WO2024020475A1 - Compositions d'hydrogel photodurcissable - Google Patents

Compositions d'hydrogel photodurcissable Download PDF

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Publication number
WO2024020475A1
WO2024020475A1 PCT/US2023/070558 US2023070558W WO2024020475A1 WO 2024020475 A1 WO2024020475 A1 WO 2024020475A1 US 2023070558 W US2023070558 W US 2023070558W WO 2024020475 A1 WO2024020475 A1 WO 2024020475A1
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composition
kpa
semi
gel
lyophilized
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PCT/US2023/070558
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English (en)
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Elaine HORN-RANNEY
Sithara NAIR
Bethany Young
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Tympanogen, Inc.
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Publication of WO2024020475A1 publication Critical patent/WO2024020475A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • C08F2/50—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light with sensitising agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/14—Materials or treatment for tissue regeneration for ear reconstruction or ear implants, e.g. implantable hearing aids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • Tympanostomy tube (TT) insertion is a very common procedure in children and adults. During TT insertion, a tiny tube is placed into the tympanic membrane (TM) to let fluid leave the middle ear. It also lets air enter the middle ear through the TM. It is most commonly performed due to chronic fluid behind the eardrum to improve hearing and for recurrent middle ear infections to decrease the frequency of infections and direct application of antibiotics topically. In most cases, tympanostomy tubes spontaneously extrude 6 to 18 months after placement with complete repair of the tympanic membrane (TM). However, in about 15% of patients a TM perforation occurs after TT extrusion.
  • the fibrous tissue around the perforation is abraded to induce an inflammatory response. If the perforation is small such as about 20% or less of the cross- sectional area of the TM, the perforation can be packed with either paper or fat taken from the earlobe. Larger perforations require a more substantial packing material, such as auto grafts of cartilage or fascia, surgical gelatin, or a synthetic polymer patch. All of these therapies require some kind of surgery, and the success rate of the therapy is highly dependent upon the skill of the surgeon.
  • the present disclosure provides a pre-lyophilization composition comprising:
  • a base comprising about 40 wt% to about 80 wt% methacrylated chitosan, about 20 wt% to about 40 wt% hyaluronic acid and about 0.01 wt% to about 0.1 wt% of a photoinitiator;
  • the present disclosure provides a pre-lyophilization composition comprising:
  • a base comprising about 40 wt% to about 80 wt% methacrylated chitosan, about 20 wt% to about 40 wt% hyaluronic acid and about 0.01 wt% to about 0.5 wt% of a photoinitiator;
  • the photoinitiator is riboflavin.
  • the composition additionally comprises about 0 wt% to about 12 wt% arginine. In embodiments, the composition additionally comprises about 0 wt% to about 20 wt% arginine.
  • the methacrylated chitosan is about 30% to about 40% methacrylated. In embodiments, the methacrylated chitosan is about 25% to about 40% methacrylated
  • the present disclosure provides a lyophilized composition prepared by lyophilization of any of the compositions of the present invention, wherein the lyophilized composition comprises about 0% to about 2% water, and wherein the lyophilized composition can be reconstituted in less than 1 minute.
  • the present disclosure provides a semi-gel composition prepared by mixing a lyophilized composition of the present disclosure with a diluent comprising water until homogenous; wherein mixing time is less than 60 seconds; wherein the viscosity of the semigel composition is about 0.01 kPa*s to about 1.0 kPa*s, as measured by rheometry; wherein the composition comprises about 80 wt% to about 99 wt% water.
  • the present disclosure provides a cured composition produced by photoirradiation of a semi-gel composition of the present invention, wherein the elastic modulus of the cured composition is about 0.05 kPa to about 20 kPa, as measured by rheometry.
  • the photoirradiation comprises irradiation of the composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 second to about 300 seconds, and a photoirradiation intensity of about 100 mW/cm 2 to about 1000 mW/cm 2 .
  • the photoirradiation comprises irradiation of the composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 second to about 300 seconds, and a photoirradiation intensity of about 100 mW/cm 2 to about 100000 mW/cm 2 .
  • the present disclosure provides a kit comprising: a lyophilized composition, a gel dispensing tray, and a light guide.
  • the present disclosure provides a method of treating a perforation of the tympanic membrane comprising:
  • the photoirradiation comprises irradiation of the composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds and a photoirradiation intensity of about 100 mW/cm 2 to about 1000 mW/cm 2 .
  • the photoirradiation comprises irradiation of the composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds and a photoirradiation intensity of about 100 mW/cm 2 to about 100000 mW/cm 2 .
  • the present disclosure provides a method of treating a perforation of the tympanic membrane in a patient in need thereof comprising:
  • FIGS. 1A-D show the perforation treatment kit components as described in Example 4.
  • Gel pouch with dry reagents FIG. 1A
  • gel application kit with dispensing tray (1), light guide (2), and chevron pouch (3) FIG. IB
  • chevron pouch with gel pouch FIG. 1C
  • outer tray with lid, dispensing tray with light guide, gel pouch with lyophilized composition and chevron pouch FIG. ID
  • the term "semi-gel composition” refers to a composition (comprising at least one polymer) that is capable of being activated to assemble into a more viscous form but that has not yet assembled.
  • the semi-gel composition is sufficiently viscous such that it can be positioned to cover a perforation without falling through to the middle ear cavity.
  • the semi -gel composition may be prepared from a dehydrated composition such as a lyophilized composition.
  • chitosan means chitosan and its derivatives and analogs (for example methacrylated chitosan).
  • hyaluronic acid means hyaluronic acid, its derivatives and analogs.
  • treating refers to improving at least one symptom of the patient’s disorder. Treating can be improving, or at least partially ameliorating a disorder.
  • the present disclosure provides semi-gel compositions that, after curing, are useful for the treatment of, among other things, a tympanic membrane rupture in a patient in need thereof, as well as compositions that are useful as intermediates in the manufacture of the semi-gel compositions.
  • the present disclosure provides pre-lyophilized compositions; lyophilized compositions; semi-gel compositions and cured compositions.
  • the pre-lyophilized compositions of the present disclosure are flowable mixtures that, upon lyophilization (or a similar technique such as spray-drying) provide shelf-stable lyophilized compositions.
  • the lyophilized compositions of the present disclosure may be reconstituted in a suitable solvent to provide a semi-gel composition that possesses suitable viscosity properties for application to, for example, a rupture in the tympanic membrane of patient in need thereof.
  • the semi-gel composition may be cured using methods that are disclosed herein to provide a cured composition (or scaffold).
  • compositions of the present disclosure comprise ingredients that are biocompatible and suitable for use in the ear, e.g., the external auditory canal, middle ear, or both.
  • the ingredients are chosen such that the resultant polymer matrix is biodegradable and may be processed and cleared by the body, e.g., by the kidneys.
  • the compositions according to this disclosure are initially a semi-gel composition for administration to a desired site in a patient's ear and are configured to cure into a polymer matrix in the ear of a patient upon activation.
  • the semi-gel composition includes one or more polymers capable of selectively assembling into a polymer matrix at a desired time under specific conditions (for example conditions found in the ear, such as the middle ear), and a diluent.
  • the semi-gel composition includes an initiator (e.g., a photoinitiator), and the semi-gel composition is cured by exposing the composition to a condition (e.g., light) thereby activating the initiator and resulting in a polymer matrix.
  • changes in, light density, pH, temperature, or ion concentration initiate spontaneous assembly of the polymer matrix.
  • the polymers are functionalized to give them crosslink ability (e.g., methacrylated) upon activation of the initiator (e.g., riboflavin).
  • the semi-gel composition is designed to cure into a polymer matrix or scaffold having a porosity and average pore size compatible with loading the resultant polymer matrix or scaffold with a therapeutic agent.
  • the porosity and average pore size are chosen to provide a desired time-dependent release profile for the loaded therapeutic agent.
  • the polymer matrix is a scaffold having sufficient stiffness and/or tackiness (for example as a result of functional groups providing cell adhesion domains) such that epithelial cells in the TM can migrate into and/or onto the scaffold and adhere and/or grow.
  • the polymer matrix or scaffold eventually degrades in situ, i.e., is biodegradable, for example after the epithelial cells have grown sufficiently to repair the perforation.
  • the present disclosure provides a pre-lyophilized composition
  • a pre-lyophilized composition comprising: (i) a base comprising methacrylated chitosan, hyaluronic acid and a photoinitiator; and (ii) a diluent.
  • the diluent comprises water.
  • the pre-lyophilized compositions provide, upon lyophilization (or a similar technique such as spray-drying), a shelf-stable lyophilized composition.
  • the present disclosure provides a pre-lyophilized composition comprising:
  • a base comprising about 40 wt% to about 80 wt% methacrylated, about 20 wt% to about 40 wt% hyaluronic acid, about 0.01 wt% to about 0.1 wt% of a photoinitiator and 0 wt% to about 20 wt% arginine;
  • the present disclosure provides a pre-lyophilized composition comprising:
  • a base comprising about 40 wt% to about 80 wt% methacrylated chitosan, about 20 wt% to about 40 wt% hyaluronic acid, about 0.01 wt% to about 0.5 wt% of a photoinitiator and 0 wt% to about 20 wt% arginine; and (ii) a diluent.
  • the base comprises about 30 wt% to about 90 wt% methacrylated chitosan, e.g. about 30 wt%, about 32 wt%, about 34 wt%, about 36 wt%, about 38 wt%, about 40 wt%, about 42 wt%, about 44 wt%, about 46 wt%, about 48 wt%, about 50 wt%, about 52 wt%, about 54 wt%, about 56 wt%, about 58 wt%, about 60 wt%, about 62 wt%, about 64 wt%, about 66 wt%, about 68 wt%, about 70 wt%, about 72 wt%, about 74 wt%, about 76 wt%, about 78 wt%, about 80 wt%, about 82 wt%, about 84 wt%, about 86 wt%, about 88
  • the methacrylated chitosan is about 10% to about 60% methacrylated, e.g. about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about
  • the methacrylated chitosan is about 21% to about 32% methacrylated. In embodiments, the methacrylated chitosan is about 21% to about 34% methacrylated. In embodiments, the methacrylated chitosan is about 21% to about 36% methacrylated. In embodiments, the methacrylated chitosan is about 25% to about 40% methacrylated. In embodiments, the methacrylated chitosan is about 30% methacrylated.
  • the molecular weight of the chitosan may range from about 100 to about 1,000,000 g/mol. In embodiments, deacetylation of the chitosan ranges from about 0 to about 100%.
  • the base comprises about 10 wt% to about 50 wt% hyaluronic acid, e.g., about 10 wt%, about 12 wt%, about 14 wt%, about 16 wt%, about 18 wt%, about 20 wt%, about 22 wt%, about 24 wt%, about 26 wt%, about 28 wt%, about 30 wt%, about 32 wt%, about 34 wt%, about 36 wt%, about 38 wt%, about 40 wt%, about 42 wt%, about 44 wt%, about 46 wt%, about 48 wt%, or about 50 wt%, including all ranges and values in between.
  • the composition comprises about 20 wt% to about 40 wt% hyaluronic acid.
  • the composition comprises about 30 wt% hyaluronic acid.
  • the molecular weight of the hyaluronic acid may range from about 100 g/mol to about 1,000,000 g/mol.
  • a “photoinitiator” typically includes an agent that forms free radicals when illuminated by light of appropriate wavelengths.
  • the photoinitiator is an aromatic carbonyl compound (e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones) or an aromatic ketone (e.g., benzophenone and thioxanthone).
  • the photoinitiator is benzophenone, dimethoxyphenyl acetophenone, 2,2- dimethoxy-2-phenylacetophenone and 2, 2-di ethoxyacetophenone, l-[4-(2-hydroxyethoxy)- phenyl]-2-hydroxy-2-methyl-l -propane- 1 -one, ethyl eosin, eosin Y, fluorescein, 2,2- dimethoxy-2-phenylacetophenone, 2-methyl-2-phenylacetonphenone, 12959, camphorquinone, rose bengal, methylene blue, erythosin, phloxime, thionine, riboflavin, and methyl green.
  • Still other photoinitiators comprise 1 -(4-Fluorphenyl)-2 -methyl -2-morpholino- 1 -propanone, l,7-bis(9-acridinyl)heptane, 1 -Chi oro-4-propoxythi oxanthone, 1 -Hydroxy cyclohexyl phenyl ketone, 2,2-Di ethoxy acetophenone, 2,3,4,4'-Tetrahydroxy Benzophenone, 2,3,4-Trihydroxybenzophenone, 2,4,6-Trimethyl benzoyl diphenyl phosphine oxide, 2,4,6- Trimethylbenzophenone, 2/4-Diethylthioxanthone, 2/4-Isopropylthioxanthone, 2-Benzyl-2- (dimethylamino)- 1 -[4-(4-morpholinyl)phenyl]- 1 -butanone, 2-Chlorothi ox
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the base comprises about 0.01 wt% to about 0.10 wt% of a photoinitiator. In embodiments, the base comprises about 0.01 wt% to about 0.5 wt% of a photoinitiator, e.g. about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.10 wt%, about 0.
  • a photoinitiator e.g. about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.10 wt%, about 0.
  • l l wt% 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.20 wt%, about 0.21 wt%, 0.22 wt%, about 0.23 wt%, about 0.24 wt%, about 0.25 wt%, about 0.26 wt%, about 0.27 wt%, about 0.28 wt%, about 0.29 wt%, about 0.30 wt%, about 0.31 wt%, about 0.32 wt%, about 0.33 wt%, about 0.34 wt%, about 0.35 wt%, about 0.36 wt%, about 0.37 wt%, about 0.38 wt%, about 0.39 wt%, about 0.40 wt%, about 0.41 wt%, 0.42 wt%, about
  • the composition comprises about 0.08 wt% to about 0.016 wt% of a photoinitiator. In embodiments, the composition comprises about 0.08 wt% to about 0.40 wt% of a photoinitiator. In embodiments, the composition comprises about 0.08 wt% of a photoinitiator. In embodiments, the composition comprises about 0.50 wt% of a photoinitiator. In embodiments, the composition comprises about 0.12 wt% of a photoinitiator. In embodiments, the composition comprises about 0.40 wt% of a photoinitiator. [0043] Applicant found that adding arginine to a composition of the present disclosure improves gel formation and the distribution of other reagents within gel. In embodiments, arginine acts as co-initiator for crosslinking.
  • the base comprises arginine.
  • the arginine is L- arginine.
  • the base comprises about 0 wt% to about 20 wt% arginine, e.g.
  • the base comprises about 6 wt% to about 12 wt% arginine. In embodiments, the base comprises about 6 wt% arginine. In embodiments, the base comprises about 9 wt% arginine.
  • the base comprises an amine catalyst, e.g., Ethyl 4- dimethylaminobenzoate (EDMAB).
  • EDMAB Ethyl 4- dimethylaminobenzoate
  • the base comprises a free-radical inhibitor, e.g., 2,6-di-tert butyl-4- methyl phenol (BHT).
  • BHT 2,6-di-tert butyl-4- methyl phenol
  • the diluent is about 0 wt% to about 99 wt% of the composition. In embodiments, the diluent is about 1 wt% to about 99 wt% of the composition, e.g.
  • the diluent is about 0 wt% to about 95 wt% of the composition. In embodiments, the diluent is about 1 wt% to about 95 wt% of the composition. In embodiments, the diluent is about 97 wt% of the composition. In embodiments, the diluent is about 1 wt% of the composition. In embodiments, the diluent is about 2 wt% of the composition. In embodiments, the diluent comprises water. In embodiments, the diluent comprises water and sodium chloride. In embodiments, the diluent comprises water and phosphate buffer. In embodiments, the diluent comprises water, sodium chloride and phosphate buffer. In embodiments the diluent is 0.9% sodium chloride in water (i.e., saline).
  • the pre-lyophilized compositions of the present disclosure may be lyophilized to produce a lyophilized composition.
  • lyophilization increases the shelf-life of compositions of the present disclosure.
  • lyophilization of the composition provides a shelf life of greater than 1 year.
  • lyophilization of the composition provides a shelf life of about 1 year.
  • the lyophilized composition is porous to allow a faster reconstitution time.
  • the porosity is introduced by lyophilization, gassing or introduction of ice particles while freezing.
  • the lyophilization parameters are critical to prevent the collapse of the material during the freeze drying process. Insufficient drying results in collapse of the gel creating dense, hard material, which becomes very difficult to reconstitute and has very poor gel consistency.
  • the lyophilized composition comprises water, methacrylated chitosan, hyaluronic acid, and a photoinitiator.
  • the lyophilized composition further comprises arginine.
  • the arginine is L-arginine.
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the present disclosure provides a lyophilized composition
  • a lyophilized composition comprising about 0 wt% to about 10 wt% water, 50 wt% to about 65 wt% methacrylated chitosan, 25 wt% to about 35 wt% hyaluronic acid, 0.10 wt% to about 0.15 wt% riboflavin, and 0 wt% to about 10 wt% arginine.
  • the present disclosure provides a lyophilized composition
  • a lyophilized composition comprising about 0 wt% to about 10 wt% water, 40 wt% to about 80 wt% methacrylated chitosan, 20 wt% to about 40 wt% hyaluronic acid, 0.01 wt% to about 0.5 wt% riboflavin, and 0 wt% to about 20 wt% arginine.
  • the lyophilized composition comprises about 0 wt% to about 10 wt% water, e.g. about 0 wt%, about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about
  • the lyophilized composition comprises about 0 wt% to about 2 wt% water. In embodiments, the lyophilized composition comprises about 0 wt% water. In embodiments, the lyophilized composition comprises about 1 wt% water. In embodiments, the lyophilized composition comprises about 2 wt% water.
  • the lyophilized composition comprises about 50 wt% to about 65 wt% methacrylated chitosan. In embodiments, the lyophilized composition comprises about 30 wt% to about 90 wt% methacrylated chitosan, e.g., about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55
  • the lyophilized composition comprises about 59 wt% methacrylated chitosan. In embodiments, the lyophilized composition comprises about 60 wt% methacrylated chitosan. In embodiments, the lyophilized composition comprises about 61 wt% methacrylated chitosan. In embodiments, the lyophilized composition comprises about 40 wt% to about 80 wt% methacrylated chitosan. In embodiments, the lyophilized composition comprises about 50 wt% to about 65 wt% methacrylated chitosan.
  • the lyophilized composition comprises about 25 wt% to about 35 wt% hyaluronic acid. In embodiments, the lyophilized composition comprises about 10 wt% to about 50 wt% hyaluronic acid e.g.
  • the lyophilized composition comprises about 29 wt% hyaluronic acid. In embodiments, the lyophilized composition comprises about 30 wt% hyaluronic acid. In embodiments, the lyophilized composition comprises about 31 wt% hyaluronic acid. In embodiments, the lyophilized composition comprises about 20 wt% to about 40 wt% hyaluronic acid. In embodiments, the lyophilized composition comprises about 25 wt% to about 35 wt% hyaluronic acid.
  • the photoinitiator is an aromatic carbonyl compound (e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones) or an aromatic ketone (e.g., benzophenone and thioxanthone).
  • aromatic carbonyl compound e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones
  • an aromatic ketone e.g., benzophenone and thioxanthone
  • the photoinitiator is benzophenone, dimethoxyphenyl acetophenone, 2,2-dimethoxy-2-phenylacetophenone and 2, 2-di ethoxyacetophenone, 1 -[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl- 1 -propane- 1-one, ethyl eosin, eosin Y, fluorescein, 2,2-dimethoxy-2-phenylacetophenone, 2-methyl-2- phenylacetonphenone, 12959, camphorquinone, rose bengal, methylene blue, erythosin, phi oxime, thionine, riboflavin, and methyl green.
  • Still other photoinitiators comprise l-(4- Fluorphenyl)-2-methyl-2-morpholino-l -propanone, l,7-bis(9-acridinyl)heptane, l-Chloro-4- propoxythi oxanthone, 1 -Hydroxy cyclohexyl phenyl ketone, 2,2-Di ethoxy acetophenone, 2,3,4,4'-Tetrahydroxy Benzophenone, 2,3,4-Trihydroxybenzophenone, 2,4,6-Trimethyl benzoyl diphenyl phosphine oxide, 2,4,6-Trimethylbenzophenone, 2/4-Diethylthioxanthone, 2/4-Isopropylthi oxanthone, 2-Benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl)phenyl]-l- butanone, 2-Chlorothioxanthone, 2-Di
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the lyophilized composition comprises about 0.10 wt% to about 0.15 wt% riboflavin.
  • the lyophilized composition comprises about 0.10 wt% to about 0.7 wt% riboflavin, e.g., about 0.10 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.20 wt%, about 0.21 wt%, 0.22 wt%, about 0.23 wt%, about 0.24 wt%, about 0.25 wt%, about 0.26 wt%, about 0.27 wt%, about 0.28 wt%, about 0.29 wt%, about 0.30 wt%, about 0.31 wt%, 0.32 wt%, about 0.33 wt%, about 0.34 wt%, about 0.35 wt%, about 0.36 wt%, about 0.37
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the lyophilized comprises about 0.11 wt% riboflavin.
  • the lyophilized composition comprises about 0.12 wt% riboflavin.
  • the lyophilized composition comprises about 0.13 wt% riboflavin.
  • the lyophilized composition comprises about 0.01 wt% to about 0.5 wt% riboflavin.
  • the lyophilized composition comprises about 0.01 wt% to about 0.15 wt% riboflavin.
  • the lyophilized composition comprises about 0 wt% to about 10 wt% arginine. In embodiments, the lyophilized composition comprises about 0 wt% to about 30 wt% arginine, e.g.
  • the lyophilized composition comprises about 8 wt% arginine. In embodiments, the arginine is L-arginine. In embodiments, the lyophilized composition comprises about 9 wt% arginine. In embodiments, the lyophilized composition comprises about 10 wt% arginine. In embodiments, the lyophilized composition comprises about 0 wt% to about 10 wt % arginine. In embodiments, the lyophilized composition comprises about 0 wt% to about 20 wt % arginine. In embodiments, the arginine is L-arginine.
  • the composition is a lyophilized composition prepared by lyophilization of any one of the pre-lyophilization compositions of the present disclosure, comprising about 0 wt% to about 2 wt% water, wherein the lyophilized composition can be reconstituted in less than 60 seconds to provide a semi-gel composition of the present disclosure.
  • the lyophilized composition comprises about 1 wt% water, about 60 wt% methacrylated chitosan, about 30 wt% hyaluronic acid, and about 9 wt% L-arginine, and 0.12 wt% riboflavin 5’ monophosphate sodium salt.
  • the lyophilized composition is sterilized, wherein the sterilization is achieved with ionizing radiation.
  • the ionizing radiation is electron beam radiation.
  • the ionizing radiation is x-ray radiation.
  • the ionizing radiation is gamma radiation.
  • sterilization partially cures the composition. In embodiments, sterilization is required to fully cure the composition. In embodiments, e-beam radiation partially cures the gel. In embodiments, x-ray radiation partially cures the gel. In embodiments, the lyophilized composition is sterilized, wherein the sterilization is achieved with ionizing radiation. In embodiments, the ionizing radiation is gamma radiation. In embodiments, gamma irradiation partially cures the composition.
  • the dose of ionizing radiation is about 10 kGy to about 70 kGy, about 10 kGy, about 12 kGy, about 14 kGy, about 16 kGy, about 18 kGy, about 20 kGy, about 22 kGy, about 24 kGy, about 25 kGy, about 26 kGy, about 28 kGy, about 30 kGy, about 32 kGy, about 34 kGy, about 36 kGy, about 38 kGy, about 40 kGy, about 42 kGy, about 44 kGy, about 46 kGy, about 48 kGy, about 50 kGy, about 52 kGy, about 54 kGy, about 56 kGy, about 58 kGy, about 60 kGy, about 62 kGy, about 64 kGy, about 66 kGy, about 68 kGy, or about 70
  • after sterilization there is a log reduction of between about 2 and about 4 in colony forming units, e.g. about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.0, including all ranges and values in between.
  • a lyophilized composition of the present disclosure is reconstituted to provide a semi-gel composition.
  • the semi-gel composition is prepared by mixing a lyophilized composition of the present disclosure with a diluent until homogenous.
  • the term "reconstitution time” means the mixing time required during reconstitution to form a homogenous mixture.
  • the mixing time is about 5 seconds to about 120 seconds, e.g., about 1 sec, about 2 sec, about 3 sec, about 4 sec, about 5 sec, about 6 sec, about 7 sec, about 8 sec, about 9 sec, about 10 sec, about 12 sec, about 14 sec, about 16 sec, about 18 sec, about 20 sec, about 22 sec, about 24 sec, about 26 sec, about 28 sec, about 30 sec, about 32 sec, about 34 sec, about 36 sec, about 38 sec, about 40 sec, about 42 sec, about 44 sec, about 46 sec, about 48 sec, about 50 sec, about 52 sec, about 54 sec, about 56 sec, about 58 sec, about 60 sec, about 65 sec, about 70 sec, about 75 sec, about 80 sec, about 85 sec, about 90 sec, about 95 sec, about 100 sec, about 110 sec, or about 120 sec, including all values or ranges therebetween.
  • reconstitution takes about 5 seconds to about 120 seconds, e.g.
  • the semi -gel composition comprises a diluent, methacrylated chitosan, hyaluronic acid, and a photoinitiator.
  • the semi-gel composition further comprises arginine.
  • the arginine is L-arginine.
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the present disclosure provides a semi-gel composition
  • a semi-gel composition comprising about 80 wt% to about 99 wt% of a diluent, about 1 wt% to about 3 wt% methacrylated chitosan, about 0.5 wt% to about 2 wt% hyaluronic acid, about 0.0010 wt% to about 0.01 wt% of a photoinitiator, and about 0 wt% to about 0.5 wt% arginine.
  • the final concentration of diluent in the semi-gel composition is about 80 wt% to about 99 wt%, e.g., about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt%, about 86 wt%, about 87 wt%, about 88 wt%, about 89 wt%, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt%, including all ranges and values in between.
  • the final concentration of diluent in the semi-gel composition is about 96 wt%. In embodiments, the final concentration of diluent in the semi-gel composition is about 97 wt%. In embodiments, the final concentration of diluent in the semi-gel composition is about 98 wt%.
  • the diluent comprises water. In embodiments, the diluent comprises water and sodium chloride. In embodiments, the diluent comprises water and phosphate buffer. In embodiments, the diluent comprises water, sodium chloride and phosphate buffer. In embodiments the diluent is 0.9% sodium chloride in water (i.e., saline).
  • the semi-gel composition is prepared by mixing any one of the compositions of the disclosure with a diluent until homogenous; wherein the final concentration of diluent is about 97 wt%; wherein mixing time is less than about 60 seconds; wherein the viscosity of the semi-gel composition is about 0.01 kPa*s to about 1.0 kPa*s, as measured by rheometry.
  • the semi-gel composition comprises about 80 wt% to about 99 wt% water, e.g about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt%, about 86 wt%, about 87 wt%, about 88 wt%, about 89 wt%, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 90 wt% to about 97 wt% water.
  • the semi-gel composition comprises about 97 wt% water.
  • the semi-gel composition comprises about 1 wt% to about 3 wt% methacrylated chitosan, e.g. about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, or about 3 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 2 wt% methacrylated chitosan.
  • the methacrylated chitosan e.g. about 1 wt%
  • the semi -gel composition comprises about 0.5 wt% to about 2 wt% hyaluronic acid, e.g. about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 1 wt% hyaluronic acid.
  • the photoinitiator is an aromatic carbonyl compound (e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones) or an aromatic ketone (e.g., benzophenone and thioxanthone).
  • the photoinitiator is benzophenone, dimethoxyphenyl acetophenone, 2,2-dimethoxy-2-phenylacetophenone and 2, 2-di ethoxyacetophenone, 1 -[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl- 1 -propane-
  • Still other photoinitiators comprise l-(4- Fluorphenyl)-2-methyl-2-morpholino-l -propanone, l,7-bis(9-acridinyl)heptane, l-Chloro-4- propoxythi oxanthone, 1 -Hydroxy cyclohexyl phenyl ketone, 2,2-Di ethoxy acetophenone, 2,3,4,4'-Tetrahydroxy Benzophenone, 2,3,4-Trihydroxybenzophenone, 2,4,6-Trimethyl benzoyl diphenyl phosphine oxide, 2,4,6-Trimethylbenzophenone, 2/4-Diethylthioxanthone, 2/4-Isopropylthi oxanthone, 2-Benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl)phenyl]-l- butanone, 2-Chlorothioxanthone, 2-Di
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the semi -gel composition comprises about 0.001 wt% to about 0.01 wt% riboflavin, e.g.
  • the semi-gel composition comprises about 0.004 wt% riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the semi-gel composition comprises about 0 wt% to about 0.5 wt% arginine, e.g., about 0 wt%, about 0.10 wt%, about 0.15 wt%, about 0.20 wt%, about 0.25 wt%, about 0.30 wt%, about 0.35 wt%, about 0.40 wt%, about 0.45 wt%, or about 0.50 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 0.3 wt% arginine.
  • the arginine is L-arginine.
  • the semi-gel composition comprises about 97 wt% water, about 2 wt% methacrylated chitosan, about 1 wt% hyaluronic acid, about 0.3 wt% L-arginine, and about 0.004 wt% riboflavin 5’ monophosphate sodium salt.
  • the viscosity of the semi-gel composition is about 0.01 kPa*s to about 1 kPa*s, as measured by rheometry, e.g., about 0.01 kPa*s, about 0.02 kPa*s, about 0.03 kPa*s , about 0.04 kPa*s, about 0.05 kPa*s, about 0.06 kPa*s, about 0.07 kPa*s, about 0.08 kPa*s, about 0.09 kPa*s, about 0.1 kPa*s, about 0.2 kPa*s, about 0.3 kPa*s, about 0.4 kPa*s, about 0.5 kPa*s, about 0.6 kPa*s, about 0.7 kPa*s, about 0.8 kPa*s, about 0.9 kPa*s, or about 1.0 kPa*s, including all ranges and values in between.
  • the viscosity of the semigel composition is about 0.01 kPa*s to about 1.0 kPa*s, as measured by rheometry. In embodiments, the viscosity of the semi-gel composition is about 0.01 kPa*s to about 0.3 kPa*s, as measured by rheometry. In embodiments, the viscosity of the semi-gel composition is about 0.5 kPa*s to about 1.0 kPa*s, as measured by rheometry.
  • the semi-gel composition is sterilized, wherein the sterilization is achieved with ionizing radiation.
  • the ionizing radiation is electron beam radiation.
  • the ionizing radiation is x-ray radiation.
  • the ionizing radiation is gamma radiation.
  • sterilization partially cures the composition. In embodiments, sterilization is required to fully cure the composition. In embodiments, e-beam radiation partially cures the gel. In embodiments, x-ray radiation partially cures the gel. In embodiments, gamma irradiation partially cures the composition.
  • the dose of ionizing radiation is about 10 kGy to about 70 kGy, about 10 kGy, about 12 kGy, about 14 kGy, about 16 kGy, about 18 kGy, about 20 kGy, about 22 kGy, about 24 kGy, about 25 kGy, about 26 kGy, about 28 kGy, about 30 kGy, about 32 kGy, about 34 kGy, about 36 kGy, about 38 kGy, about 40 kGy, about 42 kGy, about 44 kGy, about 46 kGy, about 48 kGy, about 50 kGy, about 52 kGy, about 54 kGy, about 56 kGy, about 58 kGy, about 60 kGy, about 62 kGy, about 64 kGy, about 66 kGy, about 68 kGy, or about 70
  • after sterilization there is a log reduction of between about 2 and about 4 in colony forming units, e.g. about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.0, including all ranges and values in between.
  • the semi-gel adheres to epithelial and mucosal tissue with strengths ranging from about 1 kPa to about 20 kPa, as measured using lap shear tests. In embodiments, the semi-gel adheres to epithelial and mucosal tissue with strengths ranging from about 0.1 kPa to about 20 kPa, as measured using lap shear tests, e.g., about 0.1 kPa, about 0.2 kPa, about 0.3 kPa, about 0.4 kPa, about 0.5 kPa, about 0.6 kPa, about 0.7 kPa, about 0.8 kPa, about 0.9 kPa, about 1.0 kPa, about 1.5 kPa, about 2.0 kPa, about 2.5 kPa, about 3.0 kPa, about 3.5 kPa, about 4.0 kPa, about 4.5 kPa, about 5.0 kPa, about 5.5 kPa
  • the semi -gel is a shear-thinning thixotropic material.
  • compositions according to the present disclosure include cured compositions, which are composition that are cured resulting in a polymer matrix.
  • cured composition has a sufficient stiffness and/or tackiness (for example as a result of functional groups providing cell adhesion domains) such that epithelial cells in the TM can migrate into and/or onto the scaffold and adhere and/or grow.
  • the composition of the present disclosure is a cured composition produced by photoirradiation.
  • the cured composition is prepared from photoirradiation of the semi-gel composition.
  • the viscosity or stiffness of the composition of the present disclosure is described by elastic modulus as measured by rheometry.
  • the elastic modulus can be measured as described in the literature.
  • the elastic modulus can be measured using a parallel plate rheometer test that exerts oscillating shear force on the composition.
  • the elastic modulus of the cured composition is about 0.05 kPa to about 100 kPa as measured by rheometry, e.g., about 0.05 kPa, about 0.10 kPa, about 0.15 kPa, about 0.20 kPa, about 0.25 kPa, about 0.30 kPa, about 0.35 kPa, about 0.40 kPa, about 0.45 kPa, about 0.50 kPa, about 0.55 kPa, about 0.60 kPa, about 0.65 kPa, about 0.70 kPa, about 0.75 kPa, about 0.80 kPa, about 0.85 kPa, about 0.90 kPa, about 0.95 kPa, about 1.0 kPa, about 1.5 kPa, about 2.0 kPa, about 2.5 kPa, about 3.0 kPa, about 3.5 kPa, about 4.0 kPa, about 4.5
  • the cured composition comprises a diluent, methacrylated chitosan, hyaluronic acid, and a photoinitiator.
  • the cured composition further comprises arginine.
  • the arginine is L-arginine.
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the diluent comprises water.
  • the cured composition comprises about 80 wt% to about 99 wt% diluent, 1 wt% to about 3 wt% methacrylated chitosan, 0.5 wt% to about 2 wt% hyaluronic acid, 0.001 wt% to about 0.01 wt% riboflavin, and 0 wt% to about 0.5 wt% arginine.
  • the cured composition comprises about 80 wt% to about 99 wt% diluent, e.g about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt%, about 86 wt%, about 87 wt%, about 88 wt%, about 89 wt%, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 90 wt% to about 97 wt% water. In embodiments, the semi-gel composition comprises about 97 wt% water.
  • the diluent comprises water. In embodiments, the diluent comprises water and sodium chloride. In embodiments, the diluent comprises water and phosphate buffer. In embodiments, the diluent comprises water, sodium chloride and phosphate buffer. In embodiments the diluent is 0.9% sodium chloride in water (i.e., saline).
  • the cured composition comprises about 1 wt% to about 3 wt% methacrylated chitosan, e.g. about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, or about 3 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 2 wt% methacrylated chitosan.
  • the methacrylated chitosan is
  • the cured composition comprises about 0.5 wt% to about 2 wt% hyaluronic acid, e.g. about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 1 wt% hyaluronic acid.
  • the photoinitiator is an aromatic carbonyl compound (e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones) or an aromatic ketone (e.g., benzophenone and thioxanthone).
  • aromatic carbonyl compound e.g., benzoin derivatives, benziketals, acetophenone derivatives, hydroxyalkylphenones
  • an aromatic ketone e.g., benzophenone and thioxanthone
  • the photoinitiator is benzophenone, dimethoxyphenyl acetophenone, 2,2-dimethoxy-2-phenylacetophenone and 2, 2-di ethoxyacetophenone, 1 -[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl- 1 -propane- 1-one, ethyl eosin, eosin Y, fluorescein, 2,2-dimethoxy-2-phenylacetophenone, 2-methyl-2- phenylacetonphenone, 12959, camphorquinone, rose bengal, methylene blue, erythosin, phi oxime, thionine, riboflavin, and methyl green.
  • Still other photoinitiators comprise l-(4- Fluorphenyl)-2-methyl-2-morpholino-l -propanone, l,7-bis(9-acridinyl)heptane, l-Chloro-4- propoxythi oxanthone, 1 -Hydroxy cyclohexyl phenyl ketone, 2,2-Di ethoxy acetophenone, 2,3,4,4'-Tetrahydroxy Benzophenone, 2,3,4-Trihydroxybenzophenone, 2,4,6-Trimethyl benzoyl diphenyl phosphine oxide, 2,4,6-Trimethylbenzophenone, 2/4-Diethylthioxanthone, 2/4-Isopropylthi oxanthone, 2-Benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl)phenyl]-l- butanone, 2-Chlorothioxanthone, 2-Di
  • the photoinitiator is riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the cured composition comprises about 0.001 wt% to about 0.01 wt% riboflavin, e.g., about 0.0010 wt%, about 0.0015 wt%, about 0.0020 wt%, about 0.0025 wt%, about 0.0030 wt%, about 0.0035 wt%, about 0.0040 wt%, about 0.0045 wt%, about 0.0050 wt%, about 0.0055 wt%, about 0.0060 wt%, about 0.0065 wt%, about 0.0070 wt%, about 0.0075 wt%, about 0.0080 wt%, about 0.0085 wt%, about 0.0090 wt%, about 0.0095 wt%, or about 0.0100 wt%, including
  • the cured composition comprises about 0.004 wt% riboflavin.
  • the riboflavin is riboflavin 5’ monophosphate sodium salt.
  • the cured composition comprises about 0 wt% to about 0.5 wt% arginine, e.g., about 0 wt%, about 0.10 wt%, about 0.15 wt%, about 0.20 wt%, about 0.25 wt%, about 0.30 wt%, about 0.35 wt%, about 0.40 wt%, about 0.45 wt%, or about 0.50 wt%, including all ranges and values in between.
  • the semi-gel composition comprises about 0.3 wt% arginine.
  • the arginine is L-arginine.
  • the cured composition comprises about 96.8 wt% water, about 1.936 wt% methacrylated chitosan, about 0.968 wt% hyaluronic acid, and about 0.29 wt% L-arginine, and 0.004 wt% riboflavin 5’ monophosphate sodium salt.
  • the present disclosure provides a kit comprising: a composition the present disclosure (e.g., lyophilized composition or semi-gel composition), a gel dispensing tray and a light guide.
  • a composition the present disclosure e.g., lyophilized composition or semi-gel composition
  • the kit is enclosed in a sealed tray.
  • the kit is sterilized after sealing the tray.
  • the sterilization is achieved with ionizing radiation.
  • the ionizing radiation is electron beam radiation.
  • the ionizing radiation is x-ray radiation.
  • the ionizing radiation is gamma radiation.
  • the dose of ionizing radiation is about 10 kGy to about 70 kGy, about 10 kGy, about 12 kGy, about 14 kGy, about 16 kGy, about 18 kGy, about 20 kGy, about 22 kGy, about 24 kGy, about 25 kGy, about 26 kGy, about 28 kGy, about 30 kGy, about 32 kGy, about 34 kGy, about 36 kGy, about 38 kGy, about 40 kGy, about 42 kGy, about 44 kGy, about 46 kGy, about 48 kGy, about 50 kGy, about 52 kGy, about 54 kGy, about 56 kGy, about 58 kGy, about 60 kGy, about 62 kGy, about 64 kGy, about 66 kGy, about 68 kGy, or about 70
  • after sterilization there is a log reduction of between about 2 and about 4 in colony forming units, e.g., about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.0, including all ranges and values in between.
  • the sterilized composition (e.g., the sterilized lyophilized composition or sterilized semi-gel composition) is contained within a pouch.
  • the lyophilized composition or semi-gel composition is contained within a pouch.
  • the pouch comprises a moisture barrier.
  • the pouch comprises a transparent section.
  • the pouch comprises a moisture barrier and a transparent section.
  • the pouch comprises a luer lock connector.
  • the pouch has an area of about 9 cm 2 to about 30 cm 2 , e.g., about 9 cm 2 , about 10 cm 2 , about 11 cm 2 , about 12 cm 2 , about 13 cm 2 , about 14 cm 2 , about 15 cm 2 , about 16 cm 2 , about 17 cm 2 , about 18 cm 2 , about 19 cm 2 , about 20 cm 2 , about 21 cm 2 , about 22 cm 2 , about 23 cm 2 , about 24 cm 2 , about 25 cm 2 , about 26 cm 2 , about 27 cm 2 , about 28 cm 2 , about 29 cm 2 , or about 30 cm 2 , including all ranges and values in between.
  • the pouch comprises about 0.2 mL to about 10 mL of the composition, e.g., about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL, including all ranges and values in between.
  • the composition is contained within a mixing vessel (e.g., a syringe, a sachet, vial or a tube). In embodiments, the composition is contained within a mixing syringe.
  • a mixing vessel e.g., a syringe, a sachet, vial or a tube.
  • the kit has a shelf life greater than about 1 year. In embodiments, the kit has a shelf life of about 1 year.
  • the present disclosure provides a kit comprising: a lyophilized composition, a gel dispensing tray, and a light guide.
  • the lyophilized composition is contained within a pouch.
  • the kit is enclosed in a sealed tray.
  • the present disclosure provides compositions and methods for use in treating perforations of the tympanic membrane.
  • the perforations are chronic perforations of the tympanic membrane.
  • the otologic materials comprise a semi-gel composition that is cured in situ resulting in a polymer matrix (e.g., a hydrogel scaffold).
  • the methods comprise administering the semi-gel to a desired site in a patient's ear and curing the materials in situ.
  • the methods comprise administering the semi-gel composition to an otologic packing material and curing the semigel composition after administration to the packing material.
  • the present disclosure provides a method of treating a perforation of the tympanic membrane comprising:
  • the photoirradiation comprises irradiation of the composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds and a photoirradiation intensity of about 100 mW/cm 2 to about 100000 mW/cm 2 .
  • about 50 pL to about 500 pL of the composition is applied to the tympanic membrane. In embodiments, about 10 pL to about 500 pL of the composition is applied to the tympanic membrane, e.g.
  • about 200 pL of the composition is applied to the tympanic membrane.
  • the photoirradiation comprises irradiation of semi-gel composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds, and a photoirradiation intensity of about 100 mW/cm 2 to about 1000 mW/cm 2 .
  • the photoirradiation comprises irradiation of semi-gel composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds, and a photoirradiation intensity of about 100 mW/cm 2 to about 10000 mW/cm 2 .
  • the photoirradiation comprises irradiation of semi-gel composition with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds, and a photoirradiation intensity of about 100 mW/cm 2 to about 100000 mW/cm 2 .
  • the photoirradiation comprises irradiation of a composition (e.g., semi-gel composition) with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds and a photoirradiation power of about 2 mW to about 1 W.
  • the photoirradiation comprises irradiation of a composition (e.g., semi-gel composition) with a wavelength of about 200 nm to about 800 nm, a curing time of about 1 seconds to about 300 seconds and a photoirradiation power of about 0.2 mW to about 1 W.
  • the wavelength is about 200 nm to about 800 nm, e.g. about 200 nm, about 205 nm, about 210 nm, about 215 nm, about 220 nm, about 225 nm, about 230 nm, about 235 nm, about 240 nm, about 245 nm, about 250 nm, about 255 nm, about 260 nm, about 265 nm, about 270 nm, about 275 nm, about 280 nm, about 285 nm, about 290 nm, about 295 nm, about 300 nm, about 305 nm, about 310 nm, about 315 nm, about 320 nm, about 325 nm, about 330 nm, about 335 nm, about 340 nm, about 345 nm, about 350 nm, about 355 nm, about 360 nm, about
  • the irradiation wavelength is about 450 nm.
  • the photoirradiation power is about 2 mW to about 1 W. In embodiments, the photoirradiation power is about 0.2 mW to about 1 W, e.g., about 0.2 mW, about 0.4 mW, about 0.6 mW, about 0.8 mW, about 1.0 mW, about 1.2 mW, about 1.4 mW, about 1.6 mW, about 1.8 mW, about 2 mW, about 4 mW, about 5 mW, about 6 mW, about 7 mW, about 8 mW, about 9 mW, about 10 mW, about 11 mW, about 12 mW, about 14 mW, about 16 mW, about 18 mW, about 20 mW, about 22 mW, about 24 mW, about 26 mW, about 28 mW, about 30 mW, about 32 mW, about 34 mW, about 36 mW, about 38 mW, about 32 mW,
  • the photoirradiation intensity is about 100 mW/cm 2 to about 1000 mW/cm 2 . In embodiments, the photoirradiation intensity is about 100 mW/cm 2 to about 10000 mW/cm 2 . In embodiments, the photoirradiation intensity is about 100 mW/cm 2 to about 100000 mW/cm 2 , e.g.
  • the curing time is about 1 seconds to about 300 seconds (sec), e.g. about 1 sec, about 2 sec, about 3 sec, about 4 sec, about 5 sec, about 6 sec, about 7 sec, about 8 sec, about 9 sec, about 10 sec, about 12 sec, about 14 sec, about 16 sec, about 18 sec, about 20 sec, about 22 sec, about 24 sec, about 26 sec, about 28 sec, about 30 sec, about 32 sec, about 34 sec, about 36 sec, about 38 sec, about 40 sec, about 42 sec, about 44 sec, about 46 sec, about 48 sec, about 50 sec, about 52 sec, about 54 sec, about 56 sec, about 58 sec, about 60 sec, about 65 sec, about 70 sec, about 75 sec, about 80 sec, about 85 sec, about 90 sec, about 95 sec, about 100 sec, about 110 sec, about 120 sec, about 130 sec, about 140 sec, about 150 sec, about 160 sec, about 170 sec, about 180 sec, about 190 sec, about 200 sec, about 210 sec, about 220 sec, about
  • the photoirradiation i.e., curing time
  • the photoirradiation is continuous.
  • the photoirradiation i.e., curing time
  • the photoirradiation is administered as one or more bursts, e.g., 1 burst, 2 bursts, 3 bursts, 4 bursts or 5 bursts.
  • the curing time is about 90 seconds and the photoirradiation is administered as three bursts of about 30 seconds each.
  • the photoirradiation is administered in one burst.
  • the photoirradiation is administered in two bursts.
  • the photoirradiation is administered as three bursts.
  • the time between bursts is about 5 seconds to about 30 seconds, e.g., about 1 sec, about 2 sec, about 3 sec, about 4 sec, about 5 sec, about 6 sec, about 7 sec, about 8 sec, about 9 sec, about 10 sec, about 12 sec, about 14 sec, about 16 sec, about 18 sec, about 20 sec, about 22 sec, about 24 sec, about 26 sec, about 28 sec, or about 30 sec, including all ranges and values in between.
  • the time between bursts is about 10 sec.
  • the present disclosure provides a method of treating a perforation of the tympanic membrane in a patient in need thereof comprising: (a) adding and mixing a solvent (such as saline) with any one of the lyophilized compositions of the present disclosure to form a semi-gel composition, (b) administering the semi-gel composition to the perforation site in the tympanic membrane of the patient, and (c) curing the applied semi-gel composition with photoirradiation.
  • a solvent such as saline
  • the lyophilized composition is mixed with about 0.1 mL to about 2 mL of a solvent (such as saline), e.g., about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2.0 mL, including all values or ranges therebetween.
  • a solvent such as saline
  • the lyophilized composition is mixed with about 1 mL of saline.
  • the semi-gel composition is directly applied to the perforation site in the tympanic membrane of the patient where it is cured by any one of the photoirradiation methods as described in the present disclosure.
  • the cured semi-gel composition provides a scaffold for endogenous cell migration and is replaced by newly formed tympanic membrane tissue.
  • the patient in need thereof is a child.
  • the patient in need thereof is an adolescent 18 years or age or younger.
  • the patient in need thereof is an adult.
  • the patient is 5 years old or older or about at least 5 years old.
  • the patient is 5-11 years old, e.g., about 5 years old, about 6 years old, about 7 years old, about 8 years old, about 9 years old, about 10 years old, or about 11 years old, including all values or ranges therebetween.
  • the method of the present disclosure provides a perforation treatment for the patient in need thereof, wherein the patient has at least about 1% (e.g., at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%,
  • the method of the present disclosure provides a perforation treatment for the patient in need thereof, wherein the patient has at least about 5% of tympanic membrane affected by perforation. In embodiments, the method of the present disclosure provides a perforation treatment for the patient in need thereof, wherein the patient has at least about 10% of tympanic membrane affected by perforation. In embodiments, the patient has at least about 15% of tympanic membrane affected by perforation. In embodiments, the patient has at least about 20 % of tympanic membrane affected by perforation. In embodiments, the patient has at least about 25% of tympanic membrane affected by perforation.
  • the patient has at least about 30% of tympanic membrane affected by perforation. In embodiments, the patient has at least about 50% of tympanic membrane affected by perforation. In embodiments, the patient has at least about 80% of tympanic membrane affected by perforation.
  • the methods of the present disclosure provide at least about 40% tympanic membrane perforation closure rate. In embodiments, the methods of the present disclosure provide about >50% tympanic membrane perforation closure rate. In embodiments, the methods of the present disclosure provide about >70% tympanic membrane perforation closure rate. In embodiments, the methods of the present disclosure provide about >75% tympanic membrane perforation closure rate. In embodiments, the method of the present disclosure provides about >75% tympanic membrane perforation closure rate. In embodiments, the perforation closure rate is determined by visual assessment. In embodiments, a microscope or endoscope is used for the visual assessment.
  • the methods of the present disclosure improve about >40% in pure- tone average score and/or air-bone gap compared to baseline. In embodiments, the methods of the present disclosure provide about >50% improvement in pure-tone average score compared to baseline. In embodiments, the methods of the present disclosure provide about >70% improvement in pure-tone average score compared to baseline. In embodiments, the methods of the present disclosure provide about >75% improvement in pure-tone average score compared to baseline.
  • the method provides >75% tympanic membrane perforation closure rate or pure-tone average score compared to baseline by a single application.
  • the method increases tympanic membrane perforation closure rate in about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4 months, about 5 months, or about 6 months following administration.
  • the treatment increases tympanic membrane perforation closure rate in about 3 months following administration.
  • Example 1 Sterilization of a Lyophilized Composition
  • a kit was sterilized by irradiation at a dosage of 25 kGy. Irradiated samples were incubated in culture media for 24 h and 1 week at 37 °C. Samples were then placed in the extraction media in a biosafety cabinet, with the use of disinfected instruments. After extraction, an aliquot of the extraction medium was plated on selective agar media and incubated overnight at 37 °C for identification of various microorganisms (both bacteria and fungi) that are possibly present.
  • the lyophilized composition was rehydrated with 1 mL saline and mixed for 20-30 seconds to form a semi-gel composition.
  • the semi-gel composition was applied to cover the tympanic membrane perforation with a 1 mm overlap of the margins.
  • the semi-gel was irradiated for 1.5 min using a light guide fitted to a curing light.
  • Tympanic membranes of adult male chinchillas were perforated with a laser to create perforations of similar size. Perforations that remained open for 8 weeks were deemed chronic.
  • a semi-gel composition was applied to the tympanic membrane perforations and cured with the curing light and light guide to form a cured composition.
  • Perforations healed within 3 weeks. Fourteen weeks after treatment with the cured composition, the tympanic membranes and cochlea were evaluated by histopathological analysis. Tympanic membrane perforations treated with the cured composition healed, and the regenerated tissue had the same architecture as native tympanic membrane tissue. Hair cells in the cochlea were intact, indicating that the cured composition was not ototoxic.
  • Tympanic membranes of adult guinea pigs were perforated with a surgical knife then immediately treated with a semi-gel composition.
  • the semi-gel composition was then cured using a light guide and curing light.
  • Results [0126] Perforations were monitored for 4 weeks, during which the perforations healed. Ototoxicity was evaluated by auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). Results from ABR and DPOAE tests indicated that hearing ability and hair cell integrity were not lost, indicating that the cured composition does not have any ototoxic potential.
  • ABR auditory brainstem responses
  • DPOAE distortion product otoacoustic emissions
  • FIGS. 1A-C An exemplary otologic gel kit of the present disclosure is shown in FIGS. 1A-C. The components included in the kit are shown in Table 1.
  • the otologic gel kit (i.e., otologic gel patch kit) provides a composition of the present disclosure comprising hyaluronic acid (HA), methacrylated chitosan (MeCS), and riboflavin monophosphate (RM).
  • HA hyaluronic acid
  • MeCS methacrylated chitosan
  • RM riboflavin monophosphate
  • the composition is supplied in a pouch.
  • the contents of the gel pouch are mixed with saline (1 mL of saline) prior to the time of application to a patient. After adding saline, the pouch is recapped then kneaded to mix the dry reagents with saline. After mixing, the end of the pouch is then torn off and the contents emptied into a supplied tray.
  • the uncured composition is a semi-gel that is applied directly to the perforation through the external ear canal with a curette or other preferred instrument. Upon exposure to blue light from a curing light, the semi-gel of the composition forms a stiff, three-dimensional gel patch that fills the perforation site. Animal studies show the gel material remains in situ for less than 4 weeks.
  • the following example provides a clinical study to evaluate the safety and effectiveness of the compositions of the present disclosure in repairing chronic tympanic membrane perforation.
  • the study will: i) assess the effectiveness of the composition as a gel patch in promoting the natural healing process to close chronic, >25% tympanic membrane perforation with a single application; and ii) assess safety of the composition and application procedure.
  • the study will also i) assess gel application procedural success (e.g., under variations in anatomical condition, perforation location, TMP size, and/or age of the patient); ii) measure time to apply the gel for a single application; iii) measure time from the gel patch application to tympanic membrane healing; iv) access changes in hearing in all patient population; v) assess the safety of the gel patch in the target population for the intended use; and vi) assess pain and discomfort using visual analogue scale (VAS).
  • VAS visual analogue scale
  • the primary therapeutic endpoint will be to measure complete tympanic membrane perforation closure rates that are greater than 75% reported by clinical visual assessment at Visit 5 (3 months) following application of the gel composition.
  • the safety endpoint of the incidence rate of device and procedure-related serious adverse events on and after administration will also be measured.
  • Additional secondary endpoints include: complete tympanic membrane perforation closure assessed visually at Visit 5 after successful applications of gel composition with sedation; procedural success/failure rates; median time measured in minutes to successfully complete one application procedure; baseline and Visit 5 audiogram data comparisons of pure-tone average score and air-bone gap (ABG); baseline and Visit 5 word recognition sore data comparisons; baseline and Visit 5 tympanometry measurement data comparisons of tympanic membrane mobility; and median time measured in weeks to closure of tympanic membrane perforation after treatment.
  • Perforation involves >25% of the tympanic membrane; b. Perforation has not spontaneously closed after 4 weeks of watchful waiting; c. Perforation is not actively healing; d. Perforation can be visualized by an endoscope or microscope; and e. Ear wax does not occlude the perforation.
  • Perforation is marginal (a perforation that has an area with no tympanic membrane between the perforation and the bony canal).
  • Study Design Patients will undergo screening at Visit 1. Eligible patients will undergo treatment with the otologic gel applied at Visit 2 (Day 0) and will provide a post-procedure pain score. Perforations will be monitored at one week (Visit 3) and three weeks (Visit 4) postprocedure to determine perforation closure rate. At 12 weeks (Visit 5) following procedure, perforation closure and hearing ability will be evaluated. Audiometry and tympanometry tests will be performed at Visit 5 (i.e., end of study visit). Adverse events will be observed at each visit.
  • Otologic gel application procedure The patient will be placed in a supine position on an exam room chair with their ear under a microscope or endoscope.
  • the ENT clinician will administer uncured semi-gel composition material using a clean microsurgical tool.
  • the semigel composition will be applied to the perforation so that there is approximately a 1-mm overlap of the uncured semi-gel composition and the TM tissue around the perforation. Since this procedure takes place under a microscope or endoscope, the ENT is able to be precise in covering the perforation with gel.
  • the procedure is a clean procedure and does not require sterile application. The margins of the perforation will not be manipulated or abraded prior to application of the gel composition.
  • the ENT will cure the material with the provided reusable curing light and disposable light guide.
  • the provided safety glasses will be worn by the patient, clinicians, and others present in the room.
  • the curing light emits a beeping sound intermittently during the 90-second curing time period. The entire procedure to treat the ear should take about 10 minutes.

Abstract

La présente invention concerne des compositions d'hydrogel photodurcissable et des méthodes d'utilisation pour traiter des perforations de membrane tympanique.
PCT/US2023/070558 2022-07-20 2023-07-20 Compositions d'hydrogel photodurcissable WO2024020475A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642914B2 (en) * 2008-12-30 2017-05-09 Case Western Reserve University Photocrosslinked biodegradable hydrogel
US20190307916A1 (en) * 2012-06-28 2019-10-10 The Administrators Of The Tulane Educational Fund Selectively polymerizable compositions and methods of use in vivo
US10668185B2 (en) * 2016-12-29 2020-06-02 Tempo Therapeutics, Inc. Methods of manufacturing injectable microgel scaffolds
WO2022076505A1 (fr) * 2020-10-06 2022-04-14 Gelmedix, Inc. Compositions de polymère gelma et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642914B2 (en) * 2008-12-30 2017-05-09 Case Western Reserve University Photocrosslinked biodegradable hydrogel
US20190307916A1 (en) * 2012-06-28 2019-10-10 The Administrators Of The Tulane Educational Fund Selectively polymerizable compositions and methods of use in vivo
US10668185B2 (en) * 2016-12-29 2020-06-02 Tempo Therapeutics, Inc. Methods of manufacturing injectable microgel scaffolds
WO2022076505A1 (fr) * 2020-10-06 2022-04-14 Gelmedix, Inc. Compositions de polymère gelma et leurs utilisations

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