W / o / w microemulsion for ocular administration

Abstract

To provide a sustained release microemulsion for reducing intraocular pressure (IOP), treating glaucoma, treating age-related macular degeneration (AMD), treating uveitis, and / or treating conjunctivitis; and to provide a method for treating eye diseases comprising administering the microemulsion.SOLUTION: Provided is a microemulsion (ME) containing: (a) a discontinuous internal phase containing an aqueous solution contained within an internal emulsifier; (b) a continuous oil phase containing the internal phase; and (c) an external emulsifier containing the oil phase. Also provided are a method for the use of such a microemulsion as a drug delivery device, as well as a method for treating glaucoma and reducing intraocular pressure.SELECTED DRAWING: None

Description

[Technical field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 62 / 607,429, filed December 19, 2017, and No. 62 / 728,564, filed September 7, 2018, each of which is incorporated by reference in its entirety. [Background technology]

[0002] background Primary open-angle glaucoma (POAG) accounts for 90% of glaucoma cases worldwide. It is the leading cause of irreversible blindness. POAG is characterized by progressive optic nerve damage resulting from apoptotic cell death of retinal ganglion cells. Elevated intraocular pressure (IOP) is one of the most important risk factors contributing to visual field loss in this disease. Steady-state IOP is brought about by the balance between aqueous humor (AH) production by the ciliary body (CB) and AH drainage via the trabecular meshwork (TM; canonical pathway) and, to a lesser extent, the uveoscleral or non-canonical pathway. An imbalance between AH inflow and outflow leads to changes in IOP. Both POAG and IOP are highly heritable. In humans, the heritability of IOP is estimated to be about 55%. Furthermore, although the genetic risk of elevated IOP and POAG is partially shared, several loci associated with POAG have not been associated with IOP. Therefore, identification of genetic variants that modulate IOP may provide important insights and new targets for therapeutic intervention.

[0003] Due to the importance of maintaining a firm IOP, its reduction is the first-line treatment for glaucoma.Despite the prevalence of glaucoma and its impact on society, current pharmaceuticals do not address the underlying pathophysiology that causes IOP elevation, nor do they address the genetic mutations associated with IOP modulation.In addition, due to their short half-life and short corneal residence time, they require multiple topical applications every day, which is associated with poor patient compliance. Summary of the Invention

[0004] overview In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) a discontinuous internal phase comprising an aqueous solution contained within an internal emulsifier; (b) a continuous oil phase that encompasses the internal phase; and (c) an external emulsifier that encapsulates the oil phase The present invention provides a microemulsion (ME) comprising:

[0005] In one embodiment, the ME further comprises (d) an aqueous phase surrounding the external emulsifier. In another embodiment, the internal emulsifier is propylene glycol monocaprylate or any other surfactant having a hydrophilic-lipophilic balance (HLB) value of 3 to 7, and / or any propylene glycol ester of a fatty acid, such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol monopalmitate, polyethylene glycol lauryl ether, polyethylene glycol oleyl ether, polyethylene glycol hexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, transcutol P, gelucire 50 / 13, gelucire 44 / 14, gelucire 43 / 01, any PEG mono-, di- and / or triester of any fatty acid, lecithin, egg lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, tocopherol, or any other phospholipid, and combinations thereof. In a further embodiment, the internal emulsifier is selected from the group consisting of capryol 90, lecithin, and combinations thereof.

[0006] In one embodiment, the aqueous solution is selected from the group consisting of deionized water, saline, phosphate buffered saline, artificial tears, and balanced salt solutions. In another embodiment, the oil phase is selected from the group consisting of caprylic acid (C8) and capric acid (C 10), oils consisting of any pure fatty acid ester, including but not limited to ethyl, propyl isopropyl, and butyl; esters of fatty acids, including but not limited to caproic acid, caprylic acid, capric acid, lauric acid, palmitic acid, myristic acid, or stearic acid, isopropyl myristate, isopropyl palmitate, isopropyl caproate, isopropyl caprylate, ethyl stearate, butyl laurate, and any natural oil, including but not limited to coconut oil, palm kernel oil, soybean oil, castor oil, cottonseed oil, corn oil, and olive oil; and combinations thereof. In a further embodiment, the oil phase comprises labrafac lipophile WL 1349.

[0007] In one embodiment, the external emulsifier is selected from the group consisting of caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, any other hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 to 16, polyethylene glycol mono- and / or diester of any fatty acid or mixture of fatty acids, propylene glycol, or any other alcohol including, but not limited to, glycerol, polyethylene glycol, ethanol, propanol, and isopropanol, and combinations thereof. In another embodiment, the external emulsifier comprises caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, propylene glycol, or combinations thereof.

[0008] In one embodiment, the ME comprises 0.5-35% w / w aqueous solution, 0.5-95% w / w oil phase, and 5-99% w / w emulsifier.In another embodiment, the ME comprises 10-30% w / w aqueous solution, 20-40% w / w oil phase, and 40-60% w / w emulsifier. In another embodiment, the ME comprises an aqueous solution of at least 0.5% w / w, comprises an aqueous solution of at least 1% w / w, comprises an aqueous solution of at least 2% w / w, comprises an aqueous solution of at least 3% w / w, comprises an aqueous solution of at least 4% w / w, comprises an aqueous solution of at least 5% w / w, comprises an aqueous solution of at least 6% w / w, comprises an aqueous solution of at least 7% w / w, comprises an aqueous solution of at least 8% w / w, comprises an aqueous solution of at least 9% w / w, comprises an aqueous solution of at least 10% w / w, comprises an aqueous solution of at least 11% w / w, comprises an aqueous solution of at least 12% w / w, comprises an aqueous solution of at least 13% w / w, comprises an aqueous solution of at least 14% w / w, comprises an aqueous solution of at least 15% w / w, comprises an aqueous solution of at least 16% w / w, comprises an aqueous solution of at least 17% w / w, comprising an aqueous solution of at least 18% w / w, comprising an aqueous solution of at least 19% w / w, comprising an aqueous solution of at least 20% w / w, comprising an aqueous solution of at least 25% w / w, comprising an aqueous solution of at least 30% w / w, comprising an aqueous solution of at least 35% w / w, comprising an aqueous solution of at least 40% w / w, comprising an aqueous solution of at least 45% w / w, comprising an aqueous solution of at least 50% w / w, comprising an aqueous solution of at least 55% w / w, comprising an aqueous solution of at least 60% w / w, comprising an aqueous solution of at least 65% w / w, comprising an aqueous solution of at least 70% w / w, comprising an aqueous solution of at least 75% w / w, comprising an aqueous solution of at least 80% w / w, comprising an aqueous solution of at least 85% w / w, comprising an aqueous solution of at least 90% w / w, or comprising an aqueous solution of at least 95% w / w.

[0009] In further embodiments, the aqueous solution comprises a water-soluble drug. In various embodiments, the water-soluble drug is selected from the group consisting of beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium channel blockers, such as nimodipine and pregabalin; asialogalactosylated tartrates, such as tartrates, and tartrates. Triantennary (NA3) (also known as asialo-triantennary complex N-glycans), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir ... lovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocromil, phenylephrine, azelas In another embodiment, the water-soluble drug is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, the aqueous phase comprises a hydrogel. In another embodiment, the hydrogel comprises a mucoadhesive polymer. In various further embodiments, the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL®, e.g. CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, dextran and its derivatives, pectin and its derivatives, gelatin and its derivatives, polyvinylpyrrolidone and its derivatives, N-methylpyrrolidone and its derivatives, hyaluronate and its derivatives, gellan gum and its derivatives, xanthan gum and its derivatives, agar and its derivatives, glycocholic acid and its salts or derivatives, or combinations thereof. In various other embodiments, the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL®, e.g. CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, or combinations thereof.

[0011] In one embodiment, the ME is present as small globules having a diameter of about 1 nm to about 200 nm, hi another embodiment, the ME is formulated as a topical preparation.

[0012] In another aspect, the present disclosure provides a method for reducing intraocular pressure (IOP), treating glaucoma, treating age-related macular degeneration (AMD), treating uveitis, and / or treating conjunctivitis, comprising administering to a subject having intraocular pressure, glaucoma, AMD, uveitis, and / or conjunctivitis an effective amount of ME of any embodiment or combination disclosed herein, wherein the aqueous solution comprises a water-soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis.In various embodiments, water-soluble drugs that can reduce IOP, treat glaucoma, treat AMD, treat uveitis, and / or treat conjunctivitis include beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide. calcium channel blockers, such as nimodipine and pregabalin; asialogalactosylated triantennary (NA3) (also known as asialo-triantennary complex N-glycans), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, Triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocro In another embodiment, the water-soluble drug that can reduce IOP, treat glaucoma, treat AMD, treat uveitis, and / or treat conjunctivitis is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or a combination thereof.

[0013] In one embodiment, the ME is administered to one or both eyes of the subject. In a further embodiment, administration is once per day.

[0014] In another aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) a discontinuous (dispersed) oil phase; and (b) an emulsifier that encapsulates the oil phase The present invention provides a microemulsion (ME) comprising:

[0015] In one embodiment, the ME further comprises (c) a continuous aqueous phase surrounding the emulsifier. In a further embodiment, the ME comprises an insoluble or slightly soluble drug in the discontinuous oil phase.

[0016] In a further aspect, the disclosure provides a method for treating glaucoma, comprising administering to a subject having glaucoma an inhibitor of calcium voltage-dependent channel auxiliary subunit alpha 2 delta 1 (CACNA2d1) protein in an amount effective to treat glaucoma. In one aspect, the glaucoma is primary open-angle glaucoma (POAG). In another aspect, the disclosure provides a method for reducing intraocular pressure, comprising administering to a subject in need thereof an inhibitor of CACNA2d1 protein in an amount effective to treat, reduce intraocular pressure. In one embodiment of each of these aspects, the inhibitor comprises a gabapentinoid or phenylglycine. In one embodiment, the gabapentinoid comprises pregabalin. In a further aspect, the inhibitor is administered topically. In another embodiment, the inhibitor is administered via eye drops. [The present invention 1001] (a) a discontinuous internal phase comprising an aqueous solution contained within an internal emulsifier; (b) a continuous oil phase which encompasses the internal phase; and (c) an external emulsifier that encapsulates the oil phase A microemulsion (ME). [The present invention 1002] (d) an aqueous phase surrounding the external emulsifier; The ME of the present invention 1001 further comprises: [The present invention 1003] The internal emulsifier may be propylene glycol monocaprylate or any other surfactant having an HLB value of 3 to 7, and / or any propylene glycol ester of a fatty acid, such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol monopalmitate, polyethylene glycol lauryl ether, polyethylene glycol oleyl ether, polyethylene glycol hexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, transcutol P, gelucire 50 / 13, gelucire 44 / 14, gelucire 43 / 01, any PEG mono-, di- and / or triester of any fatty acid, lecithin, egg lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, tocopherol, or any other phospholipid, and combinations thereof. [The present invention 1004] The ME of any one of claims 1001 to 1002, wherein the internal emulsifier is selected from the group consisting of capryol 90, lecithin, and combinations thereof. [The present invention 1005] The ME of any one of claims 1001 to 1004, wherein the aqueous solution is selected from the group consisting of deionized water, saline, phosphate buffered saline, artificial tears, and balanced salt solutions. [The present invention 1006] The oil phase contains caprylic acid (C8) and capric acid (C 10), oils consisting of any pure fatty acid ester including, but not limited to, ethyl, propyl, isopropyl, and butyl; esters of fatty acids including, but not limited to, caproic acid, caprylic acid, capric acid, lauric acid, palmitic acid, myristic acid, or stearic acid, isopropyl myristate, isopropyl palmitate, isopropyl caproate, isopropyl caprylate, ethyl stearate, butyl laurate, and any natural oil including, but not limited to, coconut oil, palm kernel oil, soybean oil, castor oil, cottonseed oil, corn oil, and olive oil; and combinations thereof. [The present invention 1007] Any of MEs of the present invention 1001 to 1005, wherein the oil phase contains labrafac lipophile WL 1349. [The present invention 1008] Any of the MEs of inventions 1001 to 1007, wherein the external emulsifier is selected from the group consisting of caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, any other hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 to 16, polyethylene glycol mono- and / or diester of any fatty acid or mixture of fatty acids, propylene glycol, or any other alcohol including, but not limited to, glycerol, polyethylene glycol, ethanol, propanol, and isopropanol, and combinations thereof. [The present invention 1009] The ME of any one of claims 1001 to 1008, wherein the external emulsifier comprises caprylocaproyl polyoxyl-8 glyceride, macrogolglycerol ricinoleate, propylene glycol, or a combination thereof. [The present invention 1010] Any of MEs according to claims 1001 to 1009, comprising an aqueous solution of 0.5 to 35% w / w, an oil phase of 0.5 to 95% w / w, and an emulsifier of 5 to 99% w / w. [The present invention 1011] Any of MEs according to claims 1001 to 1009, comprising an aqueous solution of 10 to 30% w / w, an oil phase of 20 to 40% w / w, and an emulsifier of 40 to 60% w / w. [The present invention 1012] The ME of any one of claims 1001 to 1011, wherein the aqueous solution contains a water-soluble drug. [The present invention 1013] The water-soluble drug may be selected from the group consisting of beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium channel blockers, such as nimodipine and pregabalin; asialogalactosylated triantennary ( NA3) (also known as asialo-triantennary complex type N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, valvo ... vir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocromil, phenylephrine, azelastine, epinastine, The ME of the present invention 1012 is selected from the group consisting of naphazoline / pheniramine, olopatadine, bepotastine, alcaftadine, pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, combinations thereof, or pharmaceutically acceptable salts thereof. [The present invention 1014] The ME of the present invention, wherein the water-soluble drug is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or a pharma- ceutically acceptable salt thereof. [The present invention 1015] The ME of any one of claims 1001 to 1014, wherein the aqueous phase comprises a hydrogel. [The present invention 1016] The ME of the present invention, wherein the hydrogel comprises a mucoadhesive polymer. [The present invention 1017] The ME of the present invention 1016, wherein the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL®, e.g. CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, dextran and its derivatives, pectin and its derivatives, gelatin and its derivatives, polyvinylpyrrolidone and its derivatives, N-methylpyrrolidone and its derivatives, hyaluronate and its derivatives, gellan gum and its derivatives, xanthan gum and its derivatives, agar and its derivatives, glycocholic acid and its salts or derivatives, or combinations thereof. [The present invention 1018] The ME of the present invention 1016, wherein the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL (registered trademark), e.g. CARBOPOL (registered trademark) 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, or combinations thereof. [The present invention 1019] Any of MEs according to claims 1001 to 1018, which exist as small globules having a diameter of about 1 nm to about 200 nm. [The present invention 1020] The ME of any one of claims 1001 to 1019, which is formulated as a topical preparation. [The present invention 1021] A method for treating an eye disease, comprising the step of administering to a subject having an eye disease an ME of any one of the present inventions 1001 to 1020 in an amount effective for treating the eye disease, wherein the aqueous solution comprises a water-soluble drug capable of treating the eye disease. [The present invention 1022] A method for reducing intraocular pressure (IOP), treating glaucoma, treating age-related macular degeneration (AMD), treating uveitis, and / or treating conjunctivitis, comprising administering to a subject having intraocular pressure, glaucoma, AMD, uveitis, and / or conjunctivitis an effective amount of ME of any of the present inventions 1001 to 1020, wherein the aqueous solution comprises a water-soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis. [The present invention 1023] The water-soluble drugs capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis include beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium channel blockers, such as cyclosporine, cyclosporine, and cyclosporine; blockers, such as nimodipine and pregabalin; asialogalactosylated triantennary (NA3) (also known as asialo-triantennary complex N-glycans), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, barazone, Clovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocromil, phenylephrine, azelas The method of any one of claims 1021 to 1022, wherein the active ingredient is selected from the group consisting of tetrahydrozoline, epinastine, naphazoline / pheniramine, olopatadine, bepotastine, alcaftadine, pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, combinations thereof, or pharma- ceutically acceptable salts thereof. [The present invention 1024] The method of any one of claims 1021 to 1022, wherein the water-soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or pharma- ceutically acceptable salts thereof. [The present invention 1025] The method of any of claims 1021 to 1024, wherein the ME is administered to one or both eyes of the subject. [The present invention 1026] The method of any one of claims 1021 to 1024, wherein said administration is performed once a day. [The present invention 1027] (a) a discontinuous (dispersed) oil phase; and (b) an emulsifier that encapsulates the oil phase A microemulsion (ME). [The present invention 1028] (c) a continuous aqueous phase surrounding the emulsifier. The ME of the present invention 1027 further comprises: [The present invention 1029] The ME of any one of claims 1027 to 1028, further comprising an insoluble or slightly soluble drug in said discontinuous oil phase. [The present invention 1030] A method for treating glaucoma, comprising administering to a subject having glaucoma an inhibitor of calcium voltage-dependent channel auxiliary subunit alpha 2 delta 1 (CACNA2d1) protein in an amount effective to treat glaucoma. [The present invention 1031] The method of claim 1029, wherein said glaucoma is primary open angle glaucoma (POAG). [The present invention 1032] A method for reducing intraocular pressure comprising administering to a subject in need thereof an inhibitor of CACNA2d1 protein in an amount effective to treat or reduce intraocular pressure. [The present invention 1033] The method of any one of claims 1030 to 1032, wherein the inhibitor comprises a gabapentinoid, phenylglycine, or a pharma- ceutically acceptable salt thereof. [The present invention 1034] The method of claim 1033, wherein the gabapentinoid comprises gabapentin, pregabalin, or a pharma- ceutically acceptable salt thereof. [The present invention 1035] The method of any one of claims 1030 to 1034, wherein the inhibitor is administered locally. [The present invention 1036] The method of any one of claims 1030 to 1035, wherein the inhibitor is administered via eye drops. [The present invention 1037] Formulations containing: (a)(i) water at a concentration of 0% to about 7% w / w of the formulation; (ii) oil in a concentration of about 6% to about 13% w / w of the formulation; (iii) capryol 90 in a concentration of about 1% to about 13% w / w of the formulation; and (iv) lecithin at a concentration of about 1% to about 13% w / w of the formulation. a primary water-in-oil (w / o) phase constituting from about 0.1% to about 40% of the formulation, (b)(i) labrasol in a concentration of about 0.1% to about 25% w / w of the formulation; (ii) cremophor EL at a concentration of about 0.1% to about 25% w / w of the formulation; (iii) propylene glycol in a concentration of 0% to about 45% w / w of the formulation; and (iv) water at a concentration of about 10% to about 99.7% w / w of the formulation; an external aqueous phase comprising 50-99.9% of the formulation, [The present invention 1038] Formulations containing: (a)(i) water at a concentration of 2% to about 7% w / w of the formulation; (ii) oil in a concentration of about 6% to about 9% w / w of the formulation; (iii) Capryol 90 in a concentration of about 3% to about 9% w / w of the formulation; and (iv) lecithin at a concentration of about 3% to about 9% w / w of the formulation. a primary water-in-oil (w / o) phase constituting from about 0.1% to about 40% of the formulation, (b)(i) labrasol in a concentration of about 5% to about 9.5% w / w of the formulation; (ii) Cremophor EL at a concentration of about 5% to about 9.5% w / w of the formulation; (iii) propylene glycol in a concentration of 5% to about 25% w / w of the formulation; and (iv) water at a concentration of about 30% to about 56% w / w of the formulation; an external aqueous phase comprising 50-99.9% of the formulation, [The present invention 1039] A method of treating an eye disease in which a subject is administered a formulation of invention 1037 or 1038. [The present invention 1040] The method of claim 1039, wherein said eye disease is IOP, glaucoma, AMD, uveitis, and / or conjunctivitis. [The present invention 1041] The method of any one of claims 1039 to 1040, wherein the formulation is administered to the eye of the patient. [The present invention 1042] The method of any of claims 1039 to 1041, wherein said formulation is administered to said patient once a day. [The present invention 1043] The method of any of claims 1039 to 1041, wherein said formulation is administered to said patient two or more times per day. [The present invention 1044] Any of the methods of inventions 1021-1026, 1030-1036, or 1040-1043, wherein the formulation reduces IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. [The present invention 1045] The formulation is effective in preventing IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about Any of the methods of the present inventions 1021 to 1026, 1030 to 1036, and 1040 to 1043, which reduces the concentration by 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. [The present invention 1046] The method of any one of claims 1039 to 1045, wherein the preparation contains a water-soluble drug. [The present invention 1047] The method of claim 1046, wherein said formulation comprises one or more of pregabalin, phenylglycine, gabapentin, or ribavirin. [The present invention 1048] The method of claim 1046, wherein the formulation comprises pregabalin. [The present invention 1049] The method of any of claims 1021-1026, 1030-1036, or 1039-1048, wherein the ME or formulation comprises at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w of water soluble drug. [The present invention 1050] The ME or formulation is about 0.3% w / w to about 1.2% w / w, about 0.3% w / w to about 1.1% w / w, about 0.3% w / w to about 1.0% w / w, about 0.3% w / w to about 0.9% w / w, about 0.3% w / w to about 0.8% w / w, about 0.4% w / w to about 1% w / w, about 0.4% w / w to about 0.9% w / w, about 0.4% w / w to about 0.8% w / w, about 0.4% w / w to about 0.7% w / w Any of methods 1021 to 1026, 1030 to 1036, or 1039 to 1048, comprising about 0.5% w / w to about 1.0% w / w, about 0.5% w / w to about 0.9% w / w, about 0.5% w / w to about 0.8% w / w, about 0.5% w / w to about 0.7% w / w, about 0.55% w / w to about 0.8% w / w, or about 0.55% w / w to about 0.7% w / w of a water-soluble drug. [The present invention 1051] Any of methods 1021-1026, 1030-1036, or 1046-1050, wherein the concentration of the water-soluble drug is at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w of the ME or formulation. [The present invention 1052] Any of methods 1021-1026, 1030-1036, or 1046-1050, wherein the concentration of the water-soluble drug is at most 0.3% w / w, at most 0.4% w / w, at most 0.5% w / w, at most 0.6% w / w, at most 0.7% w / w, at most 0.8% w / w, at most 0.9% w / w, at most 1.0% w / w, at most 1.1% w / w, or at most 1.2% w / w of the final ME or formulation. [The present invention 1053] The concentration of the water-soluble drug is about 0.3% w / w to about 1.2% w / w, about 0.3% w / w to about 1.1% w / w, about 0.3% w / w to about 1.0% w / w, about 0.3% w / w to about 0.9% w / w, about 0.3% w / w to about 0.8% w / w, about 0.4% w / w to about 1% w / w, about 0.4% w / w to about 0.9% w / w, about 0.4% w / w to about 0.8% w / w, about 0.4% w / w to about 0.4 ... Any of methods 1021 to 1026, 1030 to 1036, or 1046 to 1050, wherein the concentration is from about 0.7% w / w, from about 0.5% w / w to about 1.0% w / w, from about 0.5% w / w to about 0.9% w / w, from about 0.5% w / w to about 0.8% w / w, from about 0.5% w / w to about 0.7% w / w, from about 0.55% w / w to about 0.8% w / w, or from about 0.55% w / w to about 0.7% w / w. [The present invention 1054] Any of the methods of claims 1021-1026, 1030-1036, or 1039-1053, wherein the ME or formulation comprises a water soluble drug that reduces the symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. [The present invention 1055] Any of the methods of claims 1021-1026, 1030-1036, or 1039-1053, wherein the ME or formulation comprises a water soluble drug that reduces symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. [The present invention 1056] The ME or formulation is effective to alleviate symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20 %, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. [The present invention 1057] The method of any one of claims 1021 to 1026, 1030 to 1036, or 1039 to 1056, wherein the ME or formulation comprises a therapeutically effective amount of a water-soluble drug in the range of about 0.3% / day to about 1.2% / day. [The present invention 1058] Any of methods 1021-1026, 1030-1036, or 1039-1056, wherein the ME or formulation comprises a therapeutically effective amount of water-soluble drug in the range of at least 0.3% w / w / day, at least 0.4% w / w / day, at least 0.5% w / w / day, at least 0.6% w / w / day, at least 0.7% w / w / day, at least 0.8% w / w / day, at least 0.9% w / w / day, at least 1.0% w / w / day, at least 1.1% w / w / day, or at least 1.2% w / w / day. [The present invention 1059] The ME or formulation is about 0.3% w / w / day to about 1.2% w / w / day, about 0.3% w / w / day to about 1.1% w / w / day, about 0.3% w / w / day to about 1.0% w / w / day, about 0.3% w / w / day to about 0.9% w / w / day, about 0.3% w / w / day to about 0.8% w / w / day, about 0.4% w / w / day / day to about 1.2% w / w / day, about 0.4% w / w / day to about 1.1% w / w / day, about 0.4% w / w / day to about 1.0% w / w / day, about 0.4% w / w / day to about 0.9% w / w / day, about 0.4% w / w / day to about 0.8% w / w / day, about 0.5% w / w / day to about 1.2 ... Any of methods 1021 to 1026, 1030 to 1036, or 1039 to 1056 of the present invention, comprising a therapeutically effective amount of a water-soluble drug in the range of about 0.5% w / w / day to about 1.1% w / w / day, about 0.5% w / w / day to about 1.0% w / w / day, about 0.5% w / w / day to about 0.9% w / w / day, about 0.5% w / w / day to about 0.8% w / w / day, about 0.55% w / w / day to about 1.2% w / w / day, about 0.55% w / w / day to about 1.1% w / w / day, about 0.55% w / w / day to about 1.0% w / w / day, about 0.55% w / w / day to about 0.9% w / w / day, or about 0.55% w / w / day to about 0.8% w / w / day. [The present invention 1060] The method of any one of claims 1021 to 1026, 1030 to 1036, or 1039 to 1059, wherein said ME or formulation is administered as a single dose or is administered continuously. [The present invention 1061] The method of any of claims 1021-1026, 1030-1036, or 1039-1060, wherein the ME or formulation is administered to the patient once a day, twice a day, three times a day, once every few days, or once a week. [The present invention 1062] 10. The method of any of claims 1021-1026, 1030-1036, or 1039-1061, wherein the ME or formulation is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more, for the treatment of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis. [The present invention 1063] Any of the methods of inventions 1021-1026, 1030-1036, or 1039-1062, wherein the therapeutically effective amount of the water-soluble drug reduces the internal pressure within the eye of the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. [The present invention 1064] Any of the methods of inventions 1021-1026, 1030-1036, or 1039-1062, wherein the therapeutically effective amount of the water soluble drug reduces the internal pressure within the eye of the individual by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. [The present invention 1065] A therapeutically effective amount of a water-soluble drug reduces the intraocular pressure of an individual by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 20%. Any of the methods of the present inventions 1021 to 1026, 1030 to 1036, and 1039 to 1062, which reduces the amount of the oxidative stress by about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. [Brief description of the drawings]

[0017] [Figure 1] Simple interval maps of IOP revealed a single significant eQTL on proximal chromosome 5. Cacna2d1 was identified as a prime candidate modulating IOP. [Diagram 2] CACNA2D1 is localized in the ciliary body (CB) and trabecular meshwork (TM). [Diagram 3] Cartoon diagram showing the association of CACNA2D1 with the Cavα1 pore and the binding of pregabalin to the CACNA2D1 subunit. [Figure 4] Pregabalin suspended in hydroxypropylmethylcellulose (HPMC) dose-dependently reduces IOP in B6 mice, with the minimum concentration giving a maximal effect being 0.9% (n=5). [Diagram 5] Pregabalin (0.9%) suspended in hydroxypropylmethylcellulose (HPMC) reduces IOP by 23% in Dutch Belted rabbits (n=5). [Figure 6] Ternary phase diagram of Labrafac (oil) + transcutol P (surfactant) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 7]Pseudo-ternary phase diagram of Labrafac (oil) + transcutol P & tween80 (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 8] Ternary phase diagram of Labrafac (oil) + cremophor EL (surfactant) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 9] Pseudo-ternary phase diagram of Labrafac (oil) + cremophor EL & tween 80 (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 10] Ternary phase diagram of Labrafac (oil) + capryol 90 (surfactant) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 11] Pseudo-ternary phase diagram of Labrafac (oil) + capryol 90 & tween 80 (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 12] Pseudo-ternary phase diagram of Labrafac (oil) + capryol 90 & soy lecithin (1:1) (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 13] Pseudo-ternary phase diagram of Labrafac (oil) + capryol 90 & soy lecithin (2:1) (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 14] Pseudo-ternary phase diagram of Labrafac (oil) + transcutol P & soy lecithin (1:1) (surfactant mixture) + H2O. The w / o microemulsion is shown in the shaded area. [Figure 15] FIG. 1 is a cartoon showing the composition of multilayer ME hydrogels. [Figure 16]The pregabalin release profiles from the different formulations indicate the sustained release behavior of the MEs, which is particularly evident for CARBOPOL® ME, which gave a constant release rate lasting up to 24 hours. [Figure 17] Histograms of the cytotoxicity patterns of different pregabalin formulations containing pregabalin show the safety of the formulations on human corneal epithelial cells. [Figure 18] The viscosity histogram of pregabalin formulations shows that the formulation containing CARBOPOL® has the highest viscosity value which allows the formulation to remain on the eye for a longer period of time. [Figure 19] The histogram of mucoadhesion of pregabalin formulations shows that the ME formulation has higher mucoadhesion values ​​than the other formulations. [Figure 20] Corneal permeability profile of pregabalin formulations demonstrating that ME sustains high corneal permeability of pregabalin. [Figure 21] Slit-lamp examination after application of different pregabalin ME: (a) CARBOPOL®, (b) alginate, or (c) chitosan. [Figure 22] IOP profiles in Dutch Belted rabbits (n=5) following topical application of pregabalin in CARBOPOL® ME at concentrations ranging from 0.1 to 0.7%. [Figure 23] IOP profiles (n=5) from Dutch Belted rabbits following topical application of blank ME, pregabalin in CARBOPOL® gel, and pregabalin in CARBOPOL® ME. [Figure 24] IOP profiles (n=5) from Dutch Belted rabbits during a 21-day tachyphylaxis study using pregabalin CARBOPOL® ME. [Diagram 25] IOP profiles (n=5) from Dutch Belted rabbits during the first 24 hours of a 21-day tachyphylaxis study using pregabalin CARBOPOL® ME. [Figure 26]IOP profiles (n=5) from Dutch Belted rabbits during the final 24 hours of a 21-day tachyphylaxis study using pregabalin CARBOPOL® ME. [Figure 27] IOP profiles from B6 mice (n=5) following topical application of 0.9% pregabalin in 2% HPMC viscous eye drops. [Figure 28] IOP profiles from B6 mice (n=5) following topical application of 0.9% 2-phenylglycine in 2% HPMC viscous eye drops. [Figure 29] IOP profiles from B6 mice (n=5) following topical application of 0.9% gabapentin in 2% HPMC viscous eye drops. [Diagram 30] IOP profiles (n=5) from Dutch Belted rabbits following topical application of Lumigan, 0.01%, administered at 9:00 AM. [Diagram 31] IOP profiles (n=5) from Dutch Belted rabbits following topical application of Lumigan, 0.01%, administered at 9 pm. [Diagram 32] The ribavirin release profiles from the different formulations demonstrated sustained release behavior of the ME, which was particularly evident for CARBOPOL® ME, which gave a constant release rate lasting up to 24 hours. [Diagram 33] Histograms of cytotoxicity of different formulations containing ribavirin show the safety of our formulations on human corneal epithelial cells. [Diagram 34] The viscosity histogram shows that the ribavirin formulations containing CARBOPOL® have the highest viscosity values ​​which would allow the formulation to remain in the eye for a longer period of time. [Diagram 35] The histogram of mucoadhesion of the formulations shows that the ribavirin CARBOPOL® ME formulation has higher mucoadhesion than the other formulations. [Diagram 36] The corneal permeability profile of ribavirin formulations demonstrates that ME increases the corneal permeability of ribavirin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description All references cited are incorporated herein by reference in their entirety.

[0019] As used herein, "about" means + / - 5% of the recited parameter.

[0020] All embodiments of any aspect of this disclosure can be used in combination unless the context clearly indicates otherwise.

[0021] In one aspect, (a) a discontinuous internal phase comprising an aqueous solution contained within an internal emulsifier; (b) an oil phase that encompasses the internal phase; and (c) an external emulsifier that encapsulates the oil phase A microemulsion (ME) is disclosed comprising:

[0022] As described herein, the inventors have developed novel microemulsions (MEs) that can be used, for example, for the local delivery of water-soluble drugs. The microemulsions described herein are easy to synthesize, can be scaled to large batch sizes, are highly biocompatible, and are capable of sustained drug release.

[0023] In one embodiment, the ME further comprises (d) an aqueous phase surrounding the external emulsifier. In this embodiment, the water-soluble drug present in the aqueous phase must pass through two interfaces: the internal w / o interface (i.e., from the aqueous solution through the internal emulsifier) ​​and the external o / w interface (i.e., from the oil phase through the external emulsifier), and then it must diffuse through the aqueous phase (including but not limited to viscous hydrogels) to become available for absorption at the administration site. Due to this ingenious design, the time required for the drug to pass through all these stages is greatly extended, allowing for sustained release.

[0024] Any suitable hydrophobic internal emulsifier can be used in the ME. In various non-limiting embodiments, the internal emulsifier is propylene glycol monocaprylate or any other surfactant having a hydrophilic-lipophilic balance (HLB) value of 3 to 7 and / or any propylene glycol ester of a fatty acid, such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol monopalmitate, polyethylene glycol lauryl ether, polyethylene glycol oleyl ether, polyethylene glycol hexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, transcutol P, gelucire 50 / 13 (mixture of PEG (MW 1500) mono-, di-, and triesters of stearic acid), gelucire 44 / 14 (mixture of PEG (MW 1500) mono-, di-, and triesters of lauric acid), gelucire 43 / 01 (mixture of fatty acids C8 to C10), ... 18 The lipid is selected from the group consisting of a mixture of PEG (MW 1500) mono-, di-, triesters, any PEG mono-, di- and / or triester of any fatty acid, lecithin, egg lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, tocopherol, or any other phospholipid, and combinations thereof.

[0025] Capryol 90 is a surfactant with HLB=5. Its chemical name is propylene glycol monocaprylate (propylene glycol monoester of caprylic acid). Alternatives to propylene glycol monocaprylate may be any other surfactant with an HLB value of 3-7 and / or any propylene glycol ester of a fatty acid, such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol monopalmitate, polyethylene glycol lauryl ether, polyethylene glycol oleyl ether, polyethylene glycol hexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, etc.

[0026] Labrasol is a hydrophilic surfactant with an HLB value of 12. It consists mainly of polyethylene glycol-8 (MW 400) mono- and diesters of caprylic and capric acids with only a few mono-, di- and triglycerides. Its chemical name is caprylocaproyl polyoxyl-8 glyceride, caprylocaproyl macrogol-8 glyceride, or PEG-8 caprylic / capric glyceride. Its alternatives may be any other hydrophilic surfactant with an HLB value (10-14) and / or any polyethylene glycol mono- and / or diester of fatty acid.

[0027] Cremophor EL is a hydrophilic surfactant with HLB value = 14. Its chemical name is macrogol glycerol ricinoleate, PEG-35 castor oil, polyoxyl 35 hydrogenated castor oil, or polyoxyl-35 castor oil. Alternatives may be any other hydrophilic surfactant with HLB value (12-16) and / or any polyethylene glycol mono- and / or diester of fatty acid or fatty acid mixture.

[0028] Lecithin is a hydrophobic surfactant with an HLB value of 4-7. Its chemical name is 2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate. It is a mixture of natural phospholipids, so its replacement can be one of the following: egg lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, tocopherol, or any other phospholipid.

[0029] In one aspect, the internal emulsifier is selected from the group consisting of propylene glycol monocaprylate, lecithin, and combinations thereof.

[0030] Any suitable aqueous solution can be used in the ME. In various non-limiting embodiments, the aqueous solution is selected from the group consisting of deionized water, saline, phosphate buffered saline, artificial tears, and balanced salt solutions.

[0031] Any suitable oil phase can be used in the ME. In various non-limiting embodiments, the oil phase is selected from the group consisting of caprylic acid (C8) and capric acid (C 10 ), oils consisting of any pure fatty acid esters, including but not limited to ethyl, propyl, isopropyl, and butyl; esters of fatty acids, including but not limited to caproic acid, caprylic acid, capric acid, lauric acid, palmitic acid, myristic acid, or stearic acid, isopropyl myristate, isopropyl palmitate, isopropyl caproate, isopropyl caprylate, ethyl stearate, butyl laurate, and any natural oil, including but not limited to coconut oil, palm kernel oil, soybean oil, castor oil, cottonseed oil, corn oil, and olive oil; and combinations thereof. In one particular embodiment, the oil phase comprises labrafac lipophile WL 1349 (i.e., triglyceride esters of caprylic and capric acids).

[0032] Any suitable external emulsifier can be used in the ME. In various other embodiments, the external emulsifier is selected from the group consisting of caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, any other hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 to 16, polyethylene glycol mono- and / or diester of any fatty acid or mixture of fatty acids, propylene glycol, or any other alcohol, including but not limited to glycerol, polyethylene glycol, ethanol, propanol, and isopropanol, and combinations thereof. In various further embodiments, the external emulsifier comprises caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, propylene glycol, or combinations thereof.

[0033] Any suitable combination of the various components of the ME of the present disclosure can be used. In one embodiment, the ME comprises 0.5-35% w / w of an aqueous solution, 0.5-95% w / w of an oil phase, and 5-99% w / w of an emulsifier (i.e., internal emulsifier + external emulsifier). In another embodiment, the ME comprises 10-30% w / w of an aqueous solution, 20-40% w / w of an oil phase, and 40-60% w / w of an emulsifier. In a further embodiment, the ME comprises about 20% w / w of an aqueous solution, about 30% w / w of an oil phase, and about 50% w / w of an emulsifier. In various further embodiments, the ME comprises an aqueous solution of at least 0.5% w / w, comprises an aqueous solution of at least 1% w / w, comprises an aqueous solution of at least 2% w / w, comprises an aqueous solution of at least 3% w / w, comprises an aqueous solution of at least 4% w / w, comprises an aqueous solution of at least 5% w / w, comprises an aqueous solution of at least 6% w / w, comprises an aqueous solution of at least 7% w / w, comprises an aqueous solution of at least 8% w / w, comprises an aqueous solution of at least 9% w / w, comprises an aqueous solution of at least 10% w / w, comprises an aqueous solution of at least 11% w / w, comprises an aqueous solution of at least 12% w / w, comprises an aqueous solution of at least 13% w / w, comprises an aqueous solution of at least 14% w / w, comprises an aqueous solution of at least 15% w / w, comprises an aqueous solution of at least 16% w / w, comprises an aqueous solution of at least 17% w / w. comprising an aqueous solution of at least 18% w / w, comprising an aqueous solution of at least 19% w / w, comprising an aqueous solution of at least 20% w / w, comprising an aqueous solution of at least 25% w / w, comprising an aqueous solution of at least 30% w / w, comprising an aqueous solution of at least 35% w / w, comprising an aqueous solution of at least 40% w / w, comprising an aqueous solution of at least 45% w / w, comprising an aqueous solution of at least 50% w / w, comprising an aqueous solution of at least 55% w / w, comprising an aqueous solution of at least 60% w / w, comprising an aqueous solution of at least 65% w / w, comprising an aqueous solution of at least 70% w / w, comprising an aqueous solution of at least 75% w / w, comprising an aqueous solution of at least 80% w / w, comprising an aqueous solution of at least 85% w / w, comprising an aqueous solution of at least 90% w / w, or comprising an aqueous solution of at least 95% w / w.

[0034] In various embodiments, the external emulsifier is present in a ratio of about 10:1 to about 2:1 relative to the internal emulsifier. In various further embodiments, the external emulsifier is present in a ratio of about 9:1 to about 2:1, about 8:1 to about 2:1, about 7:1 to about 2:1, about 6:1 to about 2:1, about 5:1 to about 2:1, about 4:1 to about 2:1, about 3:1 to about 2:1, about 10:1 to about 2.5:1, about 9:1 to about 2.5:1, about 8:1 to about 2.5:1, about 7:1 to about 2.5:1, about 6:1 to about 2.5:1, about 5:1 to about 2.5:1, about 4:1 to about 2.5:1, about 3:1 to about 2.5:1, about 5 ... The ratio of the internal emulsifier to the internal emulsifier is about 10:1 to about 3:1, about 9:1 to about 3:1, about 8:1 to about 3:1, about 7:1 to about 3:1, about 6:1 to about 3:1, about 5:1 to about 3:1, about 4:1 to about 3:1, about 10:1 to about 4:1, about 9:1 to about 4:1, about 8:1 to about 4:1, about 7:1 to about 4:1, about 6:1 to about 4:1, about 5:1 to about 4:1, about 10:1 to about 5:1, about 9:1 to about 5:1, about 8:1 to about 5:1, about 7:1 to about 5:1, about 6:1 to about 5:1.

[0035] In one embodiment, the aqueous solution includes a water-soluble therapeutic agent. Any suitable water-soluble therapeutic agent can be incorporated into the aqueous solution, including, but not limited to, beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium channel blockers, such as ribavirin, ribavirin, and ribavirin; For example, nimodipine and pregabalin; asialogalactosylated triantennary (NA3) (also known as asialo-triantennary complex N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcin, trimethoprim ... Mucinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, keto These include thifen, nedocromil, phenylephrine, azelastine, epinastine, naphazoline / pheniramine, olopatadine, bepotastine, alcaftadine, pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, or combinations thereof. In certain embodiments, the water-soluble drug is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or pharma- ceutically acceptable salts thereof.

[0036] In another embodiment, the aqueous phase comprises a hydrogel (i.e., a polymer matrix in a gel or swollen network structure, and the liquid component is water or an aqueous solution, emulsion, or suspension). In one embodiment, the hydrogel comprises a mucoadhesive polymer. Any suitable mucoadhesive polymer can be used, including, but not limited to, polyacrylic acid derivatives (including, but not limited to, CARBOPOL®, e.g., CARBOPOL® 981), alginic acid and its salts or derivatives (including, but not limited to, sodium alginate), chitosan and its derivatives, dextran and its derivatives, pectin and its derivatives, gelatin and its derivatives, polyvinylpyrrolidone and its derivatives, N-methylpyrrolidone and its derivatives, hyaluronate and its derivatives, gellan gum and its derivatives, xanthan gum and its derivatives, agar and its derivatives, glycocholic acid and its salts or derivatives, or combinations thereof. In certain embodiments, the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to, CARBOPOL®, e.g., CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to, sodium alginate), chitosan and its derivatives, or combinations thereof.

[0037] The ME can be formulated for any suitable route of administration (i.e., oral, topical, intranasal, etc.) in the form of a dosage unit formulation of a water-soluble therapeutic agent loaded into the ME. The formulation can include any other ingredients appropriate for the desired route of administration, including, but not limited to, conventional pharma- ceutically acceptable carriers, adjuvants, and vehicles. In one embodiment, the ME is formulated as a topical formulation, such as for delivery to the eye.

[0038] The ME disclosed herein may be provided as ME globules (i.e., droplets). The ME globules may be of any suitable size. In one embodiment, the ME globules are about 1 nm to about 200 nm in diameter. In various further embodiments, the ME globules are about 1 nm to about 150 nm, about 1 nm to about 100 nm, about 1 nm to about 50 nm, about 1 nm to about 20 nm, about 1 nm to about 18 nm, about 1 nm to about 17 nm, about 5 nm to about 200 nm, about 5 nm to about 150 nm, about 5 nm to about 100 nm, about 5 nm to about 50 nm, about 5 nm to about 20 nm, about 5 nm to about 18 nm, about 5 nm to about 17 nm in diameter. In various further embodiments, the ME globules are about 1 nm, about 2 nm, about 3 nm, about 4 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, about 10 nm, about 15 nm, about 20 nm, about 25 nm, about 30 nm, about 35 nm, about 40 nm, about 45 nm, about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 90 nm, about 95 nm, about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm, about 160 nm, about 170 nm, about 180 nm, about 190 or about 200 nm in diameter. In other embodiments, the ME globules are at least about 1 nm, at least 2 nm, at least 3 nm, at least 4 nm, at least 5 nm, at least 6 nm, at least 7 nm, at least 8 nm, at least 9 nm, at least 10 nm, at least 15 nm, at least 20 nm, at least 25 nm, at least 30 nm, at least 35 nm, at least 40 nm, at least 45 nm, at least 50 nm, at least 55 nm, at least 60 nm, at least 65 nm, at least 70 nm, at least 75 nm, at least 80 nm, at least 90 nm, at least 95 nm, at least 100 nm, at least 110 nm, at least 120 nm, at least 130 nm, at least 140 nm, at least 150 nm, at least 160 nm, at least 170 nm, at least 180 nm, at least 190, or at least 200 nm in diameter.

[0039] In another aspect, a method for treating an eye disease is provided, comprising administering to a subject in need thereof an ME of any embodiment or combination of embodiments described herein, in an amount effective to treat the eye disease, wherein the aqueous solution comprises a water-soluble therapeutic agent capable of treating the eye disease.In various embodiments, the method is for reducing intraocular pressure (IOP), treating glaucoma, treating age-related macular degeneration (AMD), treating uveitis, and / or treating conjunctivitis, comprising administering to a subject with elevated intraocular pressure, glaucoma, AMD, uveitis, and / or conjunctivitis an ME of any embodiment or combination of embodiments described herein, in an amount effective to reduce intraocular pressure, treat glaucoma, treat AMD, treat uveitis, and / or treat conjunctivitis, wherein the aqueous solution comprises a water-soluble therapeutic agent capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis.In various embodiments, water soluble therapeutic agents capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis include beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetonitrile. tazolamide; calcium channel blockers, such as nimodipine and pregabalin; asialogalactosylated triantennary (NA3) (also known as asialo-triantennary complex N-glycans), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, Ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, The water-soluble drug that can reduce IOP, treat glaucoma, treat AMD, treat uveitis, and / or treat conjunctivitis is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or a pharmaceutically acceptable salt thereof.In one particular embodiment, the water soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis is pregabalin, and the pregabalin is present in the ME at about 0.2% to about 2% ME % w / w, and in various further embodiments, the pregabalin is present at about 0.2% to about 1.5%, about 0.2% to about 1%, about 2% to about 0.75%, about 0.3% to about 2%, about 0.3% to about 1.5%, about 0.3% to about 1. %, about 0.3% to about 0.75%, about 0.4% to about 2%, about 0.4% to about 1.5%, about 0.4% to about 1%, about 0.4% to about 0.75%, about 0.5% to about 2%, about 0.5% to about 1.5%, about 0.5% to about 1%, about 0.5% to about 0.75%, about 0.2% to about 0.6%, about 0.3% to about 0.6%, about 0.4% to about 0.6%, about 0.5% to about 0.6%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.6% ME % w / w. The ME described herein is an excellent drug delivery system for any water soluble therapeutic candidate.

[0040] In other aspects of this embodiment, the water soluble drugs disclosed herein are used to reduce IOP and / or treat glaucoma (including POAG), AMD, uveitis, and / or conjunctivitis, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, in patients suffering from one or more of the syndromes of IOP, glaucoma (including POAG), AMD, uveitis, and / or conjunctivitis. In yet another aspect of this embodiment, the water-soluble drug disclosed herein reduces, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 9 ...50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% to reduce IOP and / or treat glaucoma, AMD, uveitis, and / or conjunctivitis.

[0041] The ME disclosed herein can include a water-soluble drug in an amount sufficient to allow for habitual administration to an individual. In aspects of this embodiment, the ME disclosed herein can include, for example, at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w of the water-soluble drug. In still another aspect of this embodiment, the ME disclosed herein may be, for example, from about 0.3% w / w to about 1.2% w / w, from about 0.3% w / w to about 1.1% w / w, from about 0.3% w / w to about 1.0% w / w, from about 0.3% w / w to about 0.9% w / w, from about 0.3% w / w to about 0.8% w / w, from about 0.4% w / w to about 1% w / w, from about 0.4% w / w to about 0.9% w / w, from about 0. The composition may contain from about 0.4% w / w to about 0.8% w / w, from about 0.4% w / w to about 0.7% w / w, from about 0.5% w / w to about 1.0% w / w, from about 0.5% w / w to about 0.9% w / w, from about 0.5% w / w to about 0.8% w / w, from about 0.5% w / w to about 0.7% w / w, from about 0.55% w / w to about 0.8% w / w, or from about 0.55% w / w to about 0.7% w / w of the water-soluble drug.

[0042] The final concentration of the water-soluble drug disclosed herein in the ME disclosed herein may be any desired concentration.In one aspect of this embodiment, the final concentration of the water-soluble drug in the ME may be a therapeutically effective amount.In other aspects of this embodiment, the final concentration of the water-soluble drug in the ME may be, for example, at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w. In other aspects of this embodiment, the concentration of a water-soluble drug disclosed herein in the ME may be, for example, at most 0.3% w / w, at most 0.4% w / w, at most 0.5% w / w, at most 0.6% w / w, at most 0.7% w / w, at most 0.8% w / w, at most 0.9% w / w, at most 1.0% w / w, at most 1.1% w / w, or at most 1.2% w / w. In other aspects of this embodiment, the final concentration of the water-soluble drug in the ME is, for example, about 0.3% w / w to about 1.2% w / w, about 0.3% w / w to about 1.1% w / w, about 0.3% w / w to about 1.0% w / w, about 0.3% w / w to about 0.9% w / w, about 0.3% w / w to about 0.8% w / w, about 0.4% w / w to about 1% w / w, about 0.4% w / w to about 0.9% w / w, about The concentration may be in the range of 0.4% w / w to about 0.8% w / w, about 0.4% w / w to about 0.7% w / w, about 0.5% w / w to about 1.0% w / w, about 0.5% w / w to about 0.9% w / w, about 0.5% w / w to about 0.8% w / w, about 0.5% w / w to about 0.7% w / w, about 0.55% w / w to about 0.8% w / w, or about 0.55% w / w to about 0.7% w / w.

[0043] As used herein, "treat" or "treating" refers to achieving one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in patients who previously had the disorder; and (e) limiting or preventing the recurrence of symptoms in patients who previously were symptomatic for the disorder. Certain embodiments herein disclose, in part, treating individuals suffering from IOP, glaucoma, AMD, uveitis, and / or conjunctivitis. In these embodiments, treating can refer to reducing or eliminating the clinical symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis in individuals; or delaying or preventing the onset of the clinical symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis in individuals. For example, the term "treating" can mean reducing the symptoms of conditions characterized by IOP, glaucoma, AMD, uveitis, and / or conjunctivitis, for example, by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.The actual symptoms associated with IOP, glaucoma, AMD, uveitis, and / or conjunctivitis are well known and can be determined by those skilled in the art by considering various factors associated with each of these syndromes.Those skilled in the art will know the appropriate symptoms or indicators associated with IOP, glaucoma, AMD, uveitis, and / or conjunctivitis, and will know how to determine whether an individual is a candidate for the treatment disclosed herein.

[0044] In various embodiments, a therapeutically effective amount of a water-soluble drug disclosed herein reduces symptoms associated with IOP, glaucoma, AMD, uveitis, and / or conjunctivitis, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects, a therapeutically effective amount of a water soluble drug disclosed herein reduces symptoms associated with IOP, glaucoma, AMD, uveitis, and / or conjunctivitis, for example, by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95% or up to 100%. In yet other aspects, a therapeutically effective amount of a water soluble drug disclosed herein can reduce or eliminate symptoms associated with IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 10 ... Reduce by about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0045] The therapeutic agent (e.g., ME) for use in the methods disclosed herein may be administered as deemed appropriate by the attending medical practitioner. In one embodiment, the therapeutic agent (e.g., ME) for use in the methods disclosed herein is administered to one or both eyes of the subject. In another embodiment, administration is performed once per day. Administration may be a single dose or may be cumulative (continuous administration), which can be easily determined by one of skill in the art. For example, treatment of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis may include a single administration of an effective dose of ME comprising a water-soluble drug as disclosed herein. Alternatively, treatment of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis may include multiple administrations of an effective dose of ME comprising a water-soluble drug, administered over a range of time periods, such as once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective dose of ME comprising a water-soluble drug as disclosed herein can be administered to an individual once a day for an indefinite period of time or until the individual no longer requires therapy.Those skilled in the art will recognize that the individual's condition can be monitored throughout the course of treatment, and the effective amount of ME comprising a water-soluble drug as disclosed herein administered can be adjusted accordingly.

[0046] In various embodiments, the sustained release water-soluble drug delivery platform releases the water-soluble drug disclosed herein with substantially zero order release kinetics, for example, over a period of about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other embodiments, the sustained release water-soluble drug delivery platform releases the water-soluble drug disclosed herein with substantially zero order release kinetics, for example, over a period of at least 7 days after administration, at least 15 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[0047] In further embodiments, the water-soluble drugs and derivatives thereof of the present invention have a half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, or more.

[0048] In one embodiment, the administration period of the therapeutic agent for the treatment of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis ranges from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period during which administration is discontinued spans 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0049] In various embodiments, the water-soluble drug delivery platform releases a therapeutic agent disclosed herein with substantially zero order release kinetics, for example, over a period of about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, or about 6 days after administration. In other aspects of the embodiments, the water-soluble drug delivery platform releases a therapeutic agent disclosed herein with substantially zero order release kinetics, for example, over a period of up to 1 day after administration, up to 2 days after administration, up to 3 days after administration, up to 4 days after administration, up to 5 days after administration, or up to 6 days after administration.

[0050] In various aspects, a therapeutically effective amount of a ME comprising a water-soluble drug disclosed herein reduces the internal pressure within an individual's eye by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a ME comprising a water soluble drug disclosed herein reduces internal pressure within the eye in an individual by, for example, by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95% or up to 100%. In yet another aspect of this embodiment, a therapeutically effective amount of ME containing a water-soluble drug disclosed herein reduces intraocular pressure in an individual by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0051] As used herein, the terms "subject", "individual", or "patient", which are used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, birds, swine, horses, livestock (e.g., pigs, sheep, goats, cows), primates, or humans. In certain embodiments, the subject, individual, or patient is a human. A pharmaceutical composition comprising an ME and a water-soluble drug is administered to the subject. Typically, any subject who is a candidate for treatment is one who has some form of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis. Preoperative evaluation typically includes a routine medical history and physical examination, in addition to a thorough informed consent that discloses all associated risks and benefits of the procedure.

[0052] The therapeutic agent-containing ME for use in the methods disclosed herein can be formulated for any suitable route, including but not limited to oral, intravenous, intravaginal, intraanal, subcutaneous, intracranial, topical, intramuscular, enteral or parenteral, and can be administered via any suitable route, including but not limited to oral, intravenous, intravaginal, intraanal, subcutaneous, intracranial, topical, intramuscular, enteral or parenteral. In certain embodiments, the therapeutic agent-containing ME can be formulated for topical administration (including but not limited to formulated as eye drops) for ocular or optic application, intranasal administration, oral for various systemic diseases, transdermal application for systemic diseases, and topical for various skin disorders, and can be administered via topical administration (including but not limited to formulated as eye drops) for ocular or optic application, intranasal administration, oral for various systemic diseases, transdermal application for systemic diseases, and topical for various skin disorders. The MEs described herein can also be used as drug delivery systems to incorporate one or more water-soluble compounds of any type, including but not limited to small molecules and peptides, into a single ME.

[0053] The preparation of the ME can be carried out under any suitable conditions appropriate for the intended use. In one non-limiting embodiment, the preparation of the ME can be carried out at room temperature to completely dissolve the water-soluble drug in the pharma- ceutically acceptable solvent. However, in other embodiments of the method, the preparation of the ME can be carried out at a temperature above room temperature. In aspects of this embodiment, the preparation of the ME can be carried out at a temperature, for example, above 21°C, above 25°C, above 30°C, above 35°C, or above 37°C, above 40°C, above 42°C, above 45°C, above 50°C, above 55°C, or above 60°C. In aspects of this embodiment, the preparation of the ME can be carried out at a temperature, for example, from about 20°C to about 30°C, from about 25°C to about 35°C, from about 30°C to about 40°C, from about 35°C to about 45°C, from about 40°C to about 50°C, from about 45°C to about 55°C, or from about 50°C to about 60°C. In certain cases, the preparation of the ME can be carried out at a temperature below room temperature to completely dissolve the therapeutic agent in the solvent, however, in other aspects of the method, the preparation of the ME can be carried out at a temperature below room temperature, e.g., below 10°C, above 5°C, above 0°C, above -10°C, or above -20°C.

[0054] In one embodiment, the water-soluble drug for use with ME is pregabalin.

[0055] In another aspect, a method for treating glaucoma or reducing IOP is provided, comprising administering to a subject in need thereof an inhibitor of calcium voltage-dependent channel auxiliary subunit alpha 2 delta 1 (CACNA2D1) protein in an amount effective to treat glaucoma or reduce IOP.In one embodiment, the method is for treating glaucoma, and in one such embodiment, the glaucoma is primary open-angle glaucoma (POAG).In one embodiment, the inhibitor comprises gabapentinoid, phenylglycine, or a pharmaceutically acceptable salt thereof.In another embodiment, the gabapentinoid comprises pregabalin or a pharmaceutically acceptable salt thereof.

[0056] As used herein, the phrase "pharmaceutically acceptable salts" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts may be any salt suitable for the intended use, including, but not limited to, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid, such as acetic acid, HOOC-(CH2) n -COOH, where n is 0 to 4. Non-toxic pharmaceutical base addition salts include salts of bases such as, for example, sodium, potassium, calcium, ammonium, etc. One of ordinary skill in the art will recognize a wide variety of non-toxic pharma- ceutically acceptable addition salts.

[0057] As used herein, a subject "in need thereof" refers to a subject having the disorder or disease being treated, or susceptible to the disease or disorder, or otherwise at risk of developing the disease or disorder.

[0058] In one non-limiting example, the ME may comprise or consist of the following components: (a)(i) Water at a concentration of 0% to about 7% w / w of the formulation; (ii) oil at a concentration of about 6% to about 13% w / w of the formulation; (iii) Capryol 90 at a concentration of about 1% to about 13% w / w of the formulation; and (iv) lecithin at a concentration of about 1% to about 13% w / w of the formulation a primary water-in-oil (w / o) phase constituting about 0.1% to about 40% of the formulation, (b)(i) labrasol in a concentration of about 0.1% to about 25% w / w of the formulation; (ii) Cremophor EL at a concentration of about 0.1% to about 25% w / w of the formulation; (iii) propylene glycol in a concentration of 0% to about 45% w / w of the formulation; and (iv) Water at a concentration of about 10% to about 99.7% w / w of the formulation. The external aqueous phase comprises 50-99.9% of the formulation.

[0059] In another non-limiting example, the ME may comprise or consist of the following components: (a)(i) Water at a concentration of 2% to about 7% w / w of the formulation; (ii) oil at a concentration of about 6% to about 9% w / w of the formulation; (iii) Capryol 90 at a concentration of about 3% to about 9% w / w of the formulation; and (iv) lecithin at a concentration of about 3% to about 9% w / w of the formulation a primary water-in-oil (w / o) phase constituting about 0.1% to about 40% of the formulation, (b)(i) labrasol in a concentration of about 5% to about 9.5% w / w of the formulation; (ii) Cremophor EL at a concentration of about 5% to about 9.5% w / w of the formulation; (iii) propylene glycol at a concentration of 5% to about 25% w / w of the formulation; and (iv) Water at a concentration of about 30% to about 56% w / w of the formulation The external aqueous phase comprises 50-99.9% of the formulation.

[0060] In another aspect, microemulsions are provided that are designed as drug delivery systems for water-insoluble and slightly water-soluble drug molecules. In these embodiments, the ME is the same as above, but lacks an internal aqueous phase and an internal emulsifier. Thus, in this embodiment, the ME is (a) a discontinuous (dispersed) oil phase; and (b) an emulsifier that encapsulates the oil phase Includes.

[0061] In one embodiment, the ME further comprises (c) a continuous aqueous phase surrounding the emulsifier. In this embodiment, the oil-drug solution is emulsified in a bioadhesive aqueous phase (e.g., a hydrogel as described herein) that comprises a hydrophilic emulsifier (i.e., an emulsifier with a high HLB value).

[0062] In a further embodiment, the ME comprises an insoluble or slightly soluble drug in a discontinuous oil phase.

[0063] All embodiments disclosed above for ME can be used in this aspect as well, unless the context indicates otherwise. EXAMPLES

[0064] Cacna2d1 is identified as a gene that modulates IOP We have systematically measured IOP across a large subset of BXD families in multiple age cohorts. Using expression quantitative trait locus (QTL) mapping, correlation analysis (direct and partial Pearson tests), and stringent stepwise refinement based on single nucleotide polymorphism (SNP) analysis, we are able to identify candidate genes that modulate IOP and validate the candidate genes using mouse and human genetic data. To determine candidate gene variants modulating IOP within the chromosome 5 locus, the following stringent criteria were used: (1) the gene is located within the confidence interval of the peak eQTL; (2) the gene has cis-modulation; (3) the expression level of the gene across BXD lines is significantly correlated with elevated IOP using both linear and partial Pearson correlation analyses; (4) the gene functions in a network that can explain its role in modulating IOP; (5) the gene has sequence variants between parental lines in / near the region of the gene; (6) the gene is expressed in the eye and is localized in a region associated with modulation of IOP; (7) the gene is associated with human POAG and / or elevated IOP by either GWAS or standard linkage studies; and (8) the gene has biological relevance to glaucoma or its treatment. There were 25 positional gene candidates that were cis-regulated within the QTL peak on chromosome 5. Using our above criteria, calcium channel voltage-dependent α2δ1 subunit (Cacna2d1) emerged as the single best positional candidate (r=0.440; P=0.0003) (FIG. 1).

[0065] To further test Cacna2d1 as a candidate IOP-modulating gene, immunohistochemistry was performed to determine the localization pattern of CACNA2D1 in healthy mouse and human donor eyes. In mouse eyes, CACNA2D1 is prominently localized in the TM, CB, and ciliary muscle (CM). CACNA2D1 was observed in a punctate pattern throughout the TM and Schlemm's canal. In the CB, CACNA2D1 was highly expressed in the non-pigmented epithelium. Weak labeling was present in the CM (Figure 2).

[0066] We have shown that CACNA2D1 is expressed in both CB and TM. CACNA2D1 is also sparingly present in CM. Based on these collected data, CACNA2D1 appears to regulate IOP (Figure 3). Pregabalin, or other gabapentinoid drugs, bind to the CACNA2D1 subunit of calcium channels. The binding of the drug reduces calcium flux through the α1 pore of the calcium channel, reducing the level of intracellular calcium. Since Cacna2d1 modulates IOP, pregabalin, a gabapentinoid drug with high specificity for CACNA2D1, was evaluated for its ability to affect IOP. Pregabalin ophthalmic drops [pregabalin suspended in hydroxypropyl methylcellulose (HPMC)] dose-dependently reduce IOP in mice from 0.3 to 1.2% (Figure 4). Drops containing 0.3% drug did not produce an IOP-lowering effect compared to controls. All other concentrations of the drug reduced IOP in a dose-dependent manner. A plateau was reached at 0.9%, and there was no significant difference in drug response between 0.9% and 1.2% drug (P>0.05). The time to maximum response (T max ) values ​​were not significantly different (P>0.05). In contrast, the time required for IOP to return to baseline (T end) (P<0.0001). 1.2% pregabalin eye drops extended the duration of the IOP-lowering effect of pregabalin beyond that obtained with 0.6% pregabalin. Because there was no significant difference in the percent reduction in IOP between 0.9% and 1.2% pregabalin, 0.9% was selected as the minimum concentration required to produce a maximum reduction in IOP. When extending this analysis to additional species, we observed a similar IOP-lowering response (22.1±2.8%) in Dutch Belted rabbits following instillation of 0.9% pregabalin eye drops (FIG. 5).

[0067] Sustained-release pregabalin microemulsion formulation as a novel glaucoma therapy Primary open angle glaucoma (POAG) accounts for 90% of glaucoma cases worldwide. It is the leading cause of irreversible blindness. Elevated intraocular pressure (IOP) is the most important risk factor contributing to visual field loss in POAG. IOP is brought about by the balance between aqueous humor production and drainage. Due to the importance of a well-maintained IOP, its reduction is the first-line treatment for glaucoma. Despite the prevalence of glaucoma and its impact on society, current pharmaceuticals do not address the underlying pathophysiology that causes IOP elevation, nor do they address genetic variants associated with IOP modulation. Furthermore, due to its short half-life and short corneal residence time, it requires multiple daily topical applications, which is associated with poor patient compliance. The inventors have developed a novel sustained-release topical bioadhesive microemulsion (ME) formulation for delivery of pregabalin, an exemplary IOP-lowering drug, that would allow for once-daily administration and better patient compliance.

[0068] Formulation of bioadhesive multilayered MEs loaded with pregabalin The formulation of bioadhesive multilayered ME hydrogels was achieved in three steps. The first step involved the formation of a primary water-in-oil (w / o) ME by construction of a distinct ternary phase diagram. The second step involved further emulsification of the generated primary w / o ME into an aqueous hydrophilic surfactant solution (i.e., a surfactant with a high value of hydrophilic lipophilic balance (HLB)). The final step involved the incorporation of a bioadhesive polymer.

[0069] Construction of three-phase diagram and preparation of primary w / o ME Primary w / o MEs usually consist of an oil phase, an aqueous phase, and a single surfactant or a surfactant mixture. To determine the appropriate ratio of each component that can efficiently generate MEs, several three-phase and pseudo-three-phase diagrams were constructed using Labrafac lipophile WL 1349 as the oil phase, deionized water as the aqueous phase, and single surfactants (for three-phase diagrams) or surfactant mixtures (for pseudo-three-phase diagrams) from the following surfactants: capryol 90; labrasol, cremophor EL; transcutol P; geluccire 50 / 13; geluccire 44 / 14; geluccire 43 / 01; or soy lecithin.

[0070] The water titration method was used to generate the three-phase diagrams (Figures 6-14). In this method, oil was mixed with a surfactant or surfactant mixture in various ratios. The resulting mixture was then titrated with deionized water until the first turbidity appeared, reflecting the boundary point that distinguishes the end of the w / o ME region and the beginning of the microemulsion region. In Figures 16-14, the w / o ME region is filled in black, illustrating all possible combinations of the three components that can form an ME. By selecting any point in that region, one can determine the percentage of the three components that can be readily mixed to form a w / o ME.

[0071] Preparation of multilayer w / o / w ME Several triphasic diagrams were constructed. The diagram depicted in Figure 12 was chosen because it has the largest ME area. One point from this diagram (although other points would have worked as well) was selected and used for the formulation of a multi-layered water-in-oil-in-water (w / o / w) ME. All triphasic diagrams were constructed using percentage ratios of each component (water, surfactant / surfactant mixture and oil) from 0 to 100%. The w / o ME selected consisted of 20% water + 30% oil (labrafac lipophile WL 1349) + 50% surfactant mixture (capryol 90 and soy lecithin, 1:1). The selection of this point was based on obtaining a stable w / o primary emulsion with the highest possible amount of water in its internal phase that could dissolve the drug at the required dose. The drug concentration selected is 0.6%. To prepare the final multi-layered w / o / w ME, titration method was used to screen several surfactants with high HLB to determine which would perform well in the formulation of multi-layered w / o / w ME. The surfactants tested were cremophor EL, labrasol, tween 80, poloxamer 188, and brij 97. These surfactants can be used alone or in combination with each other or with other co-solvents such as polyethylene glycol, propylene glycol, or glycerin. Aqueous solutions of different concentrations of these surfactants were prepared. The previously selected w / o was added dropwise to these solutions under continuous stirring until the first turbidity appeared, indicating the end of ME formation and the beginning of microemulsion formation. Among these surfactants, labrasol was not used at a concentration higher than 10% as it may be irritating to rabbit eyes. Labrasol was used in combination with other surfactants (10% labrasol + 10% cremophor EL + 30% propylene glycol). Using this combination, the amount of w / o ME incorporated was 3.7 gm. Selected surfactant systems are highlighted in Table 1.

[0072] Table 1. Different surfactant systems evaluated TIFF2025029225000001.tif90150

[0073] Formulation of the final bioadhesive multilayered ME hydrogel The external aqueous phase was prepared by dissolving 10% labrasol, 10% cremophor EL, and 30% propylene glycol in distilled water. Bioadhesive polymers (CARBOPOL® 981, sodium alginate, or chitosan) were immersed in the previously prepared surfactant solution and allowed to swell overnight. The previously prepared primary drug load w / o was incorporated dropwise into this viscous polymer solution until the final transparent multilayered w / o / w ME hydrogel (Figure 15) was obtained. Table 2 lists the chemical composition of the three ME formulations tested.

[0074] Table 2. Composition of pregabalin-loaded ME TIFF2025029225000002.tif61153

[0075] Characterization of the prepared multilayered pregabalin ME hydrogels In vitro characterization In vitro characterization of pregabalin ME hydrogel included: drug release studies, cytotoxicity studies, viscosity measurements, mucoadhesion studies, and particle size and zeta potential measurements.

[0076] Drug Release Studies The sustained release behavior of pregabalin from different formulations was studied in PBS (pH 7.4) using a 1500 μl fast micro-equilibrium dialyzer (Harvard Apparatus Co., Holliston, MA) with a semipermeable regenerated cellulose membrane (molecular weight cut-off 5,000 Da). The dialyzer was kept in a thermostatically controlled shaker at 35° C. and 50 rpm. Samples were taken at predetermined time intervals over a period of 24 hours and analyzed by HPLC for their drug content. The formulations tested were CARBOPOL 0.6% pregabalin, (登録証)The four control formulations, containing alginate, chitosan, and water, as well as CARBOPOL® ME, alginate ME, and chitosan ME, containing 0.6% pregabalin. The release profiles (Figure 16) show that all control formulations exhibited rapid release behavior releasing 100% of the drug content within 3-8 hours. On the other hand, the tested MEs exhibited sustained release behavior lasting up to 24 hours.

[0077] Cytotoxicity research The in vitro cytotoxicity of the ophthalmic formulations was tested using the MTT assay method according to a known protocol. Briefly, immortalized human limbal epithelial cells (HCLE) were seeded in 96-well plates (18,000 cells / well) with 200 μl of growth medium and maintained overnight at (37° C. and 5% CO2) without disturbance to allow them to attach to the bottom of the well. The next day, the medium was removed and replaced with 200 μl of the formulation solution in growth medium. The formulation was kept in constant contact with the cells for 24 hours and then replaced with 200 μl of (1 mg / ml) MTT solution. The plate was maintained at (37° C. and 5% CO2) for 4 hours to allow the cells to reduce MTT to purple formazan crystals. After 4 hours, the MTT solution was replaced with 200 μl of DMSO to dissolve the formazan crystals. The UV absorbance of the plate was measured at 570 nm using a microplate reader spectrophotometer. The cell viability for the tested formulations was calculated as a percentage of the absorbance of the negative control (untreated cells) using their absorbance values ​​according to the following formula: Calculations were made according to TIFF2025029225000003.tif9128.

[0078] Figure 17 shows that the formulations are safe and non-toxic to corneal epithelial cells at therapeutic doses. The experiment was repeated eight times for each formulation and the results were calculated as the mean ± SEM.

[0079] viscosity research The viscosity of the formulations was measured using a Brookfield cone-and-plate rotational viscometer according to a previously published protocol. Five hundred microliters of each formulation was placed between the cone and plate and allowed to equilibrate for one minute to the operating temperature. Measurements were performed at 35°C ± 0.5. Experiments were repeated three times and results were calculated as the mean ± SEM. Figure 18 shows that the formulations containing CARBOPOL® had the highest viscosity values, which allowed the formulation to remain inside the eye for a longer period of time. This improved corneal contact time is believed to prolong the IOP-lowering effect and promote sustained release of the drug.

[0080] Mucoadhesion studies Previously published methods (Gallo EEHaJM 1990. A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharmaceutical research 7(5):491-495; Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, La Rotonda MI 2008. A novel poloxamers / hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm 70(1):199-206;Tayel SA, El-Nabarawi MA, Tadros MI, Abd-Elsalam WH 2013. Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits. Int J Pharm 443(1-2):293-305) was used to evaluate the mucoadhesiveness of the formulations. Briefly, pre-heated formulations (35° C.) were mixed with a 15% dispersion of gastric mucin (35° C.) in a 1:1 ratio. The viscosity of the formulations, mucin, and their mixtures was measured using a Brookfield cone-and-plate rotational viscometer at 35° C. The following equation: The change in viscosity of the mixture was converted to bioadhesion force using TIFF2025029225000004.tif16159.

[0081] The experiment was repeated three times and the results were calculated as the mean ± SEM. Figure 19 shows that the highest bioadhesion was present in the formulations containing chitosan, which may be due to their positive charge increasing their reaction with negatively charged mucins, thereby improving their mucoadhesion.

[0082] Particle size, polydispersity index (PDI) and zeta potential measurements After appropriate sample dilution (1:100 for particle size and PDI, and 1:1000 for zeta potential), the particle size, PDI, and zeta potential of the formulations were measured using a Zetasizer Nano ZS. The Zetasizer data for ME are listed in Table 3 as the mean ± SEM of at least three readings. The particle size data shows that all formulations had extremely small particle sizes (<20 nm) with a very narrow particle size distribution. In one aspect of the present invention, this extremely small particle size is useful for topical ophthalmic formulations because it does not cause a gritty sensation that can bother patients and affect their compliance to use the medicine, and the extremely small particle size can improve drug penetration through the cornea by passive diffusion. The charge of the zeta potential was different depending on the polymer used, which was positive for chitosan and negative for both CARBOPOL® ME and alginate ME.

[0083] Table 3. Particle size, PDI, and zeta potential of different MEs TIFF2025029225000005.tif30156

[0084] Ex vivo characterization or corneal permeability studies For corneal drug permeability studies on the different formulations, a modified Franz diffusion cell was used. The modified Franz diffusion cell consists of two vertically connected chambers (donor and receptor chambers) that are joined to each other via a spherical junction suitable for a spherical tissue (i.e., the cornea). The donor chamber had a volume of 0.5 ml and the receptor chamber had a volume of 5 ml. The receptor chamber was stirred at 50 rpm with a magnetic stirrer to allow continuous mixing of the chamber contents. The opening of the junction between the two chambers was 9 mm in diameter, where the corneal tissue was fixed and the drug was allowed to diffuse. One hundred microliters of each formulation was placed in the donor chamber. The receptor chamber was filled with 5 ml of BSS-Plus (balanced salt solution-plus) and the whole cell was surrounded by a hot water jacket to keep the temperature at 35°C. Every hour for a total period of 6 hours, a 0.5 ml sample was taken from the receptor chamber and replaced with fresh BSS-Plus kept at 35°C. The collected samples were assayed for their drug content using standard HPLC protocols. The experiment was repeated six times and the results were calculated as the mean ± SEM. The cumulative amount permeated through the cornea over 6 hours for each formulation was plotted and the data is shown in Figure 20. Pregabalin is a BCS Class I drug, which means that it is a highly permeable and highly soluble drug. Figure 20 and Table 4 show that the formulations without ME (pregabalin / water and pregabalin / CARBOPOL®) had higher permeation rates than the formulations with ME. This is due to the drug's natural ability to permeate through the cornea quickly, which given by itself does not allow for sustained release of the drug over time. All formulations containing ME had lower permeation rates than pregabalin alone. By using any formulation containing ME and the drug, sustained release is possible. Comparing the ME formulations, it was found that the formulation containing CARBOPOL® had the lowest permeation rate among all the formulations tested. This experiment confirmed the in vitro release data that ME is capable of sustaining pregabalin release for once-daily application.

[0085] Table 4. In vitro transcorneal permeability parameters of pregabalin ME and control TIFF2025029225000006.tif33152

[0086] In vivo characterization or IOP lowering studies in Dutch Belted rabbits Safety of the formulation The safety of ME formulations was tested by incorporating 100 μl of each formulation into the inferior conjunctival sac of the right eye of Dutch Belted rabbits (n=3), while the left eye served as a control. Eyes were examined hourly for any signs of irritation, such as redness, tearing, conjunctival swelling, or corneal swelling. At the end of the experiment, slit lamp examination was performed on all rabbit eyes. Figure 21 is an exemplary photograph of a slit lamp examination after application of the ME formulation. The figure shows that no signs of irritation were detected: the cornea was clear and not swollen, the lens was clear, and the aqueous humor was clear without cells or redness.

[0087] Formulation efficacy A single dose response design was used to determine the IOP lowering efficacy of the formulations. Dutch Belted (DB) rabbits (n=3) were used in the study, and during the study, each rabbit received 100 μl of the drug-loaded formulation into the inferior conjunctival sac of the right eye, while the left eye served as a control by receiving 100 μl of blank formulation. Intraocular pressure (IOP) was measured using a Tonoopen (Tono-pen AVIA Vet, Reichert) immediately prior to application of the formulation (baseline) and at predefined time intervals until it returned to its baseline value.

[0088] Figure 22 shows the IOP profile in DB rabbits following application of CARBOPOL® ME formulations containing different concentrations of pregabalin (0.1-0.7%). Up to 0.6%, there was a dose-dependent increase in the IOP-lowering efficacy of the formulation. There was no significant difference between 0.6% and 0.7% pregabalin. Therefore, 0.6% pregabalin was selected as the minimum dose giving the maximal response.

[0089] To identify the formulation that provides the greatest IOP-lowering efficacy, a single dose response design study was conducted using Dutch Belted rabbits by varying the external aqueous phase of ME. Table 5 lists the pharmacodynamic parameters calculated based on the IOP profile, and Table 6 provides a statistical comparison. Based on the results, CARBOPOL® ME provides good IOP reduction and sustained effect.

[0090] Table 5. Pharmacodynamic parameters after application of 0.6% pregabalin in different MEs in different formulations to Dutch Belted rabbits. TIFF2025029225000007.tif36139

[0091] Table 6. Statistical comparison between different pregabalin ME eye drops and control after single dose application. TIFF2025029225000008.tif37154

[0092] FIG. 23 shows a comparison of both CARBOPOL® formulations (gel and ME), demonstrating that ME significantly extends the duration of drug effect. Evaluation of the formulations was accomplished by comparing their pharmacodynamic (PD) parameters, which included the percentage of maximal reduction in IOP (%I max ), the time to maximum IOP reduction (T max ), the time required for the IOP to return to its baseline value (T end ), and area under the IOP-time curve (AUC).

[0093] Tachyphylaxis Study of Pregabalin CARBOPOL® ME To determine whether pregabalin CARBOPOL® ME could keep IOP at reduced levels after multiple dosing, a tachyphylaxis study was conducted for 21 days. One drop of pregabalin-loaded ME formulation was instilled into the right eye of Dutch Belted rabbits and blank ME was instilled into the left eye at 8 am every day for 3 weeks. IOP was measured every 1-2 hours on days 1 and 21, but twice per day on all other days. Figure 24 shows that IOP in drugged eyes was significantly higher than that in the control eyes on day 1 compared to day 21. max The results demonstrate a 30.7% reduction in IOP at 24 hours after receiving the first dose. IOP began to return toward baseline IOP, but was still reduced by 20.5% by 24 hours after receiving the first dose (Figure 25). After receiving the second dose of the ME formulation, IOP remained in the normal physiological range between 12-13 mmHg throughout the duration of the study (Figures 24 and 26).

[0094] Potency of other gabapentinoid drugs To determine whether other members of the gabapentinoid drug family are also effective in reducing IOP, the efficacy of 0.9% pregabalin, 0.9% 2-phenylglycine, and 0.9% gabapentin in 2% HPMC viscous eye drops was compared in C57Bl / 6J mice.

[0095] Pregabalin in viscous eye drops provided a maximum IOP reduction of 17.3% with an area under the curve of 65% time, returning to baseline by 6 hours (Figure 27). 2-Phenylglycine (Figure 28) and gabapentin (Figure 29) were less potent than pregabalin, but they both had a maximum IOP reduction of about 8% and an area under the curve of about 14% time. These data demonstrate that both 2-phenylglycine and gabapentin, although not as effective at reducing IOP as pregabalin, are capable of inducing an IOP-lowering response.

[0096] A non-inferiority study of pregabalin CARBOPOL® ME To determine how our pregabalin ME formulation compares to the market leader IOP lowering drug, Lumigan 0.01% was evaluated in our same Dutch Belted rabbit formulation. In humans, Lumigan is administered prior to bedtime. We evaluated administration at 9am and 9pm. There was no difference in IOP treated with Lumigan or vehicle in rabbits dosed at both 9am (Figure 30) and 9pm (Figure 31). The time of administration did not affect the lack of IOP lowering response. Thus, our pregabalin ME is non-inferior to the market leader IOP lowering drops.

[0097] Evaluation of ME compatibility with other water-soluble drugs To determine whether our pregabalin CARBOPOL® ME is compatible with other water-soluble drugs, we used the same method to synthesize and characterize ribavirin-loaded CARBOPOL® ME. Ribavirin is an antiviral drug used to treat respiratory syncytial virus infections, hepatitis C, and viral hemorrhagic fevers. It can also be used to treat viral infections of the eye, such as herpes simplex keratitis, a disease of the corneal epithelium. Ribavirin is a synthetic nucleoside analog. Its chemical name is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and its empirical formula is CH 12 It is N4O5 and has a molecular weight of 244.21. Ribavirin is a white crystalline powder. It is freely soluble in water, just like pregabalin.

[0098] Drug release studies of ribavirin Using the same method detailed above for pregabalin, the sustained release behavior of ribavirin from the different formulations was studied. The release profiles (Figure 32) demonstrate that all control formulations exhibited rapid release behavior releasing 100% of the drug content within 3-4 hours. In contrast, the tested MEs exhibited sustained release behavior lasting up to 24 hours.

[0099] Cytotoxicity study of ribavirin ME formulation The formulations were tested for in vitro cytotoxicity by MTT assay method using the same method detailed above for pregabalin. Figure 33 shows that the formulations are safe and non-toxic to corneal epithelial cells at therapeutic doses. The experiment was repeated 8 times for each formulation, and the results were calculated as mean ± SEM.

[0100] Viscosity study of ribavirin ME formulations. The viscosity of the formulations was measured using the same method detailed above for pregabalin, and Figure 34 shows that the formulation containing CARBOPOL® had the highest viscosity, which allowed the formulation to remain inside the eye for a longer period of time.

[0101] Mucoadhesion study of ribavirin ME formulation The mucoadhesiveness of the formulations was evaluated using the same method detailed above for pregabalin. Experiments were repeated three times and results were calculated as the mean ± SEM. Figure 35 shows that the highest bioadhesion was present in the formulations containing CARBOPOL®.

[0102] Particle size, polydispersity index (PDI), and zeta potential measurements of ribavirin ME formulations The particle size, PDI, and zeta potential of the ribavirin formulations were measured using the same methods detailed above for pregabalin. The Zetasizer data for ME are listed in Table 7 as the mean ± SEM of at least three readings. The particle size data shows that all formulations had extremely small particle sizes (<20 nm) with very narrow particle size distributions.

[0103] Table 7. Particle size, PDI, and zeta potential of MEs containing ribavirin TIFF2025029225000009.tif20159

[0104] Ex vivo characterization or corneal permeability studies of ribavirin ME formulations Using the same method detailed above for pregabalin, ribavirin-containing formulations were characterized.For each formulation, the cumulative amount permeated through the cornea over 6 hours was plotted, and the data is shown in Figure 36 and Table 8.Ribavirin is a BCS Class III drug, which means that it is a drug that is not highly permeable, but is highly soluble.Figure 36 shows that the ME formulation increased the permeation rate more than ribavirin alone.

[0105] Table 8. In vitro transcorneal permeability parameters of pregabalin ME and control TIFF2025029225000010.tif33152

[0106] Finally, although aspects of the present specification are emphasized by reference to certain embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocols, and / or reagents, etc., described herein. Thus, various modifications or changes to the disclosed subject matter, or alternative configurations of the disclosed subject matter, can be made in accordance with the teachings herein without departing from the spirit of the present specification. Finally, the terminology used herein is intended to describe only certain embodiments and is not intended to limit the scope of the present invention, which is defined solely by the claims. Thus, the present invention is not limited to what has been precisely shown and described.

[0107] Certain aspects of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described aspects will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to employ such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described aspects in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0108] The grouping of alternative aspects, elements, or steps of the invention should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification includes the modified group and is therefore deemed to satisfy the description of all Markush groups used in the appended claims.

[0109] Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, properties, terms, etc. used in the specification and claims should be understood to be modified in all cases by the term "about". Thus, unless otherwise indicated, the numerical parameters set forth in this specification and the appended claims are approximate values ​​that may vary. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be interpreted in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand notation for individually referring to each separate numerical value falling within the range. Unless otherwise indicated, each individual value of the numerical range is incorporated herein as if it were individually recited herein.

[0110] The terms "a," "an," "the," and similar references used in the context of describing the present invention (particularly in the context of the appended claims) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the invention and does not pose a limitation on the scope of the invention unless specifically claimed. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0111] Certain embodiments disclosed herein may be further limited in the claims using the recitations "consisting of" or "consisting essentially of." When used in the claims, whether originally filed or added by amendment, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to those materials or steps specified and which do not materially affect the basic and novel characteristics. Aspects of the invention so claimed are essentially or explicitly described and enabled herein.

[0112] All patents, patent publications, and other publications referenced or identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. Any statement as to the date or statement as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the accuracy of the dates or contents of these documents.

Claims

1. (a) a discontinuous internal phase comprising an aqueous solution contained within an internal emulsifier; (b) a continuous oil phase which encompasses the internal phase; and (c) an external emulsifier that encapsulates the oil phase A microemulsion (ME) comprising:

2. (d) an aqueous phase surrounding the external emulsifier; The ME of claim 1, further comprising:

3. The internal emulsifier may be propylene glycol monocaprylate or any other surfactant with an HLB value of 3 to 7, and / or any propylene glycol ester of a fatty acid, such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol monopalmitate, polyethylene glycol lauryl ether, polyethylene glycol oleyl ether, polyethylene glycol hexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, transcutol P, gelucire 50 / 13, gelucire 44 / 14, gelucire 43 / 01, any PEG mono-, di- and / or triester of any fatty acid, lecithin, egg lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, tocopherol, or any other phospholipid, and combinations thereof.

4. 3. The ME of claim 1 or 2, wherein the internal emulsifier is selected from the group consisting of capryol 90, lecithin, and combinations thereof.

5. The ME of any one of claims 1 to 4, wherein the aqueous solution is selected from the group consisting of deionized water, saline, phosphate buffered saline, artificial tears, and balanced salt solutions.

6. The oil phase contains caprylic acid (C 8 ) and capric acid (C 10 6. The ME of any one of claims 1 to 5, wherein the ME is selected from the group consisting of medium chain triglycerides of glyceryl ...

7. The ME according to any one of claims 1 to 5, wherein the oil phase comprises labrafac lipophile WL 1349.

8. The ME of any one of claims 1 to 7, wherein the external emulsifier is selected from the group consisting of caprylocaproyl polyoxyl-8 glyceride, macrogol glycerol ricinoleate, any other hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 to 16, polyethylene glycol mono- and / or diester of any fatty acid or mixture of fatty acids, propylene glycol, or any other alcohol including but not limited to glycerol, polyethylene glycol, ethanol, propanol, and isopropanol, and combinations thereof.

9. The ME of any one of claims 1 to 8, wherein the external emulsifier comprises caprylocaproyl polyoxyl-8 glyceride, macrogolglycerol ricinoleate, propylene glycol, or a combination thereof.

10. 10. The ME according to any one of claims 1 to 9, comprising 0.5 to 35% w / w of an aqueous solution, 0.5 to 95% w / w of an oil phase, and 5 to 99% w / w of an emulsifier.

11. 10. The ME according to any one of claims 1 to 9, comprising 10-30% w / w of an aqueous solution, 20-40% w / w of an oil phase, and 40-60% w / w of an emulsifier.

12. The ME of any one of claims 1 to 11, wherein the aqueous solution comprises a water-soluble drug.

13. The water-soluble drug may be selected from the group consisting of beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium channel blockers, such as nimodipine and pregabalin; asialogalactosylated triantennary ( NA3) (also known as asialo-triantennary complex type N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, valvo ... vir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocromil, phenylephrine, azelastine, epinastine, 13. The ME of claim 12, selected from the group consisting of naphazoline / pheniramine, olopatadine, bepotastine, alcaftadine, pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, combinations thereof, or pharmaceutically acceptable salts thereof.

14. 13. The ME of claim 12, wherein the water-soluble drug is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or a pharma- ceutically acceptable salt thereof.

15. The ME of any one of claims 1 to 14, wherein the aqueous phase comprises a hydrogel.

16. The ME of claim 15, wherein the hydrogel comprises a mucoadhesive polymer.

17. The ME of claim 16, wherein the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL®, e.g., CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, dextran and its derivatives, pectin and its derivatives, gelatin and its derivatives, polyvinylpyrrolidone and its derivatives, N-methylpyrrolidone and its derivatives, hyaluronate and its derivatives, gellan gum and its derivatives, xanthan gum and its derivatives, agar and its derivatives, glycocholic acid and its salts or derivatives, or combinations thereof.

18. The ME of claim 16, wherein the mucoadhesive polymer is selected from the group consisting of polyacrylic acid derivatives (including but not limited to CARBOPOL®, e.g., CARBOPOL® 981), alginic acid and its salts or derivatives (including but not limited to sodium alginate), chitosan and its derivatives, or combinations thereof.

19. The ME of any one of claims 1 to 18, which is present as globules having a diameter of about 1 nm to about 200 nm.

20. The ME according to any one of claims 1 to 19, formulated as a topical formulation.

21. A method for treating an eye disease comprising administering to a subject having an eye disease an ME according to any one of claims 1 to 20 in an amount effective to treat the eye disease, wherein the aqueous solution comprises a water-soluble drug capable of treating the eye disease.

22. 21. A method for reducing intraocular pressure (IOP), treating glaucoma, treating age-related macular degeneration (AMD), treating uveitis, and / or treating conjunctivitis, comprising administering to a subject having intraocular pressure, glaucoma, AMD, uveitis, and / or conjunctivitis an effective amount of ME of any one of claims 1-20 to reduce intraocular pressure, treat glaucoma, treat AMD, treat uveitis, and / or treat conjunctivitis, wherein the aqueous solution comprises a water soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treat uveitis, and / or treat conjunctivitis.

23. The water-soluble drugs capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis include beta-blockers, such as betaxolol and timolol; prostaglandin analogs, such as bimatoprost, latanoprost, and travoprost; alpha-adrenergic agonists, such as brimonidine tartrate; carbonic anhydrase inhibitors, such as brinzolamide, dorzolamide, and acetazolamide; calcium carbonate; N-blockers such as nimodipine and pregabalin; asialogalactosylated triantennary (NA3) (also known as asialo-triantennary complex N-glycans), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, barazone, Ciclovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, foscarnet, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac, ketorolac, nepafenac, lifitegrast, flurbiprofen, diclofenac, ketotifen, nedocromil, phenylephrine, Azera 23. The method of claim 21 or 22, wherein the medicament is selected from the group consisting of morphine, epinastine, naphazoline / pheniramine, olopatadine, bepotastine, alcaftadine, pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, combinations thereof, or pharmaceutically acceptable salts thereof.

24. 23. The method of claim 21 or 22, wherein the water-soluble drug capable of reducing IOP, treating glaucoma, treating AMD, treating uveitis, and / or treating conjunctivitis is selected from the group consisting of phenylglycine, gabapentin, pregabalin, and ribavirin, or pharma- ceutically acceptable salts thereof.

25. The method of any one of claims 21 to 24, wherein the ME is administered to one or both eyes of the subject.

26. The method of any one of claims 21 to 24, wherein said administration occurs once per day.

27. (a) a discontinuous (dispersed) oil phase; and (b) an emulsifier that encapsulates the oil phase A microemulsion (ME) comprising:

28. (c) a continuous aqueous phase surrounding the emulsifier.

28. The ME of claim 27, further comprising:

29. 29. The ME of claim 27 or 28, further comprising an insoluble or slightly soluble drug in the discontinuous oil phase.

30. A method for treating glaucoma, comprising administering to a subject having glaucoma an inhibitor of calcium voltage-dependent channel auxiliary subunit alpha 2 delta 1 (CACNA2d1) protein in an amount effective to treat glaucoma.

31. 30. The method of claim 29, wherein the glaucoma is primary open angle glaucoma (POAG).

32. A method for reducing intraocular pressure comprising administering to a subject in need thereof an inhibitor of CACNA2d1 protein in an amount effective to treat or reduce intraocular pressure.

33. 33. The method of any one of claims 30-32, wherein the inhibitor comprises a gabapentinoid, phenylglycine, or a pharma- ceutically acceptable salt thereof.

34. 34. The method of claim 33, wherein the gabapentinoid comprises gabapentin, pregabalin, or a pharma- ceutically acceptable salt thereof.

35. The method of any one of claims 30 to 34, wherein the inhibitor is administered locally.

36. The method of any one of claims 30 to 35, wherein the inhibitor is administered via eye drops.

37. Formulations containing: (a)(i) water at a concentration of 0% to about 7% w / w of the formulation; (ii) oil at a concentration of about 6% to about 13% w / w of the formulation; (iii) capryol 90 at a concentration of about 1% to about 13% w / w of the formulation; and (iv) lecithin, in a concentration of about 1% to about 13% w / w of the formulation; a primary water-in-oil (w / o) phase constituting from about 0.1% to about 40% of the formulation, comprising: (b)(i) labrasol in a concentration of about 0.1% to about 25% w / w of the formulation; (ii) cremophor EL, at a concentration of about 0.1% to about 25% w / w of the formulation; (iii) propylene glycol, at a concentration of 0% to about 45% w / w of the formulation; and (iv) water at a concentration of about 10% to about 99.7% w / w of the formulation; an external aqueous phase comprising 50-99.9% of the formulation,

38. Formulations containing: (a)(i) water at a concentration of 2% to about 7% w / w of the formulation; (ii) oil at a concentration of about 6% to about 9% w / w of the formulation; (iii) Capryol 90, at a concentration of about 3% to about 9% w / w of the formulation; and (iv) lecithin, at a concentration of about 3% to about 9% w / w of the formulation. a primary water-in-oil (w / o) phase constituting from about 0.1% to about 40% of the formulation, comprising: (b)(i) labrasol in a concentration of about 5% to about 9.5% w / w of the formulation; (ii) Cremophor EL, at a concentration of about 5% to about 9.5% w / w of the formulation; (iii) propylene glycol at a concentration of 5% to about 25% w / w of the formulation; and (iv) water at a concentration of about 30% to about 56% w / w of the formulation an external aqueous phase comprising 50-99.9% of the formulation,

39. 39. A method of treating an eye disease, wherein a subject is administered the formulation of claim 37 or 38.

40. 40. The method of claim 39, wherein the eye disease is IOP, glaucoma, AMD, uveitis, and / or conjunctivitis.

41. The method of any one of claims 39 to 40, wherein the formulation is administered to the eye of the patient.

42. The method of any one of claims 39 to 41, wherein the formulation is administered to the patient once daily.

43. 42. The method of any one of claims 39-41, wherein the formulation is administered to the patient two or more times per day.

44. 44. The method of any one of claims 21-26, 30-36, or 40-43, wherein the formulation reduces IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

45. The formulation is characterized in that it reduces IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 70% to about 90%, about 80% to about 100%, about 90% to about 100%, about 1 ...

44. The method of any one of claims 21-26, 30-36, or 40-43, wherein the method reduces the expression level by 0%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

46. The method of any one of claims 39 to 45, wherein the formulation comprises a water-soluble drug.

47. 47. The method of claim 46, wherein the formulation comprises one or more of pregabalin, phenylglycine, gabapentin, or ribavirin.

48. 47. The method of claim 46, wherein the formulation comprises pregabalin.

49. 49. The method of any one of claims 21-26, 30-36, or 39-48, wherein the ME or formulation comprises at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w of water soluble drug.

50. The ME or formulation may be from about 0.3% w / w to about 1.2% w / w, from about 0.3% w / w to about 1.1% w / w, from about 0.3% w / w to about 1.0% w / w, from about 0.3% w / w to about 0.9% w / w, from about 0.3% w / w to about 0.8% w / w, from about 0.4% w / w to about 1% w / w, from about 0.4% w / w to about 0.9% w / w, from about 0.4% w / w to about 0.8 ...

49. The method of any one of claims 21-26, 30-36, or 39-48, comprising about 0.7% w / w, about 0.5% w / w to about 1.0% w / w, about 0.5% w / w to about 0.9% w / w, about 0.5% w / w to about 0.8% w / w, about 0.5% w / w to about 0.7% w / w, about 0.55% w / w to about 0.8% w / w, or about 0.55% w / w to about 0.7% w / w of water soluble drug.

51. 51. The method of any one of claims 21-26, 30-36, or 46-50, wherein the concentration of the water soluble drug is at least 0.3% w / w, at least 0.4% w / w, 0.5% w / w, at least 0.6% w / w, at least 0.7% w / w, at least 0.8% w / w, at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w of the ME or formulation.

52. 51. The method of any one of claims 21-26, 30-36, or 46-50, wherein the concentration of the water-soluble drug in the final ME or formulation is at most 0.3% w / w, at most 0.4% w / w, at most 0.5% w / w, at most 0.6% w / w, at most 0.7% w / w, at most 0.8% w / w, at most 0.9% w / w, at most 1.0% w / w, at most 1.1% w / w, or at most 1.2% w / w.

53. The concentration of the water-soluble drug is from about 0.3% w / w to about 1.2% w / w, from about 0.3% w / w to about 1.1% w / w, from about 0.3% w / w to about 1.0% w / w, from about 0.3% w / w to about 0.9% w / w, from about 0.3% w / w to about 0.8% w / w, from about 0.4% w / w to about 1% w / w, from about 0.4% w / w to about 0.9% w / w, from about 0.4% w / w to about 0.8% w / w, from about 0.

51. The method of any one of claims 21-26, 30-36, or 46-50, wherein the concentration is between 4% w / w and about 0.7% w / w, between about 0.5% w / w and about 1.0% w / w, between about 0.5% w / w and about 0.9% w / w, between about 0.5% w / w and about 0.8% w / w, between about 0.5% w / w and about 0.7% w / w, between about 0.55% w / w and about 0.8% w / w, or between about 0.55% w / w and about 0.7% w / w.

54. 54. The method of any one of claims 21-26, 30-36, or 39-53, wherein the ME or formulation comprises a water soluble drug that reduces symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

55. 54. The method of any one of claims 21-26, 30-36, or 39-53, wherein the ME or formulation comprises a water soluble drug that reduces symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%.

56. The ME or formulation reduces symptoms of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 10 ...

54. The method of any one of claims 21-26, 30-36, or 39-53, comprising reducing water soluble drug by about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

57. 57. The method of any one of claims 21-26, 30-36, or 39-56, wherein the ME or formulation comprises a therapeutically effective amount of a water-soluble drug in the range of about 0.3% / day to about 1.2% / day.

58. 57. The method of any one of claims 21-26, 30-36, or 39-56, wherein the ME or formulation comprises a therapeutically effective amount of water soluble drug in the range of at least 0.3% w / w / day, at least 0.4% w / w / day, at least 0.5% w / w / day, at least 0.6% w / w / day, at least 0.7% w / w / day, at least 0.8% w / w / day, at least 0.9% w / w / day, at least 1.0% w / w / day, at least 1.1% w / w / day, or at least 1.2% w / w / day.

59. The ME or formulation may be administered in an amount of from about 0.3% w / w / day to about 1.2% w / w / day, from about 0.3% w / w / day to about 1.1% w / w / day, from about 0.3% w / w / day to about 1.0% w / w / day, from about 0.3% w / w / day to about 0.9% w / w / day, from about 0.3% w / w / day to about 0.8% w / w / day, from about 0.4 ... / w / day to about 1.2% w / w / day, about 0.4% w / w / day to about 1.1% w / w / day, about 0.4% w / w / day to about 1.0% w / w / day, about 0.4% w / w / day to about 0.9% w / w / day, about 0.4% w / w / day to about 0.8% w / w / day, about 0.5% w / w / day to about 1.2% w / w / day, about 0 57. The method of any one of claims 21-26, 30-36, or 39-56, comprising a therapeutically effective amount of water soluble drug in the range of about 0.5% w / w / day to about 1.1% w / w / day, about 0.5% w / w / day to about 1.0% w / w / day, about 0.5% w / w / day to about 0.9% w / w / day, about 0.5% w / w / day to about 0.8% w / w / day, about 0.55% w / w / day to about 1.2% w / w / day, about 0.55% w / w / day to about 1.1% w / w / day, about 0.55% w / w / day to about 1.0% w / w / day, about 0.55% w / w / day to about 0.9% w / w / day, about 0.55% w / w / day to about 0.8% w / w / day.

60. 60. The method of any one of claims 21-26, 30-36, or 39-59, wherein said ME or formulation is administered as a single dose or is administered continuously.

61. The method of any one of claims 21-26, 30-36, or 39-60, wherein the ME or formulation is administered to the patient once a day, twice a day, three times a day, once every few days, or once a week.

62. 62. The method of any one of claims 21-26, 30-36, or 39-61, wherein the ME or formulation is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more for the treatment of IOP, glaucoma, AMD, uveitis, and / or conjunctivitis.

63. The method of any one of claims 21-26, 30-36, or 39-62, wherein the therapeutically effective amount of the water soluble drug reduces internal pressure within the individual's eye by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

64. 63. The method of any one of claims 21-26, 30-36, or 39-62, wherein the therapeutically effective amount of the water soluble drug reduces internal pressure within the eye of the individual by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%.

65. A therapeutically effective amount of a water-soluble drug may reduce the internal pressure in an individual's eye by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, 63. The method of any one of claims 21-26, 30-36, or 39-62, wherein the method reduces by about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

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