Composition for ameliorating, alleviating or suppressing conjunctival congestion

Abstract

Provided is a composition for ameliorating, alleviating or suppressing conjunctival congestion. This composition for ameliorating, alleviating or suppressing conjunctival congestion in a patient contains brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient. In the composition, the concentration of brimonidine or the pharmaceutically acceptable salt thereof is about 0.0005 w / v% to about 0.02 w / v%.

Description

Composition for improving, alleviating or suppressing conjunctival congestion

[0001] The present invention relates to a composition for improving, alleviating or suppressing conjunctival hyperemia in a subject, which comprises brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, and related inventions.

[0002] Brimonidine is a selective adrenergic α2 receptor agonist that exhibits high selectivity for the adrenergic α2 receptor and is thought to have a vasoconstrictive effect. Currently, in the United States, 0.025 w / v% brimonidine tartrate eye drops "LUMIFY (registered trademark)" are sold with the efficacy or effect of "relieving bloodshot eyes caused by mild eye irritation" (Non-Patent Document 1).

[0003] Lumify Drug Facts, [online], [Retrieved April 23, 2024], Internet <URL: https: / / www.lumifydrops.com / siteassets / pdfs / Lumify-drug-facts.pdf>

[0004] There is a need for a composition that can immediately improve, alleviate, or suppress conjunctival congestion after administration, and that maintains this effect for a long period of time.

[0005] That is, the present invention relates to at least the following inventions: (1) A composition for improving, alleviating, or suppressing conjunctival hyperemia in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.0005 w / v% to about 0.02 w / v%. (2) The composition according to (1), wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.01 w / v%. (3) The composition according to (1) or (2), wherein the conjunctival hyperemia is not caused by an ocular disease. (4) The composition according to (1) or (2), wherein the conjunctival hyperemia is not caused by allergic conjunctivitis. (5) The composition according to any one of (1) to (4), wherein the composition is administered by instillation to the subject, one drop per eye at a time, up to four times a day. (6) The composition according to (5), wherein the administration interval of the composition is four hours or more. (7) The composition according to any one of (1) to (6), wherein the subject is 40 years of age or older. (8) The composition according to any one of (1) to (6), wherein the subject's pulse rate before administration of the composition is less than about 80 beats per minute. (9) The composition according to any one of (1) to (8), wherein the composition further improves the external aesthetic appearance of the subject's eyes. (10) The composition according to any one of (1) to (9), wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof. (11) The composition according to any one of (1) to (9), wherein the composition further comprises one or more additives selected from the group consisting of citric acid or a pharmaceutically acceptable salt thereof, an isotonicity agent, a preservative, and a pH adjuster. (12) The composition according to any one of (1) to (11), wherein the composition further comprises an additional active ingredient. (13) The composition according to any one of (1) to (11), wherein the composition contains only 0.01 w / v% brimonidine tartrate as an active ingredient. (14) The composition according to any one of (1) to (13), which is in the form of an eye drop. (15) The composition according to (14), wherein the eye drop is an aqueous eye drop.(16) A method for improving, alleviating, or suppressing conjunctival hyperemia in a subject, comprising the step of administering to the subject a composition comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient at a concentration of about 0.0005 w / v w / v% to about 0.02 w / v%. (17) The method according to (16), wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.01 w / v%. (18) The method according to (16) or (17), wherein the conjunctival hyperemia is not caused by an ocular disease. (19) The method according to (16) or (17), wherein the conjunctival hyperemia is not caused by allergic conjunctivitis. (20) The method according to any one of (16) to (19), wherein the composition is administered to the subject by instillation, one drop per eye at a time, up to four times a day. (21) The method according to (20), wherein the composition is administered at intervals of four hours or more. (22) The method of any of (16) to (21), wherein the subject is 40 years of age or older. (23) The method of any of (16) to (21), wherein the subject's pulse rate before administration of the composition is less than about 80 beats per minute. (24) The method of any of (16) to (23), wherein the brimonidine or pharmaceutically acceptable salt thereof is brimonidine tartrate. (25) The method of any of (16) to (24), wherein the composition is in the form of eye drops. (26) The method of (25), wherein the eye drops are aqueous eye drops. (27) A composition for improving the external aesthetic appearance of the eye in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is from about 0.0005 w / v% to about 0.02 w / v%. (28) The composition according to (27), wherein the concentration of the brimonidine or pharmaceutically acceptable salt thereof is about 0.01 w / v%. (29) The composition according to (27) or (28), wherein the composition is administered to the subject by instillation at a rate of one drop per eye up to four times a day. (30) The composition according to any one of (27) to (29), wherein the subject is 40 years of age or older. (31) The composition according to any one of (27) to (29), wherein the subject's pulse rate before administration of the composition is less than about 80 beats per minute.(32) The composition according to any one of (27) to (31), wherein the brimonidine or pharmaceutically acceptable salt thereof is brimonidine tartrate. (33) The composition according to any one of (27) to (32), wherein the composition is in the form of eye drops. (34) The composition according to (33), wherein the eye drops are aqueous eye drops. (35) A method for improving the external aesthetic appearance of a subject's eye, comprising administering to the subject a composition comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient at a concentration of about 0.0005 w / v% to about 0.02 w / v%. (36) The method according to (35), wherein the concentration of the brimonidine or pharmaceutically acceptable salt thereof is about 0.01 w / v%. (37) The method according to (35) or (36), wherein the composition is administered to the subject by instillation, one drop per eye at a time, up to four times a day. (38) The method of any of (35) to (37), wherein the subject is 40 years of age or older. (39) The method of any of (35) to (37), wherein the subject's pulse rate before administration of the composition is less than about 80 beats per minute. (40) The method of any of (35) to (39), wherein the brimonidine or pharmaceutically acceptable salt thereof is brimonidine tartrate. (41) The method of any of (35) to (40), wherein the composition is in the form of eye drops. (42) The method of (41), wherein the eye drops are aqueous eye drops. (43) Use of brimonidine or a pharmaceutically acceptable salt thereof in the manufacture of a composition for improving, alleviating, or suppressing conjunctival hyperemia in a subject, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.0005 w / v% to about 0.02 w / v%. (44) Use of brimonidine or a pharmaceutically acceptable salt thereof in the manufacture of a composition for improving the external aesthetics of the eye in a subject, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.0005 w / v% to about 0.02 w / v%.(45) Brimonidine or a pharmaceutically acceptable salt thereof for use in a method for improving, alleviating, or suppressing conjunctival hyperemia in a subject, wherein the brimonidine or pharmaceutically acceptable salt thereof is contained in the composition at a concentration of about 0.0005% to about 0.02% w / v. (46) Brimonidine or a pharmaceutically acceptable salt thereof for use in a method for improving the external aesthetics of the eye in a subject, wherein the brimonidine or pharmaceutically acceptable salt thereof is contained in the composition at a concentration of about 0.0005% to about 0.02% w / v. (47) A composition for improving, alleviating, or suppressing conjunctival hyperemia in a subject, wherein the composition comprises brimonidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.0005% to about 0.02% w / v. (48) A composition for improving the external aesthetic appearance of the eye in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.0005% w / v to about 0.02% w / v.

[0006] According to the present disclosure, it is possible to provide a composition or method therefor that exerts an immediate effect of alleviating, improving, or suppressing conjunctival congestion and that effect lasts for a long time. Furthermore, according to the present disclosure, it is possible to provide a composition or method therefor that improves the external aesthetic appearance of the eyes of a subject.

[0007] 1 shows the mean and standard error of the measured conjunctival hyperemia scores at each evaluation time point, 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration of one drop of ophthalmic solution (0.01 w / v% brimonidine ophthalmic solution, 0.025 w / v% brimonidine ophthalmic solution, or placebo ophthalmic solution) on Day 1 (*: P<0.05). This figure shows a subgroup analysis of the effect of decongestantia after administration of 0.01 w / v% brimonidine ophthalmic solution by subject age. 1 shows the change from baseline (before administration of 0.01 w / v% brimonidine ophthalmic solution on Day 1) in conjunctival hyperemia score at each evaluation time point, 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration of 0.01 w / v% brimonidine ophthalmic solution, one drop at a time, on Day 1. This figure shows a subgroup analysis of the conjunctival hyperemia relief effect after administration of 0.01 w / v% brimonidine ophthalmic solution, based on the subject's pulse rate before administration. This figure shows the change from baseline (before administration of 0.01 w / v% brimonidine ophthalmic solution on Day 1) in conjunctival hyperemia score at each evaluation time point, 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration of 0.01 w / v% brimonidine ophthalmic solution, one drop at a time, on Day 1.

[0008] The present invention will be described in detail below with reference to the preferred embodiments, but the present invention should not be understood as being limited to the following embodiments.

[0009] The present disclosure will be described below. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will take precedence. In this specification, "about" means ±10% of the following value. In this specification, time is displayed in 24-hour format unless otherwise specified.

[0010] In one embodiment, the present invention relates to a composition for improving, alleviating, or suppressing conjunctival hyperemia in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for improving, alleviating, or suppressing conjunctival hyperemia in a subject, comprising the step of administering the composition to the subject. In a further embodiment, the present invention relates to a composition for improving the external aesthetics of the eye in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for improving the external aesthetics of the eye in a subject, comprising the step of administering the composition to the subject.

[0011] As used herein, the term "subject" refers to a recipient of the composition or method for improving, alleviating, or suppressing conjunctival congestion disclosed herein, or a recipient of the composition or method for improving the external aesthetic appearance of the eye, and includes mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, etc.), with primates being preferred, and humans being particularly preferred.

[0012] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "or" and "alternative." In this specification, when it is specified that "within" a "range" of "two values," the range includes the two values ​​themselves.

[0013] In the present disclosure, "brimonidine" refers to a compound of the formula

[0014] Brimonidine or a pharmaceutically acceptable salt thereof is used as a pharmaceutical ingredient and is typically provided as brimonidine tartrate (chemical name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine mono-(2R,3R)-tartrate). Brimonidine or a pharmaceutically acceptable salt thereof is a selective adrenergic α2 receptor agonist and is generally formulated as an active ingredient in aqueous liquid preparations, particularly eye drops.

[0015] Brimonidine salts include any pharmaceutically acceptable salts, including hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, ascorbate, maleate, methanesulfonate, tartrate, and other inorganic carboxylates known to those skilled in the art, preferably tartrate.

[0016] In the present disclosure, the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.0005% to about 0.02% w / v of the composition, preferably about 0.01% w / v. As used herein, the concentration of brimonidine or a pharmaceutically acceptable salt thereof refers to the concentration converted into brimonidine tartrate, unless otherwise specified.

[0017] Conjunctival hyperemia in the present disclosure refers to a condition in which the eyes appear red due to dilation of blood vessels on the surface of the eye, such as behind the eyelids or around the white of the eye. Conjunctival hyperemia includes those caused by ocular diseases such as allergic conjunctivitis and infectious conjunctivitis due to viral or bacterial infection, as well as those caused by factors other than ocular diseases, such as eye strain, eye fatigue, mechanical eye irritation from contact lenses, dry eyes, lack of sleep, or alcohol intake, and combinations of these factors. Conjunctival hyperemia in the present disclosure is preferably not caused by an allergic reaction triggered by systemic or ocular antigen exposure, more preferably not caused by allergic conjunctivitis, even more preferably not caused by ocular diseases such as allergic conjunctivitis or infectious conjunctivitis, and most preferably not caused by ocular or ocular adnexal infections, allergic diseases, proliferative diseases, or severe dry eye syndrome. Furthermore, conjunctival hyperemia in the present disclosure may not be caused by irritation from wearing contact lenses. Improving, alleviating, or suppressing conjunctival congestion means suppressing the dilation of blood vessels on the surface of the eye around the white of the eye, thereby improving, alleviating, or suppressing conjunctival congestion, thereby exerting the effect of reducing redness or whitening (which can also be called whitening) of the eye. Improving or alleviating conjunctival congestion includes completely or partially removing conjunctival congestion, and suppressing conjunctival congestion means preventing the worsening of conjunctival congestion. Furthermore, the improvement, alleviation, or suppression of conjunctival congestion reduces redness or whitens the eye, which can also have the effect of improving the external aesthetics of the eye. In this specification, the effect of improving, alleviating, or suppressing conjunctival congestion (the effect of removing conjunctival congestion or the effect of preventing the worsening of conjunctival congestion) is also referred to as the therapeutic effect of conjunctival congestion.

[0018] The surface of the white of the eye is composed of the conjunctiva, which covers the sclera and further covers the inside of the eyelid. The conjunctival surface is primarily composed of conjunctival epithelial cells. The epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatic vessels. The conjunctiva contacts the cornea at the boundary between the white and black of the eye, and the cornea and conjunctiva constitute the outermost layer of the eye exposed to the outside world. Because the conjunctiva is exposed to the outside world, it is susceptible to bacterial and viral infections and inflammation. Even in the absence of inflammation, lack of sleep or overuse of the eyes increases blood flow to supply oxygen and nutrients to the eyes, causing conjunctival congestion. In the present disclosure, brimonidine and / or a pharmaceutically acceptable salt thereof reaches blood vessels in the conjunctiva and constricts them, thereby improving, alleviating, or suppressing congestion, reducing or whitening ocular redness, or improving the external aesthetic appearance of the eyes.

[0019] In one embodiment, the composition can be provided as eye drops or eye ointment, preferably as eye drops. In the present disclosure, the eye drops are aqueous solutions (eye drops), i.e., aqueous eye drops. An aqueous solution refers to a formulation containing at least a portion of water and used as an ophthalmic preparation or by instillation. Eye drops can be prepared according to conventional methods. Eye drops can be prepared according to known preparation methods depending on the intended use, including, but not limited to, the methods described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition. The pH of the prepared aqueous solution may be adjusted, as appropriate, using, for example, hydrochloric acid or sodium hydroxide. The eye drops may be sterilized according to conventional methods and then filled into a product container. In one embodiment, the sterilization is by filtration.

[0020] The composition of the present disclosure is administered by instillation at a rate of one drop per eye up to four times a day. The composition of the present disclosure is used for conjunctival hyperemia, preferably conjunctival hyperemia not caused by ocular disease, and the number of daily administrations can be increased or decreased as appropriate depending on the symptoms. Specifically, the composition is administered by instillation at a rate of one drop per eye once, twice, three, or four times a day. The administration interval between administrations of the composition is preferably four hours or more, and may be six hours or more. By administering one drop of the composition of the present disclosure, the therapeutic effect of conjunctival hyperemia is observed at least 240 minutes, and even up to 360 minutes after administration.

[0021] The pH of the composition of the present disclosure is, for example, about 4.0 to about 9.0, preferably about 5.0 to 8.0, and more preferably about 6.0 to about 7.0.

[0022] The composition of the present disclosure may contain any component that can be used in eye drops, provided that the effects of the present invention are not impaired. In addition to brimonidine or a pharmaceutically acceptable salt thereof, the composition may contain optional components such as additional active ingredients and additives. Such additives include, but are not limited to, tonicity agents, buffers, viscosity agents, stabilizers, preservatives, cooling agents, pH adjusters, etc. The additives contained in the composition are preferably tonicity agents, buffers, stabilizers, preservatives, and pH adjusters. More preferably, the additives contained in the composition consist solely of tonicity agents, buffers, preservatives, and pH adjusters. The buffer may also act as a stabilizer. Additional active ingredients other than brimonidine or a pharmaceutically acceptable salt thereof include, but are not limited to, cholinesterase inhibitors, antihistamines, amino acids, vitamins, anti-inflammatory agents, nonsteroidal anti-inflammatory agents, and antiallergic agents. Preferably, the additional active ingredient is an amino acid, a vitamin, or an anti-inflammatory agent. Even if the composition of the present disclosure does not contain an additional active ingredient having the effect of improving, alleviating, or suppressing conjunctival congestion, brimonidine or a pharmaceutically acceptable salt thereof can sufficiently exert the effect of improving, alleviating, or suppressing conjunctival congestion. These additional active ingredients and additives may be used alone from each category, or multiple types may be used in combination. Optional ingredients that can be added to the composition are described below, but may also be used for purposes other than the listed effects.

[0023] Examples of isotonicity agents include sugars and salts, and may further include hydrates or solvates thereof. Examples of salts that can be used include sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, and potassium dihydrogen phosphate. Examples of sugars that can be used include any monosaccharide or polysaccharide, such as cyclodextrin, xylitol, sorbitol, and mannitol. Other examples include glycerin (glycerol) and propylene glycol. Preferably, sodium chloride, potassium chloride, calcium chloride, and glycerin are used as isotonicity agents. Calcium chloride may be calcium chloride hydrate.

[0024] The concentration of the isotonic agent in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives, and / or osmotic pressure ratio, but the total amount in the composition is preferably about 0.01 w / v% to about 3.0 w / v%, more preferably about 0.02 w / v% to about 2.5 w / v%, even more preferably about 0.03 w / v% to about 2.0 w / v%, and particularly preferably about 0.05 w / v% to about 1.0 w / v%.

[0025] Examples of buffers include citrate buffers, acetate buffers, carbonate buffers, borate buffers, and phosphate buffers, and may also be hydrates or solvates thereof. Examples of borate buffers include boric acid and borax. Examples of citrate buffers include citric acid or a pharmaceutically acceptable salt thereof, preferably sodium citrate. Sodium citrate may be sodium citrate hydrate.

[0026] The concentration of the buffering agent in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives, and / or osmotic pressure ratio, but the total amount in the composition is preferably about 0.01 w / v% to about 5.0 w / v%, more preferably about 0.05 w / v% to about 3.0 w / v%, and even more preferably about 0.1 w / v% to about 2.0 w / v%.

[0027] Examples of thickening agents include cellulose polymers, synthetic polymers, and polysaccharides, and may also be hydrates or solvates thereof. Examples of cellulose polymers include methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose. Examples of synthetic polymers include carboxyvinyl polymers, polycarbophil, polyacrylic acid, polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol. Examples of polysaccharides include alginic acid, chondroitin sulfate, hyaluronic acid, xanthan gum, and salts thereof.

[0028] The concentration of the thickening agent in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives, and / or osmotic pressure ratio, but the total amount in the composition is preferably about 0.001 w / v% to about 5.0 w / v%, more preferably about 0.01 w / v% to about 2.5 w / v%, and even more preferably about 0.05 w / v% to about 1.0 w / v%.

[0029] Examples of stabilizers that can be used include citric acid or a pharmaceutically acceptable salt thereof (e.g., sodium citrate hydrate), sodium edetate hydrate, dibutylhydroxytoluene, butylhydroxyanisole, sulfites, monoethanolamine, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, and tocopherol.

[0030] The concentration of the stabilizer in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives, and / or osmotic pressure ratio, but the total amount in the composition is preferably about 0.01 w / v% to about 5.0 w / v%, more preferably about 0.02 w / v% to about 3.0 w / v%, even more preferably about 0.03 w / v% to about 2.0 w / v%, and particularly preferably about 0.05 w / v% to about 0.8 w / v%.

[0031] Examples of preservatives that can be used include benzalkonium chloride, polyhexanide (polyhexamethylene biguanide), chlorhexidine gluconate, alkylpolyaminoethylglycine hydrochloride, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, sodium chlorite, benzododecinium bromide, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, boric acid, and borax.

[0032] The concentration of the preservative in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives, and / or osmotic pressure ratio, but the total amount in the composition is preferably about 0.00005 w / v% to about 0.05 w / v%, more preferably about 0.0001 w / v% to about 0.03 w / v%, and even more preferably about 0.0002 w / v% to about 0.02 w / v%.

[0033] Examples of the cooling agent that can be used include menthol, ethanol, camphor, geraniol, borneol, lycium globulus, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, and rose oil.

[0034] The concentration of the cooling agent in the composition of the present invention can be adjusted as appropriate, taking into consideration the effect on the active ingredient, other additives and / or osmotic pressure ratio, but the total amount in the composition is about 0.0001 w / v % to about 0.2 w / v %, preferably about 0.0005 w / v % to about 0.1 w / v %, more preferably about 0.001 w / v % to about 0.05 w / v %, and particularly preferably about 0.001 w / v % to about 0.01 w / v %.

[0035] Examples of pH adjusters that can be used include acids such as hydrochloric acid, acetic acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid, citric acid, and tartaric acid, and bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, and monoethanolamine. By appropriately using a buffer and a pH adjuster, the pH of the aqueous liquid preparation can be adjusted to a predetermined pH.

[0036] The concentration of the additives may be appropriately determined depending on the type of additive used, the properties to be imparted to the composition, and the like.

[0037] As the cholinesterase inhibitor, for example, distigmine, neostigmine, pyridostigmine, ambenonium, edrophonium, or a salt thereof can be used. The cholinesterase inhibitor can be formulated for the purpose of improving the ocular accommodation function, for example.

[0038] Examples of antihistamines that can be used include diphenhydramine, chlorpheniramine, epinastine, olopatadine, and salts thereof. Antihistamines can be added to suppress itching and inflammation of the eyes.

[0039] Amino acids also refer to substances that have sulfate group instead of carboxyl group of amino acid, such as taurine.As amino acids, as examples, aspartic acid, chondroitin sulfate ester, glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine, serine, and may be their salts.As amino acids, aspartic acid, taurine, chondroitin sulfate ester are preferably included.Amino acids other than glycine may be L-amino acids, D-amino acids, or DL-amino acids.

[0040] Vitamins are a general term for organic compounds other than carbohydrates, proteins, and lipids that are necessary in trace amounts for the survival or growth of living organisms and cannot be synthesized in sufficient amounts within the organism's body. Vitamins are broadly classified into water-soluble vitamins and fat-soluble vitamins. Water-soluble vitamins include vitamin B and vitamin C (ascorbic acid). Fat-soluble vitamins include vitamins A, vitamin D, vitamin E, and vitamin K. The over-the-counter drug manufacturing and sales approval standards stipulate the vitamins to be incorporated into eye drops, and from this perspective, vitamins A, vitamin B, and vitamin E are particularly preferred.

[0041] As vitamin A, retinol and its related substances can be used. Examples of retinol-related substances include retinal, retinoic acid, and other retinoids, such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, and bexarotene. Retinol acetate and retinol palmitate are preferred from the viewpoint of formulation as eye drops. Vitamin A acts on epithelial cells to induce proliferation, and therefore can be incorporated into eye drops for the purpose of protecting the cornea and conjunctiva. Vitamin A can also be incorporated into eye drops for the treatment of ophthalmic diseases such as night blindness, conjunctival dryness, corneal dryness, and keratomalacia.

[0042] Examples of B vitamins that can be used include vitamin B1 (thiamine, etc.), vitamin B2, vitamin B3 (niacin, etc.), vitamin B5, vitamin B6, vitamin B7 (biotin, etc.), vitamin B9 (folic acid, etc.), and vitamin B12. Vitamins include derivatives such as provitamins and pharmaceutically acceptable salts. Among the B vitamins, vitamins B2, B5, B6, and B12 are preferred, particularly from the viewpoint of being incorporated into eye drops.

[0043] Examples of vitamin B2 that can be used include riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, and pharmaceutically acceptable salts thereof. Examples of salts include sodium salts and potassium salts. Flavin adenine dinucleotide sodium is preferred from the viewpoint of being formulated as an eye drop. Vitamin B2 is directly involved in oxidation-reduction, and when used as an eye drop, it promotes the enzymatic respiratory metabolism of corneal and conjunctival cells, thereby protecting the cornea and conjunctiva. Vitamin B2 can also be formulated in eye drops to treat keratitis thought to be caused by vitamin B2 deficiency or metabolic disorders.

[0044] As vitamin B5, panthenol, pantothenic acid, or derivatives thereof or salts thereof can be used. Examples thereof include panthenol, pantothenic acid, and derivatives thereof or salts thereof, such as pantethine, pantetheine, pantothenyl alcohol, pantothenyl ethyl ether, pantetheine pantothenyl alcohol, calcium pantothenate, and sodium pantothenate. From the viewpoint of use as an eye drop, panthenol, calcium pantothenate, and sodium pantothenate are preferred as vitamin B5.

[0045] Vitamin B6 may be pyridoxine, pyridoxal, pyridoxamine, or a pharmaceutically acceptable salt thereof. Vitamin B6 is involved in protein metabolism as a coenzyme for amino acid decarboxylase and aminotransferase in vivo, and may be incorporated into eye drops to suppress eye fatigue.

[0046] Vitamin B12 is a compound having a structure in which cobalt is coordinated to a corrin ring, and specific examples include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc. Vitamin B12 can be incorporated into eye drops for its pharmacological effects, such as improving tired eyes and eye strain.

[0047] Examples of vitamin E include tocopherol, tocotrienol, tocophersolan, and derivatives thereof. Tocopherol and tocotrienol may be any of α-, β-, γ-, and δ-tocopherols, and may be either d- or dl-tocopherols. From the viewpoint of use as eye drops, examples include d-α-tocopherol acetate and dl-α-tocopherol acetate.

[0048] Examples of vitamin C include ascorbic acid and its salts. Examples of vitamin D include vitamin D2 (ergosterol, ergocalciferol), D3 (7-dehydrocholesterol), previtamin D3 (cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitronic acid), vitamin D4 (dihydroergocalciferol), and vitamin D5 (dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol). Examples of vitamin K include phylloquinone (K1), menaquinone (K2), and menadione (K3).

[0049] Examples of anti-inflammatory agents that can be used include ε-aminocaproic acid, glycyrrhizinic acid, allantoin, berberine, azulene sulfonic acid, lysozyme or salts thereof, zinc sulfate, and zinc lactate.

[0050] As the nonsteroidal anti-inflammatory agent, for example, diclofenac, nepafenac, pranoprofen, bromfenac, or salts thereof can be used.

[0051] Examples of antiallergic agents that can be used include epinastine, acitazanolast, amlexanox, ibudilast, olopatadine, cromoglycate, ketotifen, cyclosporine, tranilast, pemirolast, and salts thereof.

[0052] The concentrations of these additional active ingredients may be appropriately set within a range that does not impair the effects of the present invention.

[0053] Although the composition of the present disclosure is not limited to be administered to subjects of a particular age, the effect of improving, alleviating, or suppressing conjunctival congestion was greater in subjects aged 40 or older. Thus, in some embodiments, administering the composition of the present disclosure to subjects aged 40 or older is expected to have a greater therapeutic effect on conjunctival congestion, i.e., an effect of improving, alleviating, or suppressing conjunctival congestion, or an effect of improving the external cosmetic appearance of the eye.

[0054] Although the composition of the present disclosure is not limited to administration to subjects with a specific pulse rate, the improvement, alleviation, or suppression of conjunctival congestion was more pronounced in subjects with a pulse rate of less than about 80 beats per minute before administration of the composition. Therefore, in some embodiments, administering the composition of the present disclosure to a subject with a pulse rate of less than about 80 beats per minute before administration of the composition of the present disclosure is expected to provide a greater therapeutic effect on conjunctival congestion, i.e., an improvement, alleviation, or suppression of conjunctival congestion, or an improvement in the external aesthetic appearance of the eye. The pulse rate can be measured in a seated position after the subject has rested in a seated position for at least five minutes. It is generally known that the pulse rate is measured by touching the radial artery (pulse at the wrist). Any precision-controlled device may be used to measure the pulse rate. The pulse rate is preferably measured, for example, in the morning, specifically before 10:00 AM, more specifically between 7:00 AM and 10:00 AM.

[0055] The composition of the present disclosure can be safely administered to a mammalian subject. The mammal is preferably a human. The race of the subject to which the composition of the present disclosure is administered is not particularly limited, but is preferably Asian, more preferably Japanese.

[0056] The administration period of the composition of the present disclosure is not particularly limited, but there is no safety issue even if the administration is continued for several days, and the administration may be continued for, for example, 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, or 14 days.

[0057] In the present disclosure, the "conjunctival hyperemia score" refers to a numerical value obtained by quantifying findings based on the symptoms of conjunctival hyperemia in a subject. The conjunctival hyperemia score in the present disclosure can be determined, for example, using the Ora Calibra® Ocular Hyperemia Scale (a five-point scale: none (0), mild (1), moderate (2), severe (3), and very severe (4)), as described in the Examples below. After administration of the composition of the present disclosure, it is preferable that the subject's conjunctival hyperemia score be reduced compared to before administration. It is preferable that the conjunctival hyperemia score be reduced, for example, 1 minute, 5 minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 360 minutes after administration of one drop of the composition. The composition of the present disclosure can significantly reduce the conjunctival hyperemia score compared to before administration of the composition, for example, 15 minutes, 5 minutes, and 1 minute after administration of one drop of the composition. Furthermore, the conjunctival hyperemia score 1 minute, 5 minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes after administration of one drop of the composition is preferably 1 or less, 0.5 or less, or 0. The composition of the present disclosure can maintain the subject's conjunctival hyperemia score at 0 for up to 120 minutes after the start of administration of one drop of the composition, thereby maintaining its effect. The decrease in the conjunctival hyperemia score can also be expressed as a negative change in the conjunctival hyperemia score (after administration) from the baseline (before administration). For example, the composition of the present disclosure preferably exhibits a change from baseline (before administration) in the conjunctival hyperemia score 1 minute, 5 minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 360 minutes after administration of one drop of the composition, of -2.5 to -0.1, -2.0 to -0.2, and -1.5 to -0.3. The conjunctival hyperemia score preferably exhibits a predetermined rate of decrease 1 to 60 minutes, preferably 5 to 30 minutes, more specifically 5 minutes, 15 minutes, and 30 minutes after administration of the composition of the present disclosure. The predetermined rate of decrease is 50 to 90%, preferably 70 to 85%. The rate of decrease is calculated by subtracting the score after administration from the score before administration, and expressing the difference as a percentage of the conjunctival hyperemia score before administration as 100%.In the present disclosure, a decrease in the numerical value of the conjunctival hyperemia score and a negative change in the conjunctival hyperemia score (after administration) from the baseline (before administration) mean an improvement in the conjunctival hyperemia score, and a decrease in the conjunctival hyperemia score and a negative change in the conjunctival hyperemia score (after administration) from the baseline (before administration) are also referred to as a conjunctival hyperemia removal effect.

[0058] Furthermore, the composition of the present disclosure does not weaken its effect of improving, alleviating, or suppressing conjunctival congestion even when used continuously for a certain period of time. Even when used continuously for a certain period of time, for example, 3, 5, 7, 10, 12, or 14 days, the conjunctival congestion score is reduced from that before administration of the composition 1 minute, 5 minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, or 120 minutes after starting administration of one drop of the composition, and the conjunctival congestion score is preferably reduced to 1 or less, 0.5 or less, or 0.

[0059] The composition of the present disclosure is not limited to be administered to a particular subject, but is preferably administered to a subject whose conjunctival hyperemia score before administration of the composition is greater than 0, greater than 0.5, greater than 1, or 1.5 or greater, and is preferably administered to a subject whose conjunctival hyperemia score before administration of the composition is less than 4, less than 3.5, less than 3, or 2.5 or less.

[0060] The composition of the present disclosure is not limited to administration to a specific subject, but is preferably administered to a subject who is not currently receiving treatment for an eye disease diagnosed by a physician, and more preferably to a subject who has not received treatment for an eye disease within the past two days, five days, seven days, or 14 days. It is also preferably administered to a subject who has not been diagnosed by a physician as having an eye disease. Examples of eye diseases include allergic conjunctivitis or infectious conjunctivitis, and more preferably include infections of the eye or ocular adnexa, allergic diseases, proliferative diseases, or severe dry eye syndrome.

[0061] Although the composition of the present disclosure is not limited to administration to a specific subject, it is preferably administered to a subject who does not have any subjective ocular symptoms other than conjunctival hyperemia, including one or more of itchy eyes, eye discharge, watery eyes, sore eyelids, swelling of the eyelids, blurred vision, localized hyperemia, severe eye pain, and sudden loss of vision.

[0062] The composition of the present disclosure may or may not be used in combination with other drugs that have the effect of improving, alleviating, or suppressing conjunctival hyperemia.The composition of the present disclosure can exhibit the effect of immediately and sustainedly improving, alleviating, or suppressing conjunctival hyperemia without the concomitant use of other drugs, such as corticosteroids, vasoconstrictors, or antihistamines.Therefore, despite the relatively low concentration of brimonidine or a pharmaceutically acceptable salt thereof, the composition of the present disclosure can exhibit the effect of improving, alleviating, or suppressing conjunctival hyperemia even without the concomitant use of other drugs that have the effect of improving, alleviating, or suppressing conjunctival hyperemia.

[0063] The compositions of the present disclosure are not limited to be administered to any particular subject, but are preferably administered to subjects who have not undergone eye surgery within the past 10 days, the past month, the past 3 months, or the past 6 months.

[0064] All documents mentioned herein are incorporated by reference in their entirety.

[0065] The composition of the present disclosure will be described in more detail below using examples, but the composition of the present disclosure is not limited thereto in any way.

[0066] Example 1 Confirmation of Conjunctival Hyperemia Removal Effect on Conjunctival Hyperemia Not Caused by Eye Disease In this example, a test was conducted on Japanese subjects with conjunctival hyperemia not caused by eye disease, and efficacy and safety evaluations were performed to determine the optimal clinical dose.

[0067] 1. Study Design This study was conducted in Japanese subjects (including elderly subjects aged 65 years or older) with conjunctival hyperemia not attributable to ocular disease. The study was a single-center, randomized, double-masked, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and clinical optimum dose of 0.01 w / v% or 0.025 w / v% brimonidine ophthalmic solutions administered bilaterally, one drop per eye, four times daily for 14 days. The 0.01 w / v% brimonidine ophthalmic solution contained 0.01 w / v% brimonidine tartrate, and the 0.025 w / v% brimonidine ophthalmic solution contained 0.025 w / v% brimonidine tartrate. Participants were screened to determine whether they met the inclusion and exclusion criteria listed below between 14 days and 1 day before the start of administration (Day 1). The day of screening was designated as the screening test date. Prior to screening, the physician fully explained the study and obtained written, voluntary consent from the subject. Subjects enrolled through screening were assigned to a placebo group, a 0.01 w / v% brimonidine ophthalmic solution group, or a 0.025 w / v% brimonidine ophthalmic solution group, and each group received one drop of brimonidine ophthalmic solution in each eye, four times daily, for 14 days (treatment period). On Day 1 and the final day of ophthalmic solution administration (Day 14), the ophthalmic solution was administered in each eye, one drop per day, once daily.

[0068] 2. Dosage and Administration Methods Placebo eye drops, 0.01 w / v% brimonidine eye drops, or 0.025 w / v% brimonidine eye drops shown in Table 1 below were administered to both eyes, one drop per eye, four times a day (9:00 ± 60 minutes, 13:00 ± 60 minutes, 17:00 ± 60 minutes, and 21:00 ± 60 minutes) for 14 days. On Day 1 (the start of the treatment period (the start of eye drop administration)) and Day 14 (the end of the treatment period (the final day of eye drop administration)), one drop per eye was administered once a day (9:00 ± 60 minutes). Each eye drop was used in a 5 mL eye dropper container. On Day 1 and Day 14, eye drops were administered at a medical institution, and on Days 2 to 13, eye drops were administered at home (eye drops were not administered at home on Days 1 and 14).

[0069] (A) Concomitant medications Concomitant use of the following medications (including over-the-counter drugs) was prohibited from 14 days before the start of administration until the end of the treatment period. Concomitant use of topical ocular medications that fall under 4) below was prohibited for both eyes: 1) Non-topical ocular corticosteroids 2) Non-topical ocular vasoconstrictors (e.g., topical nasal vasoconstrictors) 3) Non-topical ocular antihistamines 4) All topical ocular medications except for diagnostic drugs used in ophthalmic examinations (e.g., eye drops, eye ointments, intraocular injections, topical application to the skin around the eyelids, etc.)

[0070] (B) Concomitant Treatments The following treatments were prohibited from the screening test date until the end of the treatment period: 1) Surgery of the eye or ocular adnexa (e.g., cataract surgery, corneal refractive surgery, lacrimal surgery, various laser therapies) 2) Wearing contact lenses

[0071] 3. Selection of subjects (screening) Subjects will have conjunctival hyperemia not due to ocular disease, and both eyes will be evaluated for efficacy and safety. 3-1. Selection criteria Subjects who met all of the following selection criteria were eligible for inclusion in the study. (A) Items to be confirmed when obtaining consent: 1) Subjects who have received a sufficient explanation regarding participation and have given their own voluntary written consent. If the subject is under 20 years of age, written consent must be obtained from the subject himself / herself as well as a legal representative who will consider the subject's best interests. 2) Japanese (regardless of gender) aged 15 years or older at the time of obtaining informed consent. (B) Items to be confirmed at screening and before administration of eye drops on the first day of administration (Day 1): 3) Subjects with a conjunctival hyperemia score of greater than 1 in both eyes that is not due to ocular disease (the method for assessing the conjunctival hyperemia score will follow the method described below in "Confirmation of conjunctival hyperemia"). 4) Subjects whose average intraocular pressure measured three times in both eyes is 10.0 mmHg or more and 20.0 mmHg or less (the method for measuring intraocular pressure will follow the method described below in "Confirmation of intraocular pressure").

[0072] 3-2. Exclusion criteria: The main exclusion criteria are listed below. Subjects who met any of the following criteria were excluded from the study. (A) Items to be confirmed at screening: 1) Subjects who have previously received eye drops containing brimonidine tartrate in either eye 2) Subjects who have had eye surgery (including cosmetic eye procedures) within the past 6 months before Day 1 3) Subjects who are unable to discontinue wearing contact lenses regardless of their use 4) Subjects with a best corrected visual acuity of less than 1.0 in either eye (B) Items to be confirmed at screening and before administration of eye drops on the first day of administration (Day 1): 5) Subjects who have been diagnosed by a physician with an active or unstable disease in either eye (including infections of the eyeball or ocular adnexa, allergic diseases, proliferative diseases, and severe dry eye syndrome) 6) Subjects with glaucoma or ocular hypertension in either eye 7) Subjects who are at risk of developing eye symptoms due to allergies during the period up to the end of the treatment period 8) Persons with subjective symptoms other than conjunctival congestion (itchy eyes, eye discharge, watery eyes, sore eyelids, swelling of the eyelids, blurred vision, localized congestion, severe eye pain, sudden loss of vision, etc.) 9) Persons who are planning to use any of the drugs listed above as "Medications that should not be used in combination" or who are planning to undergo any of the treatments listed above as "Prohibited concomitant treatments" within the specified period.

[0073] 4. Examination Method 1) Confirmation of Conjunctival Hyperemia A physician observed the conjunctival hyperemia of both eyes using a slit lamp microscope or the like and assessed the conjunctival hyperemia score (Curr Eye Res. 2018 Jan; 43(1): 43-51., Optom Vis Sci. 2018 Mar; 95(3): 264-271.). The conjunctival hyperemia score was assessed using the Ora Calibra® Ocular Hyperemia Scale, where the severity of the conjunctival hyperemia symptom was scored from 0 to 4 on a 5-point scale: none (0), mild (1), moderate (2), severe (3), and very severe (4). The conjunctival hyperemia score could also be assessed in increments of 0.5. The conjunctival hyperemia score was assessed on the screening test day, Day 1 (before administration, and 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration), and Day 14 (before administration, and 1, 5, 15, and 120 minutes after administration). 2) Confirmation of intraocular pressure A physician or study collaborator measured the intraocular pressure (mmHg) of both eyes three times each using a non-contact tonometer at the time of screening and before administration of the eye drops on the day eye drops administration began (Day 1), and the average of the three measurements was obtained.

[0074] 5. Evaluation of Efficacy and Safety (A) Efficacy To evaluate efficacy, the average conjunctival hyperemia score of both eyes was used. Efficacy was evaluated using the following three items: i) Change from baseline in the period-averaged conjunctival hyperemia score 5, 15, 30, 60, 90, 120, 180, and 240 minutes after administration of eye drops on Day 1: Missing data for the change from baseline (value before administration of eye drops on Day 1) in the period-averaged conjunctival hyperemia score 5, 15, 30, 60, 90, 120, 180, and 240 minutes after administration of eye drops on Day 1 were imputed using last observation carried forward, and analysis was performed using mixed-effect models for repeated measures. The model was as follows: Change in conjunctival hyperemia score = treatment group + assessment time point + interaction between treatment group and assessment time point + baseline conjunctival hyperemia score. The variance-covariance structure was Unstructured, the estimation method was restricted maximum likelihood, and the Kenward-Roger method was used to estimate the degrees of freedom. The least-squares mean and standard error of the average change over time were calculated for each treatment group. The difference in the least-squares mean change over time between treatment groups (0.01 w / v% brimonidine ophthalmic solution group - placebo ophthalmic solution group, and 0.025 w / v% brimonidine ophthalmic solution group - placebo ophthalmic solution group) and its 95% two-sided confidence interval were calculated. A two-sided hypothesis test was performed, and adjusted P values ​​were calculated using Dunnett's multiple comparisons method. ii) Actual Measured Conjunctival Hyperemia Score at Each Evaluation Time Point on Day 1: The mean and standard error were calculated for each administration group for the actual measured conjunctival hyperemia score at each evaluation time point (1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes) after administration on Day 1. A two-tailed P value was calculated by t-test for the difference in mean values ​​between the administration groups (0.01 w / v% brimonidine ophthalmic solution administration group - placebo ophthalmic solution administration group, and 0.025 w / v% brimonidine ophthalmic solution administration group - placebo ophthalmic solution administration group).iii) Number of subjects with a conjunctival hyperemia score of 0 at each evaluation time point on Day 1 and Day 14: The number of subjects with a conjunctival hyperemia score of 0 at each evaluation time point on Day 1 and Day 14 was counted as a frequency for the 0.01 w / v% brimonidine ophthalmic solution group and the 0.025 w / v% brimonidine ophthalmic solution group.

[0075] (B) Safety To evaluate safety, adverse events were investigated. Doctors investigated adverse events from the start of administration of the eye drops to the end of the study. If there was at least a reasonable possibility of a causal relationship between the eye drops and the adverse event and the causal relationship could not be denied, the event was considered to be a causal relationship and was recorded as a side effect.

[0076] (Results) The number of subjects enrolled through screening was 17 in the 0.01 w / v% brimonidine ophthalmic solution group, 17 in the 0.025 w / v% brimonidine ophthalmic solution group, and 17 in the placebo ophthalmic solution group. (A) Efficacy i) As shown in Table 2, the least squares means of the changes from baseline (before administration of the ophthalmic solution on the day of evaluation) in the conjunctival hyperemia score at 5, 15, 30, 60, 90, 120, 180, and 240 minutes after administration of the ophthalmic solution on Day 1 were almost the same in the 0.01 w / v% brimonidine ophthalmic solution group and the 0.025 w / v% brimonidine ophthalmic solution group. ii) As shown in Figure 1, starting 5 minutes after administration of the eye drops on Day 1, both the 0.01 w / v% brimonidine ophthalmic solution group and the 0.025 w / v% brimonidine ophthalmic solution group showed a significant improvement in conjunctival hyperemia score (conjunctival hyperemia decongestant effect) compared with the placebo group, and this effect continued for up to 360 minutes after administration. In particular, a significant difference was observed between the 0.01 w / v% brimonidine ophthalmic solution group and the placebo group starting 1 minute after administration. iii) As shown in Table 3, the number of subjects who achieved a conjunctival hyperemia score of 0 at each evaluation time point on Day 1 and Day 14 was tabulated based on the frequency for the 0.01 w / v% brimonidine ophthalmic solution group and the 0.025 w / v% brimonidine ophthalmic solution group. As a result, on both Day 1 and Day 14, the number of subjects whose conjunctival hyperemia achieved a score of 0 tended to be higher in the 0.01 w / v% brimonidine ophthalmic solution group than in the 0.025 w / v% brimonidine ophthalmic solution group.

[0077] (B) Safety No adverse events were observed in either the 0.01 w / v % brimonidine ophthalmic solution administration group or the 0.025 w / v % brimonidine ophthalmic solution administration group.

[0078] From the above results, the clinical optimum dose of brimonidine ophthalmic solution was considered to be 0.01 w / v% brimonidine ophthalmic solution, one drop per eye, up to four times a day.

[0079] Example 2 Subgroup Analysis of Conjunctival Reduction Effect on Conjunctival Reduction Not Caused by Ocular Disease In this example, a test was conducted on Japanese subjects with conjunctival redness not caused by ocular disease, and the conjunctival reduction effect was confirmed as an efficacy evaluation. Regarding the conjunctival reduction effect, the subjects were divided into subgroups based on the subject's age and the subject's pulse rate before administration, and the therapeutic effect of the ophthalmic solution of the present disclosure was analyzed.

[0080] 1. Study Design This study was a multicenter, randomized, double-masked, placebo-controlled, parallel-group study conducted in Japanese subjects with conjunctival hyperemia not attributable to ocular disease to evaluate the efficacy and safety of 0.01 w / v% brimonidine ophthalmic solution administered bilaterally, one drop per eye, four times daily for 14 days. The 0.01 w / v% brimonidine ophthalmic solution contains brimonidine tartrate at a concentration of 0.01 w / v%. Screening was conducted between 14 days and 1 day before the start of ophthalmic solution administration (Day 1) to determine whether subjects met the inclusion and exclusion criteria listed below. The day of screening was designated the screening examination date. Before participants participated in the study, a physician fully explained the study to them and obtained their voluntary consent via a consent form. Subjects enrolled through screening were assigned to either a 0.01 w / v% brimonidine ophthalmic solution group or a placebo group, and each group received one drop per eye, four times a day, for 14 days (treatment period). Note that on Day 1 and the final day of ophthalmic solution administration (Day 14), one drop per eye was administered once a day to both eyes.

[0081] 2. Dosage and Administration Methods 0.01 w / v% brimonidine ophthalmic solution or placebo ophthalmic solution shown in Table 4 was administered to both eyes, one drop per eye, four times a day (9:00 ± 60 minutes, 13:00 ± 60 minutes, 17:00 ± 60 minutes, 21:00 ± 60 minutes) for 14 days. On Day 1 (the start of the treatment period (the start of ophthalmic solution administration)) and Day 14 (the end of the treatment period (the final day of ophthalmic solution administration)), one drop per eye was administered once a day (9:00 ± 60 minutes). Each ophthalmic solution was used in a 5 mL eye dropper container. On Day 1 and Day 14, eye drops were administered at a medical institution, and on Days 2 to 13, eye drops were administered at home (eye drops were not administered at home on Days 1 and 14).

[0082] (A) Concomitant medications Concomitant use of the following medications (including over-the-counter drugs) was prohibited from 14 days before the start of administration until the end of the treatment period. Concomitant use of topical ocular medications that fall under 4) below was prohibited for both eyes: 1) Corticosteroids 2) Vasoconstrictors (e.g., topical vasoconstrictors for nasal administration) 3) Antihistamines 4) All topical ocular medications except for diagnostic drugs used in ophthalmic examinations (e.g., eye drops, eye ointments, intraocular injections, topical application to the skin around the eyelids, etc.)

[0083] (B) Concomitant Treatments The following treatments were prohibited from the screening test date until the end of the treatment period: 1) Surgery of the eye or ocular adnexa (e.g., cataract surgery, corneal refractive surgery, lacrimal surgery, various laser therapies) 2) Wearing contact lenses

[0084] 3. Selection of subjects (screening) Subjects will have conjunctival hyperemia not due to ocular disease, and both eyes will be evaluated for efficacy and safety. 3-1. Selection criteria Subjects who met all of the following selection criteria were eligible for inclusion in the study. (A) Items to be confirmed when obtaining consent: 1) Subjects who have received a sufficient explanation regarding participation and have given their own voluntary written consent. If the subject is under the age of 18, written consent must be obtained from the subject in addition to a legal representative who will consider the subject's best interests. 2) Japanese (regardless of gender) aged 15 years or older at the time of obtaining consent. (B) Items to be confirmed at screening and before administration of eye drops on the first day of administration (Day 1): 3) Subjects with a conjunctival hyperemia score of more than 1 and less than 3 in both eyes that is not due to ocular disease (the method for assessing the conjunctival hyperemia score will follow the method described below in "Confirmation of conjunctival hyperemia"). 4) Subjects with an average intraocular pressure of 10.0 mmHg or more and 20.0 mmHg or less after three measurements in both eyes (the method for measuring intraocular pressure will follow the method described below in "Confirmation of intraocular pressure").

[0085] 3-2. Exclusion criteria: The main exclusion criteria are listed below. If any of the following criteria apply, the subject was excluded from the study. (A) Items to be confirmed at screening: 1) Persons who have previously received eye drops containing brimonidine tartrate in either eye. 2) Persons who have had ocular surgery (e.g., intraocular surgery, laser therapy, eye surgery involving incision of the cornea, limbus, or sclera, pterygium surgery, cosmetic eye surgery or treatment) within the past 6 months before Day 1. 3) Persons who are unable to discontinue wearing contact lenses regardless of their use. 4) Persons with best corrected visual acuity of less than 1.0 in either eye. (B) Items to be confirmed at screening and before administration of eye drops on Day 1: 5) Persons who have been diagnosed by a physician with an active or unstable disease in either eye (including infections of the eyeball or ocular adnexa, allergic diseases, proliferative diseases, and severe dry eye). 6) Persons with glaucoma or ocular hypertension in either eye. 7) Persons who are at risk of developing eye symptoms due to allergies during the period from the date of screening to the end of the treatment period. 8) Persons with subjective symptoms other than conjunctival congestion (itchy eyes, eye discharge, watery eyes, sore eyelids, swelling of the eyelids, blurred vision, localized congestion, severe eye pain, sudden loss of vision, etc.) 9) Persons who are planning to use any of the drugs listed above as "Medications that should not be used in combination" or who are planning to undergo any of the treatments listed above as "Prohibited concomitant treatments" within the specified period.

[0086] 4. Examination Method 1) Confirmation of Conjunctival Hyperemia A physician observed the conjunctival hyperemia of both eyes using a slit lamp microscope or the like and assessed the conjunctival hyperemia score (Curr Eye Res. 2018 Jan; 43(1):43-51., Optom Vis Sci. 2018 Mar; 95(3):264-271.). The conjunctival hyperemia score was assessed using the "Ora Calibra (registered trademark) Ocular Hyperemia Scale" by scoring the severity of the conjunctival hyperemia symptom from 0 to 4 on a 5-point scale: none (0), mild (1), moderate (2), severe (3), and very severe (4). The conjunctival hyperemia score could also be assessed in increments of 0.5. The conjunctival hyperemia score was assessed on the screening test day, Day 1 (before administration, 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration), and Day 14 (before administration, 1, 5, 15, and 120 minutes after administration). 2) Confirmation of pulse rate: After the subject rested in a sitting position for at least 5 minutes, the physician, study collaborator, or nurse measured the pulse rate (beats / min) in the sitting position. The test was conducted before administration of the eye drops on Day 1. The eye drops on Day 1 were administered between 8:00 and 10:00 AM. 3) Confirmation of intraocular pressure: The physician or study collaborator measured the intraocular pressure (mmHg) of both eyes three times using a non-contact tonometer at the time of screening and on the day eye drops administration began (Day 1), before administration, and the average of the three measurements was obtained.

[0087] 5. Subgroup analysis for efficacy The subjects were divided into subsets based on their age or their pulse rate before administration, and the change in conjunctival hyperemia score from baseline (before administration of the eye drops on Day 1) at each evaluation time point, 1, 5, 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after administration of the eye drops on Day 1, was calculated. The difference in the change between the 0.01 w / v% brimonidine ophthalmic solution group and the placebo group was then calculated using the following formula. Change from baseline = (mean actual conjunctival hyperemia score at each evaluation time point for each group and subgroup) - (mean actual conjunctival hyperemia score at baseline for each group and subgroup) Difference in each change between the 0.01 w / v% brimonidine ophthalmic solution group and the placebo group = (change from baseline in the 0.01 w / v% brimonidine ophthalmic solution group) - (change from baseline in the placebo group) Each change was calculated for each evaluation time point for each group and subgroup. The difference in change between the 0.01 w / v% brimonidine ophthalmic solution group and the placebo group represents the effect of 0.01 w / v% brimonidine ophthalmic solution on deconjunctival hyperemia (change from baseline in the conjunctival hyperemia score due to 0.01 w / v% brimonidine ophthalmic solution).

[0088] (Results) The number of subjects enrolled through screening was 109 in the 0.01 w / v% brimonidine ophthalmic solution group and 22 in the placebo ophthalmic solution group. The change from baseline in conjunctival hyperemia score after 0.01 w / v% brimonidine ophthalmic solution is shown in Figures 2 and 3. Subgroup analysis by age in the 0.01 w / v% brimonidine ophthalmic solution group included 92 subjects aged 40 years or older and 17 subjects under 40 years old. Subgroup analysis by age in the placebo group included 20 subjects aged 40 years or older and 2 subjects under 40 years old. The results of this subgroup analysis showed that 0.01 w / v% brimonidine ophthalmic solution was more effective in removing conjunctival hyperemia on the first day of administration in subjects aged 40 years or older than in subjects under 40 years old, particularly after 15 minutes of administration (Figure 2). It was found that in the group of subjects aged 40 years or older, a high conjunctival decongestant effect was maintained up to 480 minutes after administration on the first day of administration, compared to the group of subjects under 40 years of age.

[0089] In addition, a subgroup analysis based on pre-administration pulse rate in the 0.01 w / v% brimonidine ophthalmic solution group included 75 subjects with a pre-administration pulse rate of less than 80 beats / min and 34 subjects with a pre-administration pulse rate of 80 beats / min or higher. In the placebo group, a subgroup analysis included 14 subjects with a pre-administration pulse rate of less than 80 beats / min and 8 subjects with a pre-administration pulse rate of 80 beats / min or higher. This subgroup analysis showed that 0.01 w / v% brimonidine ophthalmic solution was more effective in removing conjunctival congestion on the day of administration in subjects with a pre-administration pulse rate of less than 80 beats / min compared to subjects with a pre-administration pulse rate of 80 beats / min or higher, particularly from 15 minutes after administration (Figure 3). It was also found that in the group of subjects with a pulse rate of less than 80 beats per minute, a high conjunctival decongestant effect was maintained up to 360 minutes after administration compared to the group of subjects with a pulse rate of 80 beats per minute or more.

[0090] When the time course of the conjunctival hyperemia score for all subjects in the 0.01 w / v% brimonidine ophthalmic solution administration group was examined, the actual conjunctival hyperemia score measurements (1 minute, 5 minutes, 15 minutes, and 120 minutes after administration of the ophthalmic solution) on Day 1 and Day 14 showed almost the same time course, confirming a similar decrease in the conjunctival hyperemia score on both Day 1 and Day 14. Therefore, it was confirmed that the conjunctival hyperemia removal effect was not weakened even when 0.01 w / v% brimonidine ophthalmic solution was administered for 14 consecutive days.

[0091] The present disclosure provides a composition for improving, alleviating, or suppressing conjunctival congestion. This technology can be used in fields such as pharmaceuticals.

Claims

1. A composition for improving, alleviating, or suppressing conjunctival hyperemia in a subject, comprising brimonidine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is from about 0.0005% w / v to about 0.02% w / v.

2. The composition of claim 1, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.01 w / v%.

3. The composition according to claim 1 or 2, wherein the conjunctival hyperemia is not caused by an ocular disease.

4. The composition of claim 1 or 2, wherein the conjunctival hyperemia is not due to allergic conjunctivitis.

5. The composition of claim 1 or 2, administered to the subject by instillation, one drop per eye, up to four times per day.

6. The composition of claim 5, wherein the interval between administrations of the composition is 4 hours or more.

7. The composition of claim 1 or 2, wherein the subject is 40 years of age or older.

8. The composition of claim 1 or 2, wherein the subject has a pulse rate of less than about 80 beats per minute prior to administration of the composition.

9. The composition of claim 1 or 2, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

10. The composition according to claim 1 or 2, which is in the form of eye drops.

11. The composition of claim 10, wherein the eye drops are aqueous eye drops.

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