# US 8,784,897 B2 · Methods of therapeutic treatment of eyes > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,784,897 B2 - Document ID: US8784897B2 - Status: Granted - Kind: B2 - Application number: 12/769,136 - Filed: 2010-04-28 - Published: 2010-11-25 - Granted: 2014-07-22 - Earliest claimed: 2006-10-25 - Assignees: Revalesio Corporation - Applicants: Gregory J. Archambeau; Anthony B. Wood; Richard L. Watson - Inventors: Gregory J. Archambeau; Anthony B. Wood; Richard L. Watson - Web page: https://patentgrep.com/patent/US8784897B2 ## CPC - A61K 33/40: Peroxides - A01N 1/126: Physiologically active agents, e.g. antioxidants or nutrients - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 9/10: Dispersions; Emulsions - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 33/00: Medicinal preparations containing inorganic active ingredients - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 27/02: Ophthalmic agents - B01F 23/233: using driven stirrers with completely immersed stirring elements - B01F 23/41: Emulsifying - B01F 23/43: using driven stirrers - B01F 27/2722: {provided with ribs, ridges or grooves on one surface} - A61K 9/5115: {Inorganic compounds} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06) ## Abstract Provided are electrokinetically-altered aqueous fluids (e.g., gas-enriched electrokinetic fluids) comprising an ionic aqueous solution of charge-stabilized oxygen-containing nanostructures in an amount sufficient to provide modulation of at least one of cellular membrane potential and cellular membrane conductivity, and therapeutic compositions and methods for use in treating an irritation, infection or inflammatory eye condition, comprising administering to, by contacting the eye of a subject in need thereof a therapeutically effective amount of an electrokinetically-altered aqueous fluid. The electrokinetically-altered fluids or therapeutic compositions and methods include electrokinetically-altered ionic aqueous fluids optionally in combination with other therapeutic agents. Other embodiments include particular routes of administration or formulations for the electrokinetically-altered fluids (e.g., electrokinetically-altered gas-enriched fluids) and therapeutic compositions for use in treating eye conditions. Certain embodiments relate to cosmetic and/or therapeutic fluids and/or methods of treatment utilizing the fluids to treat a cosmetic and/or therapeutic symptom related to eye conditions and/or diseases. ## Claims ### Claim 1 A method for treating an eye irritation, eye infection or inflammatory eye condition or disease, comprising administering to the eye of a subject in need thereof a therapeutically effective amount of an electrokinetically-altered aqueous fluid comprising an ionic aqueous solution of charge-stabilized oxygen-containing nanobubbles having an average diameter of less than 80 nanometers and stably configured in the ionic aqueous fluid in an amount sufficient for treating an eye irritation, eye infection or inflammatory eye condition or disease, or at least one symptom thereof. ### Claim 2 (depends on 1) The method of claim 1, wherein the charge-stabilized oxygen-containing nanobubbles are the major charge-stabilized gas-containing nanobubbles species in the fluid. ### Claim 3 (depends on 1) The method of claim 1, wherein the percentage of dissolved oxygen molecules present in the fluid as the charge-stabilized oxygen-containing nanobubbles is greater than 0.01%. ### Claim 4 (depends on 1) The method of claim 1, wherein the total dissolved oxygen is substantially present in the charge-stabilized oxygen-containing nanobubbles. ### Claim 5 (depends on 1) The method of claim 1, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 70 nm. ### Claim 6 (depends on 1) The method of claim 1, wherein the ionic aqueous solution comprises a saline solution. ### Claim 7 (depends on 1) The method of claim 1, wherein the fluid is superoxygenated. ### Claim 8 (depends on 1) The method of claim 1, wherein the fluid comprises a form of solvated electrons. ### Claim 9 (depends on 1) The method of claim 1, wherein alteration of the electrokinetically altered aqueous fluid comprises exposure of the fluid to hydrodynamically-induced, localized electrokinetic effects. ### Claim 10 (depends on 9) The method of claim 9, wherein exposure to the localized electrokinetic effects comprises exposure to at least one of voltage pulses and current pulses. ### Claim 11 (depends on 9) The method of claim 9, wherein the exposure of the fluid to hydrodynamically-induced, localized electrokinetic effects, comprises exposure of the fluid to electrokinetic effect-inducing structural features of a device used to generate the fluid. ### Claim 12 (depends on 1) The method of claim 1, wherein the eye irritation, eye infection or inflammatory eye condition or disease comprises at least one selected from the group consisting of dry eye, allergy irritation, corneal irritation, bacterial infection, and cellular damage. ### Claim 13 (depends on 12) The method of claim 12, wherein the eye irritation, eye infection or inflammatory eye condition or disease comprises at least one of dry eye, allergy irritation, and corneal irritation. ### Claim 14 (depends on 13) The method of claim 13, wherein the eye irritation, eye infection or inflammatory eye condition or disease comprises dry eye or allergy irritation. ### Claim 15 (depends on 1) The method of claim 1, wherein the at least one symptom of the eye irritation, eye infection or inflammatory eye condition or disease comprises at least one condition selected from the group consisting of: dry eye-related irritation, dry eye-related cellular damage, and allergic inflammation. ### Claim 16 (depends on 1) The method of claim 1, wherein the electrokinetically altered aqueous fluid modulates localized or cellular levels of nitric oxide. ### Claim 17 (depends on 1) The method of claim 1 wherein the electrokinetically altered aqueous fluid promotes a localized decrease at the site of administration of at least one cytokine selected from the group consisting of: IL-1-beta, IL-8, TNF-alpha, and TNF-beta. ### Claim 18 (depends on 1) The method of claim 1, further comprising a synergistic or non-synergistic inhibition or reduction in inflammation by simultaneously or adjunctively treating the subject with another anti-inflammatory or eye treatment agent. ### Claim 19 (depends on 18) The method of claim 18, wherein said other anti-inflammatory agent comprises a steroid or glucocorticoid steroid. ### Claim 20 (depends on 19) The method of claim 19, wherein the glucocorticoid steroid comprises budesonide or an active derivative thereof. ### Claim 21 (depends on 1) The method of claim 1, further comprising combination therapy, wherein at least one additional therapeutic agent is administered to the patient. ### Claim 22 (depends on 21) The method of claim 21, wherein, the at least one additional therapeutic agent is selected from the group consisting of: anti-microbial agent, anti-inflammatory agent, pain reliever, anesthetic, vitamin, cytokine, adjuvant, preservative, salt, MMP inhibitors, short-acting β2-agonists, long-acting β2-agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methylxanthines, β2-agonists, albuterol, levalbuterol, pirbuterol, artformoterol, formoterol, salmeterol, anticholinergics including ipratropium and tiotropium; corticosteroids including beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methyprednisolone, prednisolone, prednisone; leukotriene modifiers including montelukast, zafirlukast, and zileuton; mast cell stabilizers including cromolyn and nedocromil; methylxanthines including theophylline; combination drugs including ipratropium and albuterol, fluticasone and salmeterol, budesonide and formoterol; antihistamines including hydroxyzine, diphenhydramine, loratadine, cetirizine, and hydrocortisone; immune system modulating drugs including tacrolimus and pimecrolimus; cyclosporine; azathioprine; mycophenolatemofetil; and combinations thereof. ### Claim 23 (depends on 21) The method of claim 21, wherein the at least one additional therapeutic agent is a TSLP and/or TSLPR antagonist. ### Claim 24 (depends on 23) The method of claim 23, wherein the TSLP and/or TSLPR antagonist is selected from the group consisting of neutralizing antibodies specific for TSLP and the TSLP receptor, soluble TSLP receptor molecules, and TSLP receptor fusion proteins, including TSLPR-immunoglobulin Fc molecules or polypeptides that encode components of more than one receptor chain. ### Claim 25 (depends on 1) The method of claim 1, wherein the charge-stabilized oxygen-containing nanobubbles are stably configured in the ionic aqueous fluid in an amount sufficient to provide, upon contact of a living cell by the fluid, modulation of at least one of cellular membrane potential and cellular membrane conductivity. ### Claim 26 (depends on 25) The method of claim 25, wherein modulation of at least one of cellular membrane potential and cellular membrane conductivity comprises altering of a conformation, ligand binding activity, or a catalytic activity of a membrane associated protein. ### Claim 27 (depends on 26) The method of claim 26, wherein the membrane associated protein comprises at least one selected from the group consisting of receptors, transmembrane receptors, ion channel proteins, intracellular attachment proteins, cellular adhesion proteins, and integrins. ### Claim 28 (depends on 27) The method of claim 27, wherein the transmembrane receptor comprises a G-protein coupled receptor (GPCR). ### Claim 29 (depends on 28) The method of claim 28, wherein the GPCR interacts with a G protein α subunit. ### Claim 30 (depends on 29) The method of claim 29, wherein the G protein α subunit comprises at least one selected from the group consisting of Gαs, Gαi, Gαq, and Gα12. ### Claim 31 (depends on 30) The method of claim 30, wherein the at least one G protein α subunit is Gαq. ### Claim 32 (depends on 25) The method of claim 25, wherein modulating cellular membrane conductivity, comprises modulating whole-cell conductance. ### Claim 33 (depends on 32) The method of claim 32, wherein modulating whole-cell conductance, comprises modulating at least one linear or non-linear voltage-dependent contribution of the whole-cell conductance. ### Claim 34 (depends on 25) The method of claim 25, wherein modulation of at least one of cellular membrane potential and cellular membrane conductivity comprises modulation of a calcium-dependent cellular messaging pathway or system. ### Claim 35 (depends on 25) The method of claim 25, wherein modulation of at least one of cellular membrane potential and cellular membrane conductivity comprises modulation of phospholipase C activity. ### Claim 36 (depends on 25) The method of claim 25, wherein modulation of at least one of cellular membrane potential and cellular membrane conductivity comprises modulation of adenylate cyclase (AC) activity. ### Claim 37 (depends on 25) The method of claim 25, wherein modulation of at least one of cellular membrane potential and cellular membrane conductivity comprises modulation of intracellular signal transduction associated with at least one condition or symptom selected from the group consisting of: dry eye, allergy irritation, corneal irritation, bacterial infection, and cellular damage. ### Claim 38 (depends on 1) The method of claim 1, comprising administration of the electrokinetically-altered aqueous fluid to a cell network or layer, and further comprising modulation of an intercellular junction therein. ### Claim 39 (depends on 38) The method of claim 38, wherein the intracellular junction comprises at least one selected from the group consisting of tight junctions, gap junctions, zona adherins and desmasomes. ### Claim 40 (depends on 38) The method of claim 38, wherein the cell network or layers comprises at least one selected from the group consisting of corneal epithelial layer and corneal ‘endothelium’. ### Claim 41 (depends on 1) The method of claim 1, wherein the electrokinetically-altered aqueous fluid is oxygenated, and wherein the oxygen in the fluid is present in an amount of at least 8 ppm at atmospheric pressure. ### Claim 42 (depends on 1) The method of claim 1, wherein the electrokinetically altered aqueous fluid comprises at least one of a form of solvated electrons and electrokinetically modified or charged oxygen species. ### Claim 43 (depends on 42) The method of claim 42, wherein the form of solvated electrons or electrokinetically modified or charged oxygen species are present in an amount of at least 0.01 ppm. ### Claim 44 (depends on 42) The method of claim 42, wherein the electrokinetically-altered aqueous fluid comprises a form of solvated electrons stabilized, at least in part, by molecular oxygen. ### Claim 45 (depends on 25) The method of claim 25, wherein the ability to alter at least one of cellular membrane potential and cellular membrane conductivity persists for at least two months in a closed gas-tight container. ### Claim 46 (depends on 1) The method according to claim 1, wherein the electrokinetically-altered aqueous fluid comprises a contact lens solution or multi-use contact lens solution. ### Claim 47 (depends on 46) The method according to claim 46, wherein the contact lens solution or multi-use contact lens solution comprises a storage solution, a wetting solution, or a cleaning solution. ### Claim 48 (depends on 12) The method according to claim 12, wherein the electrokinetically-altered aqueous fluid inhibits the growth of Pseudomonas bacteria. ### Claim 49 (depends on 1) The method according to claim 1, wherein the eye irritation, eye infection or inflammatory eye condition or disease, or the at least one symptom thereof, is the result of a wound. ### Claim 50 (depends on 49) The method according to claim 49, wherein the wound is selected from the group consisting of: lacerations, abrasions, rupture, puncture wounds, chemical, thermal, or radiation-induced burns, cuts, scrapes, incisions, blisters, ulcers, and surgical wounds. ### Claim 51 (depends on 50) The method according to claim 50, wherein the surgical wound is a result of at least one surgery selected from the group consisting of: laser keratotomy, cataract removal, lens implantation or removal, corneal alterations, laser-assisted in situ keratomileusis (LASIK), intraLASIK, extracapsular surgery, phacoemulsification, vitreoretinal surgery, glaucoma procedures, neuro-ophthalmic surgery, and strabismus surgery. ### Claim 52 (depends on 12) The method of claim 12, wherein the eye irritation, eye infection or inflammatory eye condition or disease, or the at least one symptom thereof, comprises dry eye, and wherein at least one sign or symptom selected from the group consisting of: decrease in aqueous tear production, increase in tear evaporation, and increase in cellular inflammation is ameliorated. ### Claim 53 (depends on 52) The method according to claim 52, wherein said ameliorating is assessed by at least one measurement selected from the group consisting of corneal staining, conjunctival staining, tear volume, bulbar conjunctival erythema, tear film height, ocular surface healing, level of infection, level of inflammation, level of ocular surface damage, and level of inferior tear meniscus. ### Claim 54 (depends on 1) The method according to claim 1, wherein said administration comprises topically applying said fluid to said eye. ### Claim 55 (depends on 1) The method according to claim 1, wherein said treatment comprises an adjunct therapy and said subject further undergoes a primary treatment for an eye condition. ### Claim 56 (depends on 55) The method according to claim 55, wherein said primary treatment comprises administering to said subject at least one medication selected from the group consisting of artificial tears, anti-inflammatory medications, steroids, antihistamines, antibiotics, and vasoconstrictor medications. ### Claim 57 (depends on 56) The method according to claim 56, wherein said administering comprises topically or orally administering said medication to the subject. ### Claim 58 (depends on 1) The method according to claim 1, wherein said administrating comprises topically contacting said eye of the subject. ### Claim 59 (depends on 53) The method according to claim 53, wherein said treatment results in a reduction in corneal or conjuctival staining. ### Claim 60 (depends on 53) The method according to claim 53, wherein said treatment results in an increase in tear volume or tear film height. ### Claim 61 (depends on 1) The method of claim 1, wherein the amount of oxygen present in charge-stabilized oxygen-containing nanobubbles of the electrokinetically-altered fluid is at least 8 ppm at atmospheric pressure. ### Claim 62 (depends on 26) The method of claim 26, wherein the membrane associated protein comprises CCR3. ### Claim 63 (depends on 1) The method of claim 1, wherein treating the eye irritation, eye infection or inflammatory eye condition or disease, or at least one symptom thereof, comprises modulation of intracellular NF-κB expression and/or activity. ### Claim 64 (depends on 1) The method of claim 1, wherein treating comprises topical administration to the eye. ### Claim 65 (depends on 1) The method of claim 1, wherein the charge-stabilized oxygen-containing nanobubbles of the electrokinetically-altered fluid comprise at least one cation selected from the group consisting of ammonium, calcium, copper, iron, magnesium, manganese, potassium, sodium and zinc. ### Claim 66 (depends on 1) The method of claim 1, wherein a majority of the charge-stabilized oxygen-containing nanobubbles have a diameter of less than 80 nanometers. ### Claim 67 (depends on 22) The method of claim 22, wherein the MMP inhibitor comprises an inhibitor of MMP-9 and/or an inhibitor of MMP-2. ### Claim 68 (depends on 5) The method of claim 5, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 60 nm. ### Claim 69 (depends on 68) The method of claim 68, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 50 nm. ### Claim 70 (depends on 69) The method of claim 69, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 40 nm. ### Claim 71 (depends on 70) The method of claim 70, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 30 nm. ### Claim 72 (depends on 71) The method of claim 71, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 20 nm. ### Claim 73 (depends on 72) The method of claim 72, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 10 nm. ### Claim 74 (depends on 73) The method of claim 73, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 5 nm. ### Claim 75 (depends on 74) The method of claim 74, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 4 nm. ### Claim 76 (depends on 75) The method of claim 75, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 3 nm. ### Claim 77 (depends on 76) The method of claim 76, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 2 nm. ### Claim 78 (depends on 77) The method of claim 77, wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 1 nm.