Gelling solutions for administration of 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 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 may be

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 mean 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 to the inner ear for most therapeutic compounds. Oral, intravenous, and intramuscular routes of administration can be inefficient, may 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 gel time of about 45 seconds to about 60 minutes at a temperature of about 20° C.

[0007] Also provided herein is a polymeric composition comprising: about 5% to about 15% by weight of the polymeric composition of a functional polymer, the functional polymer comprising a first functional group; about 0.2% to about 0.6% by weight of the polymeric 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, the gel, when formed in the middle ear, having a residence time of at least 5 days.

[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 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, and 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, and 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] 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 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 can 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 can have a residence time of at least 5 days when formed in the middle ear. In some embodiments of any of the polymer compositions herein, the gel can 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 can 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 can be elastic. In some embodiments of any of the polymer compositions herein, the gel can be mucoadhesive. In some embodiments of any of the polymer compositions herein, the polymer composition can 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% functional polymer by weight of the polymer composition. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 10% functional polymer by weight of the polymer composition. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 0.3% to about 0.5% crosslinker by weight of the polymer composition. In some embodiments of any of the polymer compositions herein, the polymer composition may comprise about 0.4% to about 0.6% crosslinker by weight of the polymer composition.

[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 can have a residence time of at least 1 week when formed in the middle ear. In some embodiments of any of the polymer compositions herein, the gel can have a residence time of at least 2 weeks when formed in the middle ear. In some embodiments of any of the polymer compositions herein, the gel can have a residence time of at least 1 month when formed in the middle ear. 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 therapeutic agents, prophylactic agents, diagnostic or visualization agents, and combinations thereof. In some embodiments, the therapeutic or prophylactic agent can be selected from the group consisting of proteins, carbohydrates, nucleic acids, small molecules, and combinations thereof. In some embodiments, the protein can be selected from the group consisting of enzymes, growth factors, antibodies or antigen-binding fragments 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 antisense oligonucleotides, aptamers, microRNAs, short interfering RNAs, ribozymes, and combinations thereof. In some embodiments, the small molecule can be 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. In some embodiments, the small molecule can be an inhibitor of Apaf-1.

[0022] In some embodiments, the active agent may be a tyrosine kinase inhibitor. In some embodiments, the active agent may be a VEGF inhibitor. In some embodiments, the VEGF inhibitor may 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 an antigen-binding fragment thereof. In some embodiments, the antibody or an antigen-binding fragment thereof may 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 VEGFR. In some embodiments, the allosteric modulator can be cyclotraxin B. In some embodiments, the VEGF inhibitor can be at least 10 times more selective for VEGFR2 than another VEGFR. In some embodiments, the VEGF inhibitor can be at least 20 times more selective for VEGFR2 than another VEGFR. In some embodiments, the VEGF inhibitor can be at least 50 times more selective for VEGFR2 than another VEGFR.

[0023] In some embodiments, the tyrosine kinase inhibitor or VEGF inhibitor can be present in an amount sufficient to reduce swelling and lymphatic dysfunction of 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, hi some embodiments, the diagnostic or visualization agent may be selected from the group consisting of dyes, fluorophores, MRI contrast agents, 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, 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, where the functional polymer comprises a first functional group, a solution or suspension of a crosslinker, where 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) making a solution or suspension of a functional polymer, the functional polymer comprising a first functional group; (b) making a solution or suspension of a crosslinker, the crosslinker comprising 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) making a solution or suspension of a functional polymer, where 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, where 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) making a solution or suspension of a functional polymer, where the functional polymer comprises a first functional group; (b) altering the pH of a solution or suspension of a crosslinker, where 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, where a crosslinking reaction can occur between the first functional group and the second functional group to form a gel.

[0034] Further provided herein is a method of preparing a sustained release otic composition comprising: (a) forming a solution or suspension of a crosslinker, where 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, where 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 of preparing a sustained release otic composition, comprising: (a) making a solution or suspension of a crosslinker, where the crosslinker comprises a second functional group; (b) altering the pH of a solution or suspension of a functional polymer, where 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, where 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 the solution or suspension of the functional polymer. In some embodiments of any of the preparation methods provided herein, the active agent can be combined with the functional polymer prior to making the solution or suspension of the functional 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 functional polymer. In some embodiments of any of the preparation methods provided herein, 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, 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 is a method 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] Further provided herein is a method of treating an otic disease or disorder in a subject, comprising: (i) identifying the subject as having an otic disease or disorder; (ii) preparing an otic sustained release composition by any one or more of the methods described herein; and (iii) administering a therapeutically effective amount of the otic sustained release 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 may 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 from autoimmune disorders, cilia damage from infection, cilia damage from 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 may be sudden sensorineural hearing loss. In some embodiments of any of the methods of treatment provided herein, the sensorineural hearing loss may 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] Further provided herein is a method 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 is a method of treating Meniere's disease in a subject, comprising: (i) identifying the subject as having Meniere's disease; (ii) preparing an 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.

[0046] In any one or more of the methods of treatment provided herein, the administering occurs 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 occurs 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 can include 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 can include 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 can include injecting through the tympanic membrane.

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

[0048] In some embodiments, the ear disease or disorder may 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 from autoimmune disorders, cilia damage from infection, cilia damage from excess fluid or pressure, chemotherapy-induced hearing loss, and combinations thereof. In some embodiments, the sensorineural hearing loss may be sudden sensorineural hearing loss. In some embodiments, the sensorineural hearing loss may 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 a therapeutically effective amount of a tyrosine kinase inhibitor to the subject.

[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, revastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, vandetanib, and combinations thereof. In some embodiments, the VEGF inhibitor comprises an antibody or an 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 of 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 those skilled in the art to which the present invention pertains. The present invention can be carried out using methods and materials similar or equivalent to those described herein, but 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, shall control. In addition, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0053] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will become apparent from the description and drawings, and from the claims. In the claims, the word "comprising" 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 the preceding claims, wherein the polymer composition has a viscosity of about 1 mPa·s to about 1000 mPa·s. (Item 10) 10. The polymer composition according to any one of the preceding claims, 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 the preceding claims, 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 gel 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 the preceding claims, 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 according to any one of items 1 to 16, wherein the first functional group comprises a succinimidyl ester. (Item 18) 18. The polymer composition according to any one of the preceding claims, 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 according to 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 according to any one of items 23 to 25, wherein the active agent is a tyrosine kinase inhibitor. (Item 27) 27. The sustained release otic composition according to any one of items 23 to 26, wherein the active agent comprises a glucocorticoid. (Item 28) 28. The sustained release auris composition of claim 27, wherein the active agent comprises dexamethasone. (Item 29) 29. The sustained release auris 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% FD&C Blue #1, 32. The sustained release ear composition according to 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% FD&C Blue #1, 32. The sustained release auris composition of claim 30 or 31, further comprising about 0.002% by weight of butylated hydroxytoluene. (Item 34) A gel formed by 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; Administering a therapeutically effective amount of the sustained release ear 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 a sustained release ear composition according to any one of items 23 to 33 to the ear of the subject. (Item 38) 38. The method according to 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 ear composition according to 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 to the affected ear of the subject a therapeutically effective amount of a sustained release ear composition according to any one of items 80 to 124. (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 such that it contacts the round window membrane. [Brief description of the drawings]

[0054] [Figure 1A] This is the structure of pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. [Figure 1B] This is the structure of trilysine. [Figure 2A]FIG. 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] FIG. 1 is a graph of cumulative drug release (μg) for pH adjusted PEG-trilysine polymer samples (n=3) containing 6% (triangles), 3% (diamonds), or 1% (squares) dexamethasone. [Diagram 3] FIG. 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] FIG. 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 pot life of 67 min (circles), 26 min (squares), or 16 min (triangles). [Figure 5A] FIG. 1 is a graph of drug release (μg) over time (days) of 6 wt % dexamethasone gels 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]Graph of dexamethasone concentration in perilymph versus time in an in vivo study. The dots are 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 administered the P407 formulation, whose dexamethasone level is above the detection level (limit: 9500 ng / mL). [Figure 6C] The same data as in Figure 6B are plotted for both left and right ears together. [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 (min) versus years from expiration date for PEG-trilysine kits for otic compositions prepared with a 50:50 dilution of 0.23M (circles) and a 50:50 dilution of 0.25M (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 PREFERRED EMBODIMENTS

[0055] Potential side effects of systemic therapy and complications from long-term high-dose therapy can be avoided by locally applied therapy. Inner ear therapeutic agents (e.g., drugs formulated as a biocompatible gel) 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 varies in efficacy due to anatomical variations such as the presence of a pseudomembrane covering the round window membrane, the failure of the injected formulation to contact 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 also undesirable for the subject and is associated with a cumulative risk of infection, inflammation, and long-term damage to the tympanic membrane, in addition to the risk of poor compliance.

[0056] Local delivery of therapeutic agents to the inner ear usually results in higher concentrations in the inner ear fluid than with systemic application. Locally applied substances (e.g., at lower doses than those used for systemic administration) can be administered in cases where 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 treatments include sensory hair cells, afferent nerve fibers, and supporting cells of 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 are also clinical reports of the topical application of gentamicin for the treatment of Meniere's disease. Gentamicin is toxic to the sensory cells of the balance system, and by partially ablating the vestibular system, it suppresses vertigo in some subjects.Other substances that have been 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 sustained treatment of inner ear disorders.

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

[0059] Current treatments for MD are primarily focused on reducing the frequency and severity of vertigo attacks, reducing tinnitus and ear fullness, and preserving or improving hearing and quality of life. A variety of treatments are prescribed, including low-salt diets, 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 autoimmune inner ear diseases and other hearing disorders such as sudden sensorineural hearing loss (SNHL) in combination 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 increase labyrinthine circulation and improve inner ear function through ion or water transport mechanisms that affect cochlear fluid homeostasis. The corticosteroid dexamethasone has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines, reducing edema, fibrin deposition, capillary leakage, and migration of inflammatory cells.

[0061] Direct drug injection into the middle ear for managing symptoms 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 that are 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 benefit has been reported in both patient groups, 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 unresponsive 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 does more good than harm.

[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 have a significant impact on quality of life. Meniere's disease typically presents as unilateral (affecting only one ear) with no difference in the ratio of right to left ear, but eventually affects the contralateral ear in 25-40% of cases (bilateral MD). Bilateral MD is associated with increased vestibular symptoms and increased 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. As a result, children are rarely affected (Espinosa-Sanchez JM and JA Lopez-Escamez.Meniere's 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 the treatment of MD. The natural history of MD is typically a long-term progressive decline in hearing and vestibular function, as well as fluctuations in hearing and vestibular vision accompanied by periodic attacks of severe vertigo (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 well 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 noted 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) (edema), 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 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. (2007). The HLA-DRB1*1101 allele may be associated with bilateral Meniere's disease in southern European populations.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 migration of inflammatory cells. In addition to their anti-inflammatory and immunosuppressive effects in the cochlea, the mechanism of action of corticosteroids in MD also indicates that they increase labyrinthine circulation and improve inner ear function through ion or water transport mechanisms that 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 managing symptoms 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 results in significantly higher levels of steroids in the inner ear compared to systemic administration, and furthermore, avoids many of the adverse effects associated with systemic administration, such as osteoporosis, diabetes mellitus, hypertension, peptic ulcers, cataracts, and endocrine disorders (Espinosa-Sanchez, 2016).

[0076] From a historical perspective, the clinical use of corticosteroids by 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) used them to treat patients with MD and tinnitus. Clinical benefits were reported in both patient groups, and there were no adverse effects to the 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 hydrodynamics is restored (Shea et al., 1996). Following 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 Steroid 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 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 corticosteroids 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 recovery (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 intrathympanic 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 for associated symptoms of tinnitus and ear fullness, with one randomized controlled trial comparing IT 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) with the 3 mg and 12 mg doses compared to placebo (42%), as well as a 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 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 and no difference in tinnitus perception (Basura et al., 2020; Lambert et al., 2016). A statistically significant reduction in the mean number of daily dizziness attacks and number of dizziness days per month was observed (Basura et al., 2020; Lambert et al., 2016). Overall, IT steroid therapy is well tolerated and associated 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 efficacy of intrathecal steroid therapy has been difficult to assess due to the variability of treatment protocols. The number of doses, the interval between doses, the follow-up period, and the effect on the control of dizziness, tinnitus, and ear fullness vary considerably (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 has been shown to be 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.Intratympanic treatment of intractable unilateral Meniere disease:gentamicin or dexamethasone?A 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 risk of significant 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), and patients with usable hearing may be hesitant to undergo ablative cochlear therapies such as IT gentamicin, which are known to cause hearing loss. Thus, patient preference has 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 offering 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 evaluating 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 dexamethasone (n=93) was 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 Phase 3, which is currently ongoing. (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 examinations, vital signs, or electrocardiograms (ECGs) (Lambert et al., 2012).

[0086] In this study, most patients experienced at least one treatment-emergent adverse event (TEAE). The only prespecified 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 the phase 2b study, 77 patients received a single IT injection of 12 mg dexamethasone and 77 patients received 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, hearing testing, tympanometry, vital signs, clinical laboratory assessments, word recognition, and Columbia-Suicide Rating Scale (C-SSRS)) support continued evaluation of IT injections of corticosteroids, as they were well tolerated and no new risks were identified.At the end of the study, permanent TM perforation was observed in two patients treated with dexamethasone, which is 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 hallmark 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 IV 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 asymptomatic EH in the contralateral ear to be identified. 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 contrast cochlear MRI in the diagnosis of MD to find correlation between the degree of EH and hearing tests. The results demonstrate adequate correlation with auditory-vestibular function tests indicating the usefulness of IV-Gd cochlear MRI as a diagnostic method to visualize 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 with suspected 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 patients with VAIEP not caused by 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 suspected MD ears compared to 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 to 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 extensive VAIEPs, indicating that the combination of EH and increased PE is not common in patients with other VAIEPs. These findings may be useful in the differentiation of patients with dizziness due to MD (van Steekelenburg et al., 2020).

[0093] Off-label IT steroid injections are often administered to patients with MD. However, therapeutic benefit is limited, at least in part, by rapid clearance of solution formulations from the middle ear, uncertainty of drug formulation placement within the middle ear because the injections are "blind," and the presence of membrane barriers and air pockets in the middle ear. Current MD treatment guidelines (Basura, 2020) suggest administering a compounded dexamethasone sodium phosphate or methylprednisolone sodium succinate solution every 3-7 days for 3-4 sessions. Suspension gel formulations of dexamethasone have shown promise in improving vertigo 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 after 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 ears.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 time of these formulations can result in inconsistent drug distribution and release, leading to poor pharmacokinetics.

[0095] It is therefore an objective to provide a beneficial formulation that can be administered for sustained intratympanic delivery of a therapeutic, prophylactic or diagnostic agent to the inner ear over a period of 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 that is 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 the plot of active agent concentration in plasma versus time. In practice, the concentration of the active agent 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 the exposure of a subject to the active agent over time.

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

[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 limit of the calibration curve.

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

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

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

[0104] The abbreviation "DDI" stands for drug-drug interaction.

[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 are suitable for crosslinking with 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 group 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 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 that, when present at the site of action, is 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 disease state and its severity, the identity of the patient requiring treatment (e.g., age and / or weight), and the like, 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 that 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. 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, the identity of the patient in need of treatment (e.g., age and / or weight), and the like, 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 dosage of an active agent 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 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 term "enhance" or "enhancing" may refer to an increase in efficacy or a prolongation of a desired effect. In some cases, "enhance" or "enhancing" may 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" may refer to the ability of an anti-inflammatory agent to increase the efficacy or extend the duration of the effect of the active agent. As used herein, an "enhancing-effective amount" refers to an amount of an agent sufficient to enhance the effect of an active agent in a desired system. The amount of an agent that would correspond to such an amount will vary depending on factors such as the particular active agent, the condition and its severity, the identity of the patient requiring treatment (e.g., age and / or weight), and the like, 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 flow under gravity, for example, by performing a gelation reaction in a vial and then inverting the vial. In some assessments, visual inspection can determine if there is still flow of the composition. 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 having an elastic modulus. In some embodiments, the formation of a gel 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 cohesion, for example, by drop weight or compressive force (see Edsman, Katarina LM, et al. "Is there a method that can measure cohesivity? 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 gelling a liquid composition.

[0113] The term "gel duration" refers to the time until a gel breaks down, dissolves, or goes back into 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 the 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 the vessel 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 nonclinical laboratory research.

[0116] The term "hERG" may 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 that contain this subunit are also called hERG.

[0117] "I C 50 " 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 a 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 efficacy.

[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 things relating to the ear. For example, an otic composition can be a composition that is 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 components of a formulation and / or with a 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 be a salt that alters 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 both the first active agent or its pharmaceutically acceptable salt or solvate and at least one additional active agent are administered to a patient simultaneously in the form of a single composition or dose. The term "non-fixed combination" means that the first active agent or its pharmaceutically acceptable salt or solvate and at least one additional active agent are formulated as separate compositions or doses so that they 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 administration providing effective levels of the two or more compounds in the subject's body. In one embodiment, the first active agent and the second active agent are formulated as separate unit dosage forms, which are suitable for either sequential or simultaneous administration. These also apply to cocktail therapy, e.g., 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., a succinimidyl ester functionalized PEG) that can form crosslinks with a nucleophile, refers to the time after the moiety goes into solution or suspension (e.g., from a powder or solid).

[0128] The term "VEGF inhibitor" includes any agent (e.g., a small molecule, an antibody, or an 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 to (i) prevent a disease or disorder, or (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, when administered to a site of action in a patient in need of such treatment, 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 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, when administered to a patient in need of such treatment. 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, e.g., a prophylactically effective amount of an active agent can be an amount effective to prevent or reduce ototoxicity. For example, an apoptosis inhibitor 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" may refer to the time that a formulation remains at the administration site. In some embodiments, the dwell time may be the time that there is no gel visualized on the round window membrane area, for example, the time after the gel is collected at a certain time 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] "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 cleared within a single dosing interval, resulting in a plateau or constant level of drug exposure in the target structures.

[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, the 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 a bolus-type administration in which 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 about 20-60 minutes, immersing in PBS (PBS volume at least 5 times the volume of the gel) (e.g., pH 7.4), storing at 37°C, removing the gel-filled insert after 1-3 days, recording the weight after wiping off the surface fluid, and then calculating the increase in gel weight normalized by the initial gel weight.

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

[0142] The terms "transtympanic" or "intral tympanic" administration refer to administration of an active agent through the tympanic cavity, optionally through a hypodermic needle that accesses the tympanic cavity (middle ear) by penetrating the tympanic membrane (eardrum).

[0143] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, reduction in the extent of disease, stable (i.e., not worsening) state of disease, delay or slowing of progression of disease, improvement or alleviation of the condition (e.g., one or more symptoms of a 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 as described herein) calculated to produce the 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. Auricular (sometimes referred to as otic) compositions are developed to sustain the release of therapeutic, prophylactic and / or diagnostic agents in the ear, either continuously or pulsatile, 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 the ear fluid (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. The sustained release compositions can, in some cases, increase the C in the ear fluid (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. max can 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 the otic agent to the concentration of the otic agent may be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. min 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 and / or the drug concentration is C min In some embodiments, the sustained release ear composition extends the residence time of the drug in the inner ear.

[0147] In some cases, the sustained release otic composition is provided in the form of a gel, so that sustained delivery to the middle and / or inner ear can be achieved. In some such embodiments, the gel can remain intact for an extended period of time in a preferred location, such as the round window membrane. In some embodiments, the sustained release otic composition in the form of a gel can extend the residence time by at least about 2-fold, 4-fold, 10-fold, or 20-fold, and thus the AUC by about 2-fold, 4-fold, 10-fold, or 20-fold, 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 the 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, Prophylactic and Diagnostic Agents In some embodiments, the sustained release otic composition is 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 an antigen-binding fragment thereof), a carbohydrate (e.g., a glycosaminoglycan), a nucleic acid (e.g., an antisense oligonucleotide, an aptamer, a microRNA, a small interfering RNA, or a ribozyme), a small molecule, or a combination thereof. In some embodiments, the small molecule can include antibiotics, anti-tumor agents (e.g., doxorubicin), local anesthetics, steroids, hormones, apoptosis inhibitors (e.g., inhibitors of Apaf-1, see, e.g., U.S. Pat. No. 9,040,701, incorporated herein by reference in its entirety), angiogenic agents, anti-angiogenic agents (e.g., VEGF inhibitors), neurotransmitters, psychotropic agents, anti-inflammatory agents, and combinations thereof. In some embodiments, the active agent can include an anti-angiogenic agent. In some embodiments, the active agent can include an anti-angiogenic agent and a steroid. In some embodiments, the active agent includes dexamethasone. In some embodiments, the active agent is dexamethasone.

[0152] In some embodiments, the diagnostic or visualization agent may include dyes, fluorophores, MRI contrast agents (e.g., agents containing gadolinium), or other agents 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% by weight, about 0% to about 0.05% by weight, about 0% to about 0.1% by weight, about 0% to about 0.2% by weight, about 0.02% to about 0.5% by weight, about 0.05% to about 0.5% by weight, about 0.1% to about 0.5% by weight, 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% by weight, about 0.005% to about 0.0015% by weight, about 0.009% by weight, 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 may be in substantially microparticle or nanoparticle form. Without being bound to a particular theory, it is believed that in some cases, the microparticle form may aid in the controlled release of the active agent from the sustained release otic compositions described herein. In some cases, the nanoparticle form may increase the dissolution rate and deliver the active agent at a higher controlled release rate from the microparticle. In some embodiments, the microparticle may 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 an 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 an 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 may be a VEGFR kinase inhibitor such as agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, revastinib, 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 may be an allosteric regulator of VEGFR (e.g., cyclotraxin B).

[0155] In some embodiments, the VEGF inhibitor may be selective for VEGFR2 over other VEGFRs. In some embodiments, the VEGF inhibitor may exhibit at least 10-fold selectivity for VEGFR2 over another VEGFR. For example, the 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, the selectivity of VEGFR2 over another VEGFR is measured by an enzyme assay. In some embodiments, the additional VEGFR may 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, such as 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, which is incorporated herein by reference in its entirety. Both VEGF and VEGFR have variant isoforms and / or can be processed to mature forms compared to the sequences shown herein. In particular, VEGF-A has several isoforms in humans. VEGFRs can usually be spliced ​​as soluble or membrane-bound forms. In some accounts, VEGFRs are grouped together 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 Polymer compositions are also provided herein. Typically, the polymer compositions described herein include a functional polymer, a crosslinker, and water. In some embodiments, the polymer compositions described herein are injectable into the middle ear and / or inner ear, where the functional 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 by altering the pH, exposure to ions, and / or exposure to photocrosslinkers when mixing and injecting the polymer composition.

[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 placing a 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 metabolism of the subject. In some embodiments, a gel formed from the polymer compositions 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, the polymer composition can be characterized by its ability to crosslink and form a shape-conforming gel (e.g., a hydrogel), e.g., in situ. In some embodiments, a gel (e.g., 200 μL of gel) formed from the 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 if 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 to any particular theory, it is believed that elastic gels have a longer residence time at the site of administration than viscoelastic gels that 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 transition in viscosity, 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 the form of a solution or suspension and can flow by gravity throughout the middle ear or to one or more sites within the middle ear and 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 polymeric composition can be characterized by its ability to crosslink and form a gel (e.g., a hydrogel), for example, in situ, with a gelation time suitable for administration to a site (e.g., the middle ear and / or inner ear). Some polymeric compositions, such as DURASEAL®, can form a gel in 3 seconds or less, which may not be desirable 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 composition 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 composition 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, 30 minutes, about 3 minutes to about 30 minutes, about 4 minutes to about 30 minutes, about 5 minutes to about 30 minutes, about 8 minutes to about 30 minutes, about 10 minutes to about 30 minutes, about 15 minutes to about 30 minutes, about 20 minutes to about 30 minutes, about 30 seconds to about 3 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 8 minutes, about 3 minutes to about 8 minutes, about 2 minutes to about 6 minutes, about 4 minutes to about 6 minutes, about 3 minutes to about 5 minutes, or about 1 minute to about 4 minutes). In some embodiments, the polymer compositions described herein can 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 any particular theory, it is believed that the gelation time of a polymeric composition or sustained release otic composition may affect its usefulness in a clinical setting, as a rapidly gelling composition may reduce the time that the composition can be administered to the ear of a subject (e.g., by transtympanic injection). In some embodiments, the polymeric compositions or sustained release otic compositions provided herein are injectable through a 27 gauge (or larger diameter) needle for at least 10 minutes after the functional polymer and crosslinker are combined. In some embodiments, the polymeric 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 the functional polymer and crosslinker are combined.

[0168] The rate of the crosslinking reaction can be influenced by the selection of the properties of the polymer composition. For example, the pH, amount of crosslinker and functionalized polymer, and the selection of the buffer can affect the gelation time. Mixing the components with cooling slows the crosslinking reaction, allowing time for injection. In some cases, the polymer composition or sustained release otic composition can produce 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 bonds can be controlled to allow for control of the release rate over hours to weeks or longer. By using composites made from linkages 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 polymeric compositions or sustained release otic compositions described herein can exhibit less than about 150% swelling (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 polymeric 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 polymeric composition or sustained release otic composition described herein can exhibit, for example, a swelling of about 40% to about 80% (e.g., about 50% to about 70%) when incubated in excess phosphate buffered saline (PBS) at 37° C. after 7 days. In some embodiments, a gel formed from a polymeric 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, the 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 accomplished, 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 mucosal adhesion 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 the polymer compositions described herein, such compositions are referred to as sustained release otic compositions.

[0172] The active agent can be present in the polymer composition described herein in any suitable amount or concentration. 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 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 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 15% by weight, from about 0.01% to about 16% by weight, from about 0.01% to about 18% by weight, from about 0.01% to about 20% by weight, from about 0.01% to about 22% by weight, from about 0.01% to about 26% by weight, from about 0.01% to about 28% by weight, from about 0.01% to about 30 ... % to about 15% by weight, about 0.01% to about 20% by weight, about 0.01% to about 20% by weight, about 0.01% to about 40% by weight, about 0.1% to about 40% by weight, about 1% to about 40% by weight, about 2% to about 40% by weight, about 3% to about 40% by weight, about 5% to about 40% by weight, about 8% to about 40% by weight, about 10% to about 40% by weight, or about 12% to about 40% by weight. 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% by weight, about 3% to about 8% by weight, 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, 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 preferred feature of drug suspension compositions is the ability to administer a uniform dose. This is easily achieved with compositions that do not form dense precipitates during storage and can be easily redispersed by manually agitating the container. In some embodiments, the sustained release otic composition can contain particles of active agent that are easily dispersed by manual agitation and have low viscosity for ease of injection. This can be achieved in some cases by adding a flocculating agent that promotes aggregation of drug particles into loose aggregates. Flocculation efficiency can be defined as the ratio of the final deposit volume (e.g., as a percentage of the total volume) to the particle concentration. The final deposit 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 functional polymers and / or crosslinkers 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 agglomerating agent. Other amphiphilic crosslinkers, such as tetralysine, can also be used for the dual purpose of crosslinking and agglomerating 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. When the components of the sustained release otic composition are combined, 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 that contains 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] In general, the functional polymers and crosslinkers 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 an 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 may be multifunctional, meaning that the functional polymer or crosslinker contains two or more functional groups. In some embodiments, a multifunctional functional 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 may contain at least three (e.g., at least four, at least five, or more) functional groups, so 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 generating 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 the end of each branch being functionalized with a first functional group. In some embodiments, the functional polymer can include a first type of monomer, and 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, and 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 a 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 a 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 a nucleophilic functional group such as an amine (e.g., a primary amine), the functional polymer may in some cases only have an electrophilic functional group such as N-hydroxysuccinimide. For example, if the crosslinker has an electrophilic functional group such as a sulfosuccinimide, the functional polymer may in some cases have a nucleophilic functional group such as an amine (e.g., a primary amine).

[0185] The functional polymer can be present in any suitable concentration in the polymer composition described herein. In some embodiments, the functional polymer can be present in a concentration of about 5% to about 15% by weight of the polymer composition (e.g., about 5% to about 7% by weight, about 5% to about 9% by weight, about 5% to about 11% by weight, about 5% to about 13% by weight, about 7% to about 15% by weight, about 9% to about 15% by weight, about 11% to about 15% by weight, about 13% to about 15% by weight, about 7% to about 13% by weight, about 8% to about 11% by weight, about 6% to about 12% by weight, or about 7% to about 10% by weight). In some embodiments, the functional polymer can be present in a concentration of about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, 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 polymeric compositions described herein. In some embodiments, the crosslinking agent can be present in a concentration of about 0.2% to about 0.6% by weight of the polymeric 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 in a concentration of about 0.05% to about 0.6% by weight of the polymeric 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 crosslinker 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 in a concentration of about 0.05% to about 10% by weight of the polymer composition (e.g., about 0.05% to about 0.5% by weight, about 0.05% to about 1% by weight, about 0.05% to about 2% by weight, about 0.05% to about 3% by weight, about 0.05% to about 5% by weight, about 0.05% to about 7% by weight, about 0.05% to about 9% by weight, about 0.5% to about 10% by weight, about 1% to about 10% by weight, about 2% to about 10% by weight, about 3% to about 10% by weight, about 5% to about 10% by weight, about 7% to about 10% by weight, about 9% to about 10% by weight, or about 0.5% to about 2% by weight). In some embodiments, a crosslinker can be present in the 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 free base). As an illustrative example, when the crosslinker is trilysine acetate, the weight percentage of the 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 about 1.2 equivalents of the first functional group:0.8 equivalents of the second functional group to about 0.8 equivalents of the first functional group: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 about 1 equivalent of the first functional group:0.9 equivalents of the second functional group to about 0.9 equivalents of the first functional group: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 may be a modified polyethylene glycol (PEG) polymer. Exemplary modified PEG polymers include linear, branched, or multi-armed water-soluble polymers that contain multiple polyethylene glycol units and two or more examples of functional groups (e.g., as part of a monomer or as an end cap) (e.g., succinimidyl ester (e.g., N-hydroxysuccinimide ester (NHS)), sulfo-succinimidyl ester, epoxide, or similar reactive group). Multi-arm functional polymers may include a water-soluble core, such as a sugar (xylitol, erythritol), glycerol, or trimethylolpropane. Optionally, the water-soluble core may be extended by at least one biodegradable bond between each end group, which may optionally be a functional group. The biodegradable bond may optionally be a single bond, or a copolymer or homopolymer of an absorbent polymer, such as a polyhydroxy acid or polylactone.

[0190] In some embodiments, the functional polymer may include an enzymatically and / or hydrolytically cleavable linkage. For example, a molecule that is cleaved by an enzyme, such as collagenase, may be synthesized and inserted into the polymer using methods known to those skilled in the art of peptide synthesis. In some embodiments, carboxyl-terminated, amine-terminated or hydroxyl-terminated polyethylene glycol may be used as a starting material to construct a peptide sequence suitable for enzymatic cleavage, and the termini of the peptide sequence are converted to carboxylic acids by reacting succinic anhydride with the appropriate amino acid. The resulting acid groups may 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 non-ionic groups such as polyethylene oxide on the succinimide rings, improve water solubility, and NHS esters provide chemical reactivity towards 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) that includes multiple (e.g., two or more) succinimidyl functional groups (e.g., succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl gluramide, succinimidyl carbonate, or succinimidyl carboxymethyl ester) or sulfo-succinimidyl ester functional groups, and the crosslinker includes multiple amine (e.g., primary amine) functional groups. In some embodiments, the functional polymer is a 4-arm PEG with a pentaerythritol core. In some embodiments, the functional polymer is an 8-arm PEG with a hexaglycerol core. In some embodiments, the functional polymer is an 8-arm PEG with a tripentaerythritol core. In some embodiments, the multi-arm PEG can have two or more arms that terminate in a succinimidyl functional group. In some embodiments, one or more monomers of the multi-arm PEG can include 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 ). The 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 that terminate in an amine (e.g., primary amine) functional group. 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 crosslinking reaction can occur under physiological conditions. In some embodiments, the crosslinking 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 crosslinking 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 gelation 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 the 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 prior to or during administration, but the polymer composition does not gel significantly before flowing to 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. The benchmark product DURASEAL®, which is commercially available 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 about 10, and crosslinking typically occurs rapidly, with the product being able to form a gel in 3 seconds or less (see, e.g., Example 1). As described herein, by 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), longer gelation times, such as those described above in the present specification, can be achieved. 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 the appropriate addition of 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). 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, hi some such embodiments, the polymer composition may be prepared as a chilled composition and / or from one or more chilled components.

[0201] The crosslink density of the gel can be influenced by the overall molecular weight of the crosslinker and functional polymer, as well as the number of available functional groups per molecule. A functional polymer with a low molecular weight, such as about 600 Da, typically results in a higher crosslink density compared to a higher molecular weight, such as 10,000 Da. Crosslink density can also be influenced by the overall percent solids of the crosslinker and functional polymer solution. Increasing the percent solids increases the likelihood that an electrophilic group will combine with a nucleophilic group before hydrolytic inactivation. Yet another way to influence crosslink density is to adjust 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 modifiers.

[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 "thickening agent" refer to materials that enhance the dispersion of particulate matter in a solution or modify 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 K200, HPMC K25 ... Examples of thickeners include modified celluloses such as modified celluloses such as modified celluloses 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%, about 10%, or about 15% of the total weight of the 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, sodium docusate, 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® may also function as solubilizers. In some embodiments, when these solubilizers are at concentrations above their critical micelle concentration (CMC) or their solubility (e.g., bile salts), a sustained reservoir of solubilizer can be obtained. In some embodiments, the solubilizer comprises propylene glycol, PEG 300, 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 bound to the polymer by 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 called 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% by weight). In some embodiments, the concentration of poloxamer does not contribute to gel formation or cause high viscosity. In some embodiments, the polymer composition or sustained release otic composition described herein does not include a poloxamer.

[0208] In some cases, the active agent may exist in metastable solid forms such as amorphous particles, polymorphs, or salt forms where 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 crystallization of the drug.

[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 the sustained release otic composition or polymeric composition to avoid phase changes, or that improve the compatibility of excipients with containers or delivery systems, including syringes or vials, that improve the stability of the composition.

[0210] To achieve a certain isotonicity, in some embodiments, an isotonicity agent can be included. In general, endolymph has a higher osmolarity than perilymph. For example, the osmolarity of endolymph is about 304 mOsm / kg H2O, while the osmolarity of perilymph is about 294 mOsm / kg H2O.

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

[0212] Osmolarity / osmolality can be adjusted, for example, by use of appropriate salt concentrations (e.g., potassium salt concentrations) or by use of isotonicity agents, which render the composition endolymph- and / or perilymph-compatible (e.g., a gel is isotonic with the endolymph and / or perilymph). In some cases, endolymph- and / or perilymph-compatible sustained release otic compositions or polymer compositions can minimize damage 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 forms, the gel formed by the sustained release otic composition or polymer composition may be isotonic with the perilymph. An isotonic composition may be formed by including an isotonicity agent in the sustained release otic composition or polymer composition in some cases. Suitable isotonicity agents include, but are not limited to, any pharma- ceutically 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 may be optionally used to adjust isotonicity as needed. Representative salts include those with 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 may be collectively referred to as "sodium phosphate." In some cases, for example when borate is also used, phosphoric acid may be used to further modify the pH. In some embodiments, the tonicity agent may be sodium chloride.

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

[0215] The sustained release otic composition or polymeric composition may, in some embodiments, include one or more pH adjusting or buffering agents. Non-limiting examples of pH adjusting or buffering agents include acetate, bicarbonate, ammonium chloride, citrate, phosphate, borate, pharma- ceutically acceptable salts thereof, and combinations or mixtures thereof. Non-limiting examples of water-soluble buffering agents are alkali or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates, etc., such as sodium phosphate, citrates, borates, acetates, bicarbonates, carbonates, and HEPES. In some embodiments, tromethamine (TRIS) is not used in polymeric compositions or sustained release otic compositions in which the primary amine is a 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 polymeric 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 polymeric 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 polymer 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% 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 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 forms, the composition includes a mucoadhesive. In some cases, the mucoadhesive facilitates attachment to a portion 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 alginic acid 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., which is 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] The sustained release otic composition or polymeric composition may, in some embodiments, 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 decyl methyl sulfoxide), and alcohols (such as ethanol, isopropanol, glycerol, propanediol, etc.). 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, and thus 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 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 polymeric composition or sustained release otic composition can be administered using any suitable method.

[0224] Also provided herein are methods of preparing the polymer composition or sustained release otic composition. In some embodiments, the polymer composition or sustained release otic composition can be prepared by combining a solution or suspension of the functional polymer with a solution or suspension of the crosslinker. In some embodiments, the solution or suspension of the functional 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 composition or sustained release otic composition can be prepared by combining a solution or suspension of the functional polymer with a solution or suspension of the crosslinker such that the combination has a pH of about 5.5 to about 8.5.

[0225] In some embodiments, the functional 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) making a solution or suspension of the functional polymer, (b) making a solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functional 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) making a solution or suspension of the functional polymer, and (b) combining the solution or suspension of the functional 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) making a solution or suspension of the functional polymer, (b) altering the pH of the solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. In some embodiments, preparing the functional polymer or crosslinker solution or suspension can include adjusting the pH of the solution or suspension. In some embodiments, adjusting the pH of the functional 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 functional 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 functional 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) making a solution or suspension of the crosslinker, and (b) combining the solution or suspension of the functional 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 the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. In some embodiments, the polymer composition or sustained release otic composition can be prepared by (a) making a solution or suspension of the crosslinker, (b) changing the pH of the solution or suspension of the functional polymer, and (c) combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker. In some embodiments, making the solution or suspension of the functional 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 functional 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 functional 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 functional polymer, in the solution or suspension of the crosslinker, provided in a separate solution or suspension, provided as a separate solid (e.g., dry powder), provided as a solid (e.g., dry powder) and combined with the functional polymer (e.g., prior to forming a solution or suspension of the functional polymer), provided as a solid (e.g., 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., dry powder), combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker can further include combining a solution, suspension, or solid form (e.g., 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 the polymeric composition or sustained release otic composition. In some embodiments, the polymeric composition or sustained release otic composition can be administered by (i) preparing the polymeric composition or sustained release composition, e.g., by any of the methods described herein, and (ii) administering the polymeric 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 functional 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 functional 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 is performed during administration, for example, when using a dual syringe device that includes separate reservoirs of the functional 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) making a solution or suspension of the functional polymer, (b) making a solution or suspension of the crosslinker, and (c) combining the solution or suspension of the functional 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) making a solution or suspension of the functional polymer, and (b) combining the solution or suspension of the functional 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) making a solution or suspension of a functionalized polymer, (b) altering the pH of a solution or suspension of a 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) making 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 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) making 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 a solution or suspension of the crosslinker, and (ii) administering the polymer composition or sustained release otic composition to a subject.

[0234] In some embodiments of administering the polymer composition or sustained release otic composition, the active agent can be included in the solution or suspension of the functional polymer, in the solution or suspension of the crosslinker, provided in a separate solution or suspension, provided as a separate solid (e.g., dry powder), provided as a solid (e.g., dry powder) and combined with the functional polymer (e.g., prior to forming the solution or suspension of the functional polymer), or a combination thereof. In some embodiments in which the active agent is provided as a separate solution, suspension, or solid (e.g., dry powder), combining the solution or suspension of the functional polymer with the solution or suspension of the crosslinker can further include combining a solution, suspension, or solid form (e.g., 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 is performed 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) is performed 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 polymeric composition described above. Typically, the timing of step (ii) is such that administration of the sustained release otic composition or polymeric 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, hi 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 cochlear window region. In some embodiments, the sustained release otic composition does not involve any of the ossicles when administered to the ear of a subject. In some embodiments, the sustained release otic composition does not contact any of the ossicles when administered to the ear of a subject.

[0239] In some cases, administering can include 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 when administered is a liquid. In some embodiments, prior to administration, the sustained release otic composition is not exposed to a temperature greater than 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 capsuleotomy.

[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 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 can 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 referred to as a static mixer) downstream of a dual syringe injector, that can mix the components and minimize the time between initial mixing and administration to the target site. In some embodiments, methodologies and apparatus for performing in situ gelation developed for other adhesive or sealant systems, such as fibrin adhesive or sealant applications, may be used with the polymeric compositions or sustained release otic compositions described herein. See, e.g., U.S. Pat. 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 helps to place the sustained release otic composition in a desired location (e.g., on the round window membrane) and / or helps to 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 may affect the dosage required to effectively treat or prevent a disorder, including, but not limited to, the severity of the disease or disorder, previous preventions, 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 the assay.

[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 one week (eg, at least about two weeks, three weeks, one month, two months, three months, four months, five months, or six months).

[0249] In some cases, the subject being treated is an adult or child undergoing treatments 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 to be treated is an adult. In some embodiments, the subject to be 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 to be 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 a hearing test. In some embodiments, the subject is not administered the sustained release otic composition provided herein if the subject has an ongoing chronic inflammatory disease 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 in 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 benign paroxysmal positional vertigo (BPPV) symptoms, 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 toppling 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 the sustained release otic compositions 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 the sustained release otic compositions provided herein if the subject has significant abnormalities in the ear canal or tympanic membrane that preclude IT injection. In some embodiments, a subject is not administered the sustained release otic compositions 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 ear disease or disorder. In some embodiments, provided herein are methods of treating a subject having an ear 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 ear 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 ear disease or disorder, comprising (i) identifying the subject as having an ear 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 is a method 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 is a method 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 administration of the sustained release otic composition. For example, the subject may be evaluated prior to administration of 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. In some embodiments, 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 evaluation) 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. In some embodiments, 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) prior to 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 may 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 may be evaluated for severity and / or frequency of dizziness attacks. In some embodiments, the subject's hearing may be evaluated (e.g., using a hearing evaluation). In some embodiments, the subject may 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, the subject shows improvement in one or more assessments after administration of the sustained release otic composition provided herein. For example, in some embodiments, the subject can show improvement in the level of endolymphatic hydrops, perilymphatic enhancement, or both, as assessed, for example, by delayed intravenous gadolinium-enhanced 3T MRI. In some cases, the subject can show improvement in the level of endolymphatic hydrops, for example, compared to baseline levels. In some embodiments, the subject can show improvement in the level of perilymphatic enhancement, for example, compared to baseline levels. In some embodiments, the subject can show improvement in the level of both endolymphatic hydrops and perilymphatic enhancement, for example, compared to baseline levels. In some embodiments, the subject can show improvement in the level of severity and / or frequency of dizziness episodes, for example, compared to baseline levels. In some embodiments, the subject can show improvement in hearing (e.g., using a hearing assessment), for example, compared to baseline levels. In some embodiments, the subject can show improvement in Dizziness Handicap Inventory (DHI) score and / or Tinnitus Handicap Inventory (THI) score, for example, 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 average dizziness severity and frequency after administration (e.g., average over the past 4 weeks) can be compared to the baseline dizziness severity and frequency (e.g., average over the 4 weeks prior to 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, changes from baseline in hearing by 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 scans can be assessed post-administration (eg, at about day 15).

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

[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 symptoms of the condition in 1861. Researchers do not know what causes the fluid buildup in the inner ear that causes MD. Some believe it is related to blood vessel dysfunction, while others say the disease may result from an autoimmune condition, viral infection, 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 fluids.

[0263] Autoimmune inner ear disease is a rare disorder that appears in both adults and children, caused by a response of the immune system. The inner ear can be a direct target of the immune response, but 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 about 50% of AIED patients, 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 impaired ability 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 diseases, 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 develop 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 disequilibrium. Hearing loss can be permanent.

[0267] There is no treatment for all but a few symptoms and no cure. 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 a therapeutically effective amount of a tyrosine kinase inhibitor to the subject.

[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., by 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] Exemplary 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 polymeric composition in which 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. 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, A crosslinking reaction can occur between the first and second functional groups to form a gel, the gel being a polymeric composition 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 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, The polymer composition is capable of undergoing a cross-linking reaction between a first functional group and a second functional group 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 the 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 and second functional groups 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 crosslinking 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 polymeric composition in which 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. 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; A crosslinking reaction can occur between the first and second functional groups to form a gel, the gel being a polymeric composition 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 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; The polymer composition is capable of undergoing a cross-linking reaction between a first functional group and a second functional group 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 the 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 crosslinking 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 crosslinking 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 about 1% to about 10% by weight of the polymer composition of a crosslinker. Embodiment 20 is the polymer composition of any one of embodiments 9-16, wherein the polymer composition comprises from about 1% to about 5% by weight of the polymer composition of a crosslinker. 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 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 about 1 mPa·s to about 1000 mPa·s. Embodiment 29 is the polymer composition of any one of embodiments 1-28, wherein the polymer composition comprises 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 1-28, wherein the polymer composition comprises 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 1-28, 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 1-28, wherein the polymer composition comprises 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 1-28, 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 1-33, wherein the polymer composition comprises from about 0.05% to about 0.5% by weight of the polymer composition of a crosslinker. Embodiment 35 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises about 0.1% to about 0.3% by weight of the polymer composition of a crosslinker. Embodiment 36 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises about 0.2% by weight of the polymer composition of a crosslinker. Embodiment 37 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises about 0.2% to about 0.6% by weight of the polymer composition of a crosslinker. Embodiment 38 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises about 0.3% to about 0.5% by weight of the polymer composition of a crosslinker. Embodiment 39 is the polymer composition of any one of embodiments 1-33, wherein the polymer composition comprises 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 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 1-44, 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 1-45, 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 1-46, 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 1-47, 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 1-49, wherein the gel has a resorption time at 50° C. in PBS 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 1-52, 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 about 5.5 to about 8.0. Embodiment 55 is the polymer composition of any one of embodiments 1-54, 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 1-55, 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 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 1-58, 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 osmotic pressure 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 groups to the second functional groups is from about 0.8:1.2 to about 1.2:0.8. Embodiment 67 is the polymer composition of any one of embodiments 1-66, wherein the ratio of the first functional groups to the second functional groups 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 the first functional groups to the 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 1-70, 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 combinations thereof. Embodiment 73 is the polymer composition of any one of embodiments 1-72, wherein the second functional group comprises a primary amine. Embodiment 74 is the polymer composition of any one of embodiments 1-73, 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 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 auris 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 auris 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 auris composition of embodiment 82 or embodiment 83, wherein the carbohydrate is a glycosaminoglycan. Embodiment 85 is a sustained release ear composition of any one of embodiments 82 to 84, wherein the nucleic acid is selected from the group consisting of antisense oligonucleotides, aptamers, microRNAs, short interfering RNAs, ribozymes, and combinations thereof. Embodiment 86 is the sustained release ear composition of any one of embodiments 82 to 85, wherein the small molecule is selected from the group consisting of antibiotics, antitumor agents, local anesthetic agents, steroids, hormones, antiapoptotic agents, angiogenic agents, antiangiogenic agents, neurotransmitters, psychotropic agents, antiinflammatory 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 to 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, revastinib, 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 an antigen-binding fragment thereof. Embodiment 92 is the sustained release ear 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 ear composition of any one of embodiments 89 to 92, wherein the VEGF inhibitor comprises a decoy receptor. Embodiment 94 is the sustained release ear 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 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 ear composition of any one of embodiments 88-99, 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 to 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 ear composition of embodiment 106, wherein the diagnostic or visualization agent is selected from the group consisting of dyes, fluorophores, MRI contrast agents, and combinations thereof. Embodiment 108 is the sustained release otic composition of any one of embodiments 80 to 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 to 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 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, an isotonicity agent, a mucoadhesive, 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% 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% FD&C Blue #1, The sustained release otic composition of any one of embodiments 116-118, further comprising from 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% FD&C Blue #1, 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% FD&C Blue #1, 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% FD&C Blue #1, The sustained release otic composition of any one of embodiments 116-118, further comprising from 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% FD&C Blue #1, 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% FD&C Blue #1, 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 by 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, the functional polymer comprising a first functional group, a solution or suspension of a crosslinker, the crosslinker comprising 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) preparing 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 crosslinking agent 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 crosslinking agent 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 a first functional group and a second functional group to form a gel. Embodiment 129 is a method for preparing a sustained release otic composition, comprising: (a) preparing 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, where 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 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 a first functional group and a second functional group to form a gel. Embodiment 130 is a method for preparing a sustained release otic composition, comprising: (a) preparing 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, where the crosslinker comprises a second functional group; (c) combining a solution or suspension of the functional polymer with a solution or suspension of a crosslinker; A method in which a cross-linking reaction can occur between a first functional group and a second functional group to form a gel. Embodiment 131 is a method for preparing a sustained release otic composition, comprising: (a) preparing 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, the functional polymer comprising a first functional group, 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 a first functional group and a second functional group to form a gel. Embodiment 132 is a method for preparing a sustained release otic composition, comprising: (a) preparing 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, the functionalized polymer comprising a first functional group; (c) combining a solution or suspension of the functional polymer with a solution or suspension of a crosslinker; A method in which a cross-linking reaction can occur between a first functional group and a 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 making the solution or suspension of the functional polymer. Embodiment 135 is the method of embodiment 133, wherein an 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 ear 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 any one of the methods of embodiments 127 to 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 any one of the methods 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, wherein 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 ear 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 any one of the methods of embodiments 127 to 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 any one of the methods 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 is performed 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 ear 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 ear 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 liquid during administration. Embodiment 161 is the method of any one of embodiments 140 to 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 to 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 to a subject in need thereof a therapeutically effective amount of a tyrosine kinase inhibitor. 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, revastinib, 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 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 times selective for VEGFR2 over another VEGFR. Embodiment 183 is the method of any one of embodiments 168-182, 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 invention will be further understood by reference to the following non-limiting examples. EXAMPLES

[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 and PEG ester solutions. To slow the crosslinking reaction and allow for injection times into the middle ear, the pH of the trilysine solution was altered as described in Table 1 by the addition of HCl (1N HCl, Millipore). The PEG ester solution was prepared according to the package insert instructions and used within 1 hour after reconstitution. Gel times were measured at room temperature by monitoring the time when the stir bar stopped rotating.

[0275] result As shown in Table 1, adjusting the PEG-trilysine polymer trilysine solution from pH 10 to pH 8.4 successfully delayed the gelation time from 3 seconds to about 1 minute. In a previous screening study, samples prepared with trilysine solutions 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 polymers 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 when 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 plays a role in 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. For gelation time stir bar test, 100 microliters of pH adjusted trilysine drug suspension was then added to 100 microliters of PEG-trilysine polymer PEG solution in a glass vial. The time after addition that the stir bar stopped rotating was recorded.

[0280] result Addition of HCl to the trilysine polymer solution dilutes the trilysine, and when added to the PEG-trilysine polymer PEG solution, a stoichiometry less than 1:1 is obtained, but addition of drug particles results in further dilution, decreasing the 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 gel time as measured by 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 tests of drug release and gel erosion were performed using 200 μL of gel sample in an insert (CORNING TRANSWELL® 3414 insert with a polycarbonate membrane with pore size of 0.4 μm). To simulate the delivery of drugs to potential fluids in the middle ear, the insert was immersed in 45 mL of receptor fluid (PBS at pH 7.4, SIGMA-ALDRICH® P5368) in an incubator at 37°C. 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. The tests were performed using a test configuration (0.33 cm directly exposed to PBS). 2 Maximum drug release rate into PBS and the area of ​​0.33 cm 2 The drug release through a membrane with an area of ​​0.01 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 mixed by vortexing before dispensing aliquots into each insert. At the start of the study, samples were immersed in 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 the inserts, the receptor vial was manually inverted several times to ensure homogenization of the receptor solution.

[0285] The sample weight was recorded periodically after removing excess fluid with laboratory tissue. The percent swelling was calculated as the change in sample weight divided by the initial sample weight, which reflects the degree of swelling and initial crosslinking.

[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 less cross-linking, sample weight continued to increase, but gel erosion contributed to weight loss. Eventually, the gel was 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 the insert was placed on its side and during the manual mixing process before transferring the insert to a new vial.

[0287] Results in Figure 2A show that 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-induced weight loss. Upon further evaluation, samples with shorter gel duration appeared to correlate with the pot life of the PEG solution (time since PEG reconstitution) rather than dexamethasone content. For example, samples with longer time since PEG reconstitution were less cross-linked 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 breaks down to a liquid consistency, the remaining drug particles settle and spread out of the insert into the receptor fluid. This increases 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 to a lesser extent on the membrane side. Ultimately, these samples had no cloudy areas of gel. 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 polymers Materials and Methods A qualitative assessment of adhesion to tissue was performed by applying the samples to raw turkey breast. In parallel with the sample preparation of Example 4, the remaining material was pipetted onto the surface of the turkey and a small wooden stick was placed on it. After a few minutes of gelation time, the wooden stick was pulled to assess adhesion.

[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 for the 3 and 6 wt% Dex samples compared to the 0 and 1 wt% Dex samples. Furthermore, gels with higher drug loading had better cohesion, demonstrating that drug particles can improve the mechanical properties of gels, similar to filler particles that can reinforce viscoelastic materials.

[0293] Example 6: Gel 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 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 addition of 1N 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 stoichiometric ratio 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 testing was 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 samples 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 min pot life group had higher initial swelling and shorter gel duration than the <30 min pot life group. The cumulative drug release shown in Figure 4 was highly reproducible regardless of pot life until the gel eroded in the 67 min pot life group on day 17. The PEG-trilysine polymer package insert specifies that the PEG solution should be used before the 60 min pot life so that crosslinking occurs before some 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 at the following time points: They were 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 PEG pot life of 30 minutes 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 vs. 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 trilysine solution was calculated from the weight of the solution and density 1.02 g / mL. The volume of trilysine solution was multiplied by 0.08 to calculate the volume of 2N HCl to be added. After the addition of acid, the pH of the aliquot was checked. 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% dexamethasone by weight.

[0302] A POLOXAMER® 407 gel containing 6% by weight dexamethasone was prepared to serve as a comparator. A buffer solution of 0.01M PBS was prepared from PBS pH 7.4 (Sigma-Aldrich) and water for injection (CalbioChem). A 16% by weight POLOXAMER® 407 stock solution was prepared by slowly adding POLOXAMER® 407 (BASF) to cold phosphate buffer 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 gels when placed in a 30° C. incubator.

[0304] result Visualization of Erosion of PEG-Trilysine Polymer-Dex vs. POLOXAMER® 407-Dex Gel erosion was observed in UV 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 parts were first combined, vortexed in a microcentrifuge tube, and transferred to the cuvette. The cuvettes were placed in a 37 °C incubator for 10 min 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 was almost unchanged. Even at 14 days, the majority of the gel remained intact.

[0307] Drug Release of PEG-Trilysine Polymer-Dex vs. 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 fluid as described in Example 4. The two parts of PEG-trilysine polymer-Dex were first combined and vortexed in a microcentrifuge tube, then transferred to the insert. Samples were placed at 37° C. for 45 minutes to form a gel before adding pre-warmed PBS.

[0308] Within the first day, all 407-Dex samples were completely eroded and the remaining drug particles spread 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, and therefore the amount of drug released was dependent on the volume of receptor fluid (50 mL). Variable amounts of free solid drug were transferred with the insert into the next vial of receptor fluid, and eventually 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. The method utilizes an equilibrium dialysis cell (Harvard Apparatus) to create a 500uL PTFE chamber in contact with the membrane. Donor cells loaded with 480uL of formulation were gelled by heating at 37°C for 45 minutes. The cells were then submerged in a bottle containing 75mL of PBS receptor fluid and stored at 37°C. The receptor side of the equilibrium dialysis cell was left open to expose the membrane to a large volume of receptor fluid. The receptor fluid was sampled periodically after manual mixing to measure the cumulative amount of drug delivered. In this test configuration, all drug delivery occurred by permeation through the biomimetic membrane. This differs from previous drug release configurations in inserts that could release drug directly into the PBS, not just through the porous membrane of the insert. Drug permeation through the biomimetic membrane is intended 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 to a particular theory, it is believed that the micellar structure of the poloxamer gel aids in solubilizing 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 during the permeation study. 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 set-up and non-porous membrane did not allow 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 vs. 407-Dex at 37°C Aliquots of these formulations were stored at 37°C in sealed microcentrifuge tubes in a humid chamber to avoid dehydration. This configuration evaluates the integrity of the gel when stored isolated from liquid at body temperature. Both formulations showed a long gel duration of more than 21 days.

[0314] The chemically crosslinked formulation PEG-trilysine polymer-Dex was compared to the 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 will begin to erode immediately upon contact with liquids such as mucus or absorption of water from contact with tissue. Once the gel becomes liquid, it can flow out of the round window, resulting in short and variable gel duration in the target tissue. On the other hand, the in situ chemically crosslinked formulation should provide a more durable drug delivery performance due to a longer reproducible retention time in the target tissue.

[0315] Example 9: Dual role of cross-linking agent and flocculating agent A generally favorable feature of drug suspension products is the ability to administer a uniform dose. This is easily accomplished with formulations that do not form dense precipitates during storage and can be easily redispersed by manually agitating the vial. Settling of drug particles in the pH-modified trilysine drug suspension and the poloxamer formulation described in Example 8 was evaluated by visual inspection.

[0316] After 14 days or more, the pH adjusted trilysine drug suspension had a clear top layer of less than 40% of its volume, which corresponds 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 aggregates of dexamethasone that were easily dispersible.

[0317] Within a few hours, the dexamethasone particles in Dex-407 settled and greater than 90% gave rise to a clear supernatant, 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 wt% dexamethasone were prepared as described in Example 8. 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 test and control articles 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. The ABR test 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 to test the hearing of newborns in hospitals 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-fold and band-pass filtered between 300 and 3,000 Hertz (Hz) with 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 an overview 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 non-human primate ABR studies. Auditory brainstem response threshold shifts were generally minimal and consistent with increased thresholds in both groups at higher frequencies. Furthermore, hair cell analysis by 6A and immunofluorescence staining showed few missing hair cells, at levels consistent with normal aging and unlikely to be treatment-related.

[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 out to 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 polymers to the inner ear using IT injections. Furthermore, this study successfully established an African green monkey model to be used for PK and tolerability studies of novel otologic 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, plasma levels of dexamethasone decreased but remained within the detectable range 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 to 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. Points are 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. Variability in dexamethasone levels was evident between subjects at each time point (Figures 6B and 6C), but an overall progressive decrease in perilymphatic concentrations was noted over the course of the 22-day study. In Figures 6B and 6C, the vertical axis is the concentration of dexamethasone (ng / mL). The horizontal axis is time since dosing. Figure 6B: Dots are 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, whose dexamethasone levels are above the level of detection (limit: 9500 ng / mL). Figure 6C: The same data pooled for left and right 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, concentrations over time were consistent with sustained release from the depot formulation, particularly in the PEG-trilysine polymer formulation.

[0333] Sustained exposure to dexamethasone was observed in the targeted perilymphatic compartment, as demonstrated 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 in the perilymph. Variation in dexamethasone levels between ears was evident at each time point. Although there was 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 of Example 1 with hydrochloric acid, the gelation time was reduced by modifying 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 mixed manually until reconstitution was achieved.

[0337] For the gel time stir bar test, 100 microliters of the PEG ester solution was combined with 100 microliters of the trilysine solution. Additionally, the pH of an equal mixture of fresh diluent and trilysine was measured. The pH was measured without the presence of the PEG ester to avoid gel formation during pH measurement. 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 from 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 min gelation time required for intratympanic injection can be achieved by modifying the trilysine or PEG ester solutions with components that lower the pH.

[0340] Further embodiments of intratympanic injection are envisioned, including reconstituting the PEG ester powder with a single solution containing trilysine and all pH adjusting components.

[0341] Example 12: Effect of PEG functionality on gel 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 was tracked in this study by time since expiration.

[0342] Materials and Methods Samples were prepared similarly to 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 were prepared containing monobasic sodium phosphate (Millipore) and phosphoric acid (Spectrum Chemical) in water for injection at 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 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 evaluated 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 evaluated as a measure of crosslink density.

[0344] result The 50:50 diluents were tested in 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 solutions (no PEG).

[0345] Gel times of 3.5-5 minutes at 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 functionality of the PEG ester 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 for 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 the gel time by varying the solids content was investigated by the addition of water to the gel composition.

[0349] Materials and Methods From lots that demonstrated 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. Auris compositions were prepared by combining equal amounts 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 times were 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 the gel with 1 mL of distilled water overnight at room temperature and measuring the pH of the equilibration solution.

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

[0352] result Increasin...

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 a 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, 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 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, the 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 sustained release otic composition, 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 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, the 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, and the crosslinker is 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 sustained release otic composition, 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 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, the 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, said crosslinker comprising a second functional group, said 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; 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, the 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, such that 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, the 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, the functional polymer comprising a first functional group, the functional polymer being 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. The method of claim 1, 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 any one of claims 8 to 12, 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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