WO2023183603A1

WO2023183603A1 - Topical use of terbinafine and similar compounds for inflammatory ocular conditions

Info

Publication number: WO2023183603A1
Application number: PCT/US2023/016282
Authority: WO
Inventors: Zeev ELKOSHI; Ron Schlinger; Avi Avramoff
Original assignee: Taro Pharmaceutical Industries Ltd.; Taro Pharmaceuticals U.S.A., Inc.
Priority date: 2022-03-24
Filing date: 2023-03-24
Publication date: 2023-09-28

Abstract

The present disclosure provides methods of treating an inflammatory ocular condition, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine, for example, terbinafine, naftifine, or a pharmaceutically acceptable salt, conjugate or derivative thereof. The present disclosure also provides methods of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, dry-eye disease, blepharitis, uveitis or combinations thereof, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine, for example, terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof.

Description

TOPICAL USE OF TERBINAFINE AND SIMILAR COMPOUNDS FOR

INFLAMMATORY OCULAR CONDITIONS

FIELD OF THE INVENTION

[0001] The present disclosure provides for methods of treating ocular inflammation using compounds from the family of allylamines. The methods comprise contacting an ocular surface with the compounds from the family of allylamines.

BACKGROUND

[0002] Ocular inflammation, including uveitis, produces swelling in the ocular tissues and can lead to destruction of these tissues. Ocular inflammation can cause pain, redness and light sensitivity in the eye along with vision problems ranging from slightly blurred vision to severe vision loss. If ocular inflammation is left untreated, it can lead to complications such as Retinal swelling (macular edema), retina scarring, glaucoma, cataracts, optic nerve damage, retinal detachment and permanent vision loss.

[0003] Ocular inflammation is often treated with corticosteroids to reduce inflammation. Treatment with corticosteroids must be monitored for potential side effects, particularly glaucoma and cataracts. In order for the efficacy of the treatment to be maintained in many cases, treatment must be tapered under supervision of a doctor. Further, in severe cases treatment with corticosteroids may only be effective when injected into the eye, requiring administration by a medical professional.

[0004] Additional treatments for ocular inflammation, especially cases that are resistant to treatment with corticosteroids include use of immune suppressants such as methotrexate that have the potential for other side effects, including side effects in other parts of the body away from the eyes. SUMMARY OF THE INVENTION

[0005] The present disclosure is directed to a method of treating an inflammatory ocular condition, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine, e.g., terbinafine or naftifine, or pharmaceutically acceptable salt, conjugate or derivative thereof.

[0006] In some embodiments of the method of treating an inflammatory ocular condition, the inflammatory ocular condition is a non-infective inflammatory ocular condition. In some embodiments, the inflammatory ocular condition is not caused by a fungal infection. In some embodiments, the inflammatory ocular condition is not caused a bacterial infection or viral infection. In some embodiments, the inflammatory ocular condition is caused by a physical injury to the eye. In some embodiments, the inflammatory ocular condition is an autoimmune disease. In some embodiments, the inflammatory ocular condition is selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, blepharitis, dry-eye disease, uveitis or combinations thereof. In some embodiments, the inflammatory ocular condition is ocular pain, e.g., in some embodiments, the ocular pain can include one or more of the following ocular sensations of pain, e.g., Nociceptive pain, Acute nociceptive pain, Chronic nociceptive pain, Cold pain, Neuropathic pain (neuralgia), Ocular itch, Allodynia, Photoallodynia, Hyperalgesia, Ocular surface pain, Orbital pain, Retrobulbar pain, and Periorbital complex regional pain syndrome.

[0007] In some embodiments of the method of treating an inflammatory ocular condition, the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof is terbinafine, naftifine or a pharmaceutically acceptable salt conjugate or derivative thereof.

[0008] In some embodiments, the terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof is terbinafine hydrochloride, terbinafine sulfate, terbinafine phosphate, terbinafine diphosphate, terbinafine maleate, terbinafine acetate, terbinafine hydrobromide, terbinafine linoleate, terbinafine lactate or combinations thereof.

[0009] In some embodiments of the method of treating an inflammatory ocular condition, the naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof is naftifine hydrochloride, naftifine sulfate, naftifine phosphate, naftifine diphosphate, naftifine maleate, naftifine acetate, naftifine hydrobromide, naftifine linoleate, naftifine lactate or combinations thereof.

[0010] In some embodiments of the method of treating an inflammatory ocular condition, the ocular surface is the cornea, sclera, eyelid, conjunctiva, or combination thereof of the subject. In some embodiments, the composition does not comprise a mucoadhesive. In some embodiments, the composition does not comprise an additional active agent.

[0011] In some embodiments, the composition does not comprise an additional anti-fungal, antibacterial, or anti-viral agent. In some embodiments, the composition is a liquid. In some embodiments, the liquid has a viscosity of less than 50 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 20 mPa-s at 20 °C.

[0012] In some embodiments of the method of treating an inflammatory ocular condition, the composition is a semi-solid. In some embodiments, the semi-solid is a gel, cream or ointment. In some embodiments, the semi-solid has a viscosity of 500 mPa-s to 1000 Pa-s at 20 °C.

[0013] In some embodiments of the method of treating an inflammatory ocular condition, the composition is a solution, an emulsion, or a suspension. In some embodiments, the composition is a solution. In some embodiments, the composition is an emulsion. In some embodiments, the composition is a suspension. In some embodiments where the composition is a suspension, the suspension comprises a particle size D90 of less than 50 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 20 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 10 p in diameter.

[0014] In some embodiments of the method of treating an inflammatory ocular condition, the composition is administered topically via eye drops, eye spray or eye wipes.

[0015] In some embodiments of the method of treating an inflammatory ocular condition, the composition comprises about 0.01% to about 5% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the composition comprises about 0.1% to about 1% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. [0016] In some embodiments of the method of treating an inflammatory ocular condition, the composition has a tonicity equal to about 0.5% to about 1.8% sodium chloride. In some embodiments, the composition has a tonicity equal to about 0.7% to about 1.1% sodium chloride.

[0017] In some embodiments of the method of treating an inflammatory ocular condition, the composition has a pH of about 4 to about 8. In some embodiments, the composition has a pH of about 6.8 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 7.8.

[0018] In some embodiments of the method of treating an inflammatory ocular condition, the composition comprises an ophthalmically acceptable buffer, tonicity agent, osmotic pressure regulating agent, viscosity modifying agent, adhesive agent, penetrating agent, a preservative such as an antimicrobial agent, antioxidant, or chelating agent, a solubilizing agent or combinations thereof. In some embodiments, the composition is a sterile composition.

[0019] In some embodiments of the method of treating an inflammatory ocular condition, the composition is administered for more than one day. In some embodiments, the composition is administered for more than one week. In some embodiments, the composition is administered for more than 1 month. In some embodiments, the composition is administered 1 to 12 times per day. In some embodiments, the composition is administered on alternate days, e.g., every other day, every third day, every fourth day, every fifth day, every sixth day, or every week.

[0020] The present disclosure is further directed to a method of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, dry-eye disease, blepharitis, uveitis, ocular pain or combinations thereof, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine or pharmaceutically acceptable salt thereof, wherein the ocular condition is not caused by a fungal infection.

[0021] In some embodiments, the disclosure is directed to a method of treating dry-eye disease or uveitis, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. [0022] In some embodiments, the disclosure is directed to a method of reducing a symptom of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0023] In some embodiments, the disclosure is directed to a of ameliorating a symptom of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the symptom is a decrease in aqueous tear production, increase in tear evaporation, increase in cellular inflammation or combination thereof.

[0024] In some embodiments, the disclosure is directed to a method of treating a patient for an autoimmune ocular inflammatory disease (AOID), comprising administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the autoimmune ocular inflammatory disease (AOID) is dry eye disease. In some embodiments, the autoimmune ocular inflammatory disease (AOID) is uveitis.

[0025] In some embodiments, the disclosure is directed to a method for enhancing or restoring lacrimal gland tearing comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0026] In some embodiments, the disclosure is directed to a method of increasing tear production in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0027] In some embodiments, the disclosure is directed to a method of reducing the inflammation in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. [0028] In some embodiments, the disclosure is directed to a method of reducing the levels of inflammatory cytokines in the ocular secretions in a patient suffering from an AOID, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the inflammatory cytokine is a proinflammatory cytokine. In some embodiments, the proinflammatory cytokine is selected from tumor necrosis factor-al and IL- 8, IL-6, IL-la, IL-1/?, IL-12, and interferon [IFNj-y and combinations thereof. In some embodiments, the proinflammatory cytokine is selected from tumor necrosis factor-al, IL-8 and combinations thereof. In some embodiments, the proinflammatory cytokine is not tumor necrosis factor-al and IL-8. In some embodiments, the inflammatory cytokine is an anti-inflammatory cytokine.

[0029] In some embodiments, the disclosure is directed to a method of treating normal tension glaucoma in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0030] In some embodiments, the disclosure provides a method of preventing rejection of a corneal transplant in a subject, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

DETAILED DESCRIPTION

[0031] The present disclosure provides for methods of treating inflammatory ocular conditions. In some embodiments, the disclosure provides for methods of treating an inflammatory ocular condition comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine. In embodiments, the allylamine is terbinafine or naftifine, or pharmaceutically acceptable salts, conjugates or derivatives thereof. In some embodiments, the present disclosure provides for methods of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, dry-eye disease, blepharitis, uveitis, ocular pain, or combinations thereof, comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafme or pharmaceutically acceptable salt thereof, wherein the ocular condition is not caused by a fungal infection.

[0032] As used herein, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one. As used herein, “another” or “a further” may mean at least a second or more.

[0033] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the method/device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term “about” is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% or higher variability, depending on the situation. In some embodiments, one of skill in the art will understand the level of variability indicated by the term “about,” due to the context in which it is used herein It should also be understood that use of the term “about” also includes the specifically recited value.

[0034] The use of the term “or” in the claims is used to mean “and/or,” unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”

[0035] As used herein, the terms “comprising” (and any variant or form of comprising, such as “comprise” and “comprises”), “having” (and any variant or form of having, such as “have” and “has”), “including” (and any variant or form of including, such as “includes” and “include”) or “containing” (and any variant or form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0036] The use of the term “for example” and its corresponding abbreviation “e.g.,” (whether italicized or not) means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

[0037] As used herein, “between” is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y. [0038] As used herein, particle size "D10" is defined as the particle size value corresponding to cumulative size distribution at 10%, which represents the size of particles below which 10% of the sample lies.

[0039] As used herein, particle size "D50" is defined as the particle size value corresponding to cumulative size distribution at 50%, which represents the size of particles below which 50% of the sample lies.

[0040] As used herein, particle size "D90" is defined as the particle size value corresponding to cumulative size distribution at 90%, which represents the size of particles below which 90% of the sample lies.

[0041] The term "terbinafine" refers to (E)-N,6,6-trimethyl-N-(naphthalen-l-ylmethyl)hept-2- en-4-yn-l -amine (terbinafine) or a pharmaceutically acceptable salt thereof. For simplicity, as used herein, the term terbinafine includes the designated chemical entity as well as, at times, its pharmaceutically acceptable salt. The structure of terbinafine is:

[0042] In some embodiments, the terbinafine is in the form of a salt. Suitable terbinafine salts can include hydrochloride, sulfate, phosphate, diphosphate, maleate, acetate, hydrobromide, linoleate, and lactate salts. Tn some embodiments, the terbinafine can be a free acid Tn some embodiments, the terbinafine is terbinafine hydrochloride.

[0043] The term "naftifine" refers to (E)-N-methyl-N-(naphthalen-l-ylmethyl)-3-phenylprop- 2-en-l -amine (naftifine) or a pharmaceutically acceptable salt thereof. For simplicity, as used herein, the term naftifine includes the designated chemical entity as well as, at times, its pharmaceutically acceptable salt. The structure of naftifine is:

[0044] In some embodiments, the naftifine is in the form of a salt. Suitable naftifine salts can include hydrochloride, sulfate, phosphate, diphosphate, maleate, acetate, hydrobromide, linoleate, and lactate salts. In some embodiments, the naftifine can be a free acid. In some embodiments, the naftifine can be naftifine hydrochloride.

[0045] As used herein, the term "ocular surface" comprises the structures of and surrounding the eye, including the cornea, sclera, eyelids, conjunctiva and lacrimal glands. As used herein, the term "inflammatory ocular condition" refers to a condition that leads to inflammation in any part of the ocular surface. As used herein, the term "ocular condition" refers to a disease or disorder of the ocular surface, which may or may not be caused by inflammation and which may or may not occur in conjunction with ocular inflammation.

[0046] Described herein are methods of treating an inflammatory ocular condition in subjects. In embodiments of the methods, the methods comprise topically administering to an ocular surface of a subject a composition comprising an allylamine, e.g., a cyclic or bicyclic allylamine. In embodiments of the methods, the methods comprise topically administering to an ocular surface of a subject a composition comprising a compound of formula (I), or pharmaceutically acceptable salt, conjugate or derivative thereof.

In some embodiments of formula (I), X is substituted or unsubstituted C3 to C12 alkyl, alkenyl or alkynyl, or a C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, or a halogen, e.g., F, Cl, Br, or I. In some embodiments, Xis substituted or unsubstituted Cx to Cx alkyl, alkenyl or alkynyl. In some embodiments, the alkyl, alkenyl or alkynyl can be a straight-chain. In some embodiments, the alkyl, alkenyl or alkynyl is branched. In some embodiments, X is a C3 to C12 alkyl, alkenyl or alkynyl optionally interrupted with one or more of N, S or O. In some embodiments, X is an alkynyl, e.g., a branched alkynyl. In some embodiments, X is a di- or tri-alkyl alkynyl, e.g., a di- or tri- methyl alkynyl. In some embodiments, any of the alkyl, alkenyl or alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl can be optionally substituted, e.g., with one or more of C1-C3 alkyl, hydroxyl, halogens, etc. In some embodiments of formula (I), X is substituted or unsubstituted C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl. In some embodiments of formula (I), X is substituted or unsubstituted Ce cycloalkyl, aryl, cycloalkyl alkyl, or aryl alkyl. Tn some embodiments of formula (I), X is substituted or unsubstituted C<> cycloalkyl, aryl, cycloalkyl Ci- C3 alkyl, or aryl C1-C3 alkyl. In embodiments where X is substituted, X comprises one or more halogen substitutions.

[0047] In some embodiments, the methods comprise topically administering to an ocular surface of a subject a composition comprising terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the methods comprise topically administering to an ocular surface of a subject a composition comprising terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the methods comprise topically administering to an ocular surface of a subject a composition comprising naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the methods comprise topically administering to an ocular surface of a subject a composition comprising terbinafine and naftifine or pharmaceutically acceptable salts, conjugates or derivatives thereof.

[0048] The methods described herein can be used in treating various types of inflammatory ocular conditions. In some embodiments, the inflammatory ocular condition is a non-infective inflammatory ocular condition, e.g., an inflammatory ocular condition not caused by an infection. In some embodiments, the inflammatory ocular condition is not caused by a fungal infection. In some embodiments, the inflammatory ocular condition is not caused a bacterial infection or viral infection. In some embodiments, the inflammatory ocular condition is caused by a physical injury to the eye. In some embodiments, the inflammatory ocular condition is an autoimmune disease, for example, Behcet disease, lupus, multiple sclerosis, psoriasis, Reiter's syndrome, rheumatoid arthritis, Sjogren's Syndrome or thyroid diseases. In some embodiments, the inflammatory ocular condition is selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, blepharitis, dryeye disease, uveitis or combinations thereof. In some embodiments, the ocular inflammation can lead to corneal abrasions. In some embodiments, the inflammatory ocular condition is corneal abrasions, e.g., corneal abrasions caused by physical damage or other means, e.g., from an autoimmune condition. In some embodiments, the inflammatory ocular condition is caused by a corneal epithelial disorder, e.g., a corneal epithelial defect. The term corneal epithelia disorder can refer to a disorder selected out of the group consisting of age related dry eye; congenital alacrima; Riley Day syndrome (familial dysautonomia); sarcoidosis, lymphoma, AIDS, Graft vs host disease (result in lacrimal gland deficiencies); chemical and thermal burns, erythema multiforme, cicatricial pemphigoid and mucous membrane pemphigoid, trachoma (lead to lacrimal gland duct obstruction); damage of corneal, conjunctival and/or lid tissue, of lacrimal glands, of lacrimal ducts; menopause; autoimmune diseases which affect the ocular surface: such as Sjogren Syndrome, rheumatoid arthritis, systemic lupus erythematosis, polyarteritis nodosa, Wegener's granulomatosis, systemic sclerosis, primary biliary sclerosis, mixed connective tissue disease; thyroid associated diseases (such as Graves' eye disease; Hashimoto thyroiditis); diabetes, neurotrophic keratitis; loss of lacrimal secretomotor function, which might be consequence of a central nerve damage; side effect of systemic drugs such as antihistamines, beta blockers, antispasmodics, diuretics, antidepressants, sleeping pills, birth control pills, isotretinoin-type drugs, opiates, hormone replacement therapy; meibomian gland dysfunction; chronic blepharitis; Parkinson disease (low blink rate); disorders of lid aperture and lid/globe congruity: such as proptosis, high myopia, endocrine exophthalmos; may be caused by problems of lid congruity after plastic surgery, incomplete lid closure (lagophthalmos); ocular surface disorders caused by vitamin A deficiency or topical drugs (e.g. chronic glaucoma treatment) and preservatives; chronic contact lens wear; chronic allergic conjunctivitis; non-healing corneal epithelial defects, persistent corneal epithelial defects, slow-healing corneal epithelial defects, and neuropathic (neurotrophic) epithelial defects; corneal transplantation; limbal stem cell deficiency; laser eye surgery (especially laser assisted vision correction procedures such as photorefractive keratectomy (PRK), laser- assisted subepithelial keratectomy (LASEK) and laser-assisted in situ keratomileusis (LASIK)); Stevens-Johnson- Syndrome; recurrent corneal erosions; superficial punctate keratitis (SPK); glaucoma; and surgical lesions. In some embodiments, the inflammatory ocular condition is caused by a persistent corneal epithelial defect. In some embodiments, the inflammatory condition is associated with corneal transplantation. For example, in some embodiments, the inflammatory condition is associated with the rejection of the corneal transplant. In some embodiments, the inflammatory ocular condition is dry eye. In some embodiments, the dry eye is not caused a bacterial infection or viral infection. In some embodiments, the dry eye is caused by aging. In some embodiments, the dry eye is caused by a medical condition, e g., Sjogren's syndrome, allergic eye disease, rheumatoid arthritis, lupus, scleroderma, graft vs. host disease, sarcoidosis, thyroid disorders or vitamin A deficiency. Thus, in some embodiments, the disclosure provides for a method of treating allergic eye disease by topically administering to the ocular surface of a subject in need thereof a composition comprising the allylamine of Formula 1. In some embodiments, the dry eye is the result of administration of a medication, e.g., antihistamines, decongestants, hormone replacement therapy, antidepressants, and drugs for high blood pressure, acne, birth control and Parkinson's disease. In some embodiments, the dry eye is caused by corneal nerve desensitivity caused by contact lens use, nerve damage or that caused by laser eye surgery, though symptoms of dry eyes related to this procedure are usually temporary.

[0049] In some embodiments, the dry eye may be caused by increased tear evaporation, e.g., resulting from (1) posterior blepharitis (meibomian gland dysfunction), (2) reduced blinking, which tends to occur with certain conditions, such as Parkinson's disease; or when you're concentrating during certain activities, such as while reading, driving or working at a computer, (3) eyelid problems, such as the lids turning outward (ectropion) and the lids turning inward (entropion), (4) eye allergies, (5) preservatives found in topical eyedrops, (6) wind, smoke or dry air, (7) vitamin A deficiency, or combinations thereof.

[0050] In some embodiments, the inflammatory ocular condition is ocular pain. In some embodiments, the ocular pain includes Nociceptive pain, Acute nociceptive pain, Chronic nociceptive pain, Cold pain, Neuropathic pain (neuralgia), Ocular itch, Allodynia, Photoallodynia, Hyperalgesia, Ocular surface pain, Orbital pain, Retrobulbar pain, Periorbital complex regional pain syndrome, or combinations thereof.

[0051] In embodiments of the methods described herein, the terbinafine, naftifine or conjugate or derivative thereof may be in free acid form. In embodiments of the methods described herein, the terbinafine, naftifine or conjugate or derivative thereof may be in salt form. In some embodiments, the terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof is terbinafine hydrochloride, terbinafine sulfate, terbinafine phosphate, terbinafine diphosphate, terbinafine maleate, terbinafine acetate, terbinafine hydrobromide, terbinafine linoleate, terbinafine lactate or combinations thereof. In some embodiments, the terbinafine is terbinafine hydrochloride. In some embodiments, the naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof is naftifine hydrochloride, naftifine sulfate, naftifine phosphate, naftifine diphosphate, naftifine maleate, naftifine acetate, naftifine hydrobromide, naftifine linoleate, naftifine lactate or combinations thereof. In some embodiments, the naftifine is naftifine hydrochloride.

[0052] In embodiments, the methods of treating an inflammatory ocular condition involve contacting an ocular surface with the compositions described herein. In some embodiments, the ocular surface contacted is the cornea, sclera, eyelid, conjunctiva, or combination thereof of the subject.

[0053] The compositions used in the methods described herein can comprise other agents, but, in some embodiments, may not comprise certain other agents. In some embodiments, the composition does not comprise a mucoadhesive. In some embodiments, the composition does not comprise an additional active agent. In some embodiments, the composition does not comprise an additional anti-fungal, anti-bacterial, or anti-viral agent.

[0054] In embodiments of the methods of treating an inflammatory disorder described herein, the composition topically administered to an ocular surface is a liquid, as semi-solid, a solution, an emulsion or a suspension. The term “topical administration” can include any dosage form suitable for topical administration to an ocular surface, e.g., eye drops, eye sprays, eye gels, eye creams, eye emulsions, eye suspensions, eye wipes, etc. In some embodiments of the methods of treating an inflammatory ocular condition, the composition is administered to the ocular surface topically. In some embodiments, the composition is administered topically via eye drops or eye spray. In some embodiments, the composition is administered topically via eye drops. In some embodiments, the composition is administered topically via eye spray. In some embodiments, the composition is administered topically via a cream or an emulsion. In some embodiments, the composition is administered via an eye wipe.

[0055] In some embodiments, the composition is a liquid. In some embodiments, where the composition is a liquid, the liquid has a viscosity of less than 100 mPa-s at 20 °C, e.g., less than 100 mPa-s, 90 mPa-s, 80 mPa-s, 70 mPa-s, 60 mPa-s, 50 mPa-s, 40 mPa-s, 30 mPa-s, 20 mPa-s or 10 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 75 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 50 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 20 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 10 mPa-s at 20 °C. In some embodiments, the liquid has a viscosity of less than 5 mPa-s at 20 °C. In embodiments, the viscosity of the liquid is measured using standard methods in the art with a viscometer or a rheometer.

[0056] In some embodiments of the methods of treating an inflammatory ocular condition, the composition is a semi-solid. In some embodiments, the semi-solid has a viscosity of 500 mPa-s to 1000 Pa-s at 20 °C, e.g., 750 mPa-s to 500 Pa-s, 1 Pa-s to 500 Pa-s, or 10 Pa-s to 250 Pa-s at 20 °C. In some embodiments, the semi-solid has a viscosity of 1000 mPa-s to 900 Pa-s at 20 °C. In some embodiments, the semi-solid has a viscosity of 1500 mPa-s to 500 Pa-s at 20 °C. In some embodiments, the semi-solid has a viscosity of 2000 mPa-s to 200 Pa-s at 20 °C.

[0057] In some embodiments of the methods of treating an inflammatory ocular condition, the composition is a solution, an emulsion, or a suspension. In some embodiments, the composition is ophthalmically acceptable. In some embodiments, the composition is a solution. In some embodiments, the composition is an emulsion. In some embodiments, the composition is a suspension. In some embodiments where the composition is a solution, the solution is an aqueous solution. In some embodiments where the composition is a solution, the solution is an oily solution. In some embodiments where the composition is an emulsion, the emulsion is a dispersion of oily droplets in an aqueous phase, i.e., an oil-in-water or a water-in-oil suspension. [0058] In some embodiments where the composition is a suspension, the suspension contains solid particles dispersed in a liquid vehicle. In some embodiments where the composition is a suspension, the suspension comprises a particle size D90 of less than 100 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 75 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 50 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 25 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 20 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 10 p in diameter. In some embodiments, the suspension comprises a particle size D90 of less than 5 p in diameter.

[0059] In some embodiments where the composition is a suspension, the suspension comprises a particle size D50 of less than 80 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 50 p in diameter. In some embodiments, the suspension comprises a particle size D50of less than 40 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 25 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 20 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 10 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 5 p in diameter. In some embodiments, the suspension comprises a particle size D50 of less than 2 p in diameter.

[0060] In some embodiments of the methods of treating an inflammatory ocular condition, the composition comprises about 0.005% to about 10% of an allylamine. In some embodiments of the methods of treating an inflammatory ocular condition, the composition comprises about 0.005% to about 10% of formula (I)

or pharmaceutically acceptable salt, conjugate or derivative thereof, wherein X is substituted or unsubstituted C3 to C12 alkyl, alkenyl or alkynyl, or a C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl. In some embodiments, X is substituted or unsubstituted Ce to Cx alkyl, alkenyl or alkynyl. In some embodiments, the alkyl, alkenyl or alkynyl can be a straight-chain. In some embodiments, the alkyl, alkenyl or alkynyl is branched. In some embodiments, X is a C3 to C12 alkyl, alkenyl or alkynyl optionally interrupted with one or more of N, S or O. In some embodiments, X is an alkynyl, e.g., a branched alkynyl. In some embodiments, X is a di- or tri-alkyl alkynyl, e.g., a di- or tri- methyl alkynyl. In some embodiments, any of the alkyl, alkenyl or alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl can be optionally substituted, e.g., with one or more of C1-C3 alkyl, hydroxyl, etc. In some embodiments of formula (I), X is substituted or unsubstituted C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl. In some embodiments of formula (I), X is substituted or unsubstituted Ce cycloalkyl, aryl, cycloalkyl alkyl, or aryl alkyl. In some embodiments of formula (I), X is substituted or unsubstituted Ce cycloalkyl, aryl, cycloalkyl C1-C3 alkyl, or aryl C1-C3 alkyl. In some embodiments, the composition comprises about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8% about 9% or about 10% of formula (I) or pharmaceutically acceptable salt, conjugate or derivative thereof. In embodiments where X is substituted, X comprises one, two three, four or more halogen substitutions.

[0061] In some embodiments of the methods of treating an inflammatory ocular condition described herein, the composition comprises about 0.005% to about 10% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the composition comprises about 0.01% to about 5% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the composition comprises about 0.05% to about 2.5% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the composition comprises about 0.1% to about 1% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the composition comprises about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8% about 9% or about 10% terbinafine, naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof.

[0062] In some embodiments of the methods of treating an inflammatory ocular condition described herein, the composition can comprise two or more allylamines or pharmaceutically acceptable salts, conjugates or derivatives thereof. In some embodiments where two or more allylamines or pharmaceutically acceptable salts, conjugates or derivatives thereof are present, they may be present at a total concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments where two or more allylamines or pharmaceutically acceptable salts, conjugates or derivatives thereof are present, they may be present at a total concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0063] In some embodiments of the methods of treating an inflammatory ocular condition described herein, the composition can comprise both terbinafine and naftifine or pharmaceutically acceptable salts, conjugates or derivatives thereof. In some embodiments where both terbinafine and naftifine or pharmaceutically acceptable salts, conjugates or derivatives thereof are present, they may be present at a total concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments where both terbinafine and naftifine or pharmaceutically acceptable salts, conjugates or derivatives thereof are present, they may be present at a total concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0064] In some embodiments of the methods of treating an inflammatory ocular condition, the composition comprises one or more tonicity agents. Tonicity agents are known in the art, and can include, e.g., dextrose, glycerin, sodium chloride, sodium nitrate, sodium sulfate, or combinations thereof. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, the composition has a tonicity equal to about 0.5% to about 1.8% sodium chloride. In some embodiments, the composition has a tonicity equal to about 0.6% to about 1.5% sodium chloride. In some embodiments, the composition has a tonicity equal to about 0.7% to about 1.1% sodium chloride. In some embodiments, the composition has a tonicity equal to about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7% or about 1.8% sodium chloride.

[0065] In some embodiments of the methods of treating an inflammatory ocular condition, the composition comprises one or more pH adjusting agents, such as hydrochloric acid, citric acid, phosphoric acid or sodium hydroxide, or buffering agents such as citrate buffers or phosphate buffers. In some embodiments, the composition has a pH of about 4 to about 8. In some embodiments, the composition has a pH of about 6 to about 8. In some embodiments, the composition has a pH of about 6.8 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 7.8. In some embodiments, the composition has a pH of about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7 or about 7.8.

[0066] In some embodiments of the methods of treating an inflammatory ocular condition, the composition comprises one or more ophthalmically acceptable excipients. In some embodiments, the composition comprises an ophthalmically acceptable buffer, tonicity agent, osmotic pressure regulating agent, viscosity modifying agent, adhesive agent, penetrating agent, a preservative, such as an antimicrobial agent, antioxidant or chelating agent, a solubilizing agent or combinations thereof. In some embodiments, the composition is sterile. In some embodiments, an excipient may be selected from Povidone K30, hydroxy ethyl cellulose, cyclodextrin, carboxymethyl cellulose, dextran, glycerin, hypromellose, polyethylene glycol 300/ 400 (PEG 300/400), polysorbate, polyvinyl alcohol, povidone, propylene glycol, retinyl palmitate, tocopheryl acetate, magnesium ascorbyl phosphate, sodium chloride, sodium hydroxide, phenoxyethanol, alcohol, disodium EDTA, or combinations thereof. In some embodiments where the composition is a semi-solid, an excipient may be selected from white petrolatum, mineral oil, light mineral oil, lanolin or combinations thereof.

[0067] In some embodiments of the methods of treating an inflammatory ocular condition, the composition may be administered periodically for a period of time necessary to treat the inflammatory ocular condition, i.e., the composition is administered repeatedly over a period of time. In some embodiments, the composition is administered for more than one day. In some embodiments, the composition is administered for more than three days. In some embodiments, the composition is administered for more than five days. In some embodiments, the composition is administered for more than one week. In some embodiments, the composition is administered for more than two weeks. In some embodiments, the composition is administered for more than three weeks. In some embodiments, the composition is administered for more than 1 month. In some embodiments, the composition is administered for more than 3 months. In some embodiments, the composition is administered for more than 6 months. In some embodiments, if the inflammatory ocular condition is long-term or chronic, the composition is administered as needed and for a period of time sufficient to reduce or alleviate one or more symptoms associated with the ocular condition.

[0068] In some embodiments of the methods of treating an inflammatory ocular condition, the composition may be administered at a frequency necessary to treat the inflammatory ocular condition. In some embodiments, the composition is administered 1 to 12 times per day. In some embodiments, the composition is administered 2 to 10 times per day. In some embodiments, the composition is administered 3 to 8 times per day. In some embodiments, the composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times per day. In some embodiments, the composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times every other day. In some embodiments, the composition is administered as needed to reduce or alleviate one or more symptoms associated with the ocular condition.

[0069] In some embodiments of the methods of treating an inflammatory ocular condition, the composition is administered on alternate days. In some embodiments, the composition is administered six days a week, five days a week or four days a week. In some embodiments, the composition is administered three days a week. In some embodiments, the composition is administered two days a week. In some embodiments, the composition is administered one day a week. In some embodiments, the composition is administered every two days, every three days, every four days, every five days, or every six days.

[0070] In other embodiments, the present disclosure provides methods of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, i.e., allergic eye disease,, dry-eye disease, blepharitis, uveitis, ocular pain, or combinations thereof, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the ocular condition is not caused by a fungal infection. In these embodiments of treating an ocular condition, the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%. In embodiments of these methods, the allylamine is a compound of formula (I) as described herein.

[0071] In other embodiments, the present disclosure provides methods of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, i.e., allergic eye disease, dry-eye disease, blepharitis, uveitis, ocular pain, or combinations thereof, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine or pharmaceutically acceptable salt thereof, wherein the ocular condition is not caused by a fungal infection. In these embodiments of treating an ocular condition, the terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0072] In other embodiments, the present disclosure provides methods of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, i.e., allergic eye disease, diy-eye disease, blepharitis, uveitis, ocular pain, or combinations thereof, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the ocular condition is not caused by a fungal infection. In these embodiments of treating an ocular condition, the naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0073] In other embodiments, the present disclosure provides methods of preventing a corneal transplant rejection, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof. In these embodiments of preventing a corneal transplant rejection, the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%. In embodiments of these methods, the allylamine is a compound of formula (I) as described herein.

[0074] In other embodiments, the present disclosure provides methods of preventing a corneal transplant rejection the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafme or pharmaceutically acceptable salt thereof. In these embodiments of preventing a corneal transplant rejection, the terbinafme or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the terbinafme or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0075] In other embodiments, the present disclosure provides methods preventing a corneal transplant rejection, the methods comprising topically administering to an ocular surface of a subject in need thereof a composition comprising naftifine or pharmaceutically acceptable salt, conjugate or derivative thereof. In these embodiments of preventing a corneal transplant rejection, the naftifme or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.005% to about 10%, about 0.01% to about 5%, about 0.05% to about 2.5% or about 0.1% to about 1%. In some embodiments, the naftifme or pharmaceutically acceptable salt, conjugate or derivative thereof can be present in the composition at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%.

[0076] In some embodiments, as used herein, the phrase “preventing a corneal transplant rejection” refers to increasing the likelihood that a corneal transplant will be successful, e.g., not rejected, relative to a subject not receiving the allylamine formulation. In some embodiments, as used herein, the phrase “preventing a corneal transplant rejection” refers to decreasing the inflammation associated with a corneal transplantation relative to a subject not receiving the allylamine formulation, and subsequently decreasing the risk of rejection.

[0077] In some embodiments, the present disclosure provides methods of treating an ocular condition by administering an allylamine, e.g., naftifme and/or terbinafine, or pharmaceutically acceptable salt, conjugate or derivative thereof and an additional active agent. In some embodiments, the additional active agent is administered in the same dosage form, e.g., the same topical composition. In some embodiments, the additional active agent is administered in a separate dosage form, e.g., a separate topical composition. In some embodiments, the administration of the allylamine, e.g., naftifme and/or terbinafine, or pharmaceutically acceptable salt, conjugate or derivative thereof and an additional active agent occurs at the same time. In some embodiments, the administration of the allylamine, e.g., naftifme and/or terbinafine, or pharmaceutically acceptable salt, conjugate or derivative thereof and an additional active agent is alternated, e.g., the allylamine, e.g., naftifme and/or terbinafine, or pharmaceutically acceptable salt, conjugate or derivative thereof is administered during a first period of time, e.g., in the morning, bi-daily starting on a first day, bi-weekly starting on a first week, etc., and the additional active agent is administered during a second period of time, e.g., in the night, bi-daily starting on a second (and subsequent alternating) days, bi-weekly starting on a second (and subsequent alternating) weeks, etc. In some embodiments, the additional active agent is administered systemically and the allylamine, e.g., naftifme and/or terbinafine, or pharmaceutically acceptable salt, conjugate or derivative thereof is administered topically. In some embodiments, the additional active agent is selected from, alcaftadine, azelastine hydrochloride, bepotastine besilate, cetirizine hydrochloride, dexamethasone, epinastine hydrochloride, ketorolac tromethamine, loteprednol etabonate, nedocromil sodium, olopatadine hydrochloride, prednisolone acetate, cromolyn sodium, lodoxamide tromethamine, clyclosporine, hydroxypropyl cellulose, lifitegrast, loteprednol, etabonate, difluprednate, or combinations thereof.

[0078] In some embodiments, the methods of treatment as described herein can refer to a prophylaxis treatment. The term “prophylaxis treatment” refers to the treatment of an inflammatory ocular condition before any symptoms of inflammation are manifest. In some embodiments, the term “prophylaxis treatment” can refer to the reduction of incidents of an inflammatory ocular condition in a subject. In some embodiments, the term “prophylaxis treatment” can refer to the prevention of symptoms associated with an inflammatory condition. In some embodiments, the prophylactic treatment can be applied to a subject in need there, e.g., a subject who would be expected to have a higher likelihood of experiencing symptoms associated with an inflammatory ocular condition. For example, in some embodiments, the prophylactic treatment can be applied to a subject who has autoimmune disease, for example, Behcet disease, lupus, multiple sclerosis, psoriasis, Reiter's syndrome, rheumatoid arthritis, Sjogren's Syndrome or thyroid diseases, before the onset of symptoms associated with the inflammatory ocular condition. In some embodiments, the prophylactic treatment can be applied to a subject who has an increased susceptibility to an inflammatory ocular condition is selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, blepharitis, dry-eye disease, uveitis or combinations thereof.

[0079] In some embodiments, the methods of treating an inflammatory ocular condition as described herein can be used as a curative treatment. The term “curative treatment” as used herein can refer to the promotion and/or recovery from the symptoms associated with the inflammatory ocular condition.

[0080] The present disclosure provides for methods of treating the ocular conditions as provided herein. The present disclosure provides that the formulations as provided herein are suitable for administration to an ocular surface, without the appearance of significant adverse effects, e.g., toxicity, eye inflammation, eye itching, red eyes, blurred vision, allergic reactions, etc. In some embodiments, the present disclosure provides for methods of administration sufficient for the active agent to arrive at the area to be treated, e.g., the allylamine of Formula I can be localized, permeate and/or be absorbed to reach the tissue in the subject to be treated.

[0081] The disclosure provides that topical application of a composition comprising an allylamine of Formula I via eye drops, eye sprays, eye gels, eye creams, eye emulsions, eye suspensions, eye wipes as described herein to the ocular surface is suitable for the methods of treatment described herein. For example, the disclosure provides that the topical administration of a composition as described herein provides an amount (e.g., volume and/or concentration) of active agent, e.g., an allylamine of Formula I, sufficient to treat a condition as described herein, e.g., an inflammatory ocular condition, uveitis, dry eye, etc. In some embodiments, the amount of active agent administered is sufficient for treatment of the ocular condition without resulting in an adverse effect. The disclosure also provides that topical administration can allow the administration of the active agent, e.g., an allylamine of Formula I, in an amount sufficient to treat the condition without the need for inconvenient or unnecessary excesses of administrations.

[0082] The disclosure also provides for the topical administration of a composition comprising an active agent, e.g., an allylamine of Formula I, to an ocular surface, wherein the active agent resides on the ocular surface for a time sufficient to treat a condition as described herein, e.g., an inflammatory ocular condition, uveitis, dry eye, etc. In some embodiments, the disclosure provides that topical administration to the surface one time a day, two times a day, three times a day, four times a day, five times a day or six times a day is sufficient to treat a condition as described herein. In some embodiments, the disclosure provides that topical administration to the surface one time a day, two times a day, three times a day, four times a day, five times a day or six times a day is sufficient to treat a chronic ocular condition as described herein. In some embodiments, the composition comprising an active agent, e.g., an allylamine of Formula I, resides on the ocular surface for a time and in an amount sufficient to treat the ocular condition with reduced applications, e.g., the composition is only administered one time a day, two times a day, three times a day, four times a day, five times a day or six times a day. In some embodiments, the methods described herein provide for alleviation of symptoms associated with the condition for greater than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours or 24 hours. In some embodiments, the methods described herein result in improved patient compliance, for one or more of the following reasons: reduced adverse effect, ease of application, frequency of application, convenience, effectiveness, etc.

[0083] In specific embodiments, the disclosure is directed to a method of treating dry-eye disease or uveitis, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0084] In some embodiments, the disclosure is directed to a method of reducing the symptoms of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. The terms “symptoms” and “signs and symptoms” are interchangeable as described herein. Symptoms of dry eye include, but are not limited to a stinging, burning or scratchy sensation in your eyes, stringy mucus in or around your eyes, sensitivity to light, eye redness, a sensation of having something in your eyes, difficulty wearing contact lenses, difficulty with nighttime driving, watery eyes, which is the body's response to the irritation of dry eyes, blurred vision or eye fatigue, or combinations thereof.

[0085] In some embodiments, the disclosure is directed to a of ameliorating a symptom of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the symptom is a decrease in aqueous tear production, increase in tear evaporation, increase in cellular inflammation or combination thereof.

[0086] In some embodiments, the disclosure is directed to a method of treating a patient for an autoimmune ocular inflammatory disease (AOID), comprising administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the AOID is Rheumatoid arthritis, juvenile rheumatoid arthritis, Sjogren's syndrome, the seronegative spondyloarthropathies, systemic lupus erythematosus, multiple sclerosis, giant cell arteritis, and Graves' disease. In some embodiments, the autoimmune ocular inflammatory disease (AOID) is dry eye disease. In some embodiments, the autoimmune ocular inflammatory disease (AOID) is uveitis. In some embodiments, the subject having AOID as higher levels of tear cytokines such as IL-8 and tumor necrosis factor-al . Thus, in some embodiments, the disclosure provides a method of treating a patient with AOID which manifests with elevated levels of tear cytokines such as IL- 8 and tumor necrosis factor-al .

[0087] In some embodiments, the disclosure is directed to a method for enhancing or restoring lacrimal gland tearing comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0088] In some embodiments, the disclosure is directed to a method of increasing tear production in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0089] The effect of the methods described herein can be measured by methods known to the skilled artisan. In some embodiments, ocular anti-inflammatory effect in an eye, can be measured, e.g., by a lipopolysaccharide (LPS)-induced model of anterior uveitis allows for the evaluation of ocular anti-inflammatory treatments, and/or by using experimental autoimmune uveitis (EAU) as a model of certain ocular inflammatory pathologies in human. In some embodiments, treatments of specific diseases such as for dry eye can be evaluated using, e.g., Schirmer’s tear test to determine tear production and/or a corneal staining test.

[0090] In some embodiments, the disclosure provides a method of reducing inflammation in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

[0091] In some embodiments, the disclosure provides a method of reducing the levels of inflammatory cytokines in the ocular secretions, e.g., in tear fluid, of a patient suffering from inflammation of the eye by administering the allylamine such as terbinafine, naftifine, or a pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the disclosure provides a method of reducing the levels of inflammatory cytokines in the ocular secretions, e.g., tear fluid, in a patient suffering from an AOID, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifme or a pharmaceutically acceptable salt, conjugate or derivative thereof Previous studies reported that patients with autoimmune inflammatory ophthalmic diseases had higher levels of tear cytokines such as IL-8 and tumor necrosis factor-al. See, e.g., Roda et al., Dry Eye Disease and Tear Cytokine Levels — A Meta-Analysis., Int. J. Mol. Sci. 2020, 21. However, it has also been reported that allylamines such as Terbinafine increase the release of inflammatory mediators IL-8 and TNFa2. See, e.g., Mizuno et al., Terbinafine stimulates the pro- inflammatory responses in human monocytic THP-1 cells through an ERK signalling pathway, Life Sci., 2010 Oct 23;87(17-18):537-44. The present disclosure provides that even though allylamines such as Terbinafine were previously reported to increase the release of proinflammatory mediators, treatment for an ocular inflammatory condition (e.g., reduction in inflammation) can occur by topical administration to the ocular surface of the allylamine such as Terbinafine.

[0092] In some embodiments, the inflammatory cytokine which is reduced is a proinflammatory cytokine. In some embodiments, the proinflammatory cytokine is selected from tumor necrosis factor-al and IL-8, IL-6, IL-la, IL-1/?, IL-12, and interferon [fFN]-y and combinations thereof. In some embodiments, the proinflammatory cytokine is selected from tumor necrosis factor-al, IL-8 and combinations thereof. While note being bound by any particular theory, the skilled artisan can appreciate that in some embodiments, one or more proinflammatory cytokines are reduced to an extent sufficient to reduce the ocular inflammation, while other proinflammatory cytokines may not be affected, may remain the same, or may increase. In some embodiments, the proinflammatory cytokine is not tumor necrosis factor-al and IL-8. In some embodiments, the inflammatory cytokine is an anti-inflammatory cytokine.

[0093] In some embodiments, the disclosure provides a method of increasing the levels of antiinflammatory cytokines in the ocular secretions, e.g., in tear fluid, of a patient suffering from inflammation of the eye by administering the allylamine such as terbinafine, naftifme, or a pharmaceutically acceptable salt, conjugate or derivative thereof. In some embodiments, the disclosure provides a method of increasing the levels of anti-inflammatory cytokines in the ocular secretions, e.g., tear fluid, in a patient suffering from an AOID, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. While note being bound by any particular theory, the skilled artisan can appreciate that in some embodiments, one or more anti-inflammatory cytokines are increased to an extent sufficient to reduce the ocular inflammation, while other anti-inflammatory and proinflammatory cytokines may not be affected, may remain the same, or may increase.

[0094] In some embodiments, the disclosure provides a method of treating normal tension glaucoma in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. The term normal tension glaucoma, also called NTG, low-tension or normal-pressure glaucoma, as used herein refers to a condition in which the optic nerve is damaged without eye pressure exceeding the average range, e.g., 12-21 mm Hg). In some embodiments, the normal tension glaucoma is caused by, or is the result of, abnormalities in the blood flow to the optic nerve, and/or structural weakness of the optic nerve tissue. In some embodiments, the disclosure provides a method of treating primary open angle glaucoma (POAG).

[0095] All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.

EXAMPLES

Example 1 - Ophthalmic Solutions of Terbinafine

[0096] Aqueous solutions comprising Terbinafine can be formulated as sterile solutions that contain excipients, which, for example, regulate osmotic pressure, the pH, and viscosity of the preparation. As Terbinafine HC1 is a poorly water soluble drug, it is necessary to improve the solubility in order to increase its bioavailability.

[0097] A first example of an aqueous solution of Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 1: Table 1

[0098] A second example of an aqueous solution of Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 2:

Table 2

Terbinafine HC1 ; 0.2 - 0.5

Cyclodextrin H.5

Benzalkonium chloride i 0.02 - 5

Hydroxy ethylcellulose 0.2 - 1.5

Buffering and tonicity agents i To equal the pH & osmolality of tears

Water q.s to 100 mL

Example 2 - Ophthalmic Suspensions of Terbinafine

[0099] Sterile suspensions of Terbinafine HC1 may contain excipients, which, for example, regulate osmotic pressure, the pH, and viscosity of the preparation. The suspensions typically contain particles of Terbinafine HC1 that are suspended in solution, for example, micronized Terbinafine HC1 particles.

[00100] A first example of a suspension of micronized Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 3:

Table 3

Terbinafine HC1 (micronized) 0.2 - 2

Carboxymethylcellulose 0.5 - 2.5

[00101] A second example of a suspension of micronized Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 4:

Table 4

Example 3 - Ophthalmic Ointments of Terbinafine

[00102] An example of an ointment of micronized Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 5:

Table 5

Light Mineral Oil 10-30

Example 4 - Ophthalmic Gels of Terbinafine

[00103] Sterile gels of Terbinafine HC1 may contain excipients, which, for example, regulate osmotic pressure, the pH, and viscosity of the preparation. [00104] A first example of a gel of Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 6:

Table 6

[00105] In some embodiments of the first example gel, the buffer system comprises one or more of phosphoric acid, sodium hydroxide or sodium perborate.

[00106] A second example of a gel of Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 7:

Table 7

[00107] A third example of a gel of Terbinafine HC1 having increased bioavailability is prepared having the concentrations and ingredients shown in Table 8:

Table 8

[00108] In some embodiments of the third example gel, the tonicity agent comprises potassium chloride. In some embodiments of the third example gel, the buffer system comprises boric acid and sodium borate. In some embodiments of the third example gel, the lubricant comprises sodium hyaluronate. In some embodiments of the third example gel, the preservative comprises sodium chlorite.

Example 5 - Terbinafine Eye Drops

[00109] A first example of an eye drop composition of Terbinafine HC1 comprising castor oil is prepared having the concentrations and ingredients shown in Table 9:

Table 9

[00110] A second example of an eye drop composition of Terbinafine HC1 comprising PEGPLUS ((poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG)) is prepared having the concentrations and ingredients shown in Table 10. Compositions comprising PEGPLUS may help stabilize the active agent upon administration allowing for less frequent dosing.

Table 10

[00111] A third example of an eye drop composition of Terbinafine HC1 comprising hyaluronic acid is prepared having the concentrations and ingredients shown in Table 11:

Table 11

Example 6 - Treatment of Dry Eye

[00112] The formulations as described herein are administered to human subjects suffering from dry eye. The formulations are administered to the subject one time a day, two times a day, three times a day, four times a day, every three hours when awake, every two hours when awake or every hour when awake. Appropriate controls are considered and utilized. The dry eye conditions in the subject are monitored by methods known in the art, e.g., those methods as found in The Ocular Surface (2007), 5(2): 108-52. Subject are monitored daily for 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 35, 42 or 49 days. One or more of the formulations as described herein provide a reduction in a dry eye symptom in the subjects, e g., on average a greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90% reduction in a dry eye symptom in the subject after 1 week, 2 weeks, 3 weeks, and/or 4 weeks, relative to the control subjects.

Example 7 - Treatment of Uveitis

[00113] The formulations as described herein are administered to human subjects suffering from uveitis. The formulations are administered to the subject one time a day, two times a day, three times a day, four times a day, every three hours when awake, every two hours when awake or every hour when awake. Appropriate controls are considered and utilized. The uveitis conditions in the subject are monitored by methods known in the art, e.g., by an eye chart or visual acuity test, a funduscopic exam, an ocular pressure test or a slit lamp exam. Subject are monitored daily for 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 35, 42 or 49 days. One or more of the formulations as described herein provide a reduction in a uveitis symptom in the subjects, e.g., on average a greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90% reduction in a uveitis symptom in the subject after 1 week, 2 weeks, 3 weeks, and/or 4 weeks relative to the control subjects.

Example 8- Animal Models for Treatment of Allergic Conjunctivitis

[00114] Exemplary studies for testing the effect of ophthalmic allylamine in treatment of inflammatory ocular conditions in animal models are provided.

Example 8a: Mice models for Allergic Conjunctivitis by Groneberg et al.

[00115] In some embodiments, testing of the anti-allergic effects of allylamine compounds can be tested using an Ovalbumin-Induced Allergic Conjunctivitis in guinea pig, mouse and rat models, as outlined by Groneberg et al., “Animal models of allergic and inflammatory conjunctivitis,” Allergy 58: 1101-13 (2003), incorporated by reference herein in its entirety.

[00116] In some embodiments, a mouse model can be used. To establish experimental allergic conjunctivitis in a mouse model, BALB/c mice are sensitized intraperitoneally (i.p.) with 100 pg of ovalbumin (OVA) and 200 pL of 1.5% aluminum hydroxide (ALUM) on Days 0 and 7. On Days 15 and 18 of the experiment, the mice are challenged twice by topical instillation of 250 pg of OVA in the conjunctival sac. One hour prior to the OVA challenge, one or more of the allylamine formulations as described herein will be topically applied to the eye. Control group will be treated with vehicle or PBS.

[00117] Approximately 15-30 minutes after each OVA challenge, mice will be assessed for clinical symptoms and signs of allergic effects. The observed clinical signs will include conjunctival redness, lid edema, tearing and discharge. Scratching behavior will be scored by an independent observer blinded to the grouping. Blood, eyes, spleen, and cervical lymph nodes (CLN) will be collected 24 hours from the mice after the final challenge. Biomaterial collected from the mice will be used for further analysis such as measuring serum specific IgE, Th2 cytokine production, and eosinophil infiltration.

Example 8b: Guinea pig models for Allergic Conjunctivitis by Dattoli, S.D., et al.

[00118] In some embodiments, an animal model as outlined by Dattoli, S.D., et al, “DS-70, a novel and potent a 4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs,” Br J Pharmacol. 175(20):3891-3910 (2018), can be used, which is incorporated by reference herein in its entirety.

[00119] Animals, e.g., guinea pigs, can be sensitized to chicken-derived ovalbumin using aluminum hydroxide as an adjuvant to promote an IgE-mediated conjunctival allergic response. In an example using 40 animals, guinea pigs are randomly divided into eight experimental groups of five animals per group. Five groups are sensitized on days 1, 7 and 14 by an i.p. injection of 200 pg of ovalbumin with 40 mg of aluminum hydroxide suspended in 200 pL of saline, and three groups receive an i.p. injection of 200 pL of saline (control). On day 21, sensitized guinea pigs and one control group receive 30 pL of saline containing 3 mg of ovalbumin in the conjunctival fornix of both eyes; 30 and 10 min before ovalbumin challenge, three groups of sensitized animals receive 30 pL of a vehicle containing an allylamine formulation described herein, respectively, in the conjunctival fornix of both eyes and gently closing the eyelid to prolong the drug residence time in the conjunctiva. Another group of ovalbumin-sensitized guinea pigs and a control group receive 30 pL of vehicle per eye 30 and 10 min before ovalbumin challenge. The second control group receive an allylamine formulation in both eyes 30 and 10 min before topical saline administration. The last control group receive dexamethasone (30 pL of 0.1 g- 100 mL"¹; 0.1% ), 30 and 10 min before topical saline administration. Finally, an ovalbumin-sensitized guinea pig group receive 30 pL of 0.1% dexamethasone in both eyes 30 and 10 min before ovalbumin challenge.

[00120] Clinical conjunctival symptoms are rated in both eyes using the following scale: 0, no symptoms; 1, slight conjunctival redness with or without tears; 2, mild conjunctival redness with or without tears and mild chemosis; 3, mild conjunctival redness with or without tears and moderate chemosis; 4, severe conjunctival redness with tears and partial lid eversion; 5, severe conjunctival redness with tears and lids more than half closed. Photographs of both eyes can be taken to evaluate the clinical score 30 min before ocular treatments and 1, 2, 4, 6 and 24 h after ovalbumin administration. Guinea pigs are sedated, prior to ovalbumin challenge, with a mixture of Ketalar® and Rompun® (32 mg kg^-1 Ketalar and 2.3 mg kg^-1 Rompun), given i.p..

[00121] Tarsal conjunctiva are carefully excised from both eyes and divided into separate samples for subsequent investigations. One sample is fixed with a 10% buffered paraformaldehyde solution and embedded in paraffin. Slices (6 pm thick) are stained to determine the number of mast cells and eosinophils and to perform immunohistochemical (IHC) assays. Other samples are collected to quantify eosinophil peroxidase activity, cytokine and chemokine mRNA levels.

Example 8c: Guinea pig models for Allergic Conjunctivitis by Nakazaw a Y., et al.

[00122] In some embodiments, an animal model as outlined by Nakazawa Y., et al., “Model for Studying Anti- Allergic Drugs for Allergic Conjunctivitis in Animals f Open Med (Wars), 12:231- 238 (2017), can be used, which is incorporated by reference herein in its entirety.

[00123] To actively sensitize 3-week-old guinea pigs, subconjunctival injections of 2pg of ovalbumin (OA) with 2 mg of aluminum hydroxide gel are administered on day 0. On days 15, 17, and 19, 20 pL of 2.5% OA solution is instilled into the conjunctival sac as a challenge for the positive control and drug treatment groups, or PBS is instilled into the conjunctival sac for the control group. On day 19, an allylamine formulation as described herein is administered to conjunctival sac of the animals 5 and 15 min before the final challenge with OA.

[00124] Scratching behavior is evaluated. Animals are housed in a cage in the observation room to acclimatize for 2 h before the challenge with 2.5% OA, after which their behavior is recorded.

[00125] Animals are recorded by video and monitored for scratching reactions. Scratching behavior is defined as an interrupted cluster of rapid hind limb movements precisely directed to the eye. Scratching behavior is counted within 1 h from OA exposure on days 15 and 19. Scratching responses are calculated based on the number of such behaviors on day 19 divided by the number of these behaviors recorded on day 15 for the same individual. This experiment can be independently performed six times. Example 8d: Rat models for Allergic Conjunctivitis byAkyuz Unsal, A. I.., et al.

[00126] In some embodiments, an animal model as outlined by Akyuz Unsal, A.L., et al., “Effect of Pycnogenol® on an experimental rat model of allergic conjunctivitis f Graefes Arch Clin Exp Ophthalmol., 256(7): 1299-1304 (2018), can be used, which is incorporated by reference herein in its entirety.

[00127] Ovalbumin and A1(OH)3 are given seven times intraperitoneally (i.p.) every other day and ovalbumin installed everyday directly on conjunctiva to create an AC rat model. Then, the allylamine formulation is applied in the study groups. Control rats are given adjuvant A1(OH)3 i.p. and topical saline on conjunctiva. A negative control group in which only the allylamine formulation is administered i.p. and an AC positive control group which is given dexamethasone (1 mg/kg/7 days) is created. Mast cells are counted with a microscope; histological evaluation is performed with H-E and toluidine blue, mast cell tryptase, and TNF-a and TGF-P staining.

Example 8e: Rat models for Allergic Conjunctivitis by Semsettin, B., et al.

[00128] In some embodiments, an animal model as outlined by Semsettin, B., et al, “Comparison of the effects of topical cyclosporine a 0.05%, cyclosporine a 2%>, epinastine hydrochloride 0.05%, and prednisolone acetate 1% on allergic inflammation in an experimental allergic conjunctivitis model,” Cornea 32(11): 1465-9 (2013), can be used, which is incorporated by reference herein in its entirety.

[00129] Wistar Albino male rats can be used, and divided into groups. All the rats are sensitized by an intraperitoneal injection of a solution of 100 pL that contained 100 pg of ovalbumin (OVA, grade V) and 20 mg of A1(OH)3 (200 mg/mL; Sigma Immunochemicals) as an adjuvant.

[00130] Two weeks after the sensitization is done, the groups are given daily treatments for 7 days of the following: allylamine formulation drops were administered 4 times to the eyes of the rats in treatment groups. Control groups can include administration of known treatments as well as a group not administered any additional treatments.

[00131] On the 21st day of the experiment, 10 mb of ovalbumin at a concentration of 100 mg/mL prepared in saline solution with a phosphate buffer is administered to both conjunctival fomices of the eyes to challenge each rat 1 hour before the instillation of the last drop. Twenty-four hours after being challenged, the rats are clinically evaluated, and they are anesthetized using 150 mg/kg of intramuscular ketamine hydrochloride. Both eyes of the rats are exenterated including the upper and lower eyelids with conjunctiva. These tissues are fixed in a 10% neutral-buffered formalin solution. Eyes are embedded in paraffin after routine tissue follow-up, and 5-mm sections are cut for hematoxylin-eosin and toluidine blue staining. The general structure of the conjunctiva is analyzed in the sections stained with hematoxylin-eosin, whereas mast cell counts are analyzed in sections stained with toluidine blue. The general structures of the conjunctiva are evaluated by the analysis of the structure of the epithelia, edema in the connective stroma, inflammatory cell infiltration, and mast cell degranulation in the sections stained with hematoxylineosin. The changes are categorized according to their histopathological conditions as follows: none (0), slight (1), medium (2), and severe (3). By the addition of the scores of these 4 parameters, which are taken to be equivalent, histopathological score data are obtained for each rat, and the mean values are calculated for each group. The mast cells are counted in 5 different areas of the conjunctiva by using the Leica QWin Analysis System (Leica Microsystems, Buffalo Grove) with a 10- lens. Mast cells that had 5 or more extracellular granules are considered as degranulated.

Example 9- Animal Models for Treatment of Dry Eye Disease

[00132] Exemplary studies for testing the effect of ophthalmic allylamine in treatment of dry eye disease in animal models are provided.

Example 9a: Mice models for Dry Eye Disease by Jung, Y. H. et al.

In some embodiments, an animal model as outlined by Jung, Y. H., et al, "Age-Dependent Distinct Distributions of Dendritic Cells in Autoimmune Dry Eye Murine Model f Cells 10(8): 1857 (2021), can be used, which is incorporated by reference herein in its entirety.

[00133] Eight C57BL/6 (B6) male mice and eight NOD.B10.H2b male mice (The Jackson Laboratory, Bar Harbor, ME) can be used to study the effects of treatments with allylamine formations according to age. Eight-week- (n = 4) and 20-month-old (n = 4) B6 mice are included as the young and aged B6 group, while five-week- (n = 4) and 24-week-old (n = 4) NOD.B10.H2b mice are included as the young and aged NOD group. [00134] After administration of the allylamine formulations, corneal staining and tear secretion tests are performed under anesthesia (using a mixture of zoletil and xylazine at a ratio of 1 :3). Corneal staining is blindly assigned by a single experienced ophthalmologist using the National Eye Institute (NEI) scoring scheme. Fluorescein dye (0.25%) and Lissamine Green B (3%) (Sigma-Aldrich, St. Louis, MO, USA) is used for corneal staining in B6 and NOD.B10.H2b mice, respectively. The different dyes are selected for visualizing dry eyes in the two types of mice both having different levels of iris pigments, as reported in previous studies.

[00135] After placing one drop of dye on the conjunctival sac for 30 seconds, the ocular surface is gently washed with 1 mL of normal saline. Corneal staining is observed using a microscope. The B6 and NOD.B10.H2b mice are observed using cobalt blue and white light (LED) illumination, respectively. For the tear secretion test, phenol red-impregnated cotton threads (FCI Ophthalmics, Pembroke, MA, USA) are placed into the lateral canthus of mice for 60s. The average values of corneal staining scores and tear secretion results from both eyes of each mouse are used for the statistical analyses based on a protocol described in a previous study. Tear volume is adjusted by body weight for the analysis based on protocols used in previous studies because LG increased with aging and a positive correlation between body weight and LG size has been reported.

Example 9b: Mice models for Dry Eye Disease by Kim, K.H,. et al.

[00136] In some embodiments, an animal model as outlined by Kim, K.H, et al, “Effects of subconjunctival administration of anti-high mobility group box 1 on dry eye in a mouse model of Sjogren's syndrome,” PLoS One. 2017 Aug 24;12(8):e0183678, can be used, which is incorporated by reference herein in its entirety.

[00137] Ten week-old male NOD. B10.H2b mice are used as an autoimmune dry eye model, because NOD.B10.H2b mice serve as a model for studying primary Sjogren’s syndrome without development of diabetes. To investigate inhibitory effect of triggering by HMGB1 in early stage of inflammatory cascades, 10 week-old mice are chosen. A time course of clinical manifestations and inflammatory changes in the draining lymph nodes and intraorbital glands is evaluated between 10 and 16 weeks in BALB/C (n = 28), B6 (n = 32) and NOD.B10.H2b mice (n = 34). Clinical dry eye and early inflammation will be confirmed to have begun by 10 weeks (SI Fig). For the current study, 24 maleNOD. B10.H2b mice are divided into treatment (n = 18) and control groups (n = 6).

[00138] An allylamine formulation is injected subconjunctivally into both eyes twice a week for 2 weeks. A subconjunctival injection of the same volume of the allylamine formulation (without the allylamine) serves as a control.

[00139] To evaluate tear production, phenol red-impregnated cotton threads (FCI Ophthalmics, Pembrooke, MA, USA) are applied to the lateral canthus for 60 seconds, and wetting of the thread is measured in millimeters. This was performed under anesthesia with zoletil (10 mg/kg) and xylazine (14 mg/kg) (n = 10-12). The mice are included in the phenol red thread test for 10-12 weeks, and in the final analysis after sacrifice.

[00140] To evaluate the degree of corneal epithelial defects, one drop of 3% Lissamine Green B (Sigma-Aldrich, St. Louis, MO, USA) is administered to the inferior lateral conjunctival sac. This is convenient because there is no need for cobalt light excitation. The comeal surface is observed and dye staining of the cornea is scored in a blinded assay as follows: a score of 0 indicates no punctuate staining; 1 indicates less than one third of the cornea is stained; 2 indicates two thirds or less is stained; and 3 indicates more than two thirds is stained.

[00141] The whole eyeball including the superior and inferior forniceal conjunctiva is excised and fixed in formalin. Tissues are cut into 4-pm-thick sections through the superior and inferior conjunctival fomices, and subjected to PAS staining. The total number of PAS-stained cells in the superior and inferior fomices of each eye is counted by two observers in a blind study. Cell counts are averaged to determine goblet cell density in each group.

Example 9c: Mice models for Dry Eye Disease by Coursey, T.G., et al.

[00142] In some embodiments, an animal model as outlined by Coursey, T.G., et al., “ Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells, ” Mucosal Immunology 10:743-756 (2017), can be used, which is incorporated by reference herein in its entirety. Example 9d: Mice models for Dry Eye Disease by Kim, Y.J, et al.

[00143] In some embodiments, an animal model as outlined by Kim, Y.J., et al, “Comparison of Topical Application of TSG-6, Cyclosporine, and Prednisolone for Treating Dry Eye,” Cornea 35(4):536-42 (2016), can be used, which is incorporated by reference herein in its entirety.

[00144] 12-week-old NOD.B10.H2 mice are topically administered the allylamine formulations 4 times a day, 0.05% cyclosporine (Restasis) twice a day, or 1% prednisolone (Pred Forte) 4 times a day for 1 week. Aqueous tear production is measured by phenol red thread test, and corneal epithelial damage is observed with lissamine green and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Conjunctival goblet cell number is evaluated with periodic acid- Schiff staining. The levels of inflammatory cytokines are analyzed in the ocular surface (cornea and conjunctiva) and intraorbital gland. The dose-dependent effects of the allylamine formulations are tested.

[00145] The foregoing description of various embodiments provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise form disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice in accordance with the present invention. It is to be understood that the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

Example 10 - Efficacy of Terbinafine Ophthalmic Solutions in Ovalalbumin-Induced Allergic Conjunctivitis in Guinea Pigs

[00146] Preclinical efficacy of a Terbinafine ophthalmic formulation in ovalbumin-induced allergic conjunctivitis, i.e., allergic eye disease (AED), in guinea pigs was studied.

Preparation of Test Formula 1

[00147] Test Formula 1 and its corresponding placebo was prepared as in Table 12: Table 12

Administration (topical instillation)

[00148] 35 pL of Formulation 1, and Placebo were administer topically using micropipette into the conjunctival sac of both eyes as per study design groups below in Table 13:

Table 13

Experimental Procedure

[00149] On day 0, Guinea pigs were sensitized by intraperitoneal injections of 200 pg OVA in 2 ml saline with 40 mg aluminum hydroxide except saline control group. On day 7, this sensitization procedure was repeated. The saline control group was sensitized with saline.

[00150] On day 21 , Guinea pigs were instilled 35 pL of (i) Formulation 1 or (ii) Formulation 1 (Placebo) topically into both eyes as per study design. 45 min after treatment, animals were challenged with 30 pL per eye with saline solution containing 100 mg/ml OVA. The saline control group was treated with 30 pL of saline per eye.

[00151] Conjunctival clinical symptoms were observed 1, 2, 4 and 6 hours after challenge and were rated in a masked fashion on both eyes using the following scale:

0 = no symptoms

1 = slight conjunctival redness with or without tears

2 = mild conjunctival redness with or without tears and mild chemosis

3 = mild conjunctival redness with or without tears and moderate chemosis

4 = severe conjunctival redness with tears and partial lid eversion

5 = severe conjunctival redness with tears and lids more than half closed

[00152] The clinical symptom results are presented below in Table 14 and Table 15:

Table 14

Data were analysed by Two-way ANOVA followed by Bonferroni's Multiple Comparison Test. ***=p<0.001 Table 15

The evidence presented indicates the ophthalmic terbinafine formulation provided an increased inhibition of clinical symptoms compared to placebo control in AED.

[00153] The animals are euthanized 24 h after OVA challenge by CO2 asphyxiation and the whole eyeballs together with the conjunctiva and lids of animals are carefully excised and fixed in paraformaldehyde solution. The tissues are sliced into 4-pm-thick sections through superior and inferior conjunctival fomices, and sections are stained with hematoxylin and eosin or Congo red. Images are captured of stained eye sections at a magnification of 100X using Zeiss AxioAl microscope. The total number of Eosinophil’ s cells are counted per 100 pm area each section of eye.

[00154] See, e.g., Monica Baiula et al., “Eosinophil as a cellular target of the ocular anti-allergic action of mapracorat, a novel selective glucocorticoid receptor agonist,” Mol. Vis (2011) 17:3208- 23, and Monica Baiula, et al., “Mapracorat, A selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy,” Drug Design, Development and Therapy (2014) 8:745-757, both of which are incorporated herein in their entirety. [00155] All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.

Claims

WHAT IS CLAIMED IS: A method of treating an inflammatory ocular condition, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine of Formula I:

wherein X is substituted or unsubstituted C3 to C12 alkyl, alkenyl or alkynyl, or a C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl, or a pharmaceutically acceptable salt, conjugate or derivative thereof. The method of claim 1, wherein the inflammatory ocular condition is a non-infective inflammatory ocular condition. The method of claim 1, wherein the inflammatory ocular condition is not caused by a fungal infection. The method of claim 1, wherein the inflammatory ocular condition is not caused by a bacterial infection or viral infection. The method of any one of claims 1 to 4, wherein the inflammatory ocular condition is caused by a physical injury to the eye. The method of any one of claims 1 to 5, wherein the inflammatory ocular condition is an autoimmune disease. The method of any one of claims 1 to 6, wherein the inflammatory ocular condition is selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, blepharitis, dry-eye disease, uveitis, corneal epithelial disorder, or combinations thereof. The method of any one of claims 1 to 6, wherein the inflammatory ocular condition is ocular pain. The method of claim 8, wherein the ocular pain includes Nociceptive pain, Acute nociceptive pain, Chronic nociceptive pain, Cold pain, Neuropathic pain (neuralgia), Ocular itch, Allodynia, Photoallodynia, Hyperalgesia, Ocular surface pain, Orbital pain, Retrobulbar pain, Periorbital complex regional pain syndrome, or combinations thereof. The method of claim 7, wherein the corneal epithelial disorder is a corneal epithelial defect. The method of any one of claims 1 to 10, wherein the allylamine or pharmaceutically acceptable salt, conjugate or derivative thereof is terbinafine, naftifme or a pharmaceutically acceptable salt conjugate or derivative thereof. The method of claim 11, wherein the terbinafine or pharmaceutically acceptable salt, conjugate or derivative thereof is terbinafine hydrochloride, terbinafine sulfate, terbinafine phosphate, terbinafine diphosphate, terbinafine maleate, terbinafine acetate, terbinafine hydrobromide, terbinafine linoleate, terbinafine lactate or combinations thereof. The method of claim 12, wherein the naftifme or pharmaceutically acceptable salt, conjugate or derivative thereof is naftifme hydrochloride, naftifme sulfate, naftifme phosphate, naftifme diphosphate, naftifme maleate, naftifme acetate, naftifme hydrobromide, naftifme linoleate, naftifme lactate or combinations thereof. The method of any one of claims 1 to 13, wherein the ocular surface is the cornea, sclera, eyelid, conjunctiva, or combination thereof of the subject. The method of any one of claims 1 to 14, wherein the composition does not comprise a mucoadhesive. The method of any one of claims 1 to 15, wherein the composition does not comprise an additional active agent. The method of any one of claims 1 to 16, wherein the composition does not comprise an additional anti-fungal, anti-bacterial, or anti-viral agent. The method of any one of claims 1 to 17, wherein the composition is a liquid. The method of claim 18, wherein the liquid has a viscosity of less than 50 mPa-s at 20 °C. The method of claim 19, wherein the liquid has a viscosity of less than 20 mPa-s at 20 °C. The method of any one of claims 1 to 20, wherein the composition is a semi-solid. The method of claim 21, wherein the semi-solid is a gel, cream or ointment. The method of claim 20, wherein the semi-solid has a viscosity of 500 mPa-s to 1000 Pa-s at 20 °C. The method of any one of claims 1 to 17, wherein the composition is a solution, an emulsion, or a suspension. The method of claim 24, wherein the composition is a solution. The method of claim 24, wherein the composition is an emulsion. The method of claim 24, wherein the composition is a suspension. The method of claim 27, wherein the suspension comprises a particle size D90 of less than 50 p in diameter. The method of claim 28, wherein the suspension comprises a particle size D90 of less than 20 p in diameter. The method of claim 27, wherein the suspension comprises a particle size D90 of less than 10 p in diameter. The method of any one of claims 1 to 30, wherein the composition is administered topically via eye drops, eye spray or eye wipe. The method of any one of claims 1 to 31, wherein the composition comprises about 0.01% to about 5% terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. The method of any one of claims 1 to 31, wherein the composition comprises about 0.1% to about 1% terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof. The method of any one of claims 1 to 33, wherein the composition has a tonicity equal to about 0.5% to about 1.8% sodium chloride. The method of any one of claims 1 to 33, wherein the composition has a tonicity equal to about 0.7% to about 1.1% sodium chloride. The method of any one of claims 1 to 35, wherein the composition has a pH of about 4 to about 8. The method of any one of claims 1 to 35, wherein the composition has a pH of about 6.8 to about 8.0. The method of any one of claims 1 to 35, wherein the composition has a pH of about 7.0 to about 7.8. The method of any one of claims 1 to 38, wherein the composition comprises an ophthalmically acceptable buffer, tonicity agent, osmotic pressure regulating agent, viscosity modifying agent, adhesive agent, penetrating agent, preservative, antimicrobial agent, antioxidant, chelating agent, solubilizing agent or combinations thereof. The method of any one of claims 1 to 39, wherein the composition is sterile. The method of any one of claims 1 to 40, wherein the composition is administered for more than one day. The method of any one of claims 1 to 40, wherein the composition is administered for more than one week. The method of any one of claims 1 to 40, wherein the composition is administered for more than 1 month. The method of any one of claims 1 to 43, wherein the composition is administered 1 to 12 times per day. The method of any one of claims 1 to 44, wherein the composition is administered on alternate days. The method of any one of claims 1 to 45, wherein the method of treating an inflammatory ocular condition is a prophylaxis treatment. The method of any one of claims 1 to 45, wherein the method of treating an inflammatory ocular condition is a curative treatment. A method of treating an ocular condition selected from keratitis, chronic conjunctivitis, allergic conjunctivitis, dry-eye disease, blepharitis, uveitis, ocular pain, or combinations thereof, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising an allylamine of Formula T:

wherein X is substituted or unsubstituted C3 to C12 alkyl, alkenyl or alkynyl, or a C4 to C12 cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyl alkyl, heterocycle alkyl, aryl alkyl, or heteroaryl alkyl, or a pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the ocular condition is not caused by a fungal infection.

49. The method of claim 48, wherein the allylamine is terbinafine.

50. A method of treating dry-eye disease or uveitis, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

51. A method of reducing a symptom of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

52. A method of ameliorating a symptom of dry eye, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof, wherein the symptom is a decrease in aqueous tear production, increase in tear evaporation, increase in cellular inflammation or combination thereof.

53. A method of treating a patient for an autoimmune ocular inflammatory disease (AOID), comprising administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

54. The method of claim 53, wherein autoimmune ocular inflammatory disease (AOID) is dry eye disease.

55. The method of claim 53, wherein the autoimmune ocular inflammatory disease (AOID) is uveitis.

56. A method for enhancing or restoring lacrimal gland tearing comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

57. A method of increasing tear production in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

58. A method of reducing the inflammation in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

59. A method of reducing the levels of inflammatory cytokines in the ocular secretions in a patient suffering from an AOID, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

60. The method of claim 59, wherein the inflammatory cytokine is a proinflammatory cytokine.

61. The method according to claim 60, wherein the proinflammatory cytokine is selected from tumor necrosis factor-al and IL-8, IL-6, IL-la, IL-l i, IL-12, and interferon [fFN]-y and combinations thereof.

62. The method according to claim 60, wherein the proinflammatory cytokine is selected from tumor necrosis factor-al, IL-8 and combinations thereof.

63. The method according to claim 61, wherein the proinflammatory cytokine is not tumor necrosis factor-al and IL-8.

64. The method of claim 59, wherein the inflammatory cytokine is an anti-inflammatory cytokine.

65. A method of treating normal tension glaucoma in the eye of a human, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.

66. A method of preventing rejection of a corneal transplant in a subject, the method comprising topically administering to an ocular surface of a subject in need thereof a composition comprising terbinafine, naftifine or a pharmaceutically acceptable salt, conjugate or derivative thereof.