Methods and compositions for treating eye diseases

Abstract

Described herein are compositions and methods for topically administering various compounds to the eye, particularly to the posterior portion of the eye. Such compositions and methods are useful for treating various diseases and disorders, as well as for promoting general eye health.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 162,960, filed March 18, 2021, U.S. Provisional Patent Application No. 63 / 219,336, filed July 7, 2021, and U.S. Provisional Patent Application No. 63 / 283,117, filed November 24, 2021, each of which is incorporated by reference herein.

[0002] Embodiments herein are directed to the treatment of ocular diseases and the delivery of compounds to the eye. Summary of the Invention

[0003] In one embodiment, provided herein is a method of treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the periorbital skin of the eye of the patient.

[0004] In another aspect, provided herein is a method of treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the integument of the eyelid of the patient's eye.

[0005] In a further aspect, provided herein is a method for treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering to the outer skin of the eyelid of the patient a therapeutically effective amount of a compound or mixture having anti-inflammatory, antioxidant, anti-microvascular leakage, or anti-angiogenic properties. In an alternative aspect, provided herein is a method for treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering to the outer skin of the eyelid of the patient a therapeutically effective amount of a combination of two or more compounds or mixtures having anti-inflammatory, antioxidant, anti-microvascular leakage, or anti-angiogenic properties.

[0006] In an additional aspect, provided herein is a method of treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering to the periorbital skin of the patient's eye a therapeutically effective amount of a compound or mixture having anti-inflammatory, anti-oxidant, anti-microvascular leakage, or anti-angiogenic properties.

[0007] In some embodiments, the compound or mixture includes docosahexaenoic acid (DHA) for its antioxidant, anti-inflammatory, neuroprotective, analgesic, and angiogenic properties. In some embodiments, the compound or mixture includes omega-3 fatty acid for its antioxidant, anti-inflammatory, neuroprotective, analgesic, and angiogenic properties. In some embodiments, the compound or mixture includes omega-3 fatty acid ethyl ester for its antioxidant, anti-inflammatory, neuroprotective, analgesic, and angiogenic properties. In some embodiments, the compound or mixture includes omega-3 triglyceride for its antioxidant, anti-inflammatory, neuroprotective, analgesic, and angiogenic properties. In some embodiments, the compound or mixture includes omega-3 phospholipid, such as lysophosphatidylcholine (LPC)-omega-3 (LPC-DHA or LPC-EPA) and di-DHA phosphatidylcholine (PC), for its antioxidant, anti-inflammatory, neuroprotective, analgesic, and angiogenic properties. In some embodiments, the compound or mixture includes a metabolite of omega-3 fat, such as leukotriene B5, leukotriene C5, leukotriene E5, prostaglandin E3, prostaglandin I3, thromboxane A3, protectin, maresin, and resolvin. In some embodiments, the compound or mixture includes a compound having the following general structure with a difluorobiphenyl moiety:

[0008] [ka] In the formula, R is

[0009] [ka] wherein R is Cl or Br, CF3, alkyl, and H;

[0010] [ka] where R is methyl, isobutyl,

[0011] [ka] In some embodiments, the compound or mixture is of the group

[0012] [ka]

[0013] [ka] a compound selected from the group consisting of 3-[(3'-fluoro-4-fluorobiphenyl-3-carbonyl)amino]phenoxyacetic acid isopropyl ester, its free base, alcaftadine, cromolyn, dexamethasone, brimonidine, difluprednate, fluorometholone, loteprednol, rimexolone, azelastine, epinastine, emedastine fumarate, olopatadine, ophthalmic cromolyn ophthalmic), lodoxamide, nedocromil, bromfenac, diclofenac, flurbiprofen, ketorolac, nepafenac, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, azelastine brompheniramine hydrochloride, cyproheptadine, terfenadine, clemastine, levocabastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine , tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimeprazine, doxylamine, pheniramine, pyrilamine, pemirolast, chlorcyclizine, thonzylamine, cisplatin, etoposide, interferon, camptothecin and its derivatives, phenesterine, taxol and its derivatives, taxotere and its derivatives, vincristine, Blastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, flutamide, adriamycin, cyclophosphamide, actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, ampicillin, amoxicillin, cyclacillin , ampicillin, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, ceftoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, cyclosporine, gentamicin, tobramycin,Besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, azithromycin, erythromycin, bacitracin, bacitracin / polymyxin, natamycin, neomycin / polymyxin B / bacitracin, neomycin / polymyxin B / gramicidin, polymyxin B / trimethoprim, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetanicillin, tracycline, doxycycline, minocycline, aztreonam, chloramphenicol, ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate, colistin, azithromycin, augmentin, sulfamethoxazole, and trimethoprim, as well as all pharma- ceutically acceptable esters or salts, analogs, and isoforms of the foregoing compounds, and / or mixtures of at least two of the foregoing compounds.

[0014] In some embodiments, the compound or mixture has the formula:

[0015] [ka] wherein L is a linker group, each linker group is independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, or alkoxy; n are each independently selected from the group consisting of hydrogen, halogen, -OH, alkyl, and alkoxy; R n Each R′ is independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, or alkoxy; and each R′ and R″ is independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, or alkoxy.

[0016] In some embodiments, the compound or mixture has the formula:

[0017] [ka] wherein L is a linker group, each linker group is independently selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, or alkoxy; n are each independently selected from the group consisting of hydrogen, halogen, -OH, alkyl, and alkoxy; R n Each R′ is independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, cycloalkyl, heteroalkyl, or alkoxy, and each R′ and R″ is independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, cycloalkyl, heteroalkyl, or alkoxy.

[0018] In some embodiments, the compound or mixture is selected from the following families of compounds: CC motif receptor 3 (CCR3) inhibitors, vitamin A and modified forms of vitamin A (such as NCT03845582), complement factor 1q inhibitors, apurinic / apyrimidinic site endonuclease 1 / redox effector factor-1 (APE1 / Ref-1) inhibitors, steroids, endothelial cell (EC)-specific receptor tyrosine kinase Tie2 agonists (activators), angiopoietin-2 antagonists, retinol binding protein 4 (RBP4) antagonists, complement component 3 (C3) inhibitors, pan-arginylglycylaspartic acid (RGD) integrin antagonists, connexin 43 hemichannel blockers, complement component 5 inhibitors, panRGD integrin antagonists, Rho kinase inhibitors, Ref-1 inhibitors, AP endonuclease ... and combinations of two or more thereof.

[0019] In some embodiments, the disease or disorder is of the posterior segment of the eye. In some embodiments, the disease or disorder is of the anterior segment of the eye. In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease. In some embodiments, the disease or disorder is an anterior segment of the eye disease (ASED). In some embodiments, the disease or disorder is a posterior segment of the eye disease (PSED).In some embodiments, the disease or disorder is dry eye disease and ocular discomfort, irritation, pain and stress, chemical burns, anterior segment dysplasia, cataracts, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectatic disorders (including globular cornea, pellucid marginal degeneration), pseudophakic and aphakic bullous keratopathy, episcleritis, corneal ulcers, corneal dysplasia, corneal ulcers, Fuchs endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, acute and chronic uveitis. (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment including iris trauma, penetrating eye trauma, blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, tarsal adenitis, meibomian gland dysfunction, lacrimal gland obstruction, lacrimal gland obstruction, seborrheic keratitis, ultraviolet keratitis, bacterial or viral infection, refractive errors (nearsightedness, farsightedness, and astigmatism), uveitis (including acute and chronic anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis), age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy (Sickle Cell Retinopathy), and other conditions. These conditions include: various retinopathies including central serous chorioretinopathy, radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt disease, lymphangiopathy of the orbit (also known as orbital lymphangioma), or thyroid eye disease (Graves eye disease), or a combination of two or more of these.

[0020] In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease, which further comprises bleeding from the retinal or choroidal vasculature, hi some embodiments, the bleeding is caused by hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0021] In some embodiments, the retinal disease or disorder comprises plasma leakage from the retinal or choroidal vasculature, hi some embodiments, the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0022] In some embodiments, the retinal disease or disorder comprises macular edema formation involving the retinal or choroidal vasculature.

[0023] In some embodiments, the retinal disease or disorder is age-related macular degeneration (wet and dry), macular hole, macular pucker, lattice degeneration, retinal break, retinal detachment, retinal artery occlusion, branch retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric and neonatal retinal disorders, inherited retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, central serous chorioretinopathy, retinoblastoma, diabetic macular edema (DME), retinal vein occlusion, or endophthalmitis.

[0024] In some embodiments, the retinal disease or disorder is age-related macular degeneration.

[0025] In some embodiments, the disease or disorder of the posterior segment of the eye is posterior uveitis.

[0026] In some embodiments, the method further comprises administering to the patient an additional therapeutic agent, which in some embodiments is a VEGF antibody, a PDGF antibody, an FGF antibody, an SDF-1 antibody, an HIF-1 antibody, a PIGF antibody, a TNF-α antibody, an IGF-1 antibody, a VEGF receptor antagonist, a PDGF receptor antagonist, an FGF receptor antagonist, an SDF-1 receptor antagonist, an HIF-1 receptor antagonist, a PIGF receptor antagonist, a TNF-α receptor antagonist, an IGF-1 receptor antagonist, a tyrosine kinase inhibitor, a steroidal anti-inflammatory agent, or a combination thereof. anti-inflammatory agents, nonsteroidal anti-inflammatory agents, immunosuppressants, anticholinergic agents, thalidomide, prostaglandin receptor antagonists, neuroprotective agents, neuroregenerative agents, RNA interference molecules that provide neuroprotection, RNA interference molecules that promote neuroregeneration, small molecules that directly provide neuroprotection and reduce intraocular pressure, RNA interference molecules that promote neuroregeneration and reduce intraocular pressure, RNA interference that provides neuroprotection and reduce intraocular pressure, antibodies that reduce edema, bleeding, and angiogenesis, RNA interference that reduces edema, bleeding, and angiogenesis.

[0027] In some embodiments, application of the drug to the periorbital skin provides a preferred route of delivery to the sclera to prevent increase in the long axis of the eye due to stimulating changes to the sclera.

[0028] In some embodiments, drug delivery may include nanoparticles, which may be selected from the group including polymeric, lipid-based, liposomal, albumin-bound, inorganic, organic crystal, and viral-based nanoparticles.

[0029] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered prophylactically, as an acute intervention, or as needed to achieve the desired ameliorative effect.

[0030] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered as a composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition.

[0031] In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a lotion, a cream, or an ointment. In some embodiments, the composition is an ointment. In some embodiments, the ointment comprises petrolatum, beeswax, or cocoa butter. In some embodiments, the ointment comprises petrolatum and medium chain triglycerides. In some embodiments, the medium chain triglycerides comprise a mixture of C6, C8, C10, and C12 fatty acids. In some embodiments, the medium chain triglycerides comprise a mixture of caprylic and capric acids. In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 1:1 (v / v), about 2:1 (v / v), about 3:1 (v / v), about 4:1 (v / v), about 5:1 (v / v), or about 6:1 (v / v). In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 4:1 (v / v).

[0032] In some embodiments, the molecular weight of the composition is about 50 Da to about 500 Da. In some embodiments, the molecular weight of the composition is about 50 Da to about 100 Da, about 50 Da to about 150 Da, about 50 Da to about 200 Da, about 50 Da to about 250 Da, about 50 Da to about 300 Da, about 50 Da to about 350 Da, about 50 Da to about 400 Da, about 50 Da to about 450 Da, about 50 Da to about 500 Da, about 100 Da to about 150 Da, about 100 Da to about 200Da, about 100Da to about 250Da, about 100Da to about 300Da, about 100Da to about 350Da, about 100Da to about 400Da, about 100Da to about 450Da, about 100D a~about 500Da, about 150Da to about 200Da, about 150Da to about 250Da, about 150Da to about 300Da, about 150Da to about 350Da, about 150Da to about 400Da, about 15 0Da to about 450Da, about 150Da to about 500Da, about 200Da to about 250Da, about 200Da to about 300Da, about 200Da to about 350Da, about 200Da to about 400Da, Approximately 200Da to approximately 450Da, approximately 200Da to approximately 500Da, approximately 250Da to approximately 300Da, approximately 250Da to approximately 350Da, approximately 250Da to approximately 400Da, approximately 250Da to approximately 450 Da, about 250 Da to about 500 Da, about 300 Da to about 350 Da, about 300 Da to about 400 Da, about 300 Da to about 450 Da, about 300 Da to about 500 Da, about 350 Da to about 400 Da, about 350 Da to about 450 Da, about 350 Da to about 500 Da, about 400 Da to about 450 Da, about 400 Da to about 500 Da, or about 450 Da to about 500 Da. In some embodiments, the molecular weight of the composition is about 50 Da, about 100 Da, about 150 Da, about 200 Da, about 250 Da, about 300 Da, about 350 Da, about 400 Da, about 450 Da, or about 500 Da. In some embodiments, the molecular weight of the composition is at least about 50 Da, about 100 Da, about 150 Da, about 200 Da, about 250 Da, about 300 Da, about 350 Da, about 400 Da, or about 450 Da. In some embodiments, the molecular weight of the composition is at most about 100 Da, about 150 Da, about 200 Da, about 250 Da, about 300 Da, about 350 Da, about 400 Da, about 450 Da, or about 500 Da.

[0033] In some embodiments, the composition comprises an antibody. In some embodiments, the composition has a molecular weight of about 150 kDa. In some embodiments, the composition has a molecular weight of about 7 kDa. In some embodiments, the composition comprises a double-stranded siRNA. In some embodiments, the composition comprises a single-stranded siRNA. In some embodiments, the composition comprises a short oligopeptide.

[0034] In some embodiments, the short oligopeptide is a sequence of about 1 amino acid to about 6 amino acids. In some embodiments, the short oligopeptide is a sequence of about 1 amino acid to about 2 amino acids, about 1 amino acid to about 3 amino acids, about 1 amino acid to about 4 amino acids, about 1 amino acid to about 5 amino acids, about 1 amino acid to about 6 amino acids, about 2 amino acids to about 3 amino acids, about 2 amino acids to about 4 amino acids, about 2 amino acids to about 5 amino acids, about 2 amino acids to about 6 amino acids, about 3 amino acids to about 4 amino acids, about 3 amino acids to about 5 amino acids, about 3 amino acids to about 6 amino acids, about 4 amino acids to about 5 amino acids, about 4 amino acids to about 6 amino acids, or about 5 amino acids to about 6 amino acids. In some embodiments, the short oligopeptide is a sequence of about 1 amino acid, about 2 amino acids, about 3 amino acids, about 4 amino acids, about 5 amino acids, or about 6 amino acids. In some embodiments, a short oligopeptide is a sequence of at least about 1 amino acid, about 2 amino acids, about 3 amino acids, about 4 amino acids, or about 5 amino acids, in some embodiments, a short oligopeptide is a sequence of at most about 2 amino acids, about 3 amino acids, about 4 amino acids, about 5 amino acids, or about 6 amino acids.

[0035] In some embodiments, the composition comprises liposomes. In some embodiments, the composition comprises nanoparticles. In some embodiments, the average diameter of the liposomes or nanoparticles is about 0.1 μm to about 1 μm. In some embodiments, the average diameter of the liposomes or nanoparticles is about 0.1 μm to about 0.2 μm, about 0.1 μm to about 0.3 μm, about 0.1 μm to about 0.4 μm, about 0.1 μm to about 0.5 μm, about 0.1 μm to about 0.6 μm, about 0.1 μm to about 0.7 μm, about 0.1 μm to about 0.8 μm, about 0.1 μm to about 0.9 μm, about 0.1 μm to about 1 μm, about 0.2 ... m ~ about 0.3 μm, about 0.2 μm to about 0.4 μm, about 0.2 μm to about 0.5 μm, about 0.2 μm to about 0.6 μm, about 0.2 μm to about 0.7 μm, about 0.2 μm to about 0.8 μm, about 0 .2μm~about 0.9μm, about 0.2μm~about 1μm, about 0.3μm~about 0.4μm, about 0.3μm~about 0.5μm, about 0.3μm~about 0.6μm, about 0.3μm~about 0.7μm, about 0 .3μm~about 0.8μm, about 0.3μm~about 0.9μm, about 0.3μm~about 1μm, about 0.4μm~about 0.5μm, about 0.4μm~about 0.6μm, about 0.4μm~about 0.7μm, about . 0.4μm~about 0.8μm, about 0.4μm~about 0.9μm, about 0.4μm~about 1μm, about 0.5μm~about 0.6μm, about 0.5μm~about 0.7μm, about 0.5μm~about 0.8μm, about 0.5 μm to about 0.9 μm, about 0.5 μm to about 1 μm, about 0.6 μm to about 0.7 μm, about 0.6 μm to about 0.8 μm, about 0.6 μm to about 0.9 μm, about 0.6 μm to about 1 μm, about 0.7 μm to about 0.8 μm, about 0.7 μm to about 0.9 μm, about 0.7 μm to about 1 μm, about 0.8 μm to about 0.9 μm, about 0.8 μm to about 1 μm, or about 0.9 μm to about 1 μm. In some embodiments, the average diameter of the liposomes or nanoparticles is about 0.1 μm, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, or about 1 μm. In some embodiments, the average diameter of the liposomes or nanoparticles is at least about 0.1 μm, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, or about 0.9 μm.In some embodiments, the average diameter of the liposomes or nanoparticles is at most about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, or about 1 μm.

[0036] In some embodiments, the composition is a lipophilic compound. In some embodiments, the composition comprises a non-polar compound. In some embodiments, the composition comprises a polar compound. In some embodiments, the composition comprises a zwitterion.

[0037] In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant.

[0038] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the periorbital skin of at least one eye of the patient by a dropper, pump, spray, click pen, or roller / reservoir device. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the periorbital skin of at least one eye of the patient by a brush, Q-tip, fingertip, or spatula, the application process optionally being initiated with the use of a graduated dropper, syringe, click pen, or pipette.

[0039] In some embodiments, penetration into the periorbital skin may be assisted by penetration enhancers, tape-stripping, microdermabrasion, solvents, pulsed lasers, and iontophoresis to deliver macromolecules such as antibodies, siRNAs, etc. in liposomes or nanoparticles. In some embodiments, the composition can easily penetrate the skin barrier.

[0040] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the periorbital skin of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day. In some embodiments, the method includes administering the composition to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid.

[0041] In one embodiment, provided herein is a method of treating a disease or disorder of the posterior segment of the eye in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the ocular surface of the patient's eye.

[0042] In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease.

[0043] In some embodiments, the retinal disease comprises bleeding from the retinal or choroidal vasculature, hi some embodiments, the bleeding is caused by hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0044] In some embodiments, the retinal disease or disorder comprises plasma leakage from the retinal or choroidal vasculature, hi some embodiments, the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0045] In some embodiments, the retinal disease or disorder comprises macular edema formation involving the retinal or choroidal vasculature.

[0046] In some embodiments, the retinal disease or disorder is age-related macular degeneration (wet and dry), macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, branch retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric and neonatal retinal disorders, inherited retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, central serous chorioretinopathy, retinoblastoma, and endophthalmitis.

[0047] In some embodiments, the retinal disease or disorder is age-related macular degeneration.

[0048] In some embodiments, the disease or disorder of the posterior segment of the eye is posterior uveitis.

[0049] In some embodiments, the disease is a neurodegenerative eye disease.

[0050] In some embodiments, the method further comprises administering an additional therapeutic agent to the patient.In some embodiments, the additional therapeutic agent is VEGF antibody, PDGF antibody, bFGF antibody, SDF-1 antibody, HIF-1 antibody, PIGF antibody, VEGF antagonist, tyrosine kinase inhibitor, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, immunosuppressant, anticholinergic agent, thalidomide, prostaglandin receptor antagonist, or neuroprotective agent, antiangiogenic factor (e.g., PEDF), neuroregenerative agent, RNA interference that provides neuroprotection, RNA interference that promotes neuroregeneration, small molecule that directly provides neuroprotection and reduces intraocular pressure, RNA interference that promotes neuroregeneration and reduces intraocular pressure, RNA interference that provides neuroprotection and reduces intraocular pressure, antibody that reduces edema, bleeding, and angiogenesis, RNA interference that reduces edema, bleeding, and angiogenesis.

[0051] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered prophylactically, as an acute intervention, or as needed to achieve the desired ameliorative effect.

[0052] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered as a composition. In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a cream, or an ointment. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition.

[0053] In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant.

[0054] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the ocular surface of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day.

[0055] In one embodiment, provided herein is a method of treating uveitis in a patient suffering from uveitis, the method comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to an eye of the patient.

[0056] In one embodiment, provided herein is a method of treating pterygium in a patient suffering from pterygium, the method comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to an eye of the patient.

[0057] In one aspect, provided herein is a method of treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising the step of administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to an eye of the patient, wherein the ocular disease or disorder is keratoconjunctivitis, keratoconus, episcleritis, corneal ulcer, corneal dysplasia, corneal dystrophy, or Stevens-Johnson Syndrome.

[0058] In one embodiment, provided herein is a method of treating an eye disease or disorder affecting the eyelid in a patient suffering from said eye disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the eye of the patient, wherein the eye disease or disorder affecting the eyelid is blepharitis, blepharospasm, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, chalazion, blepharoplasty, lacrimal gland obstruction, seborrheic keratitis, ultraviolet keratitis, bacterial infection, or viral infection.

[0059] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface as a composition.

[0060] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally as a composition.

[0061] In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a cream, or an ointment. In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant.

[0062] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied topically by a dropper, pump, spray, click pen, or roller / reservoir device. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied topically to the periorbital skin of at least one eye by a brush, Q-tip, fingertip, or spatula, and the application process may be initiated by the use of a graduated dropper, syringe, click pen, or pipette.

[0063] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day.

[0064] In one embodiment, provided herein is a pharmaceutical composition suitable for topical periorbital administration comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine.

[0065] In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a cream, or an ointment. In some embodiments, the composition is formulated as an oily solution. In some embodiments, the composition comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition. In some embodiments, the oil is derived from a natural source. In some embodiments, the oil is derived from a plant, a plant seed, or a nut, or any combination thereof. In some embodiments, the oil comprises medium chain triglycerides. In some embodiments, the medium chain triglycerides comprise a mixture of C6, C8, C10, or C12 fatty acids.

[0066] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition. In some embodiments, the pharmaceutical composition is configured to dispense about 10 ng to about 5 mg of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine per dose.

[0067] In some embodiments, the composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, or any combination thereof.

[0068] In one aspect, provided herein is a pharmaceutical composition suitable for topical ocular surface administration comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, and polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the ratio of PEG to castor oil is about 20:1 to about 50:1. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 1% (w / w) of the composition.

[0069] In some embodiments, the composition further comprises an ocular surface lubricant. In some embodiments, the ocular surface lubricant is polyethylene glycol, propylene glycol, polyvinyl alcohol, castor oil, or glycerol. In some embodiments, the ocular surface lubricant is present in an amount of about 0.05% to about 2% (w / w) of the composition. In some embodiments, the composition further comprises a buffering agent. In some embodiments, the pharmaceutical composition has a pH of about 6.5 to about 8.5.

[0070] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition.

[0071] In one aspect, provided herein is a method for promoting eye health and preventing or treating eye disease in a subject, comprising administering a topical pharmaceutical composition comprising an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, to the periorbital skin of the eye of the subject. In some embodiments, the omega-3 fatty acid is isolated from fish tissue. In some embodiments, the omega-3 fatty acid is isolated from krill, a small shrimp-like crustacean with a large black eye and a reddish translucent body. In some embodiments, the omega-3 fatty acid is isolated from a plant source. In some embodiments, the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof. In some embodiments, the omega-3 fatty acid comprises DHA. In some embodiments, the omega-3 fatty acids are administered in an amount of about 0.01 mg to about 10,000 mg, about 0.01 mg to about 3,000 mg, about 0.01 mg to about 1,000 mg, about 0.01 mg to about 500 mg, or about 0.01 mg to about 100 mg per eye when used as eye pads, and in an amount of about 0.01 mg to about 200 mg, or about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, or about 0.01 mg to about 0.5 mg per eye per application to the periorbital skin when not used as eye pads.

[0072] In one aspect, provided herein is a method for promoting eye health and preventing or treating eye disease in a subject, comprising administering a topical pharmaceutical composition comprising omega-3 fatty acid ester, or its pharma-ceutically acceptable ethyl ester or salt, to the periorbital skin of the eye of the subject.In some embodiments, the omega-3 fatty acid ethyl ester is derived from fish tissue.In some embodiments, the omega-3 fatty acid ethyl ester is derived from plant sources.In some embodiments, the omega-3 fatty acid comprises alpha-linoleic acid ethyl, eicosapentaenoic acid ethyl, docosahexaenoic acid ethyl, or any combination thereof. In some embodiments, the omega-3 fatty acid ethyl esters are administered in an amount of about 0.01 mg to about 5000 mg, about 0.01 mg to about 3000 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 500 mg, or about 0.01 mg to about 100 mg per eye when used as an eye pad, and in an amount of about 0.01 mg to about 200 mg, or about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, or about 0.01 mg to about 0.5 mg per eye per application to the periorbital skin when not used as an eye pad.

[0073] In some embodiments, the topical pharmaceutical composition is formulated as a cream, emulsion, ointment, or oily solution. In some embodiments, the topical pharmaceutical composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, an antioxidant, a fragrance masking agent, or any combination thereof. In some embodiments, the composition further comprises a preservative.

[0074] In some embodiments, the topical pharmaceutical composition is administered using a rollerball, a click pen brush, a pump bottle, or a bottle with eye droppers, eye pads, and Q-tips.

[0075] In some embodiments, promoting eye health, preventing or treating eye disease includes treating or preventing age-related vision loss. In some embodiments, promoting eye health, preventing or treating eye disease includes treating or preventing dry eye. In some embodiments, promoting eye health, preventing or treating eye disease includes treating or preventing age-related macular degeneration. In some embodiments, promoting eye health, preventing or treating eye disease includes treating or preventing age-related macular degeneration.

[0076] In some embodiments, the topical pharmaceutical composition is administered to the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, the method comprises administering the composition to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid.

[0077] In some embodiments, administration of the composition to the periorbital skin results in a tissue concentration of omega-3 fatty acids that is at least 110 micrograms / gram higher in the retina of the subject's eye 30 minutes after administration compared to baseline.

[0078] In one aspect, provided herein is a pharmaceutical composition suitable for topical periorbital administration comprising an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and a pharma- ceutically acceptable excipient.

[0079] In some embodiments, the omega-3 fatty acid is isolated from fish tissue. In some embodiments, the omega-3 fatty acid is isolated from a plant source. In some embodiments, the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof. In some embodiments, the omega-3 fatty acid comprises DHA. In some embodiments, the omega-3 fatty acid is present in an amount of about 0.01% to about 100% (w / w) of the composition.

[0080] In some embodiments, the composition is formulated as a cream, emulsion, ointment, or oily solution.

[0081] In some embodiments, the pharmaceutical composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, an antioxidant, an aroma masking agent, or any combination thereof. In some embodiments, the composition further comprises a preservative. In some embodiments, the preservative is vitamin E.

[0082] In some embodiments, the composition further comprises a fatty acid vehicle. In some embodiments, the fatty acid vehicle is present in an amount of about 0.01% to about 99% of the composition. In some embodiments, the fatty acid vehicle is a C14 to C22 fatty acid. In some embodiments, the fatty acid vehicle comprises linoleic acid.

[0083] In some embodiments, the composition comprises an oil in an amount of about 0.01% to about 100% (w / w) of the composition. In some embodiments, the oil is derived from a natural source. In some embodiments, the oil is derived from a plant, a plant seed, or a nut.

[0084] In one aspect, provided herein is a method of treating a disease or disorder of the posterior segment of the eye in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the periorbital skin of the patient's eye. In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease. In some embodiments, the retinal disease comprises bleeding from the retinal or choroidal vasculature. In some embodiments, the bleeding is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the retinal disease or disorder comprises plasma leakage from the retinal or choroidal vasculature. In some embodiments, the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the retinal disease or disorder includes macular edema formation involving the retinal or choroidal vasculature. In some embodiments, the posterior eye disease or disorder includes age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, and other conditions. retinopathy, radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, or refractive errors (myopia, hyperopia, and astigmatism). In some embodiments, the method further comprises administering an additional therapeutic agent to the subject.In some embodiments, the additional therapeutic agent is a VEGF antibody, a small molecule VEGF antagonist, an siRNA targeting a VEGF receptor, a TNFα antibody, a small molecule TNFα receptor antagonist, an siRNA targeting a TNFα receptor, an inflammatory cytokine receptor antagonist, an antibody against an inflammatory cytokine, a tyrosine kinase inhibitor, a serine / threonine-protein kinase inhibitor, a kinase inhibitor, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an immunosuppressant, an anticholinergic agent, thalidomide, a prostaglandin receptor antagonist, a neuroprotective agent, a neurotrophic agent, a neuroregenerative agent, an ocular hypotensive agent, an antibiotic, an antiviral agent, a complement inhibitor, an interleukin receptor inhibitor, a leukotriene receptor inhibitor, an inhibitor of tumor formation and growth, an angiogenesis inhibitor, or an agent with antioxidant or anti-microvascular leakage properties. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered prophylactically, as an emergency intervention, or as needed to achieve the desired ameliorative effect. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered as a composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition. In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a lotion, a cream, or an ointment. In some embodiments, the composition is an ointment. In some embodiments, the ointment comprises petrolatum, beeswax, or cocoa butter. In some embodiments, the ointment comprises petrolatum and medium chain triglycerides. In some embodiments, the medium chain triglycerides comprise a mixture of C6, C8, C10, and C12 fatty acids. In some embodiments, the medium chain triglycerides comprise a mixture of caprylic and capric acids.In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 1:1 (v / v), about 2:1 (v / v), about 3:1 (v / v), about 4:1 (v / v), about 5:1 (v / v), or about 6:1 (v / v). In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 4:1 (v / v). In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the periorbital skin of at least one eye of the patient by a dropper, pump, spray, click pen, or roller / reservoir device. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the periorbital skin of at least one eye of the patient by a brush, Q-tip, or spatula, the application process optionally being initiated with the use of a graduated dropper, syringe, click pen, or pipette. In some embodiments, penetration of the periorbital skin is assisted by tape-stripping, microdermabrasion, solvents, pulsed lasers, iontophoresis, or combinations thereof.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the periorbital skin of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day. In some embodiments, the method includes administering the composition to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid. In some embodiments, the additional therapeutic agent is an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and the omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof are formulated and administered as a single composition.

[0085] In an additional aspect, provided herein is a method of treating a disease or disorder of the posterior segment of the eye in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the ocular surface of the patient's eye. In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease. In some embodiments, the retinal disease comprises bleeding from the retinal or choroidal vasculature. In some embodiments, the bleeding is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the retinal disease or disorder comprises plasma leakage from the retinal or choroidal vasculature. In some embodiments, the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the retinal disease or disorder comprises macular edema formation in the retinal or choroidal vasculature. In some embodiments, the posterior eye disease or disorder comprises age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, and other conditions. retinopathy, radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, or refractive errors (myopia, hyperopia, and astigmatism). In some embodiments, the retinal disease or disorder is age-related macular degeneration.In some embodiments, the disease or disorder of the posterior part of the eye is posterior uveitis. In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a small molecule VEGF antagonist, a VEGF receptor-targeting siRNA, a small molecule TNFα receptor antagonist, a TNFα receptor-targeting siRNA, an inflammatory cytokine receptor antagonist, a tyrosine kinase inhibitor, a serine / threonine-protein kinase inhibitor, a kinase inhibitor, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an immunosuppressant, an anticholinergic agent, thalidomide, a prostaglandin receptor antagonist, a neuroprotectant, a neuroregenerator, an ocular hypotensive agent, an antibiotic, an antiviral agent, a complement inhibitor, an interleukin receptor inhibitor, a leukotriene receptor inhibitor, an inhibitor of tumor formation and development, an angiogenesis inhibitor, or an agent with antioxidant or anti-microvascular leakage properties. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered as a composition, the composition being an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a cream, an ointment, in a liposome or nanoparticle. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition. In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the ocular surface of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day. In some embodiments, the additional therapeutic agent is an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is administered periorbitally as a composition.

[0086] In an additional embodiment, provided herein is a method of treating uveitis in a patient suffering from uveitis, comprising administering to an eye of the patient a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In an additional embodiment, provided herein is a method of treating a patient suffering from pterygium, comprising administering to an eye of the patient a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In an additional embodiment, provided herein is a method of treating an ocular disease or disorder in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to an eye of the patient, wherein the ocular disease or disorder is selected from the group consisting of anterior segment hypoplasia, cataract, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectatic disorders (keratoglobulosa, pellucid marginal degeneration, ocular glaucoma ... These conditions include: pseudophakic and aphakic bullous keratopathy, episcleritis, corneal ulcer, corneal dysplasia, corneal ulcer, Fuchs endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, acute and chronic uveitis (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment including iris trauma, or penetrating ocular trauma.In an additional embodiment, provided herein is a method of treating an ocular disease or disorder affecting the eyelid in a patient suffering from said ocular disease or disorder, comprising the step of administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the eye of the patient, wherein the ocular disease or disorder affecting the eyelid is blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, blepharitis, meibomian gland dysfunction, lacrimal gland obstruction, lacrimal gland obstruction, seborrheic keratitis, ultraviolet keratitis, bacterial infection, or viral infection. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface as a composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally as a composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface as a composition and applied periorbitally as a composition separately. In some embodiments, the composition is an aqueous solution, non-aqueous solution, oily solution, gel, suspension, emulsion, cream, or ointment in liposomes or nanoparticles with or without co-incorporation of siRNA or antibody. In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied topically by a dropper, pump, spray, click pen, or roller / reservoir device. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied topically to the periorbital skin of at least one eye by a brush, Q-tip, or spatula, and the application process may be initiated by the use of a graduated dropper, syringe, click pen, or pipette. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day. In some embodiments, the method further comprises administering to the periorbital skin of the patient's eye a topical pharmaceutical composition comprising an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof.

[0087] In additional aspects, provided herein is a pharmaceutical composition suitable for topical periorbital administration comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a cream, an ointment, in a liposome or nanoparticle, with or without co-incorporation of siRNA or an antibody. In some embodiments, the composition is formulated as an oily solution. In some embodiments, the composition comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition. In some embodiments, the oil is derived from a natural source. In some embodiments, the oil is derived from a plant, a plant seed, or a nut, or any combination thereof. In some embodiments, the oil comprises a medium chain triglyceride. In some embodiments, the medium chain triglyceride comprises a mixture of C6, C8, C10, or C12 fatty acids. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.00015% to about 10% (w / w) of the composition. In some embodiments, the pharmaceutical composition is configured to dispense about 0.5 micrograms (μg) to about 5 milligrams (mg) of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine per eye per administration.In some embodiments, the pharmaceutical composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof.

[0088] In an additional aspect, provided herein is a pharmaceutical composition suitable for topical ocular surface administration comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, and polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the ratio of PEG to castor oil is about 20:1 to about 50:1. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 1% (w / w) of the composition. In some embodiments, the pharmaceutical composition further comprises an ocular surface lubricant. In some embodiments, the ocular surface lubricant is polyethylene glycol, propylene glycol, polyvinyl alcohol, castor oil, or glycerol. In some embodiments, the ocular surface lubricant is present in an amount of about 0.05% to about 2% (w / w) of the composition. In some embodiments, the pharmaceutical composition further comprises a buffering agent. In some embodiments, the pharmaceutical composition has a pH of about 6.5 to about 8.5. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition.

[0089] In an additional aspect, provided herein is a method of promoting ocular health or preventing or treating ocular disease in a subject, comprising administering a topical pharmaceutical composition comprising an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, to the periorbital skin of the subject's eye. In some embodiments, the omega-3 fatty acid is isolated from fish tissue. In some embodiments, the omega-3 fatty acid is isolated from a plant source. In some embodiments, the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof. In some embodiments, the omega-3 fatty acid comprises DHA. In some embodiments, the omega-3 fatty acid comprises EPA. In some embodiments, the omega-3 fatty acid is administered in an amount of about 0.1 mg to about 3000 mg, about 0.1 mg to about 1000 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 200 mg, or about 0.1 mg to about 100 mg. In some embodiments, the topical pharmaceutical composition is formulated as a cream, emulsion, ointment, or oily solution. In some embodiments, the topical pharmaceutical composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, an antioxidant, an aroma masking agent, or any combination thereof. In some embodiments, the topical pharmaceutical composition further comprises a preservative. In some embodiments, the topical pharmaceutical composition further comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the topical pharmaceutical composition is administered using a rollerball, a click pen brush, a pump bottle, or an eye dropper bottle, and a bottle with a Q-tip.In some embodiments, promoting eye health and preventing or treating eye diseases includes, but is not limited to, dry eye disease and eye discomfort, irritation, pain and stress, chemical burns, anterior segment dysplasia, cataracts, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectatic disorders (keratoglobus, pellucid marginal degeneration, etc.). degeneration), pseudophakic and aphakic bullous keratopathy, episcleritis, corneal ulcer, corneal dysplasia, corneal ulcer, Fuchs endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, acute and chronic uveitis (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment including iris trauma, penetrating ocular trauma, blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, tarsal adenitis, meibomian gland dysfunction, lacrimal gland obstruction, seborrheic keratitis, lacrimal gland obstruction, lacrimal gland obstruction, seborrheic keratitis, ptosis ... uveal keratitis, bacterial or viral infection, age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, childhood, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy (Sickle Cell Retinopathy), These include treating or preventing various retinopathies including retinal hypertrophy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, refractive errors (myopia, hyperopia, and astigmatism), lymphatic malformation of the orbit (also known as orbital lymphangioma), thyroid eye disease (Graves' eye disease), or acute and chronic uveitis (including intermediate uveitis, posterior uveitis, and pan uveitis).In some embodiments, promoting eye health, preventing or treating eye diseases includes treating or preventing dry eye. In some embodiments, promoting eye health, preventing or treating eye diseases includes treating or preventing wet and dry age-related macular degeneration. In some embodiments, promoting eye health, preventing or treating eye diseases includes treating or preventing various retinopathies, including but not limited to diabetic retinopathy and retinopathy of prematurity. In some embodiments, the topical pharmaceutical composition is administered to the patient four times a day, three times a day, twice a day, once a day, once every other day, once every three days, once every four days, or once every seven days. In some embodiments, the method includes administering the composition to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid. In some embodiments, administration of the composition to the periorbital skin results in a tissue concentration of omega-3 fatty acids that is at least 110 micrograms / gram higher in the retina of the subject's eye 30 minutes after administration compared to baseline.

[0090] In another aspect, provided herein is a pharmaceutical composition suitable for topical periorbital administration comprising an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the omega-3 fatty acid is isolated from fish tissue. In some embodiments, the omega-3 fatty acid is isolated from a plant source. In some embodiments, the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof. In some embodiments, the omega-3 fatty acid comprises DHA. In some embodiments, the omega-3 fatty acid comprises EPA. In some embodiments, the omega-3 fatty acid is present in an amount of about 0.01% to about 100% (w / w) of the composition. In some embodiments, the composition is formulated as a cream, emulsion, ointment, or oily solution. In some embodiments, the composition further comprises an emollient, a moisturizer, a thickener, a preservative, a penetration enhancer, an antioxidant, a fragrance masking agent, or any combination thereof. In some embodiments, the formulation further comprises a preservative. In some embodiments, the preservative is vitamin E. In some embodiments, the formulation further comprises a fatty acid vehicle. In some embodiments, the fatty acid vehicle is present in an amount of about 0.1% to about 99% of the composition. In some embodiments, the fatty acid vehicle is a C14-C22 fatty acid. In some embodiments, the fatty acid vehicle comprises linoleic acid. In some embodiments, the formulation further comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the oil is derived from a natural source. In some embodiments, the oil is derived from a plant, a plant seed, or a nut. In some embodiments, the formulation further comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof.

[0091] In an additional aspect, provided herein is a method of treating a disease or disorder of the posterior segment of the eye in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, to the outer skin of the eyelid of the patient's eye. In some embodiments, the disease or disorder of the posterior segment of the eye comprises a retinal disease. In some embodiments, the retinal disease comprises bleeding from the retinal or choroidal vasculature. In some embodiments, the bleeding is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the disease or disorder of the retina comprises plasma leakage from the retinal or choroidal vasculature. In some embodiments, the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia. In some embodiments, the retinal disease or disorder includes macular edema formation involving the retinal or choroidal vasculature. In some embodiments, the posterior eye disease or disorder includes age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, and other conditions. retinopathy, radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, or refractive errors (myopia, hyperopia, and astigmatism). In some embodiments, the retinal disease or disorder is age-related macular degeneration.In some embodiments, the disease or disorder of the posterior part of the eye is posterior uveitis. In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a VEGF antibody, a small molecule VEGF antagonist, an siRNA targeting a VEGF receptor, a TNFα antibody, a small molecule TNFα receptor antagonist, an siRNA targeting a TNFα receptor, an inflammatory cytokine receptor antagonist, an antibody against an inflammatory cytokine, a tyrosine kinase inhibitor, a serine / threonine-protein kinase inhibitor, a kinase inhibitor, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an immunosuppressant, an anticholinergic agent, thalidomide, a prostaglandin receptor antagonist, a neuroprotective agent, a neurotrophic agent, a neuroregenerative agent, an intraocular pressure reducing agent, an antibiotic, an antiviral agent, a complement inhibitor, an interleukin receptor inhibitor, a leukotriene receptor inhibitor, an inhibitor of tumor formation and development, an angiogenesis inhibitor, or an agent having antioxidant or anti-microvascular leakage properties. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered prophylactically, as an emergency intervention, or as needed to achieve the desired ameliorative effect. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered as a composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.0001% to about 10% (w / w) of the composition. In some embodiments, the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a lotion, a cream, or an ointment. In some embodiments, the composition is an ointment. In some embodiments, the ointment comprises petrolatum, beeswax, or cocoa butter. In some embodiments, the ointment comprises petrolatum and medium chain triglycerides. In some embodiments, the medium chain triglycerides comprise a mixture of C6, C8, C10, and C12 fatty acids.In some embodiments, the medium chain triglyceride comprises a mixture of caprylic and capric acids. In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 1:1 (v / v), about 2:1 (v / v), about 3:1 (v / v), about 4:1 (v / v), about 5:1 (v / v), or about 6:1 (v / v). In some embodiments, the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 4:1 (v / v). In some embodiments, the composition is an aqueous solution. In some embodiments, the aqueous solution comprises polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition. In some embodiments, the composition comprises an ocular surface lubricant. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the outer skin of the patient's eyelid by a dropper, pump, spray, click pen, or roller / reservoir device. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is applied to the outer skin of the patient's eyelid with a brush, Q-tip, or spatula, and the application process is optionally initiated with the use of a graduated dropper, syringe, click pen, or pipette. In some embodiments, penetration into the eyelid skin is assisted by tape-stripping, microdermabrasion, solvents, pulsed lasers, iontophoresis, or combinations thereof.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the skin of the eyelid of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered once a day.In some embodiments, the additional therapeutic agent is an omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof. In some embodiments, the 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and the omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof are formulated and administered as a single composition.

[0092] In an additional aspect, provided herein is an active ingredient formulated for topical administration to the periorbital skin of a patient for use in the manufacture of a medicament for treating a disease or disorder of the posterior segment of the eye, the formulation delivering a therapeutically effective amount of said active ingredient formulated for topical administration to the periorbital skin of a patient to the posterior segment of the eye. In some embodiments, the active ingredient has a molecular weight of 1000 Da or less. In some embodiments, the active ingredient has a molecular weight of 200-500 Da. In some embodiments, 1 milliliter to 10 milliliters of the formulation is applied topically to the periorbital skin of one eye of the patient per use, and the active ingredient is applied topically with an eye pad. In some embodiments, 3 microliters to 100 microliters of the formulation is applied topically directly to the periorbital skin of one eye of the patient per use. In some embodiments, 0.01 milligrams to 10 grams of the active ingredient is applied topically to the periorbital skin of one eye of the patient per use, and the active ingredient is applied topically with an eye pad. In some embodiments, 0.01 milligrams to 100 milligrams of active ingredient are applied topically directly to the periorbital skin of one eye of the patient per use. In some embodiments, the formulation further comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the oil is derived from a natural source. In some embodiments, the oil is derived from a plant, a plant seed, or a nut. In some embodiments, the oil comprises a medium chain triglyceride. In some embodiments, the oil comprises soybean oil. In some embodiments, the active ingredient is an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof. In some embodiments, the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof comprises DHA. In some embodiments, the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof comprises EPA.In some embodiments, the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is present in an amount of about 0.01% to about 100% (w / w) of the composition. In some embodiments, administration of 6.7 mg of the formulation results in a tissue concentration of omega-3 fatty acid 30 that is about 110 micrograms per gram higher in the posterior segment of the patient's eye 30 minutes after administration compared to baseline. In some embodiments, the formulation further comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, the expected range of detectable active ingredient in the posterior tissue of the eye is about 0.1 μg to about 1600 μg per gram of posterior tissue. In some embodiments, the active ingredient is administered to the periorbital skin of each eye of the patient four times a day, three times a day, twice a day, or once a day. In some embodiments, the active ingredient is 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.00005% to about 10% (w / w) of the composition. In some embodiments, the formulation further comprises an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof.

[0093] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. [Brief description of the drawings]

[0094] [Figure 1] 1 illustrates the anatomy of the periorbital region of the eye. [Figure 2A]1 shows the bioavailability of JV-DE1 in the right eye of rabbits administered JV-DE1 bilaterally as a topical ocular formulation directly to the ocular surface. [Figure 2B] 1 shows the bioavailability of JV-DE1 in the left eye of rabbits administered JV-DE1 bilaterally as a topical ocular formulation directly to the ocular surface. [Figure 3A] 1 shows the bioavailability of JV-DE1 in the right eye of rabbits administered JV-DE1 as a topical ocular formulation directly to the ocular surface. [Figure 3B] 1 shows the bioavailability of JV-DE1 in the left eye of rabbits administered JV-DE1 in a topical ocular formulation directly to the ocular surface in the right eye. [Figure 4] 1 shows delivery of a compound (eg, a compound disclosed herein) to the anterior segment of the eye via the corneal route and to the posterior segment of the eye via the scleral route by non-invasive periorbital application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Provided herein is the use of the compound 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1, JV-MD2) as a treatment for ocular diseases. In some embodiments, the ocular diseases are diseases and disorders related to the posterior segment of the eye. The formulated compound achieves bioavailability in the posterior segment of the eye after application by eye drops to the ocular surface, more preferably after application to the periorbital skin. In some embodiments, the formulated compound is administered via a non-invasive ocular delivery platform (NIODP). The non-invasive ocular delivery platform (NIODP) is a combination of periorbital skin transdermal administration and a suitable drug formulation for delivering ocular drugs, particularly retinal drugs, at levels above μg / g of ocular tissue.

[0096] The disclosed embodiments are directed to the treatment of ocular diseases, including diseases of the anterior part of the eye, and unexpectedly, diseases of the posterior part of the eye. These diseases may arise from the posterior part of the eye, the anterior part of the eye, or as a result of systemic diseases, such as, but not limited to, diabetes, rheumatoid arthritis, and systemic hypertension. Formulations are included that can deliver therapeutically appropriate amounts of compounds to the posterior pole of the eye, which can be achieved by application to the ocular surface via eye drops or application to the periorbital skin surrounding the eyeball.

[0097] Also provided herein are methods and compositions for delivery of fatty acids, including omega-3 fatty acids, to the eye via periorbital administration.Surprisingly, it has been found herein that omega-3 fatty acids, including docosahexaenoic acid (DHA), can be effectively delivered to the eye, including the posterior part of the eye, and throughout the eye via periorbital administration.Such an administration route provides several advantages for DHA and other fatty acids that have oily characteristics that make administration by eye drops undesirable.Administering omega-3 fatty acids in this manner is useful for promoting eye health and preventing or treating eye diseases, including age-related macular degeneration (AMD).

[0098] Further disclosed herein are methods and compositions for delivering fatty acids, including omega-3 fatty acids, directly to the eye via administration to the external surface of the eyelid.

[0099] Disorders of the back of the eye Retinal diseases can impair vision, resulting in disability and ultimately complete vision loss. They are common, and the main risk factors are the "usual suspects": age, obesity, and smoking. Abnormalities of the retinal and choroidal vasculature, particularly hemorrhage and plasma exudation, occur as a result of systemic diseases, including diabetes, hypertension, fatty liver disease, obesity, head trauma, anemia, and leukemia.

[0100] The retina has two blood supplies, the choroidal vasculature and the retinal vasculature. The choroidal circulation provides blood-based nutrients to the retinal pigment epithelium, photoreceptors, and outer plexiform layer. The retinal circulation provides blood-borne nutrients to the inner nuclear layer, plexiform layer, ganglion layer, and nerve fiber layer. The macula is supplied by the superior and lateral branches of the central retinal artery. The retinal circulation is anatomically positioned to be a source of bleeding into the vitreous.

[0101] Diseases originating from the retina itself include, but are not limited to, age-related macular degeneration, macular holes, macular pucker, degeneration, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, branch retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric and neonatal retinal disorders, cytomegalovirus (cmv) retinal infection, uveitis, infectious retinitis, central serous retinopathy, retinoblastoma, endophthalmitis and geographic atrophy, retinitis pigmentosa, etc. Retinal neovascularization can also result from childhood myopia (Bremond-Gignac D, 2020, Med Sci, 36: 763-763). Thus, abnormalities in the vasculature are a major feature of many retinal diseases. These include hemorrhage, edema, neovascularization, inflammation, and fibrosis.

[0102] Bleeding from the choroidal and / or retinal vasculature is a significant problem. Currently, there are no "listed" drugs for the treatment of retinal hemorrhage. Anti-VEGF antibodies, which are highly effective in preventing neovascularization, are of little value in the treatment of vitreous hemorrhage (El Annan, Carvounis PE, 2014, Int Ophthalmol Clin 54: 141-153). It is well known that release of the IP receptor agonist prostacyclin (PGI2) can stimulate vasodilation and increase blood flow in the ocular microvasculature (Mori A et al., 2007, Eur J Pharmacol 570:135-141). The use of IP receptor antagonists during choroidal or retinal hemorrhage will result in significant vasoconstriction and reduced retinal hemorrhage. Platelet activating factor (PAF) is not only a mediator of ocular inflammation, but can also stimulate corneal and retinal neovascularization. Various PAF antagonists have been shown to reduce microvascular leakage in anterior uveitis (Lin N and Bazan H, et al. 1991; Rubin RM, Samples JR, et al. 1988), reduce neovascularization in corneal grafts (Cohen RA, Gebhardt BM, et al. 1992), and reduce choroidal neovascularization in a rat model (Zhang H, Yang Y, et al., 2013). The PAF antagonist properties of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine will further reduce retinal inflammation and hemorrhage.

[0103] Elevated prostacyclin levels have been reported in diabetic retinopathy (Davis TME, et al. (1981) Br Med J 282: 1259-1262; Lane LS, et al. (1982) Ophthalmol 89: 763-766). Diabetic retinopathy results from lesions in the retinal microcirculation and may also involve the choroidal microvasculature. It is the most common cause of vitreous hemorrhage. Leakage of blood into the vitreous humor can be visualized as floaters, cobwebs, or shadows in mild cases, but in severe cases can cause haziness, streaks, or even complete loss of vision. The most common cause of vitreous hemorrhage is advanced diabetic retinopathy, but vitreous hemorrhage can occur in other retinal diseases such as age-related macular degeneration, retinal vein occlusion, microaneurysms, Terson syndrome, proliferative sickle cell retinopathy, and retinal or vitreous detachment.

[0104] Angiogenesis is also a prominent feature in the development of certain retinopathies. Vascular endothelial growth factor (VEGF) can, in some cases, cause choroidal neovascularization, and anti-VEGF antibodies are widely used as an effective treatment for choroidal neovascularization. Systemically administered receptor-selective IP receptor antagonists have also been shown to be effective in preventing choroidal neovascularization, which was first disclosed in U.S. Pat. Nos. 9,295,665 and 9,321,745. Such newly formed blood vessels allow blood perfusion of tissue, but tend to bleed, allowing plasma exudation, resulting in tissue swelling (edema) and changes in retinal dimensions that are important for optimal vision. In addition to VEGF, angiogenic factors such as bFGF (D'Amore P., 1994, Invest Ophthalmol Vis Sci 35:3974-3979), PDGF, SDF-1, HIF-1 (Campochiaro PA.,2015,Prog Retin Eye Res 49:67-81), PDGF, PIGF (Noma H et al., 2020, J Clin Med 9:3457), and IGF-1 (Lin S et al,2017,Cell Prolif. 50:e12390) are involved in the pathogenesis of angiogenesis. IGF-1 promotes angiogenesis by activating the PI3K / Akt signaling pathway (Lin S et al, 2017, Cell Prolif. 50:e12390). The PI3K / AKT / mTOR signaling pathway is aberrantly activated in many tumorigenic processes and plays an important role in tumorigenesis and development. (Feng Z, Levine AJ, Trends Cell Biol. 2010 Jul; 20(7): 427-434).

[0105] A further major cause of vision loss in retinal diseases is macular edema. The macula is essential for central vision. Fluid extravasation into the macular region leads to vision impairment due to thickening and deformation of the macula. Increased blood flow has long been known to increase fluid exudation into tissues, especially prostanoid-mediated vasodilation (Williams TJ, Peck MJ (1977) Nature 270: 530-532). Reduction of prostacyclin-mediated tissue blood flow by IP receptor antagonists will ameliorate macular edema. PAF can similarly induce vasodilation and increased plasma exudation into tissues, thus contributing to macular edema in retinal degenerative and inflammatory diseases. In addition to VEGF and PDGF, MCP-1, ICAM-1, IP-10, PTX-3, IL-6, and IL-8 are also involved in the development of macular edema (Noma et al., 2020).

[0106] Retinal diseases are a major cause of vision loss. They are characterized by several pathologies, including hemorrhage, edema, neovascularization, inflammation, fibrosis, and atrophy, which can occur as single events or in a sequence. Neovascularization and the resulting sequelae can be inhibited by antibodies against vascular endothelial growth factor (VEGF). Retinal antibody therapy requires injection into the vitreous humor, located in the posterior chamber of the eyeball. Intravitreal injections are inherently undesirable. Much effort continues to be expended on reducing the frequency of antibody injections into the eye by ophthalmologists. Self-application of eye drops to the ocular surface is typical and preferred for treating ocular diseases. However, drugs applied to the ocular surface do not work properly in the posterior part of the eye (Awwad S et al., 2017, Br J Pharmacol 174: 4205-4223; Del Amo EM et al., 2017, Prog Retin Eye Res 57: 134-185). No reliable success has been demonstrated (del Amo et al., 2017). Delivery of drugs to the posterior segment of the eye by topical administration has been described as the "holy grail" (Rodrigues GA et al., 2018, Pharm Res 35: 245). Thus, a drug that reliably reaches the posterior segment and vitreous humor after topical application to the ocular surface would be a breakthrough.

[0107] IP receptor antagonism represents an alternative and additional mechanism of action for treating hemorrhage, plasma exudation, neovascularization, and macular edema associated with the retinal and choroidal vasculature, providing blood-borne nutrients to tissues located at the rear of the eye. The current mainstay of therapeutic intervention is intravitreal injection of proteins that sequester VEGF or its receptors. VEGF antibody injections into the vitreous are not without risk. Retinal antibody therapy requires injection into the posterior chamber of the eye, which is inherently undesirable. The incidence of endophthalmitis, retinal detachment, and traumatic cataract per injection was reported to be 0.16%, 0.17%, and 0.07%, respectively (Michels S,2006, Br J Ophthalmol 90: 1333-1334). With patients receiving 4 to 12 injections per year, each injection adds risk. The desire to reduce or even eliminate the number of intravitreal injections required is widely recognized. IP receptor antagonists prevent the release of VEGF, and in accordance with the present invention, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is able to achieve its retinal targeting without the need for injection.

[0108] Independently of VEGF release, IP antagonists reduce blood perfusion of the microvasculature, thereby reducing the likelihood of edema formation and hemorrhage. 4,5-Dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also assigned numerical identities RO-1138452 and JV-DE1) is unique in that it also has PAF receptor antagonist properties, which will inhibit angiogenesis and fibrosis. Since blindness is an inevitable outcome for many patients, making 4,5-Dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine invaluable to ophthalmologists who currently have only a small armamentarium of drugs effective for retinal diseases.

[0109] Provided herein is a method of treating a posterior ocular disease, retinal disease or disorder in a subject, comprising administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the subject. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the eye. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the eye.

[0110] In some embodiments, the posterior ocular disease, retinal disease or disorder is age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumor, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, retinopathy), radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathy and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt disease, or refractive errors (myopia, hyperopia, and astigmatism).

[0111] In some embodiments, the retinal disease or disorder is age-related macular degeneration (wet and dry). In some embodiments, the retinal disease or disorder is dry age-related macular degeneration. In some embodiments, the retinal disease or disorder is wet age-related macular degeneration.

[0112] In some embodiments, the retinal disease or disorder is not retinal neovascularization. In some embodiments, the retinal disease or disorder is not neovascularization. In some embodiments, the retinal disease or disorder does not include retinal neovascularization.

[0113] Uveitis Further provided herein is a method of treating uveitis, comprising administering 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to an eye of a patient. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered both periorbitally and topically to the ocular surface.

[0114] Uveitis is a disease characterized by inflammation of the part of the eye known as the uvea, which consists of three parts: the iris, the ciliary body, and the choroid. There are four types of uveitis: (1) anterior uveitis, the most common and usually less severe type, affects the iris at the front of the eye; (2) intermediate uveitis affects the ciliary body and vitreous body; (3) posterior uveitis affects the retina and choroid at the back of the eye; and (4) total uveitis affects all parts of the uvea, from the front to the back of the eye. Total uveitis is the most severe form of uveitis and also affects the lens, retina, optic nerve, and vitreous body, which can cause vision loss or blindness. 4,5-Dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine may be administered to treat anterior uveitis, intermediate uveitis, posterior uveitis, or pan uveitis, or a combination thereof. Uveitis may have an infectious or non-infectious cause. Infectious causes include bacterial, fungal, parasitic, and viral infections. Non-infectious causes include immunological problems, allergies, malignancies, and unknown causes. As a treatment of choice for most types of uveitis, including pan uveitis, corticosteroid eye drops have been used to reduce inflammation and pain, and oral medications or injections have been used to treat severe cases. Infectious uveitis can be treated with antibiotics, anthelmintics, or antivirals specific to the infectious agent, with or without corticosteroids. In cases of chronic, recurrent, severe uveitis, such as intermediate, posterior, and / or pan-uveitis, that cannot be controlled by short-term use of corticosteroids, or in cases of active inflammation that interferes with daily activities, immunomodulatory drugs (biologics) delivered by intraocular injection are needed. Thus, a method for non-invasively delivering disease-treating compounds to the posterior of the eye would provide a significant improvement over existing treatments.

[0115] myopia The treatment of myopia would further benefit from the application of therapeutic interventions to the periorbital skin, which directly overlies the sclera. A widely held concept involves that form deprivation produced by an unfocused image causes the retina to transmit signals to the sclera, which in turn produces an elongation of the long axis of the eyeball by modifications to the sclera (Wang et al., 1997; Gallego et al., 2012). Drugs delivered via the periorbital skin route could result in therapeutically effective drug levels in both the sclera and retina. Interestingly, the anti-glaucoma agents brimonidine (Carr et al., 2019) and latanoprost (El-Nimri and Wildsoet, 2018) have been reported to inhibit the progression of myopia in animal models.

[0116] Disorders of the front of the eye Also provided herein are methods for treating certain diseases and disorders associated with the anterior segment of the eye. Examples of such diseases include blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, pterygospasm, meibomian gland dysfunction, lacrimal gland obstruction, lacrimal gland obstruction, seborrheic keratitis, ultraviolet keratitis, bacterial or viral infection, anterior segment malformation, cataract, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectasia disorder (cornea bulbosus, pellucid marginal degeneration), and the like. In some embodiments, the disease or disorder includes corneal ulcers, corneal dysplasia, corneal ulcers, Fuchs endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, acute and chronic uveitis (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment including iris trauma, penetrating ocular trauma. In some embodiments, the disease or disorder includes an inflammatory disease of the anterior segment. In some embodiments, the disease or disorder is a disorder of the anterior segment associated with inflammation, hemorrhage, edema, or fibrosis. In some embodiments, these diseases or disorders can be treated with prostanoid IP receptor antagonists or inhibitors, such as 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1). In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases of the anterior segment of the eye via administration to the surface of the eye (e.g., in a drop formulation). In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases of the anterior segment of the eye via administration through the periorbital skin.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases of the anterior part of the eye via administration to the surface of the eye (e.g., in a drop formulation) and administration to the periorbital skin. In some embodiments, these diseases or disorders can be treated with omega-3 fatty acid, or its pharmaceutically acceptable ester or salt. In some embodiments, omega-3 fatty acid, or its pharmaceutically acceptable ester or salt, is administered to the periorbital part of the patient to treat diseases or disorders of the anterior part of the patient's eye.

[0117] Inflammation plays an important role in the development of certain anterior segment diseases, including dry eye, uveitis, and pterygium. VEGF has been proposed to be a core molecule in the crosstalk between inflammation and these diseases, which may explain the high incidence of coexistence of these diseases (Liu C, Song Y, et al. 2020).

[0118] IP receptor stimulation potently and highly effectively promotes VEGF release from human immune cells when macrophages are stimulated with TNFα to mimic inflammatory events. The IP antagonist, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, abolished the VEGF release induced by the IP receptor agonist cicaprost in the presence of TNFα (US9321745). Thus, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine may provide therapeutic benefit in inflammation-related anterior ocular diseases due to its anti-inflammatory effect.

[0119] Platelet activating factor (PAF) is a mediator of inflammation and can cause damage to the eye. Various PAF antagonists, such as 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1), have been shown to reduce microvascular leakage in anterior uveitis (Lin N and Bazan H, et al. 1991; Rubin RM, Samples JR, et al. 1988), reduce angiogenesis in corneal grafts, and reduce eosinophil accumulation (Cohen RA, Gebhardt BM, et al. 1992). Thus, PAF antagonists may be useful in mitigating ocular inflammatory responses, such as vascular permeability and chemotactic activity in the anterior and posterior segments of the eye (Bazan H, Yao Y, et al. 1994). Ginkgo extracts have neuroprotective properties under conditions such as hypoxia / ischemia, seizure activity, and peripheral nerve injury. One of the components of ginkgo, ginkgolide B, is a potent platelet activating factor (PAF) antagonist (Smith P, Maclennan K, et al, 1996).

[0120] pterygium Provided herein is a method of treating pterygium in a subject by administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the subject. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered both periorbitally and topically to the ocular surface. In some embodiments, treatment of pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and another anti-inflammatory agent.

[0121] Early in the disease process, pterygium is usually asymptomatic. However, there may be signs of dry eye (such as burning, itching, or tearing) as the lesion causes irregular wetting of the ocular surface. A distinctive feature of pterygium epithelial cells is their positive immunohistochemical staining for different types of matrix metalloproteinases that are not present in normal conjunctival, limbal, or corneal cells (Krachmer, JH et al. 2005). Short-term use of topical corticosteroid eye drops may be used to reduce redness and inflammation. If ocular dryness is a problem, artificial tears are used to keep the eye well lubricated. There may be more severe symptoms such as redness (due to localized tissue bleeding), swelling, and pain. In addition to anti-inflammatory properties via VEGF inhibition, IP receptor antagonists have been shown to be involved in hemorrhage suppression via inhibition of vasodilation.

[0122] One embodiment provides a method for treating pinguecula or pterygium, comprising topically administering a composition comprising an anti-inflammatory agent to the surface of the eye. In some embodiments, topically administering the anti-inflammatory agent to the surface of the eye is achieved via eye drops. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, including but not limited to cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the drug is a non-steroidal anti-inflammatory agent such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin. One embodiment provides a method for treating pinguecula or pterygium, comprising topically administering to the ocular surface a composition comprising IP and / or a PAF receptor antagonist. In some embodiments, topically administering to the ocular surface a composition comprising IP and / or a PAF receptor antagonist for treating pinguecula or pterygium is accomplished via eye drops. One embodiment provides a method for treating pinguecula or pterygium, comprising topically administering to the ocular surface a composition comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine. In some embodiments, topical administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface is accomplished using eye drops.

[0123] One embodiment provides a method for treating pinguecula or pterygium, comprising administering a composition comprising an anti-inflammatory agent to the eyelid. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, including but not limited to cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the drug is a non-steroidal anti-inflammatory agent such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin. One embodiment provides a method for treating pinguecula or pterygium, comprising administering to the eyelid a composition comprising an IP and / or PAF receptor antagonist. One embodiment provides a method for treating pinguecula or pterygium, comprising administering to the eyelid a composition comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine. In some embodiments, treating pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and another anti-inflammatory agent.

[0124] One embodiment provides a method for treating pinguecula or pterygium, comprising periorbital administration of a composition comprising an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, such as, but not limited to, cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexaacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the agent is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin. One embodiment provides a method for treating pinguecula or pterygium, comprising periorbital administration of a composition comprising an IP and / or PAF receptor antagonist.One embodiment provides a method for treating pinguecula or pterygium, comprising periorbital administration of a composition comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine.One embodiment provides a method for treating pinguecula or pterygium, comprising periorbital administration of a composition comprising an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof.

[0125] Other anterior segment disorders Further provided herein is a method of treating additional diseases of the anterior segment with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface to treat diseases of the anterior segment. In some embodiments, topical administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface to treat diseases of the anterior segment is achieved using eye drops. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered to the eyelid of a subject. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered via a combination of eye drops and periorbital or eyelid administration to treat anterior eye diseases.

[0126] Also provided herein is a method for treating anterior ocular disease with omega-3 fatty acid or its pharmaceutically acceptable ester or salt.In some embodiments, omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the periorbital region of a patient to treat anterior ocular disease or disorder of the patient.

[0127] In some embodiments, diseases of the anterior segment are anterior segment hypoplasia, cataract, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectatic disorders (including globular cornea, pellucid marginal degeneration), pseudophakic and aphakic bullous keratopathy, episcleritis, corneal ulcer, corneal dysplasia, corneal ulcer, Fuchs endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, acute and chronic uveitis (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment including iris trauma, penetrating ocular trauma.

[0128] In some embodiments, the anterior ocular disease or disorder is dry eye, dry eye disease, eye discomfort, irritation, pain, and stress, or chemical burns. In some embodiments, the omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is administered periorbitally to the patient to treat dry eye, dry eye disease, eye discomfort, irritation, pain, and stress, or chemical burns.

[0129] In some embodiments, the disease or disorder of the anterior region of the eye is a condition affecting the eyelid, hi some embodiments, the eyelid condition is blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, blepharitis, meibomian gland dysfunction, lacrimal gland obstruction, lacrimal gland obstruction, seborrheic keratitis, ultraviolet keratitis, bacterial infection, or viral infection.

[0130] In some embodiments, eyelid conditions are treated by applying 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the periorbital skin of the eye. In some embodiments, eyelid conditions are treated by applying 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the eyelid of a subject. In some embodiments, eyelid conditions are treated by applying 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface. In some embodiments, topical administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface to treat eyelid conditions is accomplished using eye drops.

[0131] In some embodiments, eyelid conditions are treated by applying an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof to the periorbital skin of the eye, hi some embodiments, eyelid conditions are treated by applying an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof to the eyelid of a subject.

[0132] Disorders that affect the front and back of the eye Also provided herein are methods for treating certain diseases and disorders associated with both the anterior and posterior segments of the eye. Examples of such diseases include orbital lymphatic malformation (i.e. orbital lymphangioma), thyroid eye disease (Graves eye disease), acute and chronic uveitis (including intermediate uveitis, posterior uveitis, and panuveitis). In some embodiments, these diseases or disorders can be treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases of the anterior segment of the eye via administration to the surface of the eye (e.g., in a drop formulation). In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases of the posterior part of the eye via administration through the periorbital skin. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can treat diseases affecting the anterior and posterior parts of the eye via administration to the surface of the eye (e.g., in a drop formulation) and to the periorbital skin. In some embodiments, these diseases or disorders can be treated with omega-3 fatty acids, or pharma- ceutically acceptable esters or salts thereof. In some embodiments, omega-3 fatty acids, or pharma-ceutically acceptable esters or salts thereof, are administered via the periorbital skin to treat both the anterior and posterior parts of the patient's eye. In some embodiments, these diseases or disorders can be treated with a combination of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acid or its pharma- ceutically acceptable ester or salt are formulated together as a single composition that is applied to the periorbital skin of a patient. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface (e.g., in a drop formulation), and omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is delivered by alternative means, such as administration to the periorbital skin of a patient.

[0133] Uveitis (including panuveitis) Uveitis is caused by an inflammatory reaction inside the eye. Uveitis treatments primarily attempt to eliminate inflammation or reduce pain. Anterior uveitis occurs at the front of the eye. It is the most common form of uveitis. Intermediate uveitis is usually seen in young adults. The center of inflammation often appears in the vitreous. Posterior uveitis is a very rare form of uveitis. It occurs primarily at the back of the eye and often involves both the retina and the choroid. Treatment depends on the type of uveitis the patient presents with. Some, such as the use of corticosteroid eye drops and injections around or inside the eye, may target the eye exclusively, while other treatments, such as immunosuppressants taken by mouth, may be used when the disease is occurring in both eyes, especially the back of both eyes. Total uveitis involving both the anterior and posterior segments may even occur.

[0134] Also provided herein is a method for treating uveitis in a subject by administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the subject. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface. In some embodiments, topical administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface is achieved using eye drops. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered via a combination of eye drops and periorbital administration.

[0135] Also provided herein is a method for treating uveitis in a patient by administering a therapeutically effective amount of omega-3 fatty acid or its pharma- ceutically acceptable ester or salt to the patient.In some embodiments, omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is administered to the periorbital region.In some embodiments, omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is administered to the eyelid of the patient.In some embodiments, the treatment of total uveitis or uveitis comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acid or its pharma- ceutically acceptable ester or salt.

[0136] One embodiment provides a method for treating pinguecula or uveitis, comprising topically administering a composition comprising an immunosuppressant to the surface of the eye.In some embodiments, topically administering the immunosuppressant to the surface of the eye for treating pinguecula or uveitis is achieved via eye drops.In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine.

[0137] One embodiment provides a method of treating pinguecula or pterygium comprising periorbital administration of a composition comprising an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine.

[0138] One embodiment provides a method of treating pinguecula or pterygium, comprising administering to the eyelid a composition comprising an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine. In some embodiments, treating pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an immunosuppressant. In some embodiments, treating pinguecula or pterygium comprises administering a therapeutically effective amount of omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof and an immunosuppressant. In some embodiments, treatment of pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, a therapeutically effective amount of an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and an immunosuppressant.

[0139] One embodiment provides a method for treating pinguecula or uveitis, comprising topically administering a composition comprising an anti-inflammatory agent to the ocular surface. In some embodiments, topically administering an anti-inflammatory agent to the ocular surface for treating pinguecula or uveitis is achieved via eye drops. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, including but not limited to cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the drug is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin.

[0140] One embodiment provides a method for treating pinguecula or pterygium, comprising periorbital administration of a composition comprising an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, such as, but not limited to, cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexaacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the agent is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin.

[0141] One embodiment provides a method for treating pinguecula or pterygium, comprising administering a composition comprising an anti-inflammatory agent to the eyelid. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, including but not limited to cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the agent is a non-steroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin. In some embodiments, treating pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an anti-inflammatory agent. In some embodiments, treating pinguecula or pterygium comprises administering a therapeutically effective amount of omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and an anti-inflammatory agent.

[0142] In some embodiments, treatment of pinguecula or pterygium comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, a therapeutically effective amount of an omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof, and an anti-inflammatory agent.

[0143] thyroid eye disease Thyroid eye disease may also be called Graves' eye disease, Graves' ophthalmopathy, or Graves' orbitopathy. Thyroid eye disease usually develops in people with an overactive thyroid gland caused by Graves' disease. Graves' disease is an autoimmune disease caused by antibodies against receptors present in thyroid cells and on the surface of cells at the back of the eye. Thyroid eye disease may cause irritation or a gritty sensation in the eye, redness or inflammation of the conjunctiva, excessive tearing or dry eyes, swelling of the eyelids, sensitivity to light, forward displacement or bulging of the eye (exophthalmos), and double vision. In more advanced cases of thyroid eye disease, patients may experience reduced eye movement, incomplete eye closure with corneal ulcers, compression of the optic nerve, and rarely, loss of vision.

[0144] Treatment of thyroid eye disease primarily attempts to eliminate inflammation or reduce pain. Treatments may include applying cold compresses to the patient's eyes, wearing sunglasses, applying eye drops, elevating the patient's head, prism glasses, steroids, eyelid surgery, eye muscle surgery, orbital decompression surgery, or antibodies against the insulin-like growth factor-1 receptor (IGF-1R).

[0145] Also provided herein is a method of treating a thyroid eye disease in a subject by administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the subject. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface. In some embodiments, topical administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the ocular surface is achieved using eye drops. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered via a combination of eye drops and periorbital administration.

[0146] Also provided herein is a method for treating a thyroid eye disease in a patient by administering a therapeutically effective amount of an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof to the patient. In some embodiments, the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is administered periorbitally. In some embodiments, the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is administered to the eyelid of the patient. In some embodiments, the treatment of the thyroid eye disease comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof.

[0147] One embodiment provides a method for treating thyroid eye disease, comprising topically administering a composition comprising an immunosuppressant to the surface of the eye.In some embodiments, topically administering the immunosuppressant to the surface of the eye for treating thyroid eye disease is achieved via eye drops.In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine.

[0148] One embodiment provides a method for treating thyroid eye disease comprising periorbital administration of a composition comprising an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine.

[0149] One embodiment provides a method of treating thyroid eye disease, comprising administering to the eyelid a composition comprising an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, mycophenolic acid, azathioprine, or cyclosporine. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an immunosuppressant. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of an omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof, and an immunosuppressant. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, ...

[0150] One embodiment provides a method for treating thyroid eye disease, comprising topically administering a composition comprising an anti-inflammatory agent to the ocular surface. In some embodiments, topically administering an anti-inflammatory agent to the ocular surface for treating thyroid eye disease is accomplished via eye drops. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, including but not limited to cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the drug is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin.

[0151] One embodiment provides a method for treating thyroid eye disease, comprising periorbital administration of a composition comprising an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, such as, but not limited to, cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexaacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the agent is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin.

[0152] One embodiment provides a method for treating thyroid eye disease, comprising administering a composition comprising an anti-inflammatory agent to the eyelid. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In another embodiment, the agent is a steroid, COX inhibitor, or prostanoid receptor inhibitor that can block single or multiple receptors. In another embodiment, the agent is a corticosteroid, such as, but not limited to, cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol fluazacort, hydrocortisone, prednisone, betamethasone, methylprednisolone, riamcinolone hexaacetonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, and triamcinolone. In another embodiment, the agent is a nonsteroidal anti-inflammatory agent, such as aspirin, diclofenac, rofecoxib, ibuprofen, or indomethacin. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and an anti-inflammatory agent. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and an anti-inflammatory agent. In some embodiments, the treatment of thyroid eye disease comprises administering a therapeutically effective amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, a therapeutically effective amount of an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and an anti-inflammatory agent.

[0153] Orbital lymphangioma Lymphangioma, also known as lymphangioma, is a multicystic focal malformation involving the lymphatic and vasculature, most commonly occurring in the head and neck and usually evident at birth or by 2 years of age. Orbital lymphangiomas characteristically involve the subconjunctival and periocular tissues. Involvement of superficial or anterior orbital structures is usually diagnosed early. In many patients, lymphangioma harbors activating mutations in the PIK3CA gene. PIK3CA is known to play a role in regulating cell proliferation by signaling through the PI3K / mTOR pathway. n-3 polyunsaturated fatty acids (PUFAs), namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2, as well as their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis (Chen Z, et al., 2014, Oncogene, 33, 4548-4557). In addition to ptosis (drooping eyelids), symptoms include swelling, intraorbital hemorrhage, exophthalmos, cellulitis (redness, swelling, and pain in the affected area of ​​the skin), and conjunctival blebs (Wiegand et al., 2013). These are all typical symptoms of inflammation that can be inhibited by JV-DE1 and omega-3 polyunsaturated fatty acids.

[0154] Provided herein is a method for treating orbital lymphangioma or any inflammatory eye disease, comprising administering 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the eye of a patient. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered periorbitally. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface (e.g., in a drop formulation). In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered both periorbitally and topically to the ocular surface.

[0155] Further provided herein is a method for treating orbital lymphangioma or any inflammatory eye disease, comprising administering omega-3 fatty acid or its pharmaceutically acceptable ester or salt to the periorbital eye of a patient.In some embodiments, omega-3 fatty acid or its pharmaceutically acceptable ester or salt is combined with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to treat orbital lymphangioma or any other inflammatory eye disease.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acid or its pharmaceutically acceptable ester or salt are formulated together as a single composition that is applied to the periorbital skin of a patient. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface (e.g., in a drop formulation) and the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is delivered by an alternative means, such as administration to the periorbital skin of the patient. In some embodiments, the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is delivered to the periorbital skin of the patient.

[0156] Currently, the main therapeutic options for treating lymphangiopathy are active observation, percutaneous drainage, surgery, sclerotherapy, laser therapy, radiofrequency ablation, or medical therapy with oral drugs, sirolimus, or sildenafil. Sclerotherapy is an umbrella term that characterizes multiple types of drugs that are injected (usually under ultrasound guidance) into the cystic space of the lesion, resulting in scar formation and a reduction in the size of the cysts and lesions. Specific drugs used in sclerotherapy for the treatment of orbital lymphangiomas include OK-432 (picinivir), sodium tetradecyl sulfate, doxycycline, ethanol, pingyangmycin, and bleomycin.

[0157] Provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of sodium tetradecyl sulfate or its salt, free acid, or ester to the periorbital skin of a patient. Also provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of doxycycline or its salt, free acid, or ester to the periorbital skin of a patient. Also provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of pingyangmycin or its salt, free acid, or ester to the periorbital skin of a patient. Also provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of bleomycin or its salt, free acid, or ester to the periorbital skin of a patient.

[0158] Although the cause of lymphangioma is unknown, many patients have activating mutations in the PIK3CA gene. PIK3CA is known to play a role in regulating cell proliferation by signaling through the PI3K / mTOR pathway. Most established mTOR inhibitors have shown tumor responses against various tumor types in clinical trials. Sirolimus, an mTOR inhibitor, has been approved by the FDA to treat lymphangioma via oral administration. In addition, n-3 polyunsaturated fatty acids (PUFAs), such as omega-3, can abrogate the activity of the mTORC1 / 2 pathway in vitro and in vivo, and have the potential for cancer prevention and tumor suppression (Chen et al., 2014). Provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of an mTOR inhibitor to the periorbital skin of a patient. In some embodiments, the mTOR inhibitor is sirolimus, idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, limpelisib, buparisib, or BGB-10188. In some embodiments, the combination of an mTOR inhibitor and an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is administered to the periorbital skin of the patient.

[0159] Also provided herein is a method for treating orbital lymphangioma by administering a therapeutically effective amount of a phosphodiesterase 5 (PDE-5) inhibitor to the periorbital skin of a patient.In some embodiments, the PDE-5 inhibitor is sildenafil.In some embodiments, the combination of a PDE-5 inhibitor and an omega-3 fatty acid or its pharma-ceutically acceptable ester or salt is administered to the periorbital skin of a patient.

[0160] JV-DE1 A solution for treating certain eye diseases is achieved herein by administering 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (JV-DE1) as eye drops to the ocular surface or by application to the periorbital skin. Unexpectedly and surprisingly, application of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine to the periorbital skin resulted in a much greater bioavailability to the vitreous humor and retina than was achieved by eye drops.

[0161] The compound 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1, RO-1138452, CAY10441) is particularly valuable in the treatment of retinal diseases. It embodies two important pharmacological properties in a single molecule. It is both a prostanoid IP receptor antagonist and a platelet activating factor (PAF) antagonist (Bley et al., 2006). At the vascular IP receptor, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine has a pA2 of 8.2 (Jones RL et al. (2006) Br J Pharmacol 149: 110-120). At the PAF receptor, it has a pK i(Bley KR et al. (2006) Br J Pharmacol 147: 335-345). Incorporating two separate and diverse pharmacological properties in a single molecule is a distinct advantage in terms of certain important aspects of drug design: bioavailability, duration of action, formulation drug compatibility, and cost of goods (Woodward DF, Wang JW (2021) Trends Med .DOI: 10.15761 / TiM.1000264).

[0162] Combination using JV-DE1 In the treatment of various eye diseases or disorders, including diseases or disorders of the posterior part of the eye, such as retinal diseases or posterior uveitis, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1, RO-1138452, CAY10441) can be combined with one or more additional therapeutic agents. The compound 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can be combined with one or more additional therapeutic agents, and the combination can be administered periorbitally, topically to the surface of the eye via eye drops, or topically to the eyelid of the subject.

[0163] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered omega-3 fatty acids including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

[0164] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a VEGF antibody or functional fragment thereof. In some embodiments, administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine reduces the amount of VEGF antibody that would otherwise need to be administered to produce the intended therapeutic effect. In some embodiments, the reduced amount of VEGF antibody is manifested as a lower dose of VEGF antibody, or preferably, fewer or less frequent injections of VEGF antibody (e.g., fewer injections into the patient's eye). In some embodiments, patients being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine are administered a small molecule VEGF receptor antagonist instead of or in addition to a VEGF antibody.

[0165] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a tyrosine kinase inhibitor.

[0166] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a steroidal anti-inflammatory agent, in some embodiments, the steroidal anti-inflammatory agent is selected from the group consisting of cortisone, prednisolone, methylprednisolone, lamicinolone, fluromethalone, medrysone, dexamethasone, lotoprednol, hexacatonide, betamethasone, paramethasone, diflorasone, fluocinonide, fluocinolone, fluticasone, and triamcinolone.

[0167] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a nonsteroidal anti-inflammatory agent, in some embodiments, the nonsteroidal anti-inflammatory agent is selected from the group consisting of ketorolac, nepafenac, amfenac, aspirin, indomethacin, flurbiprofen, ibuprofen, rofecoxib, and celecoxib.

[0168] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered an immunosuppressant.

[0169] In some embodiments, the immunosuppressant is selected from the group consisting of cyclosporine, liftegrast, methotrexate, azathioprine, inhibitors of the PI3K-AKT-mTOR signaling pathway (e.g., sirolimus, idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, limpelisib, buparisib, or BGB-10188), and agents that interfere with the activation and function of the complement pathway (e.g., POT-4, ARC1905).

[0170] In some embodiments, the patient is co-administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and cyclosporine.

[0171] In some embodiments, the patient is co-administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and lifitegrast.

[0172] In some embodiments, the patient is co-administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and methotrexate.

[0173] In some embodiments, the patient is co-administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine with azathioprine. In some embodiments, the patient is co-administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, sirolimus, idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, rimpelisib, bupallisib, or BGB-10188.

[0174] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a nicotinic anticholinergic agent, in some embodiments, the nicotinic anticholinergic agent is selected from the group consisting of hexamethonium, decamethonium, and mecamyline.

[0175] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered thalidomide.

[0176] In some embodiments, the patient treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a prostaglandin receptor antagonist.In some embodiments, the antagonist blocks multiple prostaglandin receptors.In some embodiments, the antagonist is AGN211377 and AGN225660.

[0177] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a neuroprotective agent.

[0178] In some embodiments, the neuroprotective agent is selected from the group consisting of alpha 2 adrenergic receptor agonists (e.g., brimonidine), NMDA antagonists (e.g., memantine), AMPA antagonists, Ca2+ blockers, sigma-Irs receptor agonists, pentazocine, endothelin receptor antagonists, kinin antagonists, and anti-TNFα antibodies.

[0179] In some embodiments, patients being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine are also receiving treatment with neurotrophic / neuroregenerative agents (e.g., ciliary neurotrophic factor, nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, neurotrophin 3), heat shock proteins, JNK inhibitors, synthetic bile acids (e.g., UDCA, TUDCA), progesterone, dopaminergics, neurotrophic factors, caspase inhibitors, acetyl-L-carnitine, acetylcholinesterase ... In addition, agents that interfere with the activation and function of the complement pathway, such as vinpocetine, methylphenidate ...

[0180] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered an RNA interference molecule.

[0181] In some embodiments, the RNA interference molecule may be an siRNA, miRNA, or shRNA.

[0182] In some embodiments, the RNA interference molecule is complementary to a gene sequence that codes for a protein. In some embodiments, the RNA interference molecule has a sequence that is at least partially complementary to a gene sequence that codes for a protein. In some embodiments, the presence of the RNA interference molecule results in silencing of the gene that codes for the protein. In some embodiments, the protein is a receptor. In some embodiments, a combination of at least two RNA interference molecules is further administered to the patient. In some embodiments, the combination of at least two RNA interference molecules silences genes that code for at least two proteins. In some embodiments, the protein is an enzyme. In some embodiments, the protein is selected from the group of VEGF, PDGF, bFGF, SDF-1, HIF-1, PIGF, GLUT-1, claudin intercellular adhesion molecule, HMBG-1, HuR, Ets1, GSK3β, RTP801, caspase 2-, 3-, 7-, PGC-1, ICAM1, t-PA, SNAI1, TBK1, ARMS2, TERT, ASK-1, and Nrf-2.

[0183] In some embodiments, the RNA interference molecule is a single-stranded RNA. In some embodiments, the RNA interference molecule is a double-stranded RNA. In some embodiments, the length of the strand of the RNA interference molecule is about 10 nucleotides to about 200 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is from about 10 nucleotides to about 20 nucleotides, from about 10 nucleotides to about 30 nucleotides, from about 10 nucleotides to about 40 nucleotides, from about 10 nucleotides to about 50 nucleotides, from about 10 nucleotides to about 60 nucleotides, from about 10 nucleotides to about 70 nucleotides, from about 10 nucleotides to about 80 nucleotides, from about 10 nucleotides to about 90 nucleotides, from about 10 nucleotides to about 100 nucleotides, from about 10 nucleotides to about 200 nucleotides, from about 20 nucleotides to about 30 nucleotides, from about 20 nucleotides to about 40 nucleotides, from about 20 nucleotides to about 50 nucleotides, from about 20 nucleotides to about 60 nucleotides, from about 20 nucleotides to about 70 nucleotides, from about 20 nucleotides to about 80 nucleotides, from about 20 nucleotides to about 90 nucleotides, from about 20 nucleotides to about 100 nucleotides, from about 20 nucleotides to about 200 nucleotides, from about 30 nucleotides to about 40 nucleotides, nucleotides to about 50 nucleotides, about 30 nucleotides to about 60 nucleotides, about 30 nucleotides to about 70 nucleotides, about 30 nucleotides to about 80 nucleotides, about 30 nucleotides to about 90 nucleotides, about 30 nucleotides to about 100 nucleotides, about 30 nucleotides to about 200 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 60 nucleotides, about 40 nucleotides to about 70 nucleotides, about 40 nucleotides to about 80 nucleotides, about 40 nucleotides to about 90 nucleotides, about 40 nucleotides to about 100 nucleotides, about 40 nucleotides to about 200 nucleotides, about 50 nucleotides to about 60 nucleotides, about 50 nucleotides to about 70 nucleotides, about 50 nucleotides to about 80 nucleotides, about 50 nucleotides to about 90 nucleotides, about 50 nucleotides to about 100 nucleotides, about 50 nucleotides to about 200 nucleotides, about 60 nucleotides to about 70 nucleotides, about 60 nucleotides to about 80 nucleotides,The length of the strand of the RNA interference molecule is about 10 nucleotides, about 20 nucleotides, about 60 nucleotides, about 100 nucleotides, about 60 nucleotides, about 200 nucleotides, about 70 nucleotides, about 80 nucleotides, about 70 nucleotides, about 90 nucleotides, about 70 nucleotides, about 100 nucleotides, about 70 nucleotides, about 200 nucleotides, about 80 nucleotides, about 90 nucleotides, about 100 nucleotides, about 80 nucleotides, about 200 nucleotides, about 90 nucleotides, about 100 nucleotides, about 90 nucleotides, about 200 nucleotides, or about 100 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is about 10 nucleotides, about 20 nucleotides, about 30 nucleotides, about 40 nucleotides, about 50 nucleotides, about 60 nucleotides, about 70 nucleotides, about 80 nucleotides, about 90 nucleotides, about 100 nucleotides, or about 200 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is at most about 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200 nucleotides.

[0184] In some embodiments, the RNA interference molecule can prevent the expression of a VEGF receptor or attenuate the biosynthesis of VEGF and its various isoforms.

[0185] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered an RNA interference molecule selected from the group that reduces or eliminates receptor expression or reduces the biosynthesis of PDGF, bFGF, SDF-1, HIF-1, PIGF, GLUT-1, claudin intercellular adhesion molecule, HMBG-1, HuR, Ets1, GSK3β, RTP801, caspase 2-, 3-, 7-, PGC-1, ICAM1, t-PA, SNAI1, TBK1, SRPK1, C1Q, HtrA1, ARMS2, TERT, ASK-1, and Nrf-2.

[0186] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered an antioxidant. In some embodiments, the antioxidant is selected from the group consisting of β-carotene, lutein, zeaxanthin, riboflavin, niacin, and polyunsaturated fatty acids such as docosahexaenoic acid (DHA), eicosapentanoic acid (EPA), vitamin B3, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin E, CoQ10, ghrelin, α-lipoic acid, resveratrol, flavinoids, ginkgo biloba extract, ICAPS R®, OFTAN MACULA®, and epigallocatechin-3-gallate.

[0187] In some embodiments, the patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a therapeutic antibody. In some embodiments, the therapeutic antibody is a PDGF, FGF, PIGF, SDF-1, or HIF-1 antibody. In some embodiments, the therapeutic antibody is an antibody that interferes with the activation and function of the complement pathway. In some embodiments, administration of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine reduces the amount of therapeutic antibody that would otherwise need to be administered to produce the intended therapeutic effect. In some embodiments, the reduced amount of therapeutic antibody is manifested as a lower dose of the therapeutic antibody, or preferably, fewer or less frequent injections of the therapeutic antibody (e.g., fewer injections into the patient's eye).

[0188] In some embodiments, a patient being treated with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is further administered a therapeutic epigenetic modulator of a histone protein for acylation, deacylation, methylation, or demethylation.

[0189] In some embodiments, treatment with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is paired with an additional intervention, such as laser surgery or a steroid implant.

[0190] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and the additional therapeutic agent are formulated together (e.g., as a single composition that is applied to the patient's periorbital skin). In some embodiments, the additional therapeutic agent is delivered by alternative means, such as injection, implant, or oral administration.

[0191] Omega-3 fatty acids The World Health Organization suggests that adults consume 200 to 500 milligrams of omega-3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), per day for overall health benefits. There are three main forms of omega-3 fatty acids: DHA and EPA, which are abundant in cold-water fish oils, and alpha-linolenic acid (ALA), which is usually derived from plant sources.

[0192] The retina contains high concentrations of DHA, which is not only important in maintaining normal retinal integrity and visual function, but also plays anti-inflammatory, anti-apoptotic, and neuroprotective roles in the retina and brain. In addition to its nutritional, neuroprotective, and antioxidant properties, DHA is an important precursor of resolvins and related compounds (e.g., protectins) via pathways involving cyclooxygenase and lipoxygenase enzymes that may resolve inflammatory responses in the retina and ocular surface, particularly in the lacrimal gland, where these DHA derivatives are involved in the pathogenesis of dry eye disease (Cortina and Bazan, 2011). In addition, omega-3 fatty acids, including DHA, produce local anesthetic effects. DHA has been shown to attenuate the nociceptive jaw-opening reflex in rats and may be a therapeutic and complementary alternative medicine for the prevention of acute trigeminal nociception or trigeminal neuralgia. DHA promotes the resolution of acute inflammation and potentially inhibits inflammatory and neuropathic pain.

[0193] Oral administration of mega-doses of omega-3 fatty acids, including DHA, may be beneficial for age-related macular degeneration (AMD), dry eye disease, retinitis pigmentosa, and retinopathy of prematurity.However, DHA is only found in a few food sources, making it the most difficult to orally ingest in sufficient amounts for ocular benefit.In addition, the oily nature of these compounds makes them undesirable to be directly put into the eye as eye drops.Therefore, there is a need for a delivery method that can deliver therapeutically or prophylactically appropriate amounts of omega-3 fatty acids to eye tissue.

[0194] To overcome this problem, it has surprisingly been found that administration of omega-3 fatty acids, including DHA, when administered to the periorbital skin of the eye, results in substantial biodistribution in tissues throughout the eye, including both the anterior and posterior segments of the eye.

[0195] In one aspect, provided herein is a method for delivering one or more omega-3 fatty acids to the eye, including the anterior and posterior, via administration to the periorbital skin.The omega-3 fatty acid can be derived from any suitable source.In some embodiments, the omega-3 fatty acid is isolated from fish tissue.The concentration of omega-3 in fish oil can be increased by ethylation.In some embodiments, the omega-3 fatty acid is isolated from a plant source.In some embodiments, the plant source of the omega-3 fatty acid is algae, seaweed, seaweed, spirulina, or chlorella.In some embodiments, the plant source of the omega-3 fatty acid is linseed oil.

[0196] In some embodiments, it is a C16-C24 omega-3 fatty acid, or a combination of C16-C24 omega-3 fatty acids. In some embodiments, it is a C18-C22 omega-3 fatty acid, or a combination of C18-C22 omega-3 fatty acids. In some embodiments, the omega-3 fatty acid is a very long chain monounsaturated fatty acid (VLCMUFA) or a very long chain polyunsaturated fatty acid (VLCPUFA).

[0197] In some embodiments, the omega-3 fatty acid is hexadecatrienoic acid (HTA), alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, or any combination thereof. In some embodiments, the omega-3 fatty acid comprises tetracosanoic acid, -acid, hexacosenoic acid, octacosenoic acid, or any combination thereof. In some embodiments, the omega-3 fatty acid comprises ALA, EPA, DHA, or any combination thereof. In some embodiments, the omega-3 fatty acid comprises DHA. In some embodiments, the omega-3 fatty acid comprises EPA. In some embodiments, the omega-3 fatty acid comprises ALA, hi some embodiments, the omega-3 fatty acid comprises both DHA and EPA.

[0198] In some embodiments, the omega-3 fatty acid is in the form of omega-3 ethyl ester. Once in the skin, the omega-3 ethyl ester can be converted by esterase to omega-3 free acid, which can easily pass through the intercellular lipids of the stratum corneum and pores. In some embodiments, the omega-3 fatty acid comprises DHA ester. In some embodiments, the omega-3 fatty acid comprises EPA ester. In some embodiments, the omega-3 fatty acid comprises DHA ethyl ester. In some embodiments, the omega-3 fatty acid comprises EPA ethyl ester. In some embodiments, the omega-3 fatty acid comprises both DHA and EPA esters. In some embodiments, the omega-3 fatty acid comprises both DHA and EPA ethyl esters. In some embodiments, the omega-3 fatty acid comprises omega-3-carboxylic acid (free fatty acid mainly composed of EPA and DHA). In some embodiments, the omega-3 fatty acid comprises ethyl icosapentate (ethyl ester of EPA).

[0199] In some embodiments, omega-3 fatty acid is in the form of omega-3 triglyceride.Natural fish oil contains omega-3 fatty acid EPA and DHA mainly in the form of omega-3 triglyceride.Omega-3 triglyceride has a molecular weight of about 900 Da.Once entering the skin, omega-3 triglyceride can be converted into omega-3 free acid by lipase.Omega-3 triglyceride can further pass through the intercellular lipids of the stratum corneum and pass through pores.

[0200] In some embodiments, the metabolites of omega-3 fatty acids can be administered to the periorbital skin of the eye to provide substantial biodistribution to tissues throughout the eye, including both the anterior and posterior segments of the eye. In some embodiments, the metabolites of omega-3 fatty acids can include leukotrienes or derivatives thereof. In some embodiments, the metabolites of omega-3 fatty acids can include lipoxins or derivatives thereof. In some embodiments, the metabolites of omega-3 fatty acids can include 5-series leukotrienes (LTB5, LTC5, LTD5, LTE5). In some embodiments, the metabolites of omega-3 fatty acids can include prostanoids, such as prostacyclin, thromboxane, or prostaglandin, or derivatives thereof. In some embodiments, the metabolites of omega-3 fatty acids can include 3-series prostanoids or prostaglandins. In some embodiments, the metabolites of omega-3 fatty acids can include prostaglandin A3. In some embodiments, the metabolites of omega-3 fatty acids can include prostaglandin 13. In some embodiments, the omega-3 fatty acid metabolites may include prostaglandin F2α. In some embodiments, the omega-3 fatty acid metabolites may include thromboxane A3. While EPA is important to help reduce chronic pain and inflammation anywhere in the body (e.g., for cardiovascular health or disease), DHA is best for the brain. To support brain health, the essential fatty acid supplement may have a DHA to EPA ratio of at least 4:1. In some embodiments, the essential fatty acid supplement may have a DHA to EPA ratio of 3:1. In some embodiments, the essential fatty acid supplement may have a DHA to EPA ratio of 2:1. In some embodiments, the essential fatty acid supplement may have a DHA to EPA ratio of 1:1. In some embodiments, the omega-3 fatty acid metabolites may include maresin or a derivative thereof. In some embodiments, the omega-3 fatty acid metabolites may include resolvin or a derivative thereof. In some embodiments, the omega-3 fatty acid metabolites may include protectin or a derivative thereof.

[0201] In some embodiments, provided herein is a method of promoting eye health and preventing or treating eye disease in a subject, the method comprising administering a composition comprising an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, to the eye of the subject. In some embodiments, promoting eye health, preventing or treating eye disease comprises treating or preventing age-related vision loss. In some embodiments, promoting eye health, preventing or treating eye disease comprises treating or preventing dry eye. In some embodiments, promoting eye health, preventing or treating eye disease comprises treating or preventing age-related macular degeneration. In some embodiments, promoting eye health, preventing or treating eye disease comprises treating or preventing age-related macular degeneration. In some embodiments, promoting eye health comprises treating acute inflammation and neuropathic pain. In some embodiments, promoting eye health comprises preventing acute trigeminal nociception or trigeminal neuralgia.

[0202] In some embodiments, a method for treating or preventing age-related vision loss in a subject is provided herein, comprising administering a composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt to the eye of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the periorbital skin of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the eyelid of the patient.

[0203] In some embodiments, a method for treating or preventing dry eye in a subject is provided herein, the method comprising administering a composition comprising omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof to the eye of the subject. In some embodiments, the method comprises administering a composition comprising hyaluronic acid, a hyaluronate, or a pharma- ceutically acceptable ester or salt thereof to the eye of the subject. In some embodiments, the method comprises administering a composition comprising omega-3 fatty acid and hyaluronic acid, a hyaluronate, or a pharma- ceutically acceptable ester or salt thereof to the eye of the subject. In some embodiments, the composition comprising omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is administered to the periorbital skin of the subject. In some embodiments, the composition comprising omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is administered to the eyelid of the patient.

[0204] In some embodiments, the present invention provides a method for treating or preventing age-related macular degeneration in a subject, comprising administering a composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt to the eye of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the periorbital skin of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the eyelid of the patient.

[0205] In some embodiments, the present invention provides a method for treating or preventing dry age-related macular degeneration in a subject, comprising administering a composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt to the eye of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the periorbital skin of the subject.In some embodiments, the composition comprising omega-3 fatty acid or its pharmaceutically acceptable ester or salt is administered to the eyelid of the patient.

[0206] Combinations using omega-3 fatty acids In treating various eye diseases or disorders, including retinal diseases or disorders of the rear of the eye, such as posterior uveitis, omega-3 fatty acid or its pharmaceutically acceptable ester or salt (DHA, EPA, etc.) can be combined with one or more additional therapeutic agents.Omega-3 fatty acid or its pharmaceutically acceptable ester or salt can be combined with one or more additional therapeutic agents, and this combination can be administered periorbitally or topically to the eyelid of the subject.

[0207] In some embodiments, the patient being treated with an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is further administered 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof.

[0208] In some embodiments, the patient being treated with an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is further administered a VEGF antibody, or a functional fragment thereof.

[0209] In some embodiments, the patient being treated with an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is further administered a tyrosine kinase inhibitor.

[0210] In some embodiments, the patient treated with omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is further administered a steroidal anti-inflammatory agent. In some embodiments, the steroidal anti-inflammatory agent is selected from the group consisting of cortisone, prednisolone, methylprednisolone, lamininolone, fluromethalone, medrysone, dexamethasone, lotoprednol, hexacatonide, betamethasone, paramethasone, diflorasone, fluocinonide, fluocinolone, fluticasone, and triamcinolone.

[0211] In some embodiments, the patient treated with omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is further administered a nonsteroidal anti-inflammatory agent. In some embodiments, the nonsteroidal anti-inflammatory agent is selected from the group consisting of ketorolac, nepafenac, amfenac, aspirin, indomethacin, flurbiprofen, ibuprofen, rofecoxib, and celecoxib.

[0212] In some embodiments, the patient treated with omega-3 fatty acid or its pharmaceutically acceptable ester or salt is further administered immunosuppressant.In some embodiments, the immunosuppressant is selected from the group consisting of cyclosporine, liftegrast, methotrexate, azathioprine, inhibitors of PI3K-AKT-mTOR signaling pathway (e.g., sirolimus, idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, limpelisib, buparisib, or BGB-10188), and agents that interfere with the activation and function of complement pathway (e.g., POT-4, ARC1905).

[0213] In some embodiments, the patient is co-administered an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and cyclosporine.

[0214] In some embodiments, the patient is co-administered an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, and liftegrast.

[0215] In some embodiments, the patient is co-administered an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and methotrexate.

[0216] In some embodiments, the patient is co-administered with an omega-3 fatty acid or its pharmaceutically acceptable ester or salt and azathioprine.In some embodiments, the patient is co-administered with an omega-3 fatty acid or its pharmaceutically acceptable ester or salt and an inhibitor of the PI3K-AKT-mTOR signaling pathway (e.g., sirolimus, idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, rimpelisib, buparisib, or BGB-10188).

[0217] In some embodiments, the patient being treated with an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is further administered a nicotinic anticholinergic agent. In some embodiments, the nicotinic anticholinergic agent is selected from the group consisting of hexamethonium, decamethonium, and mecamyline.

[0218] In some embodiments, the patient being treated with an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is further administered thalidomide.

[0219] In some embodiments, the patient who is treated with omega-3 fatty acid or its pharmaceutically acceptable ester or salt is further administered a prostaglandin receptor antagonist.In some embodiments, the antagonist blocks multiple prostaglandin receptors.In some embodiments, the antagonist is AGN211377 and AGN225660.

[0220] In some embodiments, the patient treated with omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is further administered a neuroprotectant.In some embodiments, the neuroprotectant is selected from the group consisting of α2 adrenergic receptor agonists (e.g., brimonidine), NMDA antagonists (e.g., memantine), AMPA antagonists, Ca2+ blockers, σ-Irs receptor agonists, pentazocine, endothelin receptor antagonists, kinin antagonists, and anti-TNFα antibodies.

[0221] In some embodiments, the patient being treated with an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is administered a neurotrophic / neuroregenerative agent (e.g., ciliary neurotrophic factor, nerve growth factor, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, neurotrophin 3), heat shock proteins, JNK inhibitors, synthetic bile acids (e.g., UDCA, TUDCA), progesterone, dopaminergics, neurotrophic factors, caspase inhibitors, acetyl-L-carnitine, acetylcholinesterase inhibitors, citicoline, amyloidosis, inflammatory bowel disease, osteoarthritis, osteoporosis ... Additionally administered are cetylcysteine, retinoids (e.g., fenretinide), emixustat, anti-protein aggregation agents, phosphodiesterase inhibitors, nicotinamide, cannabinoids, citicoline, curcumin, minocycline, edaravone, erythropoietin, estrogen, L-theanine, melatonin, minocycline, noopept, pyrroloquinoline quinone, selegiline, simvastatin, esketamine, methylphenidate, ponesimod, glatiramer acetate, paliperidone, and vinpocetine agents that interfere with complement pathway activation and function.

[0222] In some embodiments, the patient treated with omega-3 fatty acid or its pharma-ceutically acceptable ester or salt is further administered an RNA interference molecule. In some embodiments, the RNA interference molecule may be siRNA, miRNA, or shRNA. In some embodiments, the RNA interference molecule is complementary to a gene sequence that codes for a protein. In some embodiments, the RNA interference molecule has a sequence that is at least partially complementary to a gene sequence that codes for a protein. In some embodiments, the presence of the RNA interference molecule results in silencing of the gene that codes for the protein. In some embodiments, the protein is a receptor. In some embodiments, a combination of at least two RNA interference molecules is further administered to the patient. In some embodiments, the combination of at least two RNA interference molecules silences the gene that codes for at least two proteins. In some embodiments, the protein is an enzyme. In some embodiments, the protein is selected from the group of VEGF, PDGF, bFGF, SDF-1, HIF-1, PIGF, GLUT-1, claudin intercellular adhesion molecule, HMBG-1, HuR, Ets1, GSK3β, RTP801, caspase 2-, 3-, 7-, PGC-1, ICAM1, t-PA, SNAI1, TBK1, ARMS2, TERT, ASK-1, and Nrf-2.

[0223] In some embodiments, the RNA interference molecule is a single-stranded RNA. In some embodiments, the RNA interference molecule is a double-stranded RNA. In some embodiments, the length of the strand of the RNA interference molecule is about 10 nucleotides to about 200 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is from about 10 nucleotides to about 20 nucleotides, from about 10 nucleotides to about 30 nucleotides, from about 10 nucleotides to about 40 nucleotides, from about 10 nucleotides to about 50 nucleotides, from about 10 nucleotides to about 60 nucleotides, from about 10 nucleotides to about 70 nucleotides, from about 10 nucleotides to about 80 nucleotides, from about 10 nucleotides to about 90 nucleotides, from about 10 nucleotides to about 100 nucleotides, from about 10 nucleotides to about 200 nucleotides, from about 20 nucleotides to about 30 nucleotides, from about 20 nucleotides to about 40 nucleotides, from about 20 nucleotides to about 50 nucleotides, from about 20 nucleotides to about 60 nucleotides, from about 20 nucleotides to about 70 nucleotides, from about 20 nucleotides to about 80 nucleotides, from about 20 nucleotides to about 90 nucleotides, from about 20 nucleotides to about 100 nucleotides, from about 20 nucleotides to about 200 nucleotides, from about 30 nucleotides to about 40 nucleotides, nucleotides to about 50 nucleotides, about 30 nucleotides to about 60 nucleotides, about 30 nucleotides to about 70 nucleotides, about 30 nucleotides to about 80 nucleotides, about 30 nucleotides to about 90 nucleotides, about 30 nucleotides to about 100 nucleotides, about 30 nucleotides to about 200 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 60 nucleotides, about 40 nucleotides to about 70 nucleotides, about 40 nucleotides to about 80 nucleotides, about 40 nucleotides to about 90 nucleotides, about 40 nucleotides to about 100 nucleotides, about 40 nucleotides to about 200 nucleotides, about 50 nucleotides to about 60 nucleotides, about 50 nucleotides to about 70 nucleotides, about 50 nucleotides to about 80 nucleotides, about 50 nucleotides to about 90 nucleotides, about 50 nucleotides to about 100 nucleotides, about 50 nucleotides to about 200 nucleotides, about 60 nucleotides to about 70 nucleotides, about 60 nucleotides to about 80 nucleotides,The length of the strand of the RNA interference molecule is about 10 nucleotides, about 20 nucleotides, about 60 nucleotides, about 100 nucleotides, about 60 nucleotides, about 200 nucleotides, about 70 nucleotides, about 80 nucleotides, about 70 nucleotides, about 90 nucleotides, about 70 nucleotides, about 100 nucleotides, about 70 nucleotides, about 200 nucleotides, about 80 nucleotides, about 90 nucleotides, about 100 nucleotides, about 80 nucleotides, about 200 nucleotides, about 90 nucleotides, about 100 nucleotides, about 90 nucleotides, about 200 nucleotides, or about 100 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is about 10 nucleotides, about 20 nucleotides, about 30 nucleotides, about 40 nucleotides, about 50 nucleotides, about 60 nucleotides, about 70 nucleotides, about 80 nucleotides, about 90 nucleotides, about 100 nucleotides, or about 200 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides. In some embodiments, the length of the strand of the RNA interference molecule is at most about 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200 nucleotides.

[0224] In some embodiments, the RNA interference molecule can prevent the expression of a VEGF receptor or attenuate the biosynthesis of VEGF and its various isoforms.

[0225] In some embodiments, the patient being treated with an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is further administered an RNA interference molecule selected from the group that reduces or eliminates receptor expression or reduces the biosynthesis of PDGF, bFGF, SDF-1, HIF-1, PIGF, GLUT-1, claudin intercellular adhesion molecules, HMBG-1, HuR, Ets1, GSK3β, RTP801, caspase 2-, 3-, 7-, PGC-1, ICAM1, t-PA, SNAI1, TBK1, SRPK1, C1Q, HtrA1, ARMS2, TERT, ASK-1, and Nrf-2.

[0226] In some embodiments, the patient treated with omega-3 fatty acid or its pharma- ceutically acceptable ester or salt is further administered an antioxidant.In some embodiments, the antioxidant is selected from the group consisting of β-carotene, lutein, zeaxanthin, riboflavin, niacin, and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), eicosapentanoic acid (EPA), vitamin B3, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin E, CoQ10, ghrelin, α-lipoic acid, resveratrol, flavinoids, ginkgo biloba extract, ICAPS R®, OFTAN MACULA®, and epigallocatechin-3-gallate.

[0227] In some embodiments, the patient treated with omega-3 fatty acid or its pharmaceutically acceptable ester or salt is further administered therapeutic antibody. In some embodiments, the therapeutic antibody is PDGF, FGF, PIGF, SDF-1, or HIF-1 antibody. In some embodiments, the therapeutic antibody is an antibody that interferes with the activation and function of complement pathway. In some embodiments, the administration of omega-3 fatty acid or its pharmaceutically acceptable ester or salt reduces the amount of therapeutic antibody that would otherwise need to be administered to produce the intended therapeutic effect. In some embodiments, the reduced amount of therapeutic antibody is manifested as a lower dose of therapeutic antibody, or preferably as less or less frequent injection of therapeutic antibody (e.g., less injection into the patient's eye).

[0228] In some embodiments, a patient being treated with an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is further administered a therapeutic epigenetic modulator of a histone protein for acylation, deacylation, methylation, or demethylation.

[0229] In some embodiments, treatment with an omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof is paired with an additional intervention, such as laser surgery or a steroid implant.

[0230] In some embodiments, the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof and the additional therapeutic agent are formulated together (e.g., as a single composition that is applied to the patient's periorbital skin). In some embodiments, the additional therapeutic agent is delivered by alternative means, such as injection, implant, or oral administration.

[0231] Combination of JV-DE1 and omega-3 fatty acids In treating various ocular diseases or disorders, including diseases or disorders of the anterior or posterior part of the eye, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can be combined with omega-3 fatty acid or its pharma- ceutically acceptable ester or salt. The composition comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acid or its pharma- ceutically acceptable ester or salt can be combined with one or more additional therapeutic agents. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acid or its pharma- ceutically acceptable ester or salt are formulated together as a single composition that is applied to the periorbital skin of a patient. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the ocular surface (e.g., in a drop formulation) and the omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is delivered by an alternative means, such as administration to the patient's periorbital skin.

[0232] Other active ingredients and excipients In one aspect, the pharmaceutical composition suitable for topical periorbital administration provided herein may include any pharma- ceutically acceptable excipient. In some embodiments, the pharma- ceutically acceptable excipient includes one or more acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers, and optionally preservatives. In some embodiments, the pharma- ceutically acceptable excipient includes a semi-fluorinated alkane. In some embodiments, the pharma- ceutically acceptable excipient includes perfluorohexyl octane. In some embodiments, the pharma- ceutically acceptable excipient includes perfluorobutyl pentane. In some embodiments, the pharmaceutical composition suitable for topical periorbital administration includes an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and a semi-fluorinated alkane. In some embodiments, the pharmaceutical composition suitable for topical periorbital administration includes an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and perfluorohexyl octane. In some embodiments, the pharmaceutical composition suitable for topical periorbital administration includes an omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof, and perfluorobutyl pentane. In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and a semifluorinated alkane. In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and perfluorohexyl octane. In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and perfluorobutyl pentane. In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, an omega-3 fatty acid, and a semifluorinated alkane.In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, an omega-3 fatty acid, and perfluorohexyl octane. In some embodiments, a pharmaceutical composition suitable for topical periorbital administration comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, an omega-3 fatty acid, and perfluorobutyl pentane.

[0233] Periorbital skin injection In the treatment of retinal diseases, drugs applied topically as eye drops are known to not reach the target tissue or to be bioavailable only at pharmacologically inappropriate concentrations in the posterior segment of the eye. Although successes have been claimed following studies in small rodents with small eyes, these successes do not translate to species with eye dimensions similar to those of the human eye (del Amo et al., 2017). Where success has been reported from human-sized eyes, this has resulted from inadequate experimental design. The drug itself must be detected and quantified directly, rather than estimated from techniques involving histology. After ocular administration, drugs are often absorbed into the bloodstream and thereby delivered to the retina. Plasma or blood levels must be monitored and reported. Furthermore, satisfactory retinal bio-disposition can only be achieved by adequate tissue sampling. Drug retention must be established in the vitreous humor, neural retina, and underlying posterior sclera. There must be no cross-contamination during tissue sampling. Systemic blood levels of the drug must be measured. In addition to the above considerations, a final imperative is that the drug is administered unilaterally. Eye drops containing the drug formulation must be applied to one eye and the other eye as a control. A complete display of results from drug-treated and untreated control eyes as well as plasma / blood must be reported numerically at all measured time points. If the drug levels in the posterior segment tissues of treated and untreated eyes are within experimental error, then retinal bioavailability is the result of absorption from the systemic circulation (blood-mediated delivery).

[0234] There are suboptimal experimental designs when drug bioavailability in the retina and vitreous humor is claimed. The following provide examples of common experimental deficiencies: (1) Acheampong AA et al. (2002) Drug Metab Disp 30: 421-429: Sampling cross-contamination (del Amo et al., 2017); (2) 2001, U.S. Patent No. 6,242,442. Bilateral topical administration, blood levels not reported; (3) 2016, U.S. Patent No. 9,446,026. bilateral ocular administration, (4) Hu S, Koevery S (2016) J Ocular Pharmacol Ther 32: 203-210: rabbit eyes, (5) Kadam RS et al. (2011) Drug Metab Disp 39: 1529-1537: no untreated eye as control, (6) Kiuchi K et al. (2008) Invest Ophthalmol Vis Sci 49: 1705-1711: drug levels not measured, only biological effects in mouse eyes after topical application, (7) Chastain JE et al. (2016) Exp Eye Res 145: 58-67: inadequate reporting of data from contralateral control eyes and plasma.

[0235] Thus, there is a need for improved delivery methods of compounds for treating diseases of the posterior part of the eye. Surprisingly, it has been found that periorbital administration of various compounds, including 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine and omega-3 fatty acids, results in substantial biodistribution of the compounds throughout the eye. Furthermore, application to the periorbital skin provides a retinal delivery route through the vitreous humor and is not impeded by the retinal pigment epithelium, Bruch's membrane, and blood-retinal barrier. Figure 1 shows a diagram of the ocular anatomy, including the periorbital region that overlies the globe of the eye.

[0236] Application of the compound to the periorbital skin will result in drug delivery to the sclera and retina via the episcleral route, with the aim of preventing the overall elongation that may be associated with myopia. The episcleral route of delivery may be particularly advantageous in children, who represent the largest myopic patient population, as it avoids the unwanted nociceptive effects and inconvenience of eye drops.

[0237] In addition to oral administration, topical eye drops are one of only two currently available non-invasive mechanisms for ocular delivery. Of topical eye drop administration, there are potentially two routes to deliver drugs to the posterior segment of the eye: first, the "scleral route," where the drug diffuses from the ocular surface to the conjunctiva through scleral aqueous channels to reach the retina; and second, the "corneal route," where the drug penetrates the corneal surface, aqueous humor, lens / iris / ciliary body, vitreous humor, and then to the retina. There are multiple publications reporting local delivery of potential therapeutics at pharmacologic effective doses to the back of the eye in small animal models, but these have not been successfully translated to larger species with relevant ocular anatomy, physiology, and size of the eyeball similar to that of the human eye. Oral administration is another currently available method of non-invasively transporting ocular drugs and nutrients. Although oral drugs may have a certain chance of reaching the retina via the systemic circulation, it has been difficult to achieve effective pharmacologically effective doses in the target tissue. Therefore, high-dose non-invasive retinal drug delivery remains a large unmet medical need and the most desirable method of intraocular drug delivery.

[0238] The ability to administer compounds via the periorbital route of administration offers several advantages over other types of administration. Self-administration by the patient is possible. This is in stark contrast to retinal implants, retinal injections, and photocoagulation procedures, all of which must be performed by a physician in a medical facility. The side effects of invasive intravitreal injections (endophthalmitis, retinal detachment, and traumatic cataracts) are completely avoided.

[0239] Administration to the periorbital skin is also advantageous in many respects compared to eye drops. These advantages include avoidance of reflex blinking and discomfort associated with eye drops. Since the skin is more robust and resistant to exogenously administered substances than the highly sensitive cornea, larger amounts of drugs can be administered more frequently and in preservative-free formulations. Furthermore, the eye is much more sensitive to irritation than the surrounding skin. Thus, periorbital delivery allows for the delivery of much higher dose strengths, since high concentrations of active ingredients in eye drops often cause eye irritation that is not observed on the skin.

[0240] Specifically, the studies reported herein revealed extremely high concentrations of small molecules in the retina after application of an "average" amount (approximately 160 micrograms) of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (Table 1). Consideration of the data reported in Table 1 reveals that administration to the periorbital skin allows for the good maintenance of extremely high drug concentrations over at least one day. Mass balance estimates are consistent with drug application being largely confined to the recipient's eye. This is in stark contrast to eye drops, where only a small percentage of drug is delivered to the interior of the eyeball. Taken together, it is proposed that administration to the periorbital skin allows molecules to reach targets embedded in "hard-to-reach" neuronal elements in the retina. Beneath the periorbital skin, the ora serrata does not appear to present a significant barrier to molecules and particulate matter.

[0241] Topical Ocular Administration to the Ocular Surface In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered via topical ocular administration to the surface of the eye. Administration to the ocular surface has several distinct advantages over other forms of administration that deliver therapeutic agents to the retina and vitreous humor. These advantages include the ability to self-administer, ease of self-administration, rapid delivery of the compound to the ocular surface, and the ability to rapidly achieve high concentrations at the ocular surface. In some embodiments, administration to the ocular surface also provides sufficient biodistribution to structures at the rear of the eye, such as the retina. In some embodiments provided herein, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is administered topically to the surface of the eye, such as in an eye drop formulation. In some embodiments, the 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine composition is formulated for topical ocular administration to the ocular surface of the eye as an aqueous solution, a non-aqueous solution, an oily solution, an oil, a gel, a hydrogel, a lotion, an ointment, a dispersion, an emulsion, a cream, or a suspension.

[0242] formulation Compositions for administration to the periorbital skin Provided herein, in some embodiments, are compositions suitable for application to the periorbital skin area of ​​a subject's eye. In some embodiments, these compositions may be administered via a non-invasive ocular delivery platform (NIODP).

[0243] In some embodiments, the composition is in the form of an aqueous solution, a non-aqueous solution, an oily solution, an oil, a gel, a hydrogel, a lotion, an ointment, a dispersion, an emulsion, a cream, and a suspension. In some embodiments, the composition is in the form of an ointment, a cream, or a lotion. In some embodiments, the composition is in the form of an ointment. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of a non-aqueous solution. In some embodiments, the composition is in the form of an oily solution. In some embodiments, the composition is in the form of an oil. In some embodiments, the composition is in the form of a gel. In some embodiments, the composition is in the form of a hydrogel. In some embodiments, the composition is in the form of a lotion. In some embodiments, the composition is in the form of an ointment. In some embodiments, the composition is in the form of a dispersion. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of a cream. In some embodiments, the composition is in the form of a suspension.

[0244] In some embodiments, the composition comprises a semi-solid oil-based base. In some embodiments, the composition comprises a petroleum base, a mineral oil, a polyol, a triglyceride, or any combination thereof. In some embodiments, the composition comprises a petroleum base. In some embodiments, the composition comprises petroleum jelly. In some embodiments, the composition comprises petroleum jelly, a triglyceride, or any combination thereof. In some embodiments, the composition comprises petroleum jelly and a triglyceride. In some embodiments, the composition comprises petroleum jelly, beeswax, or cocoa butter. In some embodiments, the composition comprises beeswax. In some embodiments, the composition comprises cocoa butter.

[0245] In some embodiments, the composition comprises an oil. In some embodiments, the composition comprises an oil or a mixture of oils. In some embodiments, the composition comprises a compound provided herein (e.g., an omega-3 fatty acid or 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine) mixed with one or more oils. In some embodiments, the composition comprises one or more compounds provided herein (e.g., an omega-3 fatty acid and 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine) mixed with one or more oils. In some embodiments, the composition comprises one or more oils derived / derived from a plant, a plant seed, or a nut. In some embodiments, the plant, plant seed, or nut is coconut, palm kernel, soybean, sesame, olive, vegetable, sunflower, or other plant source, or any combination thereof.

[0246] In some embodiments, the composition is mostly oil.In some embodiments, the composition comprises oil in an amount of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition.In some embodiments, the composition is essentially composed of oil and active ingredient (e.g., 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine).

[0247] In some embodiments, the composition comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises oil in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition, hi some embodiments, the composition comprises oil in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition.

[0248] In some embodiments, the composition comprises a triglyceride. In some embodiments, the triglyceride is a medium-chain or long-chain triglyceride. In some embodiments, the triglyceride is derived from a natural source. In some embodiments, the triglyceride is derived from a plant, a plant seed, or a nut. In some embodiments, the plant, plant seed, or nut comprises a portion of a coconut, palm kernel, soybean, sesame seed or plant, olive, sunflower seed or plant, or other vegetable or plant source, or any combination thereof.

[0249] In some embodiments, the composition is mostly triglyceride.In some embodiments, the composition comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition.In some embodiments, the composition is essentially composed of triglyceride and active ingredient (e.g., 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine).

[0250] In some embodiments, the composition comprises triglycerides in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition.

[0251] In some embodiments, the triglyceride is a medium chain triglyceride. In some embodiments, the medium chain triglyceride comprises two or three medium length fatty acids. In some embodiments, the medium chain triglyceride comprises C6 or larger fatty acids. In some embodiments, the medium chain triglyceride comprises C6-C12 fatty acids. In some embodiments, the medium chain triglyceride comprises a mixture of C6-C12 fatty acids. In some embodiments, the medium chain triglyceride comprises a fatty acid selected from C6, C8, C10, and C12 fatty acids, or mixtures thereof. In some embodiments, the medium chain triglyceride comprises caproic acid, caprylic acid, capric acid, lauric acid, or any combination thereof. In some embodiments, the medium chain triglyceride comprises caprylic acid, capric acid, or a combination thereof. In some embodiments, the medium chain triglyceride chain comprises caprylic acid and capric acid. In some embodiments, the medium chain triglycerides contain caprylic and capric acids in a ratio of about 4:1 (w / w), about 4:3 (w / w), about 3:1 (w / w), about 3:2 (w / w), about 1:1 (w / w), about 2:3 (w / w), about 1:3 (w / w), about 3:4 (w / w), or about 1:4 (w / w). In some embodiments, the ratio is about 1:1 (w / w) to about 4:1 (w / w). In some embodiments, the ratio is about 3:2 (w / w). In some embodiments, the medium chain triglycerides contain at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% C6-C12 fatty acids compared to other fatty acids (w / w).

[0252] In some embodiments, the composition is predominantly medium chain triglycerides. In some embodiments, the composition comprises medium chain triglycerides in an amount of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition. In some embodiments, the composition consists essentially of a medium chain triglyceride and an active ingredient (eg, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine).

[0253] In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition.

[0254] In some embodiments, the medium chain triglycerides are derived from natural sources. In some embodiments, the medium chain triglycerides are derived from coconut, palm, or palm kernel, or combinations thereof. In some embodiments, the medium chain triglycerides are derived from coconut or palm. In some embodiments, the medium chain triglycerides are oils extracted from palm or palm endosperm. In some embodiments, the medium chain triglycerides are National Food (NF) grade (NF) or United States Pharmacopeia (USP) grade.

[0255] In some embodiments, the composition comprises a mixture of petrolatum and medium chain triglycerides. In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 10:1 (v / v) to about 1:2 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 6:1 (v / v) to about 1:1 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 6:1 (v / v) to about 1:1 (v / v), about 5:1 (v / v) to about 1:1 (v / v), about 4:1 (v / v) to about 1:1 (v / v), about 3:1 (v / v) to about 2:1 (v / v), or about 3:2 (v / v) to about 1:1 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 1:1 (v / v), about 2:1 (v / v), about 3:1 (v / v), about 4:1 (v / v), about 5:1 (v / v), or about 6:1 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 1:1 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 2:1 (v / v). In some embodiments, the ratio of petrolatum to medium chain triglycerides is about 4:1 (v / v).

[0256] In some embodiments, the composition further comprises an emollient, hi some embodiments, the emollient is selected from the group consisting of vegetable oils, mineral oils, aromatic oils, essential fatty acids, fatty acids, fatty acid esters, and fatty acid alcohols.

[0257] In some embodiments, the composition further comprises a moisturizer, in some embodiments, the moisturizer is selected from the group consisting of propylene glycol, aloe vera, lactic acid, glyceryl triacetate, lithium chloride, polydextrose, quillaja, sodium hexametaphosphate, glycerol, sorbitol, xylitol, maltitol, and castor oil.

[0258] In some embodiments, the composition further comprises a thickening agent, hi some embodiments, the thickening agent is selected from the group consisting of fatty acids, fatty acid esters, and fatty acid alcohols.

[0259] In some embodiments, the composition further comprises a preservative. In some embodiments, the preservative is selected from the group consisting of sodium borate / boric acid, polyhexamethylene biguanide (phmb), parabens (parahydroxybenzoic acid derivatives, phenylmercuric nitrate, benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorbutanol, methylparaben, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, propylparaben, and thimerosal.

[0260] In some embodiments, the composition does not include a preservative, hi some embodiments, the composition does not include benzalkonium chloride.

[0261] In some embodiments, the composition further comprises an antimicrobial agent, hi some embodiments, the antimicrobial agent is selected from the group consisting of basil, oregano, thyme, citrus oils and monoterpenes, sesquiterpenes, and phenylpropanoids.

[0262] In some embodiments, the composition further comprises a penetration enhancer. In some embodiments, the penetration enhancer is selected from the group consisting of ethanol, isopropyl alcohol, d-hexanol, octanol, doctanol, myristyl alcohol, ethyl acetate, oleoyl acetate, isopropyl myristate, azone, carbamide, glyceryl monooleate, octyl salicylate, propylene glycol, dipropylene glycol, 1,2-butylene glycol, oleic acid, N-methyl-2-pyrrolidone, 2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, dimethyl sulfoxide, decyl methyl sulfoxide, sodium lauryl sulfate, Span 80, Tween 80, cineol, eugenol, D-limonene, menthol, menthane, cyclodextrin, hyaluronic acid, and vitamin E.

[0263] In some embodiments, the composition further comprises an odor masking agent.The odor masking agent is particularly suitable for compositions that comprise components derived from animal tissues that may have residual odor (e.g., omega-3 fatty acids derived from fish).In some embodiments, the odor masking agent is an essential oil (e.g., flower, fruit, wood, mint, herb, or other essential oil).

[0264] Compositions of JV-DE1 for administration to the periorbital skin In some embodiments, compositions provided herein suitable for administration to the periorbital skin include 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine as an active ingredient. The composition including 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine can be any of the compositions provided herein. In some embodiments, the composition includes a medium chain triglyceride.

[0265] In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.00005% to about 10% (w / w) of the composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.00005% to about 0.0005%, about 0.00005% to about 0.005%, about 0.00005% to about 0.05%, about 0.00005% to about 0.5%, about 0.00005% to about 1%, about 0.00005% to about 10%, about 0.0005% to about 0.005% of the composition. , about 0.0005% to about 0.05%, about 0.0005% to about 0.5%, about 0.0005% to about 1%, about 0.0005% to about 10%, about 0.005% to about 0.05%, about 0.005% to about 0.5%, about 0.005% to about 1%, about 0.005% to about 10%, about 0.05% to about 0.5%, about 0.05% to about 1%, about 0.05% to about 10%, about 0.5% to about 1%, about 0.5% to about 10%, or about 1% to about 10% (w / w). In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% (w / w) of the composition. In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is present in an amount of about 0.005% to about 0.3% (w / w) of the composition.In some embodiments, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine is from about 0.005% to about 0.01%, from about 0.005% to about 0.03%, from about 0.005% to about 0.06%, from about 0.005% to about 0.1%, from about 0.005% to about 0. 0.3%, about 0.01% to about 0.03%, about 0.01% to about 0.06%, about 0.01% to about 0.1%, about 0.01% to about 0.3%, about 0.03% to about 0.06%, about 0.03% to about 0.1%, about 0.03% to about 0.3%, about 0.06% to about 0.1%, about 0.06% to about 0.3%, or about 0.1% to about 0.3% (w / w).

[0266] In some embodiments, the compositions provided herein are configured to dispense a set amount of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine per dose. In some embodiments, the compositions are configured to dispense about 10 ng to about 5 mg of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine per dose. In some embodiments, the compositions are configured to dispense about 1 microgram to about 500 micrograms of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine per dose. In some embodiments, the composition may contain, per administration, about 1 microgram to about 5 micrograms, about 1 microgram to about 10 micrograms, about 1 microgram to about 25 micrograms, about 1 microgram to about 50 micrograms, about 1 microgram to about 75 micrograms, about 1 microgram to about 100 micrograms, about 1 microgram to about 200 micrograms, about 1 microgram to about 300 micrograms, about 1 microgram to about 400 micrograms, about 1 microgram to about 500 micrograms, about 5 micrograms to about 10 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 75 micrograms, grams, about 5 micrograms to about 100 micrograms, about 5 to about 200 micrograms, about 5 to about 300 micrograms, about 5 to about 400 micrograms, about 5 to about 500 micrograms, about 10 micrograms to about 25 micrograms, about 10 micrograms to about 50 micrograms, about 10 micrograms to about 75 micrograms, about 10 micrograms to about 100 micrograms, about 10 to about 200 micrograms, about 10 to about 300 micrograms, about 10 to about 400 micrograms, about 10 to about 500 micrograms, about 25 micrograms to about 50 micrograms, about 25 micrograms to about 75 micrograms, about 25 micrograms to about 100 micrograms, about 25 to about 200 micrograms,about 25 to about 300 micrograms, about 25 to about 400 micrograms, about 25 to about 500 micrograms, about 50 micrograms to about 75 micrograms, about 50 micrograms to about 100 micrograms, about 50 to about 200 micrograms, about 50 to about 300 micrograms, about 5 to about 400 micrograms, about 50 to about 500 micrograms, about 75 micrograms to about 100 micrograms, about 75 to about 200 micrograms, about 75 to about 300 micrograms, about 75 to about 400 The dispenser is configured to dispense about 100 to about 500 micrograms, about 75 to about 500 micrograms, about 100 to about 200 micrograms, about 100 to about 300 micrograms, about 100 to about 400 micrograms, about 100 to about 500 micrograms, about 200 to about 500 micrograms, about 300 to about 500 micrograms, or about 400 to about 500 micrograms of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine.

[0267] Compositions of omega-3 fatty acids for administration to the external eyelid or periorbital skin - Patents.com In some embodiments, compositions suitable for topical periorbital skin administration provided herein include an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, these compositions may be administered via a non-invasive ocular delivery platform (NIODP).

[0268] In some embodiments, compositions suitable for topical external eyelid skin administration provided herein comprise an omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and a pharma- ceutically acceptable excipient.

[0269] In some embodiments, the omega-3 fatty acid is present in the composition in an amount of about 0.01% to about 100% (w / w) of the composition. In some embodiments, the omega-3 fatty acid is present in an amount of about 0.01% to about 50% (w / w) of the composition. In some embodiments, the omega-3 fatty acid is present in an amount of about 1% to about 50% (w / w) of the composition. In some embodiments, the omega-3 fatty acids comprise about 1% to about 5%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 75%, about 5% to about 100%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 5 ... % to about 75%, about 10% to about 100%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 75%, about 20% to about 100%, about 30% to about 40%, about 30% to about 50%, about 30% to about 75%, about 30% to about 100%, about 40% to about 50%, about 40% to about 75%, about 40% to about 100%, about 50% to about 75%, about 50% to about 100%, or about 75% to about 100% (w / w). In some embodiments, the omega-3 fatty acids are present in an amount of up to about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% (w / w) of the composition. In some embodiments, the omega-3 fatty acids are present in an amount of about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 20% to about 25%, about 20% to about 30%, or about 25% to about 30% (w / w) of the composition.In some embodiments, the omega-3 fatty acid is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 In some embodiments, the omega-3 fatty acid is present in an amount of 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (w / w). In some embodiments, the omega-3 fatty acid is administered alone (e.g., without a vehicle).

[0270] In some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid from about 0.1 mg to about 3000 mg, from about 0.1 mg to about 1000 mg, from about 0.1 mg to about 500 mg, from about 0.1 mg to about 300 mg, from about 0.1 mg to about 200 mg, from about 0.1 mg to about 100 mg. In some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid from about 0.1 mg to about 100 mg. In some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid of about 0.1 mg to about 1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 10 mg to about 20 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 20 mg to about 50 mg, about 20 mg to about 100 mg, or about 50 mg to about 100 mg. In some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid of about 0.1 mg, about 1 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg. In some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid of at least about 0.1 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg, hi some embodiments, the composition is configured to deliver an amount of omega-3 fatty acid of at most about 1 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg.

[0271] In some embodiments, the composition comprises a vehicle for delivery of omega-3 fatty acids. In some embodiments, the vehicle comprises an oil. In some embodiments, the vehicle comprises an oil or a mixture of oils. In some embodiments, the vehicle comprises omega-3 fatty acids dissolved in one or more oils. In some embodiments, the oil is derived from a natural source. In some embodiments, the vehicle comprises one or more oils derived from a plant, a plant seed, or a nut. In some embodiments, the plant, plant seed, or nut is soybean, sesame, olive, vegetable, sunflower, or other plant source, or any combination thereof.

[0272] In some embodiments, the vehicle is an oil. In some embodiments, the composition comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the oil comprises about 50% to about 99% (w / w) of the composition. In some embodiments, the oil comprises about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99% (w / w) of the composition. In some embodiments, the oil comprises about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% (w / w) of the composition.

[0273] In some embodiments, the vehicle comprises a triglyceride. In some embodiments, the triglyceride is a medium-chain or long-chain triglyceride. In some embodiments, the triglyceride is derived from a natural source. In some embodiments, the triglyceride is derived from a plant, a plant seed, or a nut. In some embodiments, the plant, plant seed, or nut comprises a portion of a coconut, palm kernel, soybean, sesame seed or plant, olive, sunflower seed or plant, or other vegetable or plant source, or any combination thereof.

[0274] In some embodiments, the composition comprises triglycerides in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises triglycerides in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the triglycerides comprise about 50% to about 99% (w / w) of the composition. In some embodiments, the triglyceride comprises about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99% (w / w) of the composition. In some embodiments, the triglyceride comprises about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% (w / w) of the composition.

[0275] In some embodiments, the triglyceride is a medium chain triglyceride. In some embodiments, the medium chain triglyceride comprises two or three medium length fatty acids. In some embodiments, the medium chain triglyceride comprises C6 or larger fatty acids. In some embodiments, the medium chain triglyceride comprises C6-C12 fatty acids. In some embodiments, the medium chain triglyceride comprises a mixture of C6-C12 fatty acids. In some embodiments, the medium chain triglyceride comprises a fatty acid selected from C6, C8, C10, and C12 fatty acids, or mixtures thereof. In some embodiments, the medium chain triglyceride comprises caproic acid, caprylic acid, capric acid, lauric acid, or any combination thereof. In some embodiments, the medium chain triglyceride comprises caprylic acid, capric acid, or a combination thereof. In some embodiments, the medium chain triglyceride chain comprises caprylic acid and capric acid. In some embodiments, the medium chain triglycerides contain caprylic and capric acids in a ratio of about 4:1 (w / w), about 4:3 (w / w), about 3:1 (w / w), about 3:2 (w / w), about 1:1 (w / w), about 2:3 (w / w), about 1:3 (w / w), about 3:4 (w / w), or about 1:4 (w / w). In some embodiments, the ratio is about 1:1 (w / w) to about 4:1 (w / w). In some embodiments, the ratio is about 3:2 (w / w). In some embodiments, the medium chain triglycerides contain at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% C6-C12 fatty acids compared to other fatty acids (w / w).

[0276] In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises medium chain triglycerides in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the medium chain triglycerides comprise about 50% to about 99% (w / w) of the composition. In some embodiments, the medium chain triglycerides comprise about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99% (w / w) of the composition. In some embodiments, the medium chain triglycerides comprise about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% (w / w) of the composition.

[0277] In some embodiments, the medium chain triglycerides are derived from natural sources. In some embodiments, the medium chain triglycerides are derived from coconut, palm, or palm kernel, or combinations thereof. In some embodiments, the medium chain triglycerides are derived from coconut or palm. In some embodiments, the medium chain triglycerides are oils extracted from palm or palm endosperm. In some embodiments, the medium chain triglycerides are National Food (NF) grade (NF) or United States Pharmacopeia (USP) grade.

[0278] In some embodiments, the vehicle is a fatty acid vehicle. In some embodiments, the fatty acid vehicle is an unsaturated fatty acid. In some embodiments, the fatty acid vehicle is a C14-C22 fatty acid. In some embodiments, the fatty acid vehicle is a C14-C22 unsaturated fatty acid. In some embodiments, the fatty acid vehicle comprises linoleic acid.

[0279] In some embodiments, the fatty acid vehicle comprises about 1% to about 100% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises from about 50% to about 99% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99% (w / w) of the composition. In some embodiments, the fatty acid vehicle comprises about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% (w / w) of the composition.

[0280] In some embodiments, administration of the composition to a patient via a non-invasive ocular delivery platform provides a physiologically relevant amount of omega-3 fatty acids to at least one portion of the eye.

[0281] In some embodiments, the part of the eye is the upper eyelid, the cornea, the retina, or any combination thereof.

[0282] In some embodiments, administration of the composition to a patient provides a therapeutic or other beneficial amount of omega-3 fatty acids to at least one portion of the eye.

[0283] In some embodiments, the part of the eye is the upper eyelid, the cornea, the retina, or any combination thereof.

[0284] In some embodiments, administration of the composition to a patient results in a level of omega-3 fatty acids in the upper eyelid 30 minutes after administration that is at least 10 μg / g, at least 50 μg / g, at least 100 μg / g, at least 150 μg / g, at least 200 μg / g, at least 250 μg / g, at least 300 μg / g, at least 350 μg / g, at least 400 μg / g, or at least 500 μg / g above baseline levels.

[0285] In some embodiments, administration of the composition to a patient results in a level of omega-3 fatty acids in the cornea 30 minutes after administration that is at least 10 μg / g, at least 15 μg / g, at least 20 μg / g, at least 25 μg / g, at least 30 μg / g, at least 35 μg / g, at least 40 μg / g, at least 50 μg / g, at least 60 μg / g, or at least 70 μg / g above baseline levels.

[0286] In some embodiments, administration of the composition to a patient results in a level of omega-3 fatty acids in the retina 30 minutes after administration that is at least 10 μg / g, at least 15 μg / g, at least 20 μg / g, at least 25 μg / g, at least 30 μg / g, at least 35 μg / g, at least 40 μg / g, at least 45 μg / g, at least 50 μg / g, at least 60 μg / g, or at least 70 μg / g, at least 80 μg / g, at least 90 μg / g, at least 100 μg / g, at least 110 μg / g, or at least 120 μg / g above baseline levels.

[0287] Compositions for local ocular administration of JV-DE1 Further provided herein are compositions of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (also known as JV-DE1) suitable for topical ocular administration. In some embodiments, the topical ocular administration is to the surface of the eye. In some embodiments, the composition is formulated as an eye drop. In some embodiments, the composition is formulated as an aqueous solution, a non-aqueous solution, an oily solution, an oil, a gel, a hydrogel, a lotion, an ointment, a dispersion, an emulsion, a cream, in a liposome, or in a nanoparticle, or in a suspension. In some embodiments, the composition is formulated as an aqueous solution. In some embodiments, the topical ocular administration is to the periorbital skin of the patient.

[0288] In some embodiments, the composition comprises a polyoxyl castor oil. In some embodiments, the polyoxyl castor oil is a poly(alkylene oxide) castor oil. In some embodiments, the polyoxyl castor oil comprises poly(alkylene oxide) subunits selected from poly(ethylene glycol) (PEG), poly(propylene glycol), or any combination thereof.

[0289] In some embodiments, the polyoxyl castor oil is PEGylated castor oil. In some embodiments, the molar ratio of PEG to castor oil in the PEGylated castor oil ranges from about 20:1 to about 50:1. In some embodiments, the molar ratio of PEG to castor oil is from about 25:1 to about 45:1, or from about 30:1 to about 40:1. In some embodiments, the molar ratio of PEG to castor oil is about 35:1. In some embodiments, the polyoxyl castor oil is polyoxyl 35 castor oil.

[0290] In some embodiments, the polyoxyl castor oil is present in an amount of about 0.1% to about 20%, 0.1% to about 15%, 0.1% to about 10%, or 0.1% to about 5% (w / w) of the composition. In some embodiments, the polyoxyl castor oil is present in an amount of about 0.1% to about 5% (w / w) of the composition. In some embodiments, the polyoxyl castor oil is present in an amount of about 0.1% to about 0.5%, about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 5%, about 0.5% to about 1%, about 0.5% to about 2%, about 0.5% to about 5%, about 1% to about 2%, about 1% to about 5%, or about 2% to about 5% (w / w) of the composition. In some embodiments, the polyoxyl castor oil is present in an amount of about 0.5% to about 1.5% (w / w) of the composition. In some embodiments, the polyoxyl castor oil is present in an amount of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%. In some embodiments, the polyoxyl castor oil is present in an amount of about 0.5% to about 1.5%, about 0.6% to about 1.4%, about 0.7% to about 1.3%, about 0.8% to about 1.2%, or about 0.9% to about 1.1% (w / w) of the composition.

[0291] In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 20%, 0.1% to about 15%, 0.1% to about 10%, or 0.1% to about 5% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.1% to about 0.5%, about 0.1% to about 1%, about 0.1% to about 2%, about 0.1% to about 5%, about 0.5% to about 1%, about 0.5% to about 2%, about 0.5% to about 5%, about 1% to about 2%, about 1% to about 5%, or about 2% to about 5% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.5% to about 1.5% (w / w) of the composition. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%. In some embodiments, polyoxyl 35 castor oil is present in an amount of about 0.5% to about 1.5%, about 0.6% to about 1.4%, about 0.7% to about 1.3%, about 0.8% to about 1.2%, or about 0.9% to about 1.1% (w / w) of the composition.

[0292] In some embodiments, the composition further comprises an ocular surface lubricant. In some embodiments, the ocular surface lubricant is selected from polyethylene glycol, propylene glycol, polyvinyl alcohol, castor oil, or glycerol. In some embodiments, the ocular surface lubricant is glycerol.

[0293] In some embodiments, the ocular surface lubricant is present in an amount of about 0.05% to about 2% (w / w) of the composition. In some embodiments, the ocular surface lubricant is present in an amount of about 0.05% to about 0.5% (w / w) of the composition. In some embodiments, the ocular surface lubricant is present in an amount of about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, or about 0.5% (w / w) of the composition. In some embodiments, the ocular surface lubricant comprises about 0.05% to about 0.1%, about 0.05% to about 0.15%, about 0.05% to about 0.2%, about 0.05% to about 0.25%, about 0.05% to about 0.3%, about 0.05% to about 0.4%, about 0.05% to about 0.5%, about 0.1% to about 0.15%, about 0.1% to about 0.2%, about 0.1% to about 0.25%, about 0.1% to about 0.3%, about 0.1% to about 0.4%, about 0.1% to about 0.5%, or about 0.15% of the composition. about 0.2%, about 0.15% to about 0.25%, about 0.15% to about 0.3%, about 0.15% to about 0.4%, about 0.15% to about 0.5%, about 0.2% to about 0.25%, about 0.2% to about 0.3%, about 0.2% to about 0.4%, about 0.2% to about 0.5%, about 0.25% to about 0.3%, about 0.25% to about 0.4%, about 0.25% to about 0.5%, about 0.3% to about 0.4%, about 0.3% to about 0.5%, or about 0.4% to about 0.5% (w / w).

[0294] In some embodiments, the composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from triethanolamine (Tris), histidine, bicarbonate, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS). In some embodiments, the buffering agent is Tris. In some embodiments, the composition comprises Tris buffered saline.

[0295] In some embodiments, the composition comprises an oil. In some embodiments, the composition comprises an oil or a mixture of oils. In some embodiments, the composition comprises 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine mixed in one or more oils. In some embodiments, the composition comprises one or more oils derived from a plant, a plant seed, or a nut. In some embodiments, the plant, plant seed, or nut is soybean, sesame, olive, vegetable, sunflower, or other plant source, or any combination thereof. In some embodiments, the oil comprises a triglyceride. In some embodiments, the oil comprises a medium chain triglyceride.

[0296] In some embodiments, the composition is mostly oil. In some embodiments, the composition comprises oil in an amount of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, at least about 99.96%, at least about 99.97%, at least about 99.98%, or at least about 99.99% (w / w) of the composition. In some embodiments, the composition consists essentially of oil and 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine.

[0297] In some embodiments, the composition comprises an oil in an amount of about 1% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1% to about 20%, about 1% to about 40%, about 1% to about 60%, about 1% to about 80%, about 1% to about 100%, about 20% to about 40%, about 20% to about 60%, about 20% to about 80%, about 20% to about 100%, about 40% to about 60%, about 40% to about 80%, about 40% to about 100%, about 60% to about 80%, about 60% to about 100%, or about 80% to about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of about 1%, about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of at least about 1%, about 20%, about 40%, about 60%, or about 80% (w / w) of the composition. In some embodiments, the composition comprises an oil in an amount of up to about 20%, about 40%, about 60%, about 80%, or about 100% (w / w) of the composition. In some embodiments, the composition has a pH of about 6.5 to about 8.5. In some embodiments, the composition has a pH of about 6.7 to about 8.3, about 7.0 to about 8.0, about 7.2 to about 7.8, or about 7.3 to about 7.7. In some embodiments, the composition has a pH of about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0298] In some embodiments, the composition comprises omega-3 fatty acid or its pharma- ceutically acceptable ester or salt. In some embodiments, the omega-3 fatty acid is isolated from fish tissue. In some embodiments, the omega-3 fatty acid is isolated from plant sources. In some embodiments, the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof.

[0299] Treatment Provided herein is a method for treating disease and disorder provided herein using the compound provided herein.In some embodiments, the compound is 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine.In some embodiments, the compound is omega-3 fatty acid.

[0300] In some embodiments, the compound is administered to each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day, or any combination thereof (e.g., variable dosing protocol).In some embodiments, the compound is administered to each eye of the patient once a week, twice a week, three times a week, once every two weeks, or once every three weeks.In some embodiments, the compound is administered to each eye of the patient once a day.

[0301] In some embodiments, the compound is administered twice a day, once a day, once every other day, once every 3 days, once every 4 days, or once every 7 days, or any combination thereof (e.g., variable dosing protocol) to one eye of the patient. In some embodiments, the compound is administered once a week, twice a week, three times a week, once a week, once every 2 weeks, or once every 3 weeks to one eye of the patient. In some embodiments, the compound is administered once a day to one eye of the patient.

[0302] In some embodiments, the compound is administered ad libitum to one or both eyes.

[0303] In some embodiments, the compound is administered to the ocular surface of the eye, hi some embodiments, the compound is administered by a dropper, pump, spray, click pen, or tube.

[0304] In some embodiments, the compound is applied to periorbital skin using a device.In some embodiments, the device is a dropper, a pump, a spray, a click pen, or a tube reservoir device.In some embodiments, the compound is topically administered by a brush, a Q-tip, or a spatula.

[0305] In some embodiments, the compound is applied to the periorbital skin using an eye pad. An eye pad, also known as an eye patch, is a small (and can be sterile) pad large enough to cover the periorbital area of ​​the eye, and is specifically designed for the absorption of formulations for periorbital or eyelid administration. In some embodiments, the eye pad contains a preselected dose of active ingredient. The subject may apply the eye pad to the periorbital skin for a certain period of time. The time may depend on the desired dose of the desired active ingredient. In some embodiments, the eye pad may be applied to the patient's periorbital skin for 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, or 1 hour.

[0306] In some embodiments, the device releases a preselected dosage evenly onto the patient's periorbital skin. In some embodiments, the compound is applied to the periorbital skin by a roller device. In some embodiments, the compound is applied to the periorbital skin by a Q-tip. In some embodiments, the compound is applied to the periorbital skin by a spatula. In some embodiments, the application process may begin with the use of a graduated dropper, syringe, click pen, or pipette.

[0307] It may be beneficial to use a preservative-free formulation. In some embodiments, the compound is packaged in a single-use container. In some embodiments, the single-use container is a blow-fill-seal capsule. In some embodiments, the single-use container is a softgel capsule. In some embodiments, the compound is packaged in a multi-use container. In some embodiments, the multi-use container is an airless pump or a drop bottle. In some embodiments, the packaging is designed to minimize fishy odors that may be caused by oxidation of omega-3 fatty acids.

[0308] In some embodiments, the compound is administered to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid. In some embodiments, the compound is administered above the upper eyelid. In some embodiments, the compound is administered below the lower eyelid. In some embodiments, the compound is administered both above the upper eyelid and below the lower eyelid.

[0309] In some embodiments, penetration through periorbital skin is increased by penetration enhancers, tape-stripping, microdermabrasion, solvents, pulsed lasers, and iontophoresis, which have been found to be useful for delivering macromolecules, e.g., antibodies, siRNA, in liposomes or nanoparticles (Fukuta et al. (2020) J Control Release 10: 323-332.).

[0310] In some embodiments, the compound is applied to eyelid skin using a device.In some embodiments, the device is a dropper, a pump, a spray, a click pen, or a tube reservoir device.In some embodiments, the compound is topically administered by a brush, a Q-tip, or a spatula.

[0311] In some embodiments, the device releases a preselected dosage evenly onto the patient's eyelid skin. In some embodiments, the compound is applied to the eyelid skin by a roller device. In some embodiments, the compound is applied to the eyelid skin by a Q-tip. In some embodiments, the compound is applied to the eyelid skin by a spatula. In some embodiments, the application process may begin with the use of a graduated dropper, syringe, click pen, or pipette.

[0312] In some embodiments, penetration through the eyelid skin is increased by penetration enhancers, tape-stripping, microdermabrasion, solvents, pulsed lasers, and iontophoresis, which have been found to be useful for delivering macromolecules, e.g., antibodies, siRNA, in liposomes or nanoparticles (Fukuta et al. (2020) J Control Release 10: 323-332.).

[0313] In some embodiments, the compounds are administered prophylactically, as an acute intervention, or as needed to achieve a desired ameliorative effect.

[0314] Specific Definitions As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about" when referring to a number or range of numbers means that the number or range of numbers referred to is an estimate within experimental variability (or within statistical experimental error), and thus the number or range of numbers may vary between 1%-15% of the stated number or range of numbers. The term "comprising" (and related words such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other embodiments, embodiments such as, for example, any composition, method, or process described herein may "consist of" or "consist essentially of" the recited features.

[0315] "Treating" or "treatment" as used herein includes any approach to obtain a beneficial or desired outcome in a subject's disease, including a clinical outcome. Beneficial or desired clinical outcomes may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, amelioration of the disease, reduction in recurrence of the disease. Treatment may prevent the disease from occurring, i.e., alleviate the symptoms of the disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of the above.

[0316] As used herein, "treat" and "treatment" may include preventive treatment. The treatment method includes administering a therapeutically effective amount of an active agent to a subject. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period will depend on various factors, such as the severity of the disease, the age of the patient, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective dosage of the agent used for treatment or prevention may increase or decrease during the course of a particular treatment or prevention regimen. As a result, changes in dosage will occur, which may be evident by standard diagnostic assays known in the art. In some instances, long-term administration may be required. For example, the composition is administered to the subject for a period of time sufficient to treat the patient with a certain amount.

[0317] An "effective amount", "therapeutically effective amount", or "pharmaceutical effective amount" refers to an amount of an active agent effective for retinal disease or other ocular disease, including effects ranging from a detectable amount of improvement to a substantial reduction / amelioration of symptoms or cure of a disease or condition. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising an agent described herein that is required to clinically significantly reduce an ocular disease. For example, for a given aspect (e.g., length of episode), a therapeutically effective amount will exhibit at least a 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or 100% increase or decrease. The effectiveness of a therapeutic agent may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.

[0318] The term "periorbital" refers to the area surrounding the eye socket.

[0319] The term "preorbital" refers to the area in front of the eye socket or eye socket.

[0320] The term "eyelid" refers to the movable fold of skin that covers the eye.

[0321] "OD" refers to the right eye.

[0322] "OS" refers to the left eye.

[0323] "OU" refers to both eyes.

[0324] "Periorbital administration" includes administration to the periorbital skin and specifically excludes administration to the upper eyelid, lower eyelid, and eyelid margin.

[0325] The term "lotion" describes an emulsion liquid dosage form, usually intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0326] The term "cream" describes a semi-solid dosage form of an emulsion, usually containing >20% water and volatile materials, and / or <50% hydrocarbons, waxes, or polyols as a vehicle. Creams are more viscous than lotions. This dosage form is usually intended for external application to the skin (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0327] The term "ointment" describes a semi-solid dosage form, usually containing <20% water and volatile materials, and / or >50% hydrocarbons, waxes, or polyols as a vehicle, which is usually intended for external application to the skin or mucous membranes (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0328] The term "solution" describes a clear, homogenous liquid dosage form that contains one or more chemicals dissolved in a solvent or a mixture of solvents that are miscible with each other (US FDA Drug Nomenclature Monograph, number C-DRG-00201).

[0329] The term "suspension" refers to a heterogeneous mixture containing solid particles large enough to precipitate.

[0330] "Emulsion" includes, but is not limited to, oil-in-water emulsions, water-in-oil emulsions, -9 The term "microemulsion" refers to the particle size of the emulsion.

[0331] A "formulation" and a "composition" are intended to be equivalent and refer to a composition of matter suitable for pharmaceutical use (i.e., producing a similar therapeutic effect while possessing acceptable pharmacokinetic and toxicological properties).

[0332] An "emollient" is an agent that softens and soothes the skin.

[0333] A "moisturizer" is a moisture-absorbing agent that keeps the skin moist.

[0334] A "penetration enhancer" is an agent that improves transdermal drug delivery.

[0335] "Thickening agents" increase the viscosity of the formulation to achieve optimal application properties.

[0336] The "ocular surface" is the cornea and sclera, and the associated bulbar conjunctiva.

[0337] An "ophthalmically acceptable composition" is a composition that can be administered to the eye.

[0338] "Pharmaceutically acceptable" is used equivalently to physiologically acceptable. In certain embodiments, a pharma- ceutically acceptable composition or preparation includes agents for buffering and preservation during storage, and may include buffers and carriers for appropriate delivery depending on the route of administration.

[0339] The terms "subject", "patient" and "individual" are not intended to be limiting and are generally interchangeable. That is, an individual described as a "patient" does not necessarily have a given disease, but may simply be seeking medical advice. The term "subject" as used herein includes all members of the animal kingdom that are susceptible to suffering from the indicated disorder. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0340] As used herein, "topical," "topical application," "topical administration," and "administering topically" are used interchangeably herein and, unless otherwise specified, include administration to the ocular surface or periorbital skin of a subject. Topical application or administration may also result in delivery of an active agent directly to the eye.

[0341] The term combination refers to separate entities used together to achieve improved or optimal therapeutic benefit and safety. In the simplest case, a combination can be a combination of two therapeutic agents at a fixed dose administered simultaneously. In this case, the components may be formulated separately or mixed together in a single formulation. However, to achieve satisfactory disease control, the doses of the therapeutic agents and the relative timing of their administration may require some flexibility. For example, in a combination of two therapies, one of the two treatments may be administered first to establish its baseline level of improvement before adding the other (second) drug. Drug combinations may include administration of drugs by different formulations, methods of administration, and different routes of administration. As an illustrative example, 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine may be applied topically to the periorbital skin with an intravitreal injection of a VEGF antibody, an intravenously administered VEGF antibody, or a topically administered VEGF antibody to the periorbital skin, with or without 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine present in the same formulation. Further permutations of delivery routes and methods are contemplated.

[0342] "Topical formulation" and "topical pharmaceutical composition" are used interchangeably herein and include formulations suitable for topical application to the eye. Where specified, topical formulations may be suitable for either topical application to the surface of the eye, topical application to the periorbital skin of the eye, or both. Topical formulations may be used, for example, to provide therapeutic benefits to their users.

[0343] IP receptors are cell surface proteins that belong to the G protein-coupled receptor superfamily. The major endogenous ligands of IP receptors are prostacyclin (PGI2), prostaglandin E1 (PGE1), and 19(S)-HETE (Woodward D, et al. (2011) Pharmacol Rev 63:471-538; Tunara S et al. (2016) PLOS one 11:0163633).

[0344] Platelet-activating factor (PAF) receptor is furthermore a cell surface protein that belongs to the G protein-coupled receptor superfamily (Ishii S et al. (2002) PGs & Other Lipid Med 68-69: 599-609).

[0345] SiRNA refers to the same entity variously described as small interfering RNA, small inhibitory RNA, and short interfering RNA.

[0346] Embodiment Embodiment 1. A method of treating a disease or disorder of the posterior segment of the eye in a patient suffering from said disease or disorder, comprising administering a therapeutically effective amount of an omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, to the integument of the eyelid of the patient's eye, wherein the omega-3 fatty acid is formulated for delivery to the posterior segment of the eye.

[0347] Embodiment 2. The method of embodiment 1, wherein the disease or disorder of the posterior segment of the eye comprises a retinal disease.

[0348] Embodiment 3. The method of embodiment 2, wherein the retinal disease comprises bleeding from the retinal or choroidal vasculature.

[0349] Embodiment 4. The method of embodiment 3, wherein the bleeding is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0350] Embodiment 5. The method of embodiment 2, wherein the retinal disease or disorder comprises plasma leakage from the retinal or choroidal vasculature.

[0351] Embodiment 6. The method of embodiment 5, wherein the plasma leakage is caused by systemic hypertension, diabetes, fatty liver disease, obesity, shaken baby syndrome, head trauma, anemia, or leukemia.

[0352] Embodiment 7. The method of embodiment 2, wherein the retinal disease or disorder comprises macular edema formation involving the retinal or choroidal vasculature.

[0353] Embodiment 8. Diseases or disorders of the posterior segment of the eye include age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, pediatric, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, retinopathy, radiation / solar retinopathy, central serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, uveitis (including intermediate uveitis, posterior uveitis, and pan uveitis), or refractive errors (myopia, hyperopia, and astigmatism).

[0354] Embodiment 9. The method of any one of embodiments 205-211, wherein the retinal disease or disorder is age-related macular degeneration.

[0355] Embodiment 10. The method of embodiment 1, wherein the disease or disorder of the posterior segment of the eye is posterior uveitis.

[0356] Embodiment 11. The method of any one of embodiments 1 to 10, further comprising administering an additional therapeutic agent to the patient.

[0357] Embodiment 12. The method of embodiment 11, wherein the additional therapeutic agent is a VEGF antibody, a small molecule VEGF antagonist, an siRNA targeting a VEGF receptor, a TNFα antibody, a small molecule TNFα receptor antagonist, an siRNA targeting a TNFα receptor, an inflammatory cytokine receptor antagonist, an antibody against an inflammatory cytokine, a tyrosine kinase inhibitor, a serine / threonine-protein kinase inhibitor, a kinase inhibitor, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an immunosuppressant, an anticholinergic agent, thalidomide, a prostaglandin receptor antagonist, a neuroprotectant, a neurotrophic agent, a neuroregenerator, an ocular hypotensive agent, an antibiotic, an antiviral agent, a complement inhibitor, an interleukin receptor inhibitor, a leukotriene receptor inhibitor, an inhibitor of tumor formation and development, an angiogenesis inhibitor, or an agent with antioxidant or anti-microvascular leakage properties.

[0358] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the omega-3 fatty acid or a pharma- ceutically acceptable ester or salt thereof is administered prophylactically, as an acute intervention, or as needed to achieve the desired ameliorative effect.

[0359] Embodiment 14. The method of any one of embodiments 1-13, wherein the omega-3 fatty acid or a pharma-ceutically acceptable ester or salt thereof is administered as a composition.

[0360] Embodiment 15. The method of embodiment 1, wherein the omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is present in an amount of about 0.0001% to about 10% (w / w) of the composition.

[0361] Embodiment 16 The method of embodiment 14 or 15, wherein the composition is an aqueous solution, a non-aqueous solution, an oily solution, a gel, a suspension, an emulsion, a lotion, a cream, or an ointment.

[0362] Embodiment 17. The method of any one of embodiments 14 to 16, wherein the composition is an ointment.

[0363] Embodiment 18. The method of embodiment 17, wherein the ointment comprises petrolatum, beeswax, or cocoa butter.

[0364] Embodiment 19. The method of embodiment 17 or 18, wherein the ointment comprises petrolatum and medium chain triglycerides.

[0365] Embodiment 20. The method of embodiment 19, wherein the medium chain triglycerides comprise a mixture of C6, C8, C10, and C12 fatty acids.

[0366] Embodiment 21. The method of embodiment 19 or 20, wherein the medium chain triglycerides comprise a mixture of caprylic and capric acids.

[0367] Embodiment 22. The method of any one of embodiments 17-21, wherein the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 1:1 (v / v), about 2:1 (v / v), about 3:1 (v / v), about 4:1 (v / v), about 5:1 (v / v), or about 6:1 (v / v).

[0368] Embodiment 23. The method of embodiment 22, wherein the ointment comprises petrolatum and medium chain triglycerides in a ratio of about 4:1 (v / v).

[0369] Embodiment 24. The method of any one of embodiments 14 to 16, wherein the composition is an aqueous solution.

[0370] Embodiment 25. The method of embodiment 24, wherein the aqueous solution comprises polyoxyl castor oil.

[0371] Embodiment 26. The method of embodiment 25, wherein the polyoxyl castor oil is polyethylene glycol (PEG)-ylated castor oil.

[0372] Embodiment 27. The method of embodiment 25 or 26, wherein the polyoxyl castor oil is polyoxyl 35 castor oil.

[0373] Embodiment 28. The method of embodiment 27, wherein the polyoxyl 35 castor oil is present in an amount of about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, or about 0.1% to about 20% (w / w) of the composition.

[0374] Embodiment 29. The method of any one of embodiments 24-28, wherein the composition comprises an ocular surface lubricant.

[0375] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is applied to the integument of the eyelid of the patient's eye by means of a dropper, pump, spray, click pen, or roller / reservoir device.

[0376] Embodiment 31. The method of any one of embodiments 1 to 29, wherein the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, is applied to the outer skin of the eyelid of the patient's eye by means of a brush, Q-tip, or spatula, and the application process is optionally initiated by the use of a graduated dropper, syringe, click pen, or pipette.

[0377] Embodiment 32. The method of any one of embodiments 1 to 31, wherein penetration into the eyelid skin is assisted by tape-stripping, microdermabrasion, solvents, pulsed lasers, iontophoresis, or combinations thereof.

[0378] Embodiment 33. The method of any one of embodiments 1-32, wherein the omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is administered to the skin of the eyelid of each eye of the patient four times a day, three times a day, twice a day, once a day, once every other day, once every third day, once every fourth day, or once every seventh day.

[0379] Embodiment 34. The method of embodiment 33, wherein the omega-3 fatty acid, or a pharma-ceutically acceptable ester or salt thereof, is administered once a day.

[0380] Embodiment 35. The method of embodiment 11, wherein the additional therapeutic agent is 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof.

[0381] Embodiment 36. The method of embodiment 35, wherein the omega-3 fatty acid, or a pharma- ceutically acceptable ester or salt thereof, and 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof, are formulated and administered as a single composition. EXAMPLES

[0382] Example 1: Rabbit study of topical ocular administration of JV-DE1 to the surface of both eyes A retinal bioavailability study was performed with 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine (assigned the code designation JV-DE1). This study suggested that the compound formulated in eye drops and administered bilaterally to the anterior ocular surface was bioavailable in the retina. This pharmacokinetic and ocular tissue distribution study of JV-DE1 was performed in New Zealand rabbits. Briefly, five rabbits (male) were administered JV-DE1 by eye drop at a dose of 0.12 mg / eye in both eyes. Blood samples (1 mL) were collected at 0, 0.5, 2, 4, 8, and 24 hours after a single ocular administration to both eyes. At each time point, one animal was euthanized after blood collection and then ocular tissue samples were collected from both eyes. Aqueous humor, bulbar conjunctiva, anterior sclera, posterior sclera (optic nerve exit area), retina, cornea, ciliary body, and iris were collected and weighed. The samples were then stored in an ultra-low temperature freezer. The drug concentrations in the samples were then determined by LC-MS / MS method. The results are shown in Figure 2A (right eye) and Figure 2B (left eye).

[0383] Plasma concentrations of JV-DE1 were low in New Zealand rabbits after ocular administration. max was approximately 2ng / mL at 0.5 hours post-dose with good clearance at 24 hours post-dose. JV-DE1 was widely distributed in ocular tissues, with no significant difference between the left and right eyes because drug administration was bilateral. JV-DE1 ocular tissue levels were well maintained over 8 hours post-dose but declined by 24 hours. The cornea, anterior sclera, and bulbar conjunctiva had the highest levels of JV-DE1 in both eyes, but JV-DE1 levels were lower in these structures located within the eye. The most significant finding was the unexpectedly high levels of JV-DE1 in the retina and the posterior sclera, which underlies and supports the retina. These data, together with the low plasma levels, provided a clear indication that JV-DE1 in a formulation containing polyoxyl 35 castor oil as an excipient was able to deliver therapeutically effective drug concentrations to the retina and posterior pole of the eye.

[0384] Example 2: Rabbit study of topical ocular administration of JV-DE1 to the surface of one eye A monocular drug application study was performed to verify that drug delivery of JV-DE1 was essentially limited to ocular redistribution other than via blood circulation after contact of the eye drops with the anterior ocular surface tissue. JV-DE1 was formulated in 2.4% CrEL and 0.2% glycerol in TBS pH 7.6. CrEL is polyoxyl 35 castor oil. Other names for polyoxyl 35 castor oil include macrogol glycerol ricinoleate, PEG-35 castor oil, and polyoxyl 35 hydrogenated castor oil. Briefly, for in vivo kinetics experiments, JV-DE1 was administered to one eye (OD) via eye drops at a dose of 0.12 mg / eye. Blood samples (1 mL) were collected 0, 0.5, 2, 6, and 24 hours after single ocular administration of the eye drops. At each of the above time points, one animal was euthanized after blood collection, and selected ocular tissue samples were collected from both eyes. Aqueous humor, bulbar conjunctiva, anterior sclera, posterior sclera (optic nerve exit area), retina, cornea, ciliary body, and iris were collected and weighed. The samples were then stored in an ultra-low temperature freezer. The JV-DE1 concentration in the samples was then determined by LC-MS / MS method. Figure 3A shows the concentration of JV-DE1 in various parts of the eye administered with JV-DE1 at various time points. Figure 3B shows the concentration of JV-DE1 in various parts of the eye not administered with JV-DE1 at various time points after administration to the contralateral eye.

[0385] Plasma JV-DE1 concentrations were low in New Zealand rabbits after monocular administration. maxwas approximately 0.95 ng / mL at 0.5 hours post-dose, with complete clearance by 24 hours post-dose. JV-DE1 was widely distributed in ocular tissues in compound-treated eyes (OD). The concentration of JV-DE1 at ocular tissue levels was well maintained for 8 hours post-dose, but declined by 24 hours. The cornea, anterior sclera, and bulbar conjunctiva had the highest levels of JV-DE1 in treated eyes, which were approximately 100-fold higher than the JV-DE1 levels in the ciliary body / iris, posterior sclera, and retina. The most significant finding was the unexpected level of JV-DE1 in the vitreous humor. In the contralateral untreated eye (OS), the compound was only detected in the cornea, posterior sclera, and retina. However, the JV-DE1 levels in the retina of the contralateral untreated eye were 10-fold lower than those of the treated eye. These data, together with the low plasma levels, indicated that 90% of the drug reached the retina at pharmaceutical levels via intraocular redistribution of eye drops administered topically to the ocular surface, with only approximately 10% reaching the retina via delivery from the bloodstream.

[0386] Example 3: Cynomolgus monkey study of JV-DE1 administered to the periorbital skin of one eye Additional experiments with JV-DE1 were performed including determining its in vivo kinetics following topical application to the periorbital skin surrounding the anterior portion of the eyeball.

[0387] JV-DE1 was formulated in medium chain triglyceride (MCT) oil. An amount of approximately 0.16 mg of JV-DE1 formulation was administered to one eye (OD) by circumferential topical application to the periorbital skin surrounding the anterior part of the eyeball. Blood samples (1 mL) were collected at 0, 0.5, 2, 6, and 24 hours after a single administration to the periorbital skin of the right eye (OD). At each of the pre-specified time points above, one animal was euthanized after blood collection and selected ocular tissue samples were collected from both eyes. The following representative tissues were collected: upper eyelid, cornea, retina, and vitreous humor. The JV-DE1 concentration in the samples was subsequently determined by LC-MS / MS methodology. The results are summarized in Table 1 below.

[0388] [Table 1]

[0389] Plasma concentrations of JV-DE1 were low in cynomolgus monkeys after a single dose of monocular periorbital administration. max The concentration of JV-DE1 in the retina was >200- to >500-fold higher than that in the cornea.

[0390] The ocular distribution of JV-DE1 following application to periorbital skin was quite different from the distribution associated with conventional eye drop administration to the ocular surface. Delivery of the compound to the posterior segment following periorbital administration was substantially greater than delivery of the compound to the cornea. In contrast, eye drop administration delivered much more JV-DE1 to the cornea and other anterior segment tissues (Figures 2A, 2B, 3A) than periorbital delivery. Nevertheless, both routes of administration did not significantly affect the JV-DE1 pK obtained for human IP and PAF receptors. i According to the pK values, therapeutically relevant concentrations of JV-DE1 could be delivered to the retina and cornea (Bley et al., 2006). A surprising finding was that periorbital or eye drop administration of JV-DE1 to the retina significantly increased the pK values ​​at IP and PAF receptors. i The results show that the retinal and vitreous humor levels of JV-DE1 are significantly higher than the vitreous humor levels, resulting in complete antagonism over a 24-hour period. The high and consistent levels of JV-DE1 delivered to the retina and vitreous humor suggest that a significant amount of the drug delivered to the eye remains in the eye. The rapid accumulation of JV-DE1 in the vitreous humor and retina suggests a nearly "open pathway" for certain drug penetration under certain conditions.

[0391] The biodistribution of compounds delivered to the eyelids through the periorbital skin layer has not been the subject of experimental investigations before. It is known from a vast repository of patient experience that bimatoprost applied to the upper eyelid margin does not reach the periorbital skin because hyperpigmentation-induced skin discoloration above the eyelid margin does not occur. High levels of JV-DE1 were achieved in the upper eyelid after application to the periorbital skin (see Table 1). JV-DE1 was administered at a dose of 165.30 ± 4.65 μg / eye (mean ± SEM) via NIODP to the right eye (OD) of monkeys in this pharmacokinetic and biodistribution study. For convenience of sample processing, only the upper eyelid was harvested. After 24 hours, a significant amount of drug remained in the upper eyelid / periorbital region. Similar amounts of drug, greater than 1000 ng / g (i.e., >1 μg / g), were found in the retina and remained at such high levels at all tested time points after administration. On the other hand, drug levels were lowest in the cornea and vitreous humor. Drug levels retained in the retina were more than 200-fold higher than in the cornea at each test time point: 0.5, 3, 6, and 24 hours after dosing. JV-DE1 had its maximum concentration of 23929.5 ng / g (23.9 μg / g) in the retina at 6 hours after dosing, while plasma concentrations remained below 0.3 ng / ml, near the lower limit of quantification (LLOQ, 0.1 ng / ml).

[0392] Example 4: Cynomolgus Monkey Study of Periorbital Administered Docosahexaenoic Acid Delivery of compounds to the posterior tissues of the eye, especially the retina, by application to the periorbital skin is not restricted or limited to JV-DE1. This is supported by the results obtained with a significantly different compound, docosahexaenoic acid (DHA), shown in Table 2. An oily solution containing 14.85 mg / mL β-carotene + 198.02 mg / mL DHA in linoleic acid was administered to one eye (OD) by circumferential topical application to the periorbital skin surrounding the anterior part of the eyeball. Blood samples (1 mL) were collected 0, 0.5, 2, 6, and 24 hours after a single administration to the periorbital skin of one eye (OD). At each of the pre-specified time points above, one animal was euthanized after blood collection and selected ocular tissue samples were collected from both eyes. The following representative tissues were collected: upper eyelid, cornea, retina, and vitreous humor. DHA concentrations in the samples were determined by LC-MS / MS methods. The results are summarized in Table 2 below. DHA was administered to the left eye of monkeys in a pharmacokinetic and biodistribution study via NIODP at a dose of 6775.1 ± 92.5 μg / eye (mean ± SEM). Again, only the upper eyelid was collected for convenience of sample processing. Significant amounts of DHA (>10 μg / g) remained in the upper eyelid / periorbital region, retina, and cornea at all study time points: 0.5, 3, 6, and 24 hours after dosing. DHA rapidly reached a maximum value of 110.9 μg / g in the retina at 0.5 hours after dosing. In the vitreous humor, DHA remained below the limit of quantification (BLQ) with a lower limit of quantification (LLOQ) of 0.5 μg / ml (Figure 3). Compared to BLQ baseline, plasma concentrations of DHA ranged from 1.2 to 3.1 μg / ml, equivalent to 3.65 to 9.4 mM (MW 328.5) via NIODP. max This was 5 hours after administration.

[0393] [Table 2]

[0394] Plasma levels of docosahexaenoic acid (DHA) remained essentially stable throughout the 24-hour experimental time course. They were 2.2, 3.1, 2.1, and 1.2 μg / mL at 0.5, 3, 6, and 24 hours after dosing, respectively. This plasma concentration of DHA was found to be significantly elevated approximately 2-6 fold above its endogenous level (<0.5 μg / ml) in monkeys. This implies that NIODP delivery may also be beneficial to achieve higher systemic circulation of DHA for the systemic health of the human body. More DHA omega-3 clinical trials for AMD treatment and other retinal diseases must be conducted using the NIODP route. NIODP has the potential to eliminate or significantly reduce the need for injections into the eye, thus disrupting the current method of choice for retinal drug delivery. Compared to JV-DE1, DHA penetrated ocular tissues rapidly and was rapidly reduced at the site of application in the upper eyelid.

[0395] Conversely, the β-carotene component of the formulation was not readily taken up and biodistributed following administration, as shown in Table 3. Thus, not all compounds are readily taken up and distributed to the posterior segment of the eye.

[0396] [Table 3]

[0397] The administration of compound applied to the skin around the orbit surprisingly provides therapeutically and beneficially effective amount to the posterior segment of the eye, as well as to the surface and eyelid of the eye.The application to the orbit is particularly advantageous for delivering compound to the retina.The administration route shown includes, without being limited by theory, the preferred penetration of the vitreous humor and retina after the administration of the orbit includes bypassing the lens, which suggests that in the case of eye drops, the passage of the drug from the anterior segment to the posterior segment of the eye, including the retina, is a major obstacle.

[0398] Example 5: Non-invasive Periorbital Ocular Drug Delivery Drugs are dissolved and delivered to both anterior and posterior parts of the eye through non-invasive and non-irritating formulations by administration to the periorbital skin of the eye.Drugs that are lipophilic are preferably delivered to these parts of the eye.When the drug passes through the stratum corneum of the periorbital skin, the drug can passively diffuse through the conjunctiva into the scleral water channel.Drugs that can be ionized at physiological pH in the scleral water channel are preferably delivered to the posterior part of the eye, overcoming the restrictions caused by protective anatomical and physiological barriers that limit access to the retina.

[0399] Example 6: Endogenous DHA Levels in Ocular Tissues The biodistribution of DHA in ocular tissues after administration to periorbital skin shown in Table 2 is not due to the endogenous level of DHA (DHA originates from within the organism and is not due to any external factors). The endogenous level of DHA in ocular tissues is negligible. Table 4 shows the endogenous level of DHA present in ocular tissues, measured in μg / mL. Prior to the measurements in Table 4, the patients were not administered any drug formulations.

[0400] [Table 4]

[0401] Example 7: Endogenous β-carotene levels in ocular tissues The biodistribution of β-carotene in ocular tissues after administration to the periorbital skin shown in Table 3 is not due to endogenous levels of β-carotene (β-carotene originates from within the organism and is not due to any external factors). The endogenous levels of β-carotene in ocular tissues are negligible. Table 5 shows the endogenous levels of β-carotene present in ocular tissues, measured in μg / mL. The patients had not been administered any drug formulations prior to the measurements in Table 5.

[0402] [Table 5]

[0403] Example 8: Non-invasive Eyelid Ocular Drug Delivery The drug is dissolved and delivered to both the anterior and posterior segments of the eye via a non-invasive and non-irritating formulation by administration to the eyelid skin. Drugs that are lipophilic are preferably delivered to these parts of the eye. Once the drug has passed through the stratum corneum of the eyelid skin, the drug can passively diffuse through the conjunctiva into the scleral water channel. For example, DHA and JV-DE1 are both lipophilic, that is, both compounds have a predicted lipophilicity index of 1 or greater. The predicted lipophilicity index (log P value) of DHA is about 6.8. The predicted lipophilicity index (log P value) of JV-DE1 is about 3.36. Drugs that may be ionizable at physiological pH in the scleral water channel are preferably delivered to the posterior segment of the eye, overcoming the limitations imposed by protective anatomical and physiological barriers that limit access to the retina. For example, DHA has a physiological charge of -1. Similarly, JV-DE1 has a physiological charge of +1. Compounds with more than one ionization center at physiological pH are more likely to reach the posterior segment of the eye.

[0404] Example 9: Comparison of a non-invasive ocular delivery platform with eye drops for drug delivery of JV-DE1 and DHA The non-invasive ocular delivery platform (NIODP) is a combination of transdermal administration to the periorbital skin and a suitable drug formulation to deliver ocular drugs, especially retinal drugs, at levels above μg / g of ocular tissue. It was demonstrated that high doses (>1 μg / g) of JV-DE1, which has ocular anti-inflammatory and anti-microvascular leakage properties, can be delivered to the anterior chamber of the eye as eye drops, and to the posterior chamber of the eye, especially the retina, via NIODP. The biodistribution dose gradient of JV-DE1 administered as eye drops was cornea ≥ conjunctiva ≥ anterior sclera ≒ iris ≥ ciliary body ≥ posterior sclera ≥ aqueous humor ≥ retina. The biodistribution via NIODP was eyelid ≥ retina ≥ cornea ≥ vitreous humor. Docosahexaenoic acid (DHA), an omega-3 antioxidant, was also administered via NIODP. For DHA, the dose gradient for administration via NIODP was eyelid ≈ retina > cornea >> vitreous humor = 0. JV-DE1 administered as eye drops achieved high concentrations in the cornea, but was trapped in the iris and ciliary body, and the concentration in the anterior aqueous humor remained very low (almost as low as the concentration in the retina) and appeared to have lost momentum for further diffusion through the vitreous humor to the retina. On the other hand, JV-DE1 remained in a good concentration gradient through the scleral route from the conjunctiva through the posterior sclera to the retina. Thus, the retinal distribution of less than 60 ng / g of JV-DE1 eye drops is likely via the scleral route rather than via the corneal route.

[0405] Similarly, JV-DE1 and DHA also appear to reach the retina via the scleral route when delivered by NIODP, since the drug in the vitreous humor was either significantly lower (JV-DE1) or BLQ (DHA), even though the drug concentration was high in the cornea (DHA). This observation is consistent with previous reports that, via conjunctival / scleral injection (under the periorbital skin), nonionic nomicelles were able to reach the retina by diffusing through the scleral water channels rather than diffusing to the retina through the corneal route. Scleral water channels are a network of collagen fibers, proteoglycans, and glycoproteins in an aqueous medium. Depending on the physicochemical properties of the drug, such as molecular weight, radius, charge, and lipophilicity, the scleral route provides an easier route for certain drugs to bypass the anterior segment barriers (lens, iris, and ciliary body) and carry the drug to the posterior part of the eye.

[0406] As summarized in Figure 4, when administered via the eye drop route, most drugs are delivered through the corneal route and only occasionally reach the retina at negligible levels. However, when applied via the NIODP route, once penetrating through the stratum corneum of the periorbital skin, the drug can either passively diffuse through the scleral water channels ("scleral route") to the retina or take the corneal route to the anterior segment. NIODP can deliver compounds at high doses to the anterior segment via the corneal route and to the posterior segment via the scleral route, whereas eye drops deliver drugs (JV-DE1) to the anterior segment of the eye mostly via the corneal route. The effective drug concentration in the target tissue determines the success of the treatment of target diseases such as dry eye disease (DED) and other anterior ocular inflammatory diseases (AOID), age-related macular degeneration (AMD), other posterior ocular inflammatory diseases (POID) and neurodegenerative eye diseases, and the success of preventing the progression of the resulting vision loss and irritation associated with these inflammatory and neurodegenerative diseases.

[0407] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the present invention be limited by the specific examples provided within the specification. Although the present invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. Furthermore, it will be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions described herein, which depend upon a variety of conditions and variables. It will be understood that various alternatives to the embodiments of the present invention described herein may be utilized in the practice of the present invention. It is therefore contemplated that the present invention shall cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the present invention, and that methods and structures within the scope of the claims, and equivalents thereof, are covered thereby.

Claims

1. A topical pharmaceutical composition comprising an active agent, or a pharma- ceutical acceptable free acid, ester, or salt thereof, for use in a method for promoting ocular health or preventing or treating ocular disease in a subject, the method comprising the step of administering the topical pharmaceutical composition to the periorbital skin or eyelid of the subject's eye.

2. The topical pharmaceutical composition of claim 1, wherein the active agent is selected from an omega-3 fatty acid, an omega-3 ethyl ester, or an omega-3 triglyceride.

3. The topical pharmaceutical composition of claim 2, wherein the omega-3 fatty acid comprises alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or any combination thereof.

4. A topical pharmaceutical composition described in any one of claims 2 to 3, wherein the omega-3 fatty acid is administered in an amount of about 0.1 mg to about 3000 mg.

5. The topical pharmaceutical composition of any one of claims 1 to 3, wherein the topical pharmaceutical composition is formulated as a cream, emulsion, ointment, or oily solution.

6. The topical pharmaceutical composition of any one of claims 1 to 3, further comprising a skin softener, a moisturizer, a thickener, a preservative, a penetration enhancer, an antioxidant, an aroma masking agent, or any combination thereof.

7. The topical pharmaceutical composition of any one of claims 1 to 3, further comprising 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imidazol-2-amine, or a pharma- ceutically acceptable ester or salt thereof.

8. The topical pharmaceutical composition of any one of claims 1 to 3, wherein the topical pharmaceutical composition is administered using an applicator such as a rollerball, a click pen brush, a pump bottle, or an eye drop bottle, or a bottle with a Q-tip, or a fingertip.

9. Promoting ocular health or preventing or treating ocular diseases includes, but is not limited to, dry eye disease and ocular discomfort, irritation, pain and stress, chemical burns, anterior segment dysplasia, cataracts, iritis, pterygium, keratoconjunctivitis, keratitis, conjunctivitis, keratoconus, ectatic disorders (including globular cornea, pellucid marginal degeneration), pseudophakic and aphakic bullous keratopathy, episcleritis, corneal ulcers, corneal dysplasia, corneal ulcers, Fuchs' endothelial dystrophy and other corneal dystrophies (including lattice, granular, patchy, and map-dot fingerprint), ocular cicatricial pyelonephritis, ocular keratoconid ... Small pox, Stevens-Johnson syndrome, acute and chronic uveitis (anterior uveitis, intermediate uveitis), trauma to the cornea, conjunctiva, and anterior segment of the eye including iris trauma, penetrating eye trauma, blepharitis, blepharospasm, chalazion, ptosis, coloboma, cutis laxa, ectropion, entropion, trichiasis, styes, blepharoplasty, meibomian gland dysfunction, lacrimal gland obstruction, seborrheic keratitis, photokeratitis, bacterial or viral infection, age-related macular degeneration (wet and dry), dry and wet macular degeneration, lattice degeneration, macular hole, macular blepharoplasty Pucker, lattice degeneration, retinal breaks, retinal detachment, retinal artery occlusion, retinal vein occlusion, central retinal vein occlusion, intraocular tumors, childhood, neonatal, or inherited retinal disorders, hereditary retinal dystrophies, geographic atrophy, retinitis pigmentosa (including Leber's congenital amaurosis), cytomegalovirus (cmv) retinal infection, infectious retinitis, retinoblastoma, endophthalmitis, chorioretinitis, myopic macular degeneration and normal tension glaucoma, retinal degeneration in glaucoma, including but not limited to diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, radiation / solar retinopathy, medium 4. The topical pharmaceutical composition according to any one of claims 1 to 3, comprising treating or preventing various retinopathies including cardiac serous chorioretinopathy, hypertensive retinopathy, peripheral retinopathies and neuropathy, macular edema, retinal hemorrhage, diabetic macular edema, diabetic macular ischemia, geographic atrophy, Stargardt's disease, refractive errors (myopia, hyperopia, and astigmatism), lymphatic malformation of the orbit (also known as orbital lymphangioma), thyroid eye disease (Graves' eye disease), or acute and chronic uveitis (including intermediate uveitis, posterior uveitis, pan uveitis).

10. A topical pharmaceutical composition described in any one of claims 1 to 3, wherein promoting ocular health or preventing or treating ocular diseases includes treating or preventing wet and dry age-related macular degeneration.

11. A topical pharmaceutical composition described in any one of claims 1 to 3, wherein promoting ocular health or preventing or treating ocular disease includes treating or preventing diabetic retinopathy or retinopathy of prematurity.

12. The topical pharmaceutical composition of any one of claims 1 to 3, wherein the topical pharmaceutical composition is administered to a patient four times a day, three times a day, twice a day, once a day, once every other day, once every three days, once every four days, or once every seven days.

13. A topical pharmaceutical composition described in any one of claims 1 to 3, wherein the topical pharmaceutical composition is administered to the periorbital skin above the upper eyelid, below the lower eyelid, or both above the upper eyelid and below the lower eyelid.

14. A topical pharmaceutical composition described in any one of claims 1 to 3, wherein the topical pharmaceutical composition is administered to the eyelid.

15. The topical pharmaceutical composition of claim 1, wherein the active agent is selected from an antibody, a peptide, or an RNA interference molecule selected from siRNA, miRNA, or shRNA.

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