution (no PEG).

[0345] Gel times of 3.5-5 minutes at a 0.23M 50:50 dilution were obtained for kits tested up to 1.7 years after the expiration date (see Figure 8). When the diluent strength was increased to 0.25M, gel times increased to approximately 5-6 minutes. The majority of kits tested more than 3 years after the expiration date had gel times of approximately 12-15 minutes due to reduced PEG ester functionality in these older kits.

[0346] A higher amount of swelling was observed in otic compositions prepared from older kits with longer gel times, consistent with reduced functionality and lower crosslink density.

[0347] Otic compositions prepared with a 50:50 diluent had a gel duration of 3-4 weeks for kits containing higher functionality PEG and approximately 1 week for kits containing lower functionality PEG at accelerated conditions of 50°C. Gel duration at 37°C was 2-3 weeks for low PEG functionality compositions. Testing is ongoing and gel duration of otic compositions prepared with higher functionality PEG will exceed 5 weeks.

[0348] Example 13: Effect of solids content on gel time The ability to fine-tune gel time by varying the solids content was investigated by adding water to the gel composition.

[0349] Materials and Methods From lots demonstrating higher functionality, samples were prepared as described in Example 12. PEG aliquots were reconstituted in a diluent containing 50:50 monobasic sodium phosphate (Millipore) and phosphoric acid (Spectrum Chemical) at 0.30 M strength. Otic compositions were prepared by combining equal volumes of trilysine and PEG solutions, and optionally additional water for injection, to increase the final volume by 10% or 20%, thereby reducing the solids content by up to 20%.

[0350] Gel time was measured by the stir bar test at room temperature (approximately 20° C.) by combining 100 microliters of the PEG ester solution with 100 microliters of the trilysine solution and any additional water. The pH of the final gel was measured by equilibrating 1 mL of distilled water with the gel overnight at room temperature and measuring the pH of the equilibrated solution.

[0351] Samples were also prepared in inserts and submerged in PBS at 37°C for gravimetric assessment of swelling.

[0352] result Increasing the diluent strength to 0.30M extended the gel time to 9.5 minutes compared to gel times of 4.6 and 5.6 minutes for the 0.23 and 0.25M diluents in Example 12. Reducing the solids content by 10 and 20% further extended the gel time to 10.7 and 11.8 minutes.

[0353] The pH of these final ear gel compositions ranged from 6.68 to 6.75. After submersion in PBS at 37°C for 2 days, the percent swelling of the gel with the highest solids content was 45%. Reducing the solids content by 20% reduced the percent swelling to 36%.

[0354] Example 14: Reproducibility of gel formation and swelling Three polymer compositions (C1-C3) were prepared and evaluated for gel formation parameters and swelling, as described in Table 5. Percent swelling was determined gravimetrically using an insert containing 0.20 mL of the composition in a bottle containing 200 mL of PBS at 37 °C. Ambient gelation was determined using a rotating stir bar test, where gelation was identified as the sample coating the stir bar (e.g., the stir bar and gel rotating as a unit) or the stir bar ...

Claims

1. A method for preparing a sustained release otic composition, the method comprising the steps of combining (i) a solution or suspension of a functional polymer, the functional polymer comprising a first functional group, the functional polymer being pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; (ii) a solution or suspension of a crosslinker, the crosslinker comprising a second functional group, the crosslinker being trilysine or a salt thereof; and (iii) an active agent to form the sustained release otic composition, wherein the functional polymer is present in an amount of about 5% to about 15% by weight of the sustained release otic composition and the crosslinker is present in the sustained release otic composition in an amount of about 0.05% to about 0.6% by weight of the sustained release otic composition, and wherein a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

2. A method for preparing a sustained-release otic composition, said method comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group, the functional polymer being pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; (b) preparing a solution or suspension of a crosslinker, the crosslinker comprising a second functional group, the crosslinker being trilysine or a salt thereof; (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker to form a sustained release otic composition; whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the otic composition, the crosslinking agent is present in the otic composition in an amount of about 0.05% to about 0.6% by weight of the otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

3. A method for preparing a sustained-release otic composition, said method comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group, the functional polymer being pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; (b) combining the solution or suspension of the functional polymer with a solution or suspension of a crosslinker; wherein the crosslinker comprises a second functional group, the crosslinker being trilysine or a salt thereof, such that the functional polymer is present in an amount of about 5% to about 15% by weight of the otic composition, the crosslinker is present in the otic composition in an amount of about 0.05% to about 0.6% by weight of the otic composition, and a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

4. A method for preparing a sustained-release otic composition, said method comprising: (a) forming a solution or suspension of a functional polymer, the functional polymer comprising a first functional group, the functional polymer being pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; (b) changing the pH of a solution or suspension of a crosslinker, wherein the crosslinker comprises a second functional group, and the crosslinker is trilysine or a salt thereof; (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker; wherein a cross-linking reaction can occur between the first functional group and the second functional group to form a gel; The sustained release otic composition has a pH of 8.4 or less. method.

5. A method for preparing a sustained-release otic composition, said method comprising: (a) preparing a solution or suspension of a crosslinker, the crosslinker comprising a second functional group, the crosslinker being trilysine or a salt thereof; (b) combining said solution or suspension of said crosslinker with a solution or suspension of a functional polymer; the functional polymer comprises a first functional group, the functional polymer being pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, whereby the functional polymer is present in an amount of about 5% to about 15% by weight of the sustained release otic composition, and the crosslinker is present in the sustained release otic composition in an amount of about 0.05% to about 0.6% by weight of the sustained release otic composition; a cross-linking reaction can occur between the first functional group and the second functional group to form a gel; method.

6. A method for preparing a sustained-release otic composition, said method comprising: (a) preparing a solution or suspension of a crosslinker, the crosslinker comprising a second functional group, the crosslinker being trilysine or a salt thereof; (b) changing the pH of a solution or suspension of a functional polymer, wherein the functional polymer comprises a first functional group, and the functional polymer is pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate; (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker; wherein a cross-linking reaction can occur between the first functional group and the second functional group to form a gel; The sustained release otic composition has a pH of 8.4 or less. method.

7. The method of claim 1, wherein the functional polymer is in solid form.

8. The method of claim 1, wherein an active agent is present in the solution, suspension or powder mixture of the functional polymer.

9. The method of claim 8, wherein the active agent is combined with the functional polymer prior to the step of preparing the solution or suspension of the functional polymer.

10. The method of claim 8, wherein the active agent is combined with the solution or suspension of the functional polymer.

11. A method according to any one of claims 1 to 10, wherein the step of combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker comprises combining the solution or suspension of the functional polymer and the solution or suspension of the crosslinker with an activator.

12. The method of claim 1, wherein an activator is present in the solution or suspension of the crosslinker.

13. The method of claim 8, wherein the active agent is provided as a solid.

14. The method of any one of claims 8 to 12, wherein the active agent is provided as a solution or suspension.

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