Thermo-sensitive Anti-fungal hydrogel compositions and methods of use

Abstract

A hydrogel composition for intranasal delivery of an antifungal (amphotericin B) at an infection site, specifically the nasal mucosa and upper respiratory tract.

Description

THERMO-SENSITIVE ANTI-FUNGAL HYDROGEL COMPOSITIONS AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international application claims the benefit of U.S. Provisional Patent Application No. 63 / 558,992, filed on February 28, 2024, which is incorporated by reference herein in its entirety.BACKGROUND1. Field

[0002] The present disclosure relates to thermo-sensitive anti-fungal hydrogel compositions and methods for treating fungal infections.2. Description of Related Art

[0003] Invasive fungal infections are difficult to treat and require high dose systemic antifungals that are nephrotoxic and often result in patient death due to inability to deliver a high enough dose to quell the infection. There exists a need in the art for compositions and methods for treating fungal infections.BRIEF SUMMARY

[0004] The instant disclosure relates to an anti-fungal hydrogel composition comprising a polymer, a carrier, and an effective amount of an anti-fungal agent.

[0005] In an embodiment, the hydrogel compositions can reversibly crosslink upon heating to a temperature ranging from 25 °C to 40°C. In an embodiment, the hydrogel compositions can reversibly crosslink upon heating to a temperature of about 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, or 40°C.

[0006] In an embodiment, the hydrogel compositions can reversibly crosslink at a temperature just under body temperature, optionally at about 28°C.

[0007] In an embodiment, the polymer is polyhydroxy ethyl methacrylate, poly (2- hydroxyethyl methacrylate), ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), Eudragits® (copolymer of poly(ethylacrylate, methyl-methacrylate, and chloro trimethyl- ammonioethyl methacrylate), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), optionally PLGA microparticles, PLGA nanoparticles, optionally PLGA microparticles loaded with an anti-fungal agent, PLGA nanoparticles loaded with an anti-fungal agent, polycaprolactone, polyvinyl pyrrolidone (PVP), poly methyl methacrylate (PMMA), poly-(N-Isopropyl acrylamide) (PNIPAM), poly(ethylenimine), polyethylene glycol) (PEG), polypropylene glycol) (PPG), block copolymers, optionally PEG-PPG-PEG, optionally PEG- PPG, a cyclodextrin, optionally cyclodextrin a, cyclodextrin P, cyclodextrin y, or a combination thereof, a carbomer, an alginates, optionally sodium alginate, a starch, a dextran, cellulose, optionally methylcellulose, a gum, optionally acacia, tragacanth, guar gum, or a combination thereof, chitosan, collagen, gelatine, a microbial polymers, optionally polyhydroxy butyrate, an arginine derivative, a polyacids, optionally PLA, Polymethacrylate, Poly aspartate, alginates, polystyrene sulphonic acid, or a combination thereof, a polybases, optionally chitosan, poly-L- Lysine, polyallylamine, polyethylene amine, poly amidoamine dendrimer, or a combination thereof, poly-(N-Isopropyl acrylamide) (PNIPAM), poly-(N-Vinylcaprolactam), poly(N,N- dimethyl acrylamide), poly (methyl vinyl ether), a dendrimer, or a combination thereof.

[0008] In an embodiment, the polymer is Poloxamer 407.

[0009] In an embodiment, the composition can further comprise hyaluronic acid.

[0010] In an embodiment, the composition can further comprise microparticles loaded with an anti-fungal agent, optionally for delayed release.

[0011] In an embodiment, the composition can further comprise nanoparticles loaded with an anti-fungal agent, optionally for delayed release.

[0012] In an embodiment, the composition can further comprise liposomes, optionally dispersed in the polymer, optionally phosphatidylcholine-based liposomes with cholesterol.

[0013] In an embodiment, the anti-fungal agent is conjugated to the polymer.

[0014] In an embodiment, the anti-fungal agent is a polyene, azole, allylamine, echinocandin, or a combination thereof.

[0015] In an embodiment, the anti-fungal agent is clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nystatin, amphotericin B, optionally amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD), or a combination thereof.

[0016] In an embodiment, the anti-fungal agent is amphotericin B.

[0017] In an embodiment, the effective amount of the anti-fungal agent, optionally Amphotericin B, in the composition ranges from about 1 mg / mL to 100 mg / mL (w / v).

[0018] In an embodiment, the effective amount of the anti-fungal agent is between about 1 mg / mL and 10 mg / mL, 10 mg / mL and 50 mg / mL, 20 mg / mL and 80 mg / mL, or 25 mg / mL and 75 mg / mL (w / v).

[0019] In an embodiment, the effective amount of the anti-fungal agent in the composition is about 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 61 mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 70 mg / mL, 71 mg / mL, 72 mg / mL, 73 mg / mL, 74 mg / mL, 75 mg / mL, 76 mg / mL, 77 mg / mL, 78 mg / mL, 79 mg / mL, 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, or 100 mg / mL (w / v).

[0020] In an embodiment, the effective amount of the anti-fungal agent in the composition ranges from about 1 mg / mL to 30 mg / mL (w / v).

[0021] In an embodiment, the amount of the polymer, optionally Poloxamer 407, in the composition ranges from about 1% to 50% (w / v).

[0022] In an embodiment, the amount of the polymer is between about 1% and 10%, 10% and 50%, 20% and 80 %, or 25% and 75% (w / v).

[0023] In an embodiment, the polymer in the composition is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% (w / v).

[0024] In an embodiment, the amount of the polymer in the composition ranges from about 15% to 20% (w / v).

[0025] In an embodiment, the composition is a pharmaceutical composition.

[0026] In an embodiment, the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

[0027] In an embodiment, the carrier is sterile saline, water, phosphate buffered saline (PBS), Ringer’s lactate solution, sodium bicarbonate buffered solution, Tris buffered solution, HEPES buffered solution, or a combination thereof.

[0028] In an embodiment, the composition further comprises hyaluronic acid, polyglutamic acid, glycerin, polyethylene glycol, polyethylene, or a combination thereof.

[0029] In an embodiment, the composition is formulated for administration to the oral cavity, larynx, nasal cavity, optionally sinus, lungs, vagina, rectum, or a combination thereof.

[0030] In an embodiment, the composition is formulated an emulsion, gel, aerosol, cream, ointment, optionally nasal spray, nasal drops, nasal gel, for administration by a specialized catheter, aerosol, mist, or a combination thereof.

[0031] In an embodiment, the composition is in a unit dosage form.

[0032] In an embodiment, the composition can further comprise an anti-viral drug.

[0033] In an embodiment, the anti-viral drug is TAMIFLU® (oseltamivir phosphate), RELENZA® (zanamivir), RAPIVAB® (peramivir), XOFLUZA® (baloxavir marboxil), Abacavir, Acycovir, Adefovir, Ampligen, Amprenavir, Umifenovir, Atzanavir, Atripla, Biktarvy, Boceprevir, Bulevirtide, Cidofovir, Cobicistate, Combivir, Daclatasvir, Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine, Edoxudine,Efavirenz, Elvitegravir, Emitcitabine, Enfuvirtide, Entecavir, Etravirine, Famciclovir, Fomivirsen, Fosmprevavir, Foscarnet, Ganciclovir, Ibacitabine, Ibalizumab, Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir, Lopinavir, Lovride, Maraviroc, Methiszone, Morxydine, Nelfinavir, Nexavir, Nitaxanide, Norvir, Oseltamivir, Penciclovir, Peramivir, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Reltegravir, Remdesivir, Ribovirin, Rilpivirine, Rilpivirine, Rimadtadine, Ritonavir, Saquinavir, Sofosbuvir, Stavudine, Taribavirin, Telarevir, Telbivudine, Tenofovir alafenamide, Tenofovir disoproxil, Tipranavir, Tromatadine, Truvada, Umifenovir, Truvada, Umifenovir, Valaciclovir, Vicriviroc, Vidarabine, Zalcitabine, Zanamivir, Zidovudine, or a combination thereof.

[0034] The instant disclosure further relates to a method for treating a subject suffering from a fungal infection comprising administering the hydrogel composition of any of the previous embodiments.

[0035] In an embodiment, the fungal infection is a respiratory fungal infection.

[0036] In an embodiment, the fungal infection is invasive fungal sinusitis, optionally chronic invasive fungal sinusitis.

[0037] In an embodiment, the fungal infection is allergic fungal sinusitis (AFS).

[0038] In an embodiment, the fungal infection is mycetoma fungal sinusitis.

[0039] In an embodiment, the fungal infection is caused by Candida spp, Aspergillus spp, and the Mucorales optionally Candida albicans, Candida glabrala, Candida auris, Aspergillus fumigalus, Aspergillus niger, Histoplasma capsulatum, Coccidioides immilislposadasii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, Emmonsia pasleuriana, Talaromyces marneffei or any combination thereof.

[0040] In an embodiment, the fungal infection is caused by Aspergillus fumigatus.

[0041] In an embodiment, the administration can comprise subcutaneous, topical, nasal, inhalation, oral administration, or a combination of routes.

[0042] In an embodiment, the subject is administered the composition prior to the onset of fungal infection. In an embodiment, the subject is administered the composition prior to the onset of signs and / or symptoms of fungal infection.

[0043] In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes prior to the onset of fungal infection. In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes prior to the onset of signs and / or symptoms of fungal infection.

[0044] In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of the fungal infection. In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of signs and / or symptoms of the fungal infection.

[0045] In an embodiment, the subject is administered the composition after the onset of fungal infection. In an embodiment, the subject is administered the composition after the onset of signs and / or symptoms of fungal infection.

[0046] In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes after the onset of fungal infection.

[0047] In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes after the onset of signs and / or symptoms of fungal infection.

[0048] In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of fungal infection. In an embodiment, the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of signs and / or symptoms of fungal infection.

[0049] In an embodiment, the subject is a mammal.

[0050] In an embodiment, the mammal is a human, dog, cat, horse, cow, pig, ferret, or primate.

[0051] In an embodiment, the hydrogel composition is delivered by syringe.

[0052] In an embodiment, following administration, the hydrogel composition crosslinks.

[0053] In an embodiment, following administration, the hydrogel composition is viscoelastic.

[0054] The instant disclosure further relates to the use of a composition comprising an effective amount of the hydrogel composition of any of the previous embodiments, for the manufacture of a medicament for the treatment of a fungal infection.

[0055] The instant disclosure further relates to a composition for the treatment of a fungal infection comprising an effective amount of the hydrogel composition as described herein.

[0056] The instant disclosure further relates to a method of preparing the hydrogel composition as described herein, wherein the method comprises combining the polymer, the anti-fungal agent and the carrier to provide a pre-mix composition; and heating the pre-mix composition to a temperature above 30 °C.BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG. 1 depicts loading of [Pluronic F127] hydrogels with amphotericin B.

[0058] FIG. 2 depicts details on mechanical properties of a subset of potential gel formulations, (a) 20% weight / volume (w / v) pluronic Fl 27 (PLF127) G’ (black) and G” (grey), (b-e) Modifications of 20% PLF gels with (b) 4 mg / ml Amphotericin B, (c) 25 mg / ml Amphotericin B, (d) 0.5% w / v hyaluronic acid (AH), (e) 1.0% HA. (f-g) 15% PLF with (g) 25 mg / ml Amphotericin B, (h) 2% HA.DETAILED DESCRIPTION

[0059] Before the subject disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present disclosure will be established by the appended claims.Definitions

[0060] Unless otherwise indicated, all terms used herein have the same meaning as they would to one skilled in the art.

[0061] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0062] “Effective amount,” as used herein, refers broadly to the amount of the active agent, e.g., hydrogel anti-fungal agents and anti-viral agents, to have a therapeutic effect on the subject. The therapeutic effect includes, but is not limited to, limiting fungal growth and activity, relief from the fungal infection, preventing fungal infection(s), treating fungal infections, relief from viral infection, preventing viral infection(s) and treating viral infection.

[0063] “Molecular weight,” as used herein, generally refers to the relative average chain length of the bulk polymer, unless otherwise specified. In practice, molecular weight can be estimated or characterized using various methods including gel permeation chromatography (GPC) or capillary viscometry. GPC molecular weights are reported as the weight-average molecular weight (Mw) as opposed to the number-average molecular weight (Mn). Capillary viscometry provides estimates of molecular weight as the inherent viscosity determined from a dilute polymer solution using a particular set of concentration, temperance, and solvent conditions.

[0064] “Hydrophilic,” as used herein, relates to the property of having affinity for water. For example, hydrophilic polymers (or hydrophilic polymer segments) are polymers (or polymer segments) which are primarily soluble in aqueous solutions and / or have a tendency to absorb water. In general, the more hydrophilic a polymer is, the more that polymer tends to dissolve in, mix with, or be wetted by water.

[0065] “Hydrophobic” as used herein refers to substance that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water.

[0066] “Mammal,” as used herein, refers broadly to warm-blooded vertebrate animals of the class Mammalia, characterized by a covering of hair on the skin and, in the female, milkproducing mammary glands for nourishing the young. Mammals include, but are not limited to, humans, domestic and farm animals, and zoos, sports, or pet animals. Examples of mammals include but are not limited to alpacas, armadillos, capybaras, cats, camels, chimpanzees, chinchillas, cattle, dogs, gerbils, goats, gorillas, hamsters, horses, humans, lemurs, llamas, mice, non-human primates, pigs, rats, sheep, shrews, squirrels, and tapirs. Mammals include but are not limited to bovine, canine, equine, feline, murine, ovine, porcine, primate, and rodent species. Mammals also include any and all those listed on the Mammal Species of the World maintained by the National Museum of Natural History, Smithsonian Institution in Washington D.C. Similarly, the term “subject” or “patient” includes both human and veterinary patients (subjects).

[0067] “Substantially free,” as used herein, refers broadly to the presence of a specific component in an amount less than 1%, preferably less than 0.1% or 0.01%. More preferably, theterm “substantially free” refers broadly to the presence of a specific component in an amount less than 0.001%. The amount can be expressed as w / w or w / v depending on the composition.

[0068] “ Treatment,” as used herein, refers broadly to alleviating signs and / or symptoms of an infection, disease or injury condition. Treatment may encompass prophylactic measures, wherein the therapeutic composition is administered prior to the onset of signs and / or symptoms or exposure to the pathogen, disease or injury condition to lessen the development of signs and / or symptoms of an infection, a disease or injury condition. Treatment may encompass prophylactic measures, wherein the therapeutic composition is administered prior to the development of signs and / or symptoms or exposure to the pathogen, disease or injury condition to lessen the development of signs and / or symptoms of an infection, a disease or injury condition. Treatment may encompass therapeutic measures, wherein the therapeutic composition is administered after the onset of signs and / or symptoms or exposure to the pathogen, disease or injury condition to lessen the development of signs and / or symptoms of an infection, a disease or injury condition. Treatment may encompass therapeutic measures, wherein the therapeutic composition is administered after the development of signs and / or symptoms or exposure to the pathogen, disease or injury condition to lessen the development of signs and / or symptoms of an infection, a disease or injury condition.

[0069] “Unit dosage form,” as used herein, refers broadly to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the composition of the present invention, alone or in combination with other active agents, calculated in an amount sufficient to produce the desired effect, in association with a pharmaceutically acceptable diluent, carrier, or vehicle, where appropriate.

[0070] “Hydrogel”, as used herein, refers broadly to cross-linked polymeric networks swollen in aqueous media. The crosslinking may be based on covalent bonds, hydrogen bonds, or other intermolecular interactions including van der Waals interactions. The crosslinking may be induced by a change in concentration, pH or temperature. The aqueous media may be water, saline, buffer, or salt-based buffers such as phosphate buffer, or sodium bicarbonate buffered solutions. The rheology of the hydrogel may be elastic, viscoelastic or shear thinning.Anti-Fungal Treatments

[0071] Current standard of care for anti-fungal agent (e.g., Amphotericin B) delivery is intravenous administration of liposomal anti-fungal agent (e.g., Amphotericin B). It is possible to splash this drug on the local resection site after removing fungal infected tissues.

[0072] The disadvantages with existing methods are that local injection and lavage are limited in terms of concentration / volume that can be loaded. Soaked gauze, local injection, and lavage alldo not allow for controlled delivery. Advantages of the hydrogel described herein include but are not limited to that they hydrogel can be implanted (for example via nasal gastric tube) to treat a smaller area. Hydrogel is flexible and is not physically limited as bulky gauze packing. Local drug delivery hydrogel could strengthen the local effects of anti-fungal agent (e.g., Amphotericin B) while decreasing the amount of anti-fungal agent (e.g., Amphotericin B) delivered systemically, improving patient care.Thermo-Sensitive Hydrogel

[0073] The hydrogel compositions described herein can comprise a polymer, a carrier, and an anti-fungal agent. The polymer can reversibly cross link just under body temperature (about 28°C). The crosslinking temperature of the hydrogel varies with relative concentrations of components. The crosslinking temperature of the hydrogel ranges from 25 °C to 40 °C. The compositions are viscoelastic to ensure the gel is clearable by a patient via coughing or nasal discharge.

[0074] The polymer may be one or more homopolymers, or copolymers including random copolymers and block copolymers. Poloxamers are a family of triblock copolymers with a central block of hydrophobic polypropylene oxide (PPO) flanked by two hydrophilic polyethyleneoxide (PEO) blocks. The hydrogel composition described herein can comprise poloxamers. Poloxamer 407 (for example, registered trademarks of Pluronic® F127 by BASF Laboratories and Synperonic PE / F127® by ICP Laboratories), is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). The approximate lengths of the two PEG blocks in Poloxamer 407 are about 101 repeat units, while the approximate length of the propylene glycol block is 56 repeat units. The average molecular weight of Poloxamer 407 is about 12,600 Da.

[0075] The hydrogel composition described herein can comprise Poloxamer 407 at a concentration of 15% to 20% weight / volume is combined in sterile saline, water, or any other salt-based solution with an anti-fungal agent (e.g., Amphotericin B) in dry crystalline form from about 1 mg / ml to 30mg / ml final concentration which results in a suspension of an anti-fungal agent (e.g., Amphotericin B (hydrophobic)) within the Poloxamer 407 hydrogel that can be applied at room temperature (about 25°C) via syringe or similar apparatus to the nasal cavity of an affected patient. In addition to dry anti-fungal agent (e.g., Amphotericin B), a liposomal antifungal agent (e.g., Amphotericin B) (phosphatidyl choline + cholesterol liposomes) can be combined with Poloxamer 407 to generate 15 to 20% w / v Poloxamer 407 gels combined with liposomal anti-fungal agent (e.g., Amphotericin B). Furthermore, addition of hyaluronic acid can improve mucoadhesive properties of the gel and does not hinder gelation.

[0076] Furthermore, the anti-fungal agent may be covalently bonded to the polymer. In other words, the anti-fungal agent may be conjugated to the polymer. The conjugation may be carried out using any of the known methods in the art, such as but not limited to anhydride or acid chloride reactions with amine or alcohol groups to yield ester or amide bonds linking the antifungal agent to the polymer. For example, amphotericin B may be directly conjugated to the polymer in the hydrogel.Invasive Fungal Infections

[0077] Invasive fungal infections, especially in the nasal cavity, can be fatal. With COVID19, cases of mucormycosis spiked in places like India, where patients with diabetes received steroids for lung inflammation that gave a high sugar and low immunity environment for the fungus to thrive. Outside of COVID19, mucormycosis is seen in patients with immunodeficiencies such as those undergoing treatment for cancer or autoimmune disease. Patients that have fungal infections in the sinuses are subject to extreme surgeries to remove the dead and infected areas followed by high dose intravenous antifungals that result in nephrotoxicity and patient death. A higher local concentration of antifungals would result in decreased systemic antifungal dosing and possibly prolong life and promote clearance of invasive fungal infections. Barriers to developing these products include inclusion of proper stakeholders in therapeutic development - engineers, infectious disease clinicians, ENT surgeons, patients, and other caregivers - as well as establishment of an easy-to-translate material that can quickly give some increase in health span to patients.

[0078] Currently clinically used methods of local administration of antifungals to the respiratory tract include gauze packing soaked with antifungals and a lavage of the affected tissue surface with the liposomal intravenous solution. Utilizing the self-healing, thermoresponsive, and mucoadhesive hydrogel compositions and methods described herein, a clinician can deliver a gel via a modified nasal -gastric (NG) tube and syringe which would be compatible with bedside care of a patient. As it is self-healing and visco- elastic, there is no risk of the material breaking off and being lodged in the trachea as it can be cleared through the stomach like native mucus. The hydrogel described herein has further advantages in that it is self-healing, can solidify in the mucosal tract, and can be cleared through the stomach if solidified portion breaks off. For example, the hydrogel described herein can deliver amphotericin B that can solidify in nasal tract and be cleared by the body (for example via coughing or stomach) if a piece breaks off.

[0079] Furthermore, with a high local drug concentration and easy administration, this could be applied routinely to a patient while they are within hospital care.

[0080] The hydrogel composition can comprise a pluronic F127 (PLF127) based hydrogel for intranasal delivery of amphotericin B at an infection site, specifically the nasal mucosa and upper respiratory tract. The hydrogel composition described herein does not cross-link per se, but rather forms a set of hydrogen and van der Waals based bonds that lead to a stable gel assembly at body temperature. The inventors surprising discovered that amphotericin modulates the specific gelling temperatures and features. The resultant advantage is having a gel formed at body temperature (37°C) and this will allow for sustained local delivery. Normally when a drug is administered intranasally, particularly a hydrophobic drug like amphotericin, it will be rapidly cleared along with the mucus coating the nasal epithelium. The hydrogel compositions described herein will mix with the mucus and gel at the epithelial surface, localizing the hydrogel composition described herein at the site of infection for longer than the drug on its own.Polymers

[0081] The polymer can be polyhydroxy ethyl methacrylate, poly (2-hydroxy ethyl methacrylate), ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), Eudragits® (copolymer of poly(ethylacrylate, methyl-methacrylate, and chloro trimethyl-ammonioethyl methacrylate), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), optionally PLGA microparticles, PLGA nanoparticles, optionally PLGA microparticles loaded with an anti-fungal agent, PLGA nanoparticles loaded with an anti-fungal agent, polycaprolactone, polyvinyl pyrrolidone (PVP), poly methyl methacrylate (PMMA), poly-(N-Isopropyl acrylamide) (PNIPAM), poly(ethylenimine), a cyclodextrin, optionally cyclodextrin a, cyclodextrin P, cyclodextrin y, or a combination thereof, a carbomer, an alginates, optionally sodium alginate, a starch, a dextran, cellulose, optionally methylcellulose, a gum, optionally acacia, tragacanth, guar gum, or a combination thereof, chitosan, collagen, gelatine, a microbial polymers, optionally polyhydroxy butyrate, an arginine derivative, a polyacid, optionally PLA, Polymethacrylate, Poly aspartate, alginates, polystyrene sulphonic acid, or a combination thereof, a polybases, optionally chitosan, poly-L-Lysine, polyallylamine, polyethylene amine, poly amidoamine dendrimer, or a combination thereof, poly-(N-Isopropyl acrylamide) (PNIPAM), poly-(N-Vinylcaprolactam), poly(N,N-dimethyl acrylamide), poly (methyl vinyl ether), a dendrimer, or a combination thereof. The polymer can be Poloxamer 407. The polymer can be PNIPAM. The polymer can be chitosan. The polymer can be a dendrimer.

[0082] The composition can further comprise microparticles loaded with an anti-fungal agent, optionally for delayed release. The composition can further comprise nanoparticles loaded with an anti-fungal agent, optionally for delayed release. The composition can further comprise liposomes, optionally dispersed in the polymer. The composition can further comprise anti-fungal agent conjugated to the polymer. The relative concentrations of components including polymer, anti-fungal agent, carriers and other excipients can be varied for fine-tuning the release kinetics of the hydrogel.

[0083] Biocompatible polymers can be used in the compositions and methods described herein. The biocompatible polymer(s) can be biodegradable.

[0084] Exemplary polymers include, but are not limited to, cyclodextrin-containing polymers, in particular cationic cyclodextrin-containing polymers, such as those described in U.S. Pat. No. 6,509,323; polymers prepared from lactones, such as poly(caprolactone) (PCL), polyp- caprolactone) (PsCL); polyhydroxy acids and copolymers thereof such as poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(D,L- lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co- PEO-co-D,L-lactide), poly(L-lactide-co-PPO-co-D,L-lactide), and blends thereof; polyalkyl cyanoacrylate, polyurethanes; polyamino acids such as poly(lysine), poly-L-lysine (PLL), poly(valeric acid), poly(glutamic acid), and poly-L-glutamic acid; hydroxypropyl methacrylate (HPMA); polyanhydrides; polyacids such as poly(acrylic acid) (PA) poly(methacrylic acid) (PMA), and poly(butyric acid); polyesters such as esters of polyacrylic acid and polymethacrylic acid such as poly(methyl methacrylate) (PMMA), poly (methyl acrylate) (PMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly (2-ethylhexyl methacrylate) (jointly referred to herein as “polyacrylic acids”); polyorthoesters; poly(ester amides); polyamides such as poly-(N- Isopropyl acrylamide) (PNIPAM), poly-(N-vinylcaprolactam), and poly(N,N-dimethyl acrylamide); poly(ester ethers); polycarbonates; polyalkylenes such as polyethylene and polypropylene; polyalkylene glycols such as poly(ethylene glycol) (PEG), polypropylene glycol) (PPG) and block copolymers thereof, polyalkylene oxides such as poly(ethylene oxide) (PEO), polypropylene oxide) (PPO) and block copolymers thereof such as polyalkylene oxide diblock copolymer, polyalkylene oxide triblock copolymers (“PLURONICS®”); polyalkylene terephthalates such as poly(ethylene terephthalate); ethylene vinyl acetate polymer (EVA); polyvinyl alcohols (PVA); polyvinyl ethers; polyvinyl esters such as poly(vinyl acetate); polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone (PVP); polysiloxanes; polystyrenes such as poly(styrene) (PS) and poly(methoxystyrene); celluloses including derivative celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers,cellulose esters, nitro celluloses, hydroxypropylcellulose, hydroxypropylmethyl cellulose and carboxymethylcellulose; polydioxanone and its copolymers; polyhydroxyalkanoates; polypropylene fumarate; polyoxymethylene; pol oxamers such as Pol oxamer 407, Pol oxamer 338, Pol oxamer 188; trimethylene carbonate; and poly phosphazenes. Examples of preferred natural polymers include proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate. Copolymers of the above, such as random, block, or graft copolymers, or blends of the polymers listed above can also be used.

[0085] Functional groups on the polymer can be capped to alter the properties of the polymer and / or modify (e.g., decrease or increase) the reactivity of the functional group. For example, the carboxyl termini of carboxylic acid containing polymers, such as lactide- and glycolide- containing polymers, may optionally be capped, e.g., by esterification, and the hydroxyl termini may optionally be capped, e.g. by etherification or esterification.

[0086] Copolymers of PEG (or PEO) or derivatives thereof with any of the polymers described herein can be used to make the polymeric particles. The PEG or derivatives can be located in the interior positions of the copolymer. Alternatively, the PEG or derivatives may locate near or at the terminal positions of the copolymer. For example, one or more of the polymers above can be terminated with a block of polyethylene glycol. The core polymer can be a blend of pegylated polymer and non-pegylated polymer, wherein the base polymer is the same (e.g., PLGA and PLGA-PEG) or different (e g., PLGA-PEG and PL A).

[0087] The weight average molecular weight can vary for a given polymer but is generally from about 1000 Daltons to 1,000,000 Daltons, 1000 Daltons to 500,000 Dalton, 1000 Daltons to 250,000 Daltons, 1000 Daltons to 100,000 Daltons, 5,000 Daltons to 100,000 Daltons, 5,000 Daltons to 75,000 Daltons, 5,000 Daltons to 50,000 Daltons, or 5,000 Daltons to 25,000 Daltons.

[0088] The amount of the polymer, optionally Poloxamer 407, in the composition can range from about 1% to 50% (w / v).

[0089] The amount of the polymer can be between about 1% and 10%, 10% and 50%, 20% and 80 %, or 25% and 75% (w / v).

[0090] The amount of the polymer in the hydrogel composition can be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% (w / v).

[0091] The amount of the polymer in the composition can range from about 15% to 20% (w / v).Anti-Fungal Agents

[0092] The anti-fungal agent can be a polyene, azole, allylamine, echinocandin, or a combination thereof. The anti-fungal agent can be clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, itraconazole, voriconazole, caspofungin, anidulafungin, micafungin, nystatin, amphotericin B, optionally amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD), or a combination thereof. The anti-fungal agent can be amphotericin B.Hydrogel Compositions

[0093] The hydrogel compositions described herein can comprise a polymer (e.g., Poloxamer 407), an anti-fungal agent (e.g., Amphotericin B), and a carrier (e.g., saline, water), and optionally a humectant (e.g., hyaluronic acid). The anti-fungal agent (e.g., Amphotericin B) can be in a crystalline form, optionally further comprising deoxycholate or in a liposomal form, optionally comprising phosphatidylcholine and cholesterol.Routes of Administration

[0094] The hydrogel compositions comprising a polymer, carrier, and an anti-fungal agent described herein can be administered subcutaneously, intramuscularly, topically, orally, rectally, vaginally, nasally, or by a route as necessitated by the condition. The hydrogel can further comprise one or more humectant, for example hyaluronic acid (HA). Another route of administration for the hydrogel compositions described herein is nasal administration, preferably by aerosol. One route of administration for the compositions described herein is administration to an epithelial surface. For example, the hydrogel compositions described herein can be administered to oral cavity, nasal cavity, neural tissue, vagina, rectum, or a combination thereof. The compositions described herein can be formulated for administration to the nasal cavity, oral cavity, vagina, rectum, or a combination thereof, for example, as an emulsion, gel, optionally vaginal gel, suppository, optionally vaginal suppository, foam, vaginal tablets, cream, optionally vaginal cream, vaginal ring, enema, optionally micro-enema, large-volume enema, by a specialized catheter, or a combination thereof.

[0095] The hydrogel compositions comprising a polymer, carrier, and an anti-fungal agent described herein can be administered prior to development of the fungal infection, optionally prior to onset of signs and / or symptoms of the fungal infection, optionally prior to development of signs and / or symptoms of the fungal infection e.g., as a prophylactic measure. For example, prior to development of symptoms of a fungal infection, the subject can be administered a composition comprising a polymer, carrier, and an anti-fungal agent described herein. Forexample, the subject can be administered the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes prior to the onset of fungal infection, optionally prior to onset of signs and / or symptoms of the fungal infection, optionally prior to development of signs and / or symptoms of the fungal infection. The subject can be administered the hydrogel composition comprising a polymer, carrier, and an antifungal agent described herein about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of fungal infection, optionally prior to onset of signs and / or symptoms of the fungal infection, optionally prior to development of signs and / or symptoms of the fungal infection. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the possibility of exposure to the fungal pathogen, for example prior to surgery. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to surgery. The preferred timing for administration is at least 1 day prior to the onset of fungal infection, for example at least 1 day prior to surgery.

[0096] The hydrogel compositions comprising a polymer, carrier, and an anti-fungal agent described herein can be administered after development of the fungal infection, e.g., as a therapeutic measure. For example, after the onset of signs and / or symptoms of a fungal infection, the subject can be administered a composition comprising a polymer, carrier, and an anti-fungal agent described herein. For example, the subject can be administered the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 120, 180, 240, 360, 420, 480, 540 or 600 minutes after the onset of fungal infection, optionally after onset of signs and / or symptoms of the fungal infection. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of fungal infection, optionally after onset of signs and / or symptoms of the fungal infection. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may beadministered about 1, 2, 3, 4, 5, 6, or 7 days after the possibility of exposure to the fungal pathogen, for example after surgery. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after exposure to the fungal pathogen, for example after surgery. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after surgery. In some embodiments, the hydrogel composition comprising a polymer, carrier, and an anti-fungal agent described herein may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 120, 180, 240, 360, 420, 480, 540 or 600 minutes after surgery.

[0097] The hydrogel compositions comprising a polymer, carrier, an anti-fungal agent and optionally an anti-viral agent described herein can be administered prior to infection by a virus, optionally prior to onset of signs and / or symptoms of the viral infection, e.g., as a prophylactic measure. For example, the subject can be administered a hydrogel composition comprising a polymer, carrier, an anti-fungal agent and optionally an anti-viral agent described herein when the subject is at risk of a viral infection. The subject can be administered the composition comprising a polymer, carrier, an anti-fungal agent and optionally an anti-viral agent described herein about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of viral infection, optionally prior to onset of signs and / or symptoms of the viral infection. The preferred timing of administration is about 1 day prior to infection by a virus. The preferred route of administration is nasal administration.

[0098] The hydrogel compositions comprising a polymer, carrier, an anti-fungal agent and optionally an anti-viral agent described herein can be administered after infection by a virus, e.g., as a therapeutic measure. The subject can be administered the composition comprising a polymer, carrier, an anti-fungal agent and optionally an anti-viral agent described herein about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of viral infection. In some embodiments, the timing of administration is within 1 day, optionally within 2 days, optionally within 3 days, optionally within 4 days, optionally within 7 days, optionally within 14 days, after infection by a virus, optionally after onset of signs and / or symptoms of the viral infection.Effective Amount

[0099] The effective amount of the anti-fungal agent, optionally Amphotericin B, in the hydrogel composition can range from about 1 mg / mL to 100 mg / mL (w / v).

[0100] The effective amount of the anti-fungal agent can be between about 1 mg / mL and 10 mg / mL, 10 mg / mL and 50 mg / mL, 20 mg / mL and 80 mg / mL, or 25 mg / mL and 75 mg / mL (w / v).

[0101] The effective amount of the anti-fungal agent in the hydrogel composition can be about 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 61 mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 70 mg / mL, 71 mg / mL, 72 mg / mL, 73 mg / mL, 74 mg / mL, 75 mg / mL, 76 mg / mL, 77 mg / mL, 78 mg / mL, 79 mg / mL, 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, or 100 mg / mL (w / v).

[0102] The effective amount of the anti-fungal agent in the hydrogel composition can range from about 1 mg / mL to 30 mg / mL (w / v).

[0103] The dose used in a particular formulation or application will be determined by the requirements of the particular type of disease and the constraints imposed by the characteristics and capacities of the carrier materials.Pharmaceutical Compositions

[0104] The hydrogel compositions described herein can be formulated as a pharmaceutical composition comprising a polymer, carrier, and an anti-fungal agent and pharmaceutically acceptable carrier. The preferred carrier is an aqueous medium such as saline, phosphate-buffered saline, water, or a mixture thereof. Pharmaceutically acceptable carriers include, but are not limited to, excipient, lubricant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

[0105] Pharmaceutically acceptable antioxidants included but are not limited to ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotenes, including beta-carotene (P-carotene)and retinol (vitamin A), a-tocopherol (alpha-tocopherol, vitamin E), ubiquinol (coenzyme Q), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tertbutylhydroquinone (TBHQ), lutein, selenium, manganese, zeaxanthin, or a combination thereof. The antioxidant can be a-tocopherol (alpha-tocopherol, vitamin E).

[0106] Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils, or organic esters. Pharmaceutically acceptable carriers can be a liquid, including but not limited to water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. The pharmaceutical carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, or urea. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. The pharmaceutical composition may comprise water, glycerin, phospholipids, or a mixture thereof. Other examples of suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences (Alfonso Gennaro ed., Krieger Publishing Company (1997);Remington’s: The Science and Practice of Pharmacy, 21st Ed. (Lippincot, Williams & Wilkins (2005); Modem Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002).

[0107] The hydrogel compositions described herein can be formulated for administration to the oral cavity, nasal cavity, vagina, rectum, or a combination thereof, for example, as an emulsion, gel, optionally aerosol, nasal spray, nasal drops, nasal gel, cream, ointment , or a combination thereof.

[0108] The hydrogel composition described herein can further comprise an anti-viral drug. The anti-viral drug can be TAMIFLU® (oseltamivir phosphate), RELENZA® (zanamivir), RAPIVAB® (peramivir), XOFLUZA® (baloxavir marboxil), Abacavir, Acycovir, Adefovir, Ampligen, Amprenavir, Umifenovir, Atzanavir, Atripla, Biktarvy, Boceprevir, Bulevirtide, Cidofovir, Cobicistate, Combivir, Daclatasvir, Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine, Edoxudine,Efavirenz, Elvitegravir, Emitcitabine, Enfuvirtide, Entecavir, Etravirine, Famciclovir, Fomivirsen, Fosmprevavir, Foscamet, Ganciclovir, Ibacitabine, Ibalizumab, Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir, Lopinavir, Lovride, Maraviroc, Methiszone, Morxydine, Nelfinavir, Nexavir, Nitaxanide, Norvir, Oseltamivir, Penciclovir, Peramivir, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Reltegravir, Remdesivir, Ribovirin, Rilpivirine, Rilpivirine, Rimadtadine, Ritonavir, Saquinavir, Sofosbuvir, Stavudine, Taribavirin, Telarevir, Telbivudine, Tenofovir alafenamide, Tenofovir disoproxil, Tipranavir, Tromatadine, Truvada, Umifenovir, Truvada,Umifenovir, Valaciclovir, Vicriviroc, Vidarabine, Zalcitabine, Zanamivir, Zidovudine, or a combination thereof.Method of Treating Fungal Infections

[0109] The hydrogel compositions described herein can be used in methods for treating a subject suffering from a fungal infection comprising administering the hydrogel composition described herein to a subject in need.

[0110] The fungal infection can be a respiratory fungal infection. The fungal infection can be invasive fungal sinusitis, optionally chronic invasive fungal sinusitis. The fungal infection can be allergic fungal sinusitis (AFS). The fungal infection can be mycetoma fungal sinusitis. The fungal infection can be caused by any fungi that affect humans or animals. The fungal infection can be caused by one or more of Candida spp, Aspergillus spp, and the Mucorales including but not limited to Candida albicans, Candida glabrala, Candida auris, Aspergillus fumigatus, and Aspergillus niger. The fungal infection can be caused by Candida albicans, Candida glabrata, Candida auris, Aspergillus fumigatus, Aspergillus niger, Histoplasma capsulatum, Coccidioides immitislposadasii , Blastomyces dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, Emmonsia pasteuriana, Talaromyces marneffei or any combination thereof. The fungal infection can be caused by Aspergillosis fumigatus.[OHl] The administration of the hydrogel compositions described herein can comprise subcutaneous, topical, nasal, inhalation, oral administration, or a combination of routes.

[0112] The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes prior to the onset of fungal infection, optionally prior to onset of signs and / or symptoms of the fungal infection. The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of the fungal infection, optionally prior to onset of signs and / or symptoms of the fungal infection. The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes after the onset of fungal infection. The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60 minutes after the onset of signs and / or symptoms of fungal infection. The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of fungal infection. The subject can be administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of signs and / or symptoms of fungal infection. The subject can be a mammal. The mammal can be a human, dog, cat, horse, cow, pig, ferret, or primate.

[0113] The hydrogel composition can be delivered by syringe. The hydrogel composition is viscoelastic.

[0114] Further, use of a composition comprising an effective amount of the hydrogel composition of described herein for the manufacture of a medicament for the treatment of a fungal infection.

[0115] A composition for the treatment of a fungal infection can comprise an effective amount of the hydrogel composition described herein.EXAMPLESEXAMPLE 1AMPHOTERICIN B FORMULATIONS

[0116] The inventors unexpectedly found that formulations ranging from 15 - 20% PLF loaded with amphotericin B are able to form a gel or form semi-solids at 37°C but are liquid / viscous at room temperature (25°C). Fig. 1A-B. Addition of hyaluronic acid (HA) which can assist in mucoadhesion resulted in an increased shear viscosity at room temperature and did not interfere with the ability of formulations to generate semi-solids (self-healing hydrogels) at 37°C. Fig. 1A. While 15% PLF did not form a gel alone, addition of amphotericin B at 25 mg / ml induced gelation at higher temperatures and can be modified by further altering amphotericin concentrations. Fig. 1A. These gels revealed reversible gelation wherein they were liquid at room temperature (25°C), solid at 37°C and then returned to liquid after cooling to room temperature. Fig. IB A detailed characterization of mechanical properties of these hydrogels is shown in Figure 2.

[0117] The inventors surprising discovered that a large amount of Amphotericin B could be loaded into the hydrogel and it could still cross-link. This was unexpected because the inventors expected that the 25mg / ml would somehow disrupt the cross-linking in hydrogel formulation, but this was not the case.

[0118] In reference to FIG. 1, 20% PLF not loaded with drug (first stripped bar) shows that the formulation gels and when the 20% PLF is loaded with drug 25 mg / ml amp (third stripped bar), it still gels similarly to unloaded 20% PLF. FIG. 1 also shows that 15% PLF not loaded with drug(fourth stripped bar) does not gel (low stripped bar). However, when 15% PLF is loaded with 25mg / ml amp (fifth stripped bar) then the formulation gels (stripped bar is higher than unloaded case).

[0119] High drug formulation allowed for cross-linking at a lower concentration of polymer than was expected. For example, the 15% gel formulation is under the critical gelling concentration of polymer. When the 15% formulation was loaded with drug, it unexpectedly started to cross-link at 40°C even though the formulation was under the critical gelling concentration of the polymer. This is shown in the mechanical testing data through an increase in stiffness which was not expected. The increased stiffness is desirable as it will stay in place when administered to a patient.

[0120] All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.

[0121] It will be understood that each of the elements described above, or two or more together may also find a useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of the present disclosure that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended claims. The foregoing embodiments are presented by way of example only; the scope of the present disclosure is to be limited only by the following claims.

Claims

CLAIMSWhat is claimed is:

1. An anti-fungal hydrogel composition comprising a polymer, a carrier, and an effective amount of an anti-fungal agent.

2. The hydrogel composition of claim 1, wherein the polymer is selected from the group consisting of: polyhydroxy ethyl methacrylate; poly (2-hydroxy ethyl methacrylate); ethyl cellulose; hydroxypropyl methyl cellulose (HPMC); copolymer of poly(ethylacrylate, methyl-methacrylate, and chloro trimethyl-ammonioethyl methacrylate; polylactic acid (PLA); polylactic-co-glycolic acid (PLGA), optionally PLGA microparticles, PLGA nanoparticles, optionally PLGA microparticles loaded with an anti-fungal agent, PLGA nanoparticles loaded with an anti-fungal agent; polycaprolactone; polyvinyl pyrrolidone (PVP); poly methyl methacrylate (PMMA); poly-(N-Isopropyl acrylamide) (PNIPAM); poly(ethylenimine); polyethylene glycol) (PEG); polypropylene glycol) (PPG); block copolymers, optionally PEG-PPG-PEG, optionally PEG-PPG; a cyclodextrin, optionally cyclodextrin a, cyclodextrin P, cyclodextrin y, or a combination thereof; a carbomer; an alginate; optionally sodium alginate; a starch; a dextran; cellulose; optionally methylcellulose; a gum; optionally acacia; tragacanth; guar gum; or a combination thereof; chitosan; collagen; gelatine; a microbial polymer; optionally polyhydroxy butyrate; an arginine derivative; a polyacid; optionally PLA; Polymethacrylate; Poly aspartate; alginate; polystyrene sulphonic acid; or a combination thereof; a polybase, optionally chitosan, poly-L-Lysine, polyallylamine, polyethylene amine, poly amidoamine dendrimer, or a combination thereof; poly-(N-Isopropyl acrylamide) (PNIPAM); poly-(N-Vinylcaprolactam); poly(N,N-dimethyl acrylamide); poly (methyl vinyl ether); a dendrimer, and a combination thereof.

3. The hydrogel composition of claim 1 or 2, wherein the polymer is Poloxamer 407.

4. The hydrogel composition of any one of claims 1-3, wherein the composition further comprises hyaluronic acid.

5. The hydrogel composition of any one of claims 1-4, wherein the composition further comprises microparticles loaded with an anti-fungal agent, optionally for delayed release.

6. The hydrogel composition of any one of claims 1-5, wherein the composition further comprises nanoparticles loaded with an anti-fungal agent, optionally for delayed release.

7. The hydrogel composition of any one of claims 1-6, wherein the composition further comprises liposomes, optionally dispersed in the polymer, optionally phosphatidylcholine-based liposomes with cholesterol.

8. The hydrogel composition of any one of claims 1-7, wherein the anti-fungal agent is conjugated to the polymer.

9. The hydrogel composition of any one of claims 1-8, wherein the anti-fungal agent is selected from the group consisting of: a polyene, an azole, an allylamine, an echinocandin, and a combination thereof.

10. The hydrogel composition of any one of claims 1-9, wherein the anti-fungal agent is selected from the group consisting of: clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nystatin, amphotericin B, optionally amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD), and a combination thereof.

11. The hydrogel composition of any one of claims 1-10, wherein the anti-fungal agent is amphotericin B.

12. The hydrogel composition of any one of claims 1-11, wherein the effective amount of the anti-fungal agent, optionally Amphotericin B, in the composition ranges from about 1 mg / mL to 100 mg / mL (w / v).

13. The hydrogel composition of any one of claims 1-12, wherein the effective amount of the anti-fungal agent is about 1 mg / mL to about 10 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 80 mg / mL, or about 25 mg / mL to about 75 mg / mL (w / v).

14. The hydrogel composition of any one of claims 1-13, wherein the effective amount of the anti-fungal agent in the composition is about: 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL,51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 61 mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 70 mg / mL, 71 mg / mL, 72 mg / mL, 73 mg / mL, 74 mg / mL, 75 mg / mL, 76 mg / mL, 77 mg / mL, 78 mg / mL, 79 mg / mL, 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, or 100 mg / mL (w / v).

15. The hydrogel composition of any one of claims 1-14, wherein the effective amount of the anti-fungal agent in the composition is about 1 mg / mL to about 30 mg / mL (w / v).

16. The hydrogel composition of any one of claims 1-15, wherein the amount of the polymer, optionally Poloxamer 407, in the composition is about 1% to about 50% (w / v).

17. The hydrogel composition of any one of claims 1-16, wherein the amount of the polymer is about 1% to about 10%, about 10% to about 50%, about 20% to about 80 %, or about 25% to about 75% (w / v).

18. The hydrogel composition of any one of claims 1-17, wherein the polymer in the composition is about: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% (w / v).

19. The hydrogel composition of any one of claims 1-18, wherein the amount of the polymer in the composition is about 15% to about 20% (w / v).

20. The hydrogel composition of any one of claims 1-19, wherein the composition is a pharmaceutical composition.

21. The hydrogel composition of any one of claims 1-20, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

22. The hydrogel composition of any one of claims 1-21, wherein the carrier is sterile saline, water, phosphate buffered saline (PBS), Ringer’s lactate solution, sodium bicarbonate buffered solution, or a combination thereof.

23. The hydrogel composition of any one of claims 1-22, wherein the composition further comprises hyaluronic acid, polyglutamic acid, glycerin, polyethylene glycol, polyethylene, or a combination thereof.

24. The hydrogel composition of any one of claims 1-23, wherein the composition is formulated for administration to the oral cavity, larynx, nasal cavity, optionally sinus, lungs, vagina, rectum, or a combination thereof.

25. The hydrogel composition of any one of claims 1-24, wherein the composition is formulated as an emulsion, a gel, an aerosol, a cream, an ointment, optionally a nasal spray, nasal drops, or nasal gel; and is formulated for administration by a specialized catheter, aerosol, mist, or a combination thereof.

26. The hydrogel composition of any one of claims 1-25, wherein the composition is in unit dosage form.

27. The hydrogel composition of any one of claims 1-26, wherein the composition further comprises an anti-viral drug.

28. The hydrogel composition of claim 27, wherein the anti-viral drug is selected from the group consisting of: oseltamivir phosphate; zanamivir; peramivir; baloxavir marboxil; Abacavir; Acycovir; Adefovir; Ampligen; Amprenavir; Umifenovir; Atzanavir; Atripla; Biktarvy; Boceprevir; Bulevirtide; Cidofovir; Cobicistate; Combivir; Daclatasvir; Darunavir; Delavirdine; Descovy; Didanosine; Docosanol; Dolutegravir; Doravirine; Edoxudine;Efavirenz; Elvitegravir; Emitcitabine; Enfuvirtide; Entecavir; Etravirine; Famciclovir; Fomivirsen; Fosmprevavir; Foscarnet; Ganciclovir; Ibacitabine; Ibalizumab; Idoxuridine; Imiquimod; Imunovir; Indinavir; Lamivudine; Letermovir; Lopinavir; Lovride; Maraviroc; Methiszone; Morxydine; Nelfinavir; Nexavir; Nitaxanide; Norvir; Oseltamivir; Penciclovir; Peramivir; Penciclovir; Peramivir; Pleconaril; Podophyllotoxin; Reltegravir; Remdesivir; Ribovirin; Rilpivirine; Rilpivirine; Rimadtadine; Ritonavir; Saquinavir; Sofosbuvir; Stavudine; Taribavirin; Telarevir; Telbivudine; Tenofovir alafenamide; Tenofovir disoproxil; Tipranavir; Tromatadine; Truvada; Umifenovir; Truvada; Umifenovir; Valaciclovir; Vicriviroc; Vidarabine; Zalcitabine; Zanamivir; Zidovudine; and a combination thereof.

29. A method for treating a subject suffering from a fungal infection, comprising administering the hydrogel composition of any one of claims 1-28 to said subject.

30. The method of claim 29, wherein the fungal infection is a respiratory fungal infection, optionally a upper respiratory tract infection or a nasal mucosa infection.

31. The method of claim 29 or 30, wherein the fungal infection is invasive fungal sinusitis, optionally chronic invasive fungal sinusitis.

32. The method of any one of claims 29-31, wherein the fungal infection is allergic fungal sinusitis (AFS).

33. The method of any one of claims 29-32, wherein the fungal infection is mycetoma fungal sinusitis.

34. The method of any one of claims 29-33, wherein the fungal infection is caused by one or more of Candida spp., Aspergillus spp., or Mucorales, optionally Candida albicans, Candida glabrala, Candida auris, Aspergillus fumigalus, Aspergillus niger, Histoplasma capsulatum, Coccidioides immilis! posadasii , Blastomyces dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, Emmonsia pasleuriana, Talaromyces marneffei or any combination thereof.

35. The method of any one of claims 29-34, wherein the fungal infection is caused by Aspergillus fumigatus.

36. The method of any one of claims 29-35, wherein the administration comprises a route selected from the group consisting of: subcutaneous, topical, nasal, inhalation, oral, and a combination of said routes.

37. The method of any one of claims 29-36, wherein the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 minutes prior to the onset of fungal infection, optionally prior to the onset of signs and / or symptoms of fungal infection.

38. The method of any one of claims 29-37, wherein the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, or 30 days prior to the onset of the fungal infection, optionally prior to the onset of signs and / or symptoms of fungal infection.

39. The method of any one of claims 29-38, wherein the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes after the onset of fungal infection, optionally after the onset of signs and / or symptoms of fungal infection.

40. The method of any one of claims 29-39, wherein the subject is administered the composition about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after the onset of fungal infection, optionally after the onset of signs and / or symptoms of fungal infection.

41. The method of any one of claims 29-40, wherein the subject is a mammal.

42. The method of claim 41, wherein the mammal is a human, dog, cat, horse, cow, pig, ferret, or primate.

43. The method of any one of claims 29-42, wherein the hydrogel composition is delivered by syringe.

44. The method of any one of claims 29-43, wherein, following administration, the hydrogel composition crosslinks to form a gel.

45. The method of any one of claims 29-44, wherein, following administration, the hydrogel composition is viscoelastic.

46. Use of a composition comprising an effective amount of the hydrogel composition of any one of claims 1-28 for the manufacture of a medicament for the treatment of a fungal infection.

47. A composition for the treatment of a fungal infection comprising an effective amount of the hydrogel composition of any one of claims 1-28.

48. A method of preparing the hydrogel composition of any one of claims 1-28, wherein the method comprises combining the polymer, the anti-fungal agent and the carrier to provide a pre-mix composition; and heating the pre-mix composition to a temperature above 30 °C.

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