Brimonidine liquid formulation

Abstract

To improve the stability of a liquid preparation for ophthalmic use that comprises brimonidine and / or a salt thereof.SOLUTION: The present inventors have found that the stability can be improved by adding an anti-inflammatory and astringent agent. Based on this finding, provided is a liquid preparation for ophthalmic use that comprises brimonidine and / or a salt thereof and an anti-inflammatory and astringent agent.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a liquid preparation containing brimonidine and / or a salt thereof.

Background Art

[0002] Brimonidine and its salts are known as α-2 adrenergic receptor agonists. The human eye has many α-2 adrenergic receptors (hereinafter sometimes abbreviated as α-2 receptors), and agonists of α-2 receptors have the effect of reducing intraocular pressure by suppressing aqueous humor production and promoting the outflow of aqueous humor through the uveoscleral outflow pathway. Based on this effect, α-2 receptor agonists have conventionally been used for the treatment of glaucoma and ocular hypertension. In addition, agonists of α-2 receptors have the effect of causing a reduction in the lumen size of α-2 receptor-rich arterioles, particularly terminal arterioles. This effect causes vasoconstriction, reduces eye redness, and increases whiteness, thereby improving the aesthetic appearance of the eye (Patent Document 1: Japanese Patent No. 5671459; Patent Document 2: Japanese Patent No. 5738890).

[0003] Formulation technologies focusing on formulation stability are being investigated for formulations using brimonidine and / or its salts in combination with timolol and / or its salts. For example, Patent Document 3 (JP 2009-533462) discloses that a composition containing approximately 1 to 4.5 mM brimonidine and approximately 2 to 16 mM timolol, with a pH of approximately 7 to 8.5, can suppress the generation of degradation products and improve stability. Furthermore, Patent Document 4 (JP 2017-222707) discloses that by encapsulating eye drops containing brimonidine and / or its salts, and brinzolamide and / or its salts, in a transparent container having a maximum transmittance of 67% or less for light at wavelengths of 360 to 460 nm and a maximum transmittance of 78% or less for light at wavelengths of 600 to 680 nm, the degradation of brimonidine and / or its salts due to light exposure can be suppressed, and formulation stability can be ensured. Furthermore, Patent Document 5 (Japanese Patent Publication No. 2020-33290) discloses that by including an amino compound such as chlorhexidine in an aqueous composition containing brimonidine, the decrease in the content of brimonidine in the aqueous composition during high-temperature storage can be suppressed.

[0004] When formulating eye drops, one or more active ingredients are combined with well-known additives. However, it's not possible to arbitrarily combine active ingredients and additives during formulation; the compatibility between active ingredients and between active ingredients and additives must be considered, and the overall stability, efficacy, and safety of the formulation must be evaluated. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Patent No. 5671459 [Patent Document 2] Patent No. 5738890 [Patent Document 3] Special Publication No. 2009-533462 [Patent Document 4] Japanese Patent Publication No. 2017-222707 [Patent Document 5] Japanese Patent Publication No. 2020-33290 [Overview of the project] [Problems that the invention aims to solve]

[0006] Brimonidine and / or its salts must have high stability in order to be formulated as an ophthalmic liquid formulation to relieve or suppress conjunctival hyperemia. [Means for solving the problem]

[0007] Therefore, the present inventors investigated ingredients that improve the stability of brimonidine and / or its salts, and found that the stability of brimonidine and / or its salts can be improved by incorporating at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or its salts and zinc salts.

[0008] As one embodiment of the present invention, the following ophthalmic liquid formulation is provided. [1] An ophthalmic liquid preparation containing at least one anti-inflammatory and astringent agent selected from the group consisting of 0.01 w / v% to 0.05 w / v% brimonidine and / or its salts, berberine and / or its salts, and zinc salts. [2] The ophthalmic liquid preparation according to item 1, wherein the berberine and / or salt thereof is berberine sulfate. [3] An ophthalmic liquid formulation according to item 1 or 2, wherein the concentration of berberine and / or its salt is 0.005 to 0.025 w / v%. [4] An ophthalmic liquid formulation as described in any one of items 1 to 3, having a pH of 5.0 to 9.0. [5] The ophthalmic liquid preparation described in item 1, wherein the zinc salt is zinc lactate or zinc sulfate. [6] The ophthalmic liquid formulation according to item 1 or 4, wherein the concentration of the zinc salt is 0.05 to 0.25 w / v%. [7] An ophthalmic liquid preparation according to any one of items 1, 5, and 6, wherein the pH is 5.0 to 7.0.

[0009] Furthermore, as an embodiment of the present invention, the following light stabilization method is provided. [8] A method for photostabilizing brimonidine and / or a salt in an ophthalmic liquid formulation, characterized by incorporating at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or a salt thereof and zinc salts, in an ophthalmic liquid formulation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof.

[0010] Furthermore, as an embodiment of the present invention, the following light stabilizer is provided. [9] A photostabilizer for brimonidine and / or salts used in ophthalmic liquid formulations containing 0.01-0.05 w / v% brimonidine and / or salts thereof, the photostabilizer comprising at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or salts thereof and zinc salts. [Effects of the Invention]

[0011] According to the present invention, the stability of an ophthalmic liquid formulation containing brimonidine and / or a salt thereof can be improved by adding at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or a salt thereof, and zinc salts. [Modes for carrying out the invention]

[0012] Terms used herein are understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Numerical ranges specified herein include their lower and upper limits.

[0013] (definition) In this specification, "brimonidine" refers to the compound with the IUPAC name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine. Also, in this specification, unless otherwise specified, the concentration of brimonidine and / or its salt is the concentration converted to brimonidine tartrate.

[0014] In this specification, "low-concentration brimonidine" refers to brimonidine at a concentration of 0.05 w / v% or less.

[0015] In this specification, an "ophthalmic liquid preparation" is an aqueous liquid preparation with water as the base, and refers to an ophthalmic preparation, particularly a preparation used for eye drops.

[0016] In this specification, "photo stability" refers to the degree to which the content of brimonidine and / or its salt in the preparation is maintained after the ophthalmic liquid preparation is exposed to a certain amount of light.

[0017] In this specification, "photo stabilization" means suppressing the decrease in the content of brimonidine and / or its salt in the ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, and maintaining a higher residual rate of brimonidine and / or its salt. As an example, after filling an ophthalmic liquid preparation containing brimonidine and / or its salt into a colorless glass ampoule and exposing it to white light of 600,000 lx·hr, compared with the case where it does not contain at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or its salt, and zinc salt, it means that the content of brimonidine and / or its salt is maintained, that is, the residual rate of brimonidine and / or its salt is higher.

[0018] In this specification, a "photo stabilization method" means a method performed to suppress the decrease in the content of brimonidine and / or its salt in the ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation and maintain a higher residual rate of brimonidine and / or its salt.

[0019] As used herein, the "light stabilizer" refers to an agent formulated to suppress the decrease in the content of brimonidine and / or its salt in an ophthalmic liquid preparation due to exposure to a certain amount of light and to maintain a higher residual rate of brimonidine and / or its salt.

[0020] (Description of Preferred Embodiments) Preferred embodiments of the present invention are described below. It is understood that the embodiments provided below are for better understanding of the present invention and that the scope of the present invention should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present invention by referring to the descriptions in this specification. It is also understood that the following embodiments can be used alone or in combination.

[0021] An ophthalmic liquid preparation according to an embodiment of the present invention contains brimonidine and / or its salt, and further contains at least one anti-inflammatory and astringent agent selected from the group consisting of berberine and / or its salt, and zinc salt.

[0022] Examples of the salt of brimonidine include any salt as long as it is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, ascorbate, maleate, methanesulfonate, tartrate, and other inorganic carboxylates well known to those skilled in the art, and preferably tartrate.

[0023] In the present invention, low-concentration brimonidine refers to brimonidine at a concentration of 0.05 w / v% or less. As an example, the upper limit of the concentration may be 0.04 w / v% or 0.03 w / v% from the viewpoint of preventing side effects. The lower limit of the concentration is not limited as long as brimonidine is contained, but 0.01 w / v% may be used, and as an example, 0.015 w / v% or 0.02 w / v% may be used in view of the effect of this agent.

[0024] In the present invention, the anti-inflammatory and astringent agent may be selected from berberine and / or its salts and zinc salts. Any salt that is pharmaceutically acceptable can be used as a salt of berberine. Examples of pharmaceutically acceptable salts of berberine include chloride, hydrochloride, sulfate, tannate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, ascorbate, maleate, methanesulfonate, tartrate, and other inorganic carboxylate salts well known to those skilled in the art. For example, berberine chloride, berberine sulfate, and berberine tannate may be used. Berberine and / or its salts may be in hydrate form. For example, zinc sulfate, zinc lactate, zinc chloride, zinc bromide, zinc iodide, zinc nitrate, zinc phosphate, zinc oxalate, zinc carbonate, and zinc acetate may be used as zinc salts. From the viewpoint of incorporating into eye drops, for example, zinc sulfate and zinc lactate may be used. The zinc salt may be in hydrate form.

[0025] The concentration of the anti-inflammatory and astringent agent can be appropriately selected depending on its type, and more preferably within the range permitted for inclusion in eye drops. Berberine and / or its salt can be included at a concentration of 0.001 to 0.05 w / v%. From the viewpoint of improving stability and exhibiting anti-inflammatory and astringent effects, the lower limit of the concentration of berberine and / or its salt can be selected to be, for example, 0.002 w / v%, 0.005 w / v%, or 0.0125 w / v%. From the viewpoint of inclusion in eye drops, the upper limit of the concentration of berberine and / or its salt can be selected to be 0.03 w / v%, or 0.025 w / v%. The concentration of zinc salt can be included at a concentration of 0.025 to 0.5 w / v%. From the viewpoint of improving stability and exhibiting anti-inflammatory and astringent effects, the lower limit of the concentration of zinc salt can be selected to be, for example, 0.05 w / v%, 0.02 w / v%, or 0.125 w / v%. From the perspective of incorporating it into eye drops, the upper limit for the concentration of zinc and / or its salt can be selected as 0.3 w / v% or 0.25 w / v%.

[0026] The conjunctiva is a membrane that covers the sclera, the white of the eye, and the inside of the eyelid, and is mainly composed of conjunctival epithelial cells. The epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatic vessels. The conjunctiva is in contact with 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 that is exposed to the outside world. Because the conjunctiva is exposed to the outside world, it is easily invaded by bacteria and viruses, and inflammation is likely to occur. Even when inflammation is not present, lack of sleep or overuse of the eyes can increase blood flow to supply oxygen and nutrients to the eyes, causing redness. In this invention, for brimonidine and / or its salts to exert the effects of relieving redness, reducing eye redness, or whitening, it is necessary for the active ingredient of the eye drop formulation to reach and act on the capillaries in the conjunctiva.

[0027] In the present invention, the ophthalmic liquid formulation is an aqueous liquid formulation based on water, but may further contain any liquid base that can be used for eye drops. The ophthalmic liquid formulation of the present invention is prepared to have a pH and osmotic pressure acceptable for use as eye drops. The pH of the ophthalmic liquid formulation can be adjusted to 5.0 to 9.0 using a pH adjuster depending on the ingredients, for example, 5.5 to 8.5. When berberine and / or its salts are added to the ophthalmic liquid formulation, the pH can be adjusted to 5.0 to 9.0, and further, a pH of 5.5 to 8.5 can be selected. On the other hand, when zinc salts are added to the ophthalmic liquid formulation, precipitation occurs at high pH, ​​so the pH can be adjusted to 5.0 to 7.5, for example, a pH of 5.0 to 7.0, and further, a pH of 5.5 to 6.5 can be selected. As an example of the osmotic pressure ratio of the ophthalmic liquid formulation, the amount of ingredients added to the ophthalmic liquid formulation is adjusted so that it is preferably 0.5 to 2.5, more preferably 0.7 to 1.5.

[0028] The ophthalmic liquid formulation of the present invention is preferably an eye drop. The ophthalmic liquid formulation of the present invention may also be a liquid formulation that relieves or suppresses eye redness. Relieving or suppressing eye redness means increasing the whiteness of the white part of the eye, and can also be called eye whitening. From the viewpoint of relieving or suppressing eye redness, the ophthalmic liquid formulation of the present invention preferably contains a low concentration of brimonidine and / or a salt thereof.

[0029] Inflammation is one of the causes of conjunctival congestion. On the other hand, brimonidine and / or its salts act via α-2 receptors, constricting blood vessels and eliminating congestion, but they do not eliminate the cause. Therefore, in ophthalmic liquid formulations containing brimonidine and / or its salts that alleviate or suppress conjunctival congestion, it is preferable to include anti-inflammatory and astringent agents from the viewpoint of suppressing the underlying inflammation.

[0030] For liquid formulations with low photostability, light-shielding containers can be used. However, eye drops are used over a certain period after opening. Using light-shielding containers for eye drops makes it difficult to check the remaining amount and any abnormalities in the contents, so it is desirable to use transparent containers for eye drops. Therefore, providing formulations with high photostability is important. Alternatively, colored transparent containers can be used instead of light-shielding containers.

[0031] The ophthalmic liquid formulation of the present invention may contain any component that can be used in eye drops, as long as it does not impair the effects of the present invention. In addition to brimonidine tartrate, which is the active ingredient of the present invention, any other active ingredients and additives may be included. Examples of such optional components include, but are not limited to, decongestants, focusing function improvers, anti-inflammatory and astringent agents, antihistamines, vitamins, moisturizing and nutritional components, sulfonamides, preservatives, pH adjusters, isotonic agents, thickeners, antioxidants, solubilizers, stabilizers, surfactants, fragrances, or cooling agents. Only one of each category of active ingredients and additives may be used, or multiple types may be used in combination. The following describes optional components, but they may be used for purposes other than those listed. For example, ethanol, which is used as a cooling agent, may also be added to the ophthalmic liquid formulation as a preservative. Although the anti-inflammatory and astringent agents used in this invention are listed as examples of optional components, this does not mean that these components are optional. Rather, it means that other components different from the anti-inflammatory and astringent agents contained in the ophthalmic liquid formulation of this invention may be further added for anti-inflammatory and astringent purposes.

[0032] Vitamins are a general term for organic compounds other than carbohydrates, proteins, and lipids that are essential nutrients in trace amounts for the survival or growth of living organisms, but which cannot be synthesized in sufficient quantities within the organism's body. Vitamins are broadly classified into water-soluble vitamins and fat-soluble vitamins. Examples of water-soluble vitamins include vitamin B and vitamin C (ascorbic acid). Examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, and vitamin K. The manufacturing (import) approval standards for over-the-counter drugs specify the vitamins that can be included in eye drops, and from this perspective, vitamin A, vitamin B, or vitamin E are particularly preferred.

[0033] As vitamin A compounds, retinol and related substances can be used. Examples of retinol-related substances include retinal, retinoic acid, retinol palmitate, and other retinoids, such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, and bexarotene. From the viewpoint of formulation as eye drops, retinol palmitate or retinol acetate is preferred. Since vitamin A compounds act on epithelial cells and induce proliferation, they can be incorporated into eye drops for purposes such as corneal and conjunctival protection. They can also be incorporated into eye drops for the treatment of ophthalmic diseases such as night blindness, conjunctival xerosis, corneal xerosis, and corneal malacia.

[0034] As B vitamins, vitamin B1 (thiamine, etc.), vitamin B2, vitamin B3 (niacin, etc.), vitamin B5, vitamin B6, vitamin B7 (biotin, etc.), vitamin B9 (folic acid, etc.), or vitamin B12 may be used. Vitamins include derivatives such as provitamins and pharmacovigilant salts. Among B vitamins, vitamins B2, B5, B6, or B12 are particularly preferred from the viewpoint of being incorporated into eye drops.

[0035] As vitamin B2, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, or pharmaceutically acceptable salts thereof may be used. Examples of salts include sodium salts and potassium salts. From the viewpoint of formulation as eye drops, flavin adenine dinucleotide sodium is preferred. Vitamin B2 is directly involved in oxidation-reduction and, when used as eye drops, promotes enzymatic respiration metabolism of corneal and conjunctival cells, thereby providing a protective effect on the cornea and conjunctiva. Vitamin B2 may also be incorporated into eye drops for the treatment of keratitis suspected to be related to vitamin B2 deficiency or metabolic disorders.

[0036] As vitamin B5, panthenol, pantothenic acid, or their derivatives or salts can be used. Examples of derivatives or salts of panthenol, pantothene, pantothenyl alcohol, pantothenyl ethyl ether, pantothene pantothenyl alcohol, calcium pantothenate, and sodium pantothenate are examples of panthenol, pantothene, pantothenyl alcohol, calcium pantothenate, and sodium pantothenate. From the viewpoint of use as eye drops, panthenol, calcium pantothenate, or sodium pantothenate are preferred as vitamin B5.

[0037] As vitamin B6, pyridoxal, pyridoxamine, pyridoxine, or pharmaceutically acceptable salts thereof can be used. From the viewpoint of use as eye drops, pyridoxine hydrochloride is preferred. Vitamin B6 is involved in protein metabolism in the body as a coenzyme for amino acid decarboxylases and aminotransferases, and can be incorporated into eye drops to suppress eye strain.

[0038] Vitamin B12 is a compound having a structure in which cobalt is coordinated to the choline ring. Specific examples include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate. Vitamin B12 can be included in eye drops for its pharmacological effects, such as improving tired eyes and eye strain.

[0039] As vitamin E derivatives, tocopherol, tocotrienol, tocofersolan, or their derivatives may be used. Tocopherol and tocotrienol may be α-, β-, γ-, or δ-, and may be either the d-isomer or the dl-isomer. From the viewpoint of use as eye drops, d-α-tocopherol acetate can be given as an example.

[0040] Examples of vitamin C include ascorbic acid or 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 (dihydrotachisterol, calcipotriol, tacalcitol, paricalcitol). Examples of vitamin K include phylloquinone (K1), menaquinone (K2), and menadione (K3).

[0041] Epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof may be used as decongestants.

[0042] Neostigmine methylsulfate can be used as an agent to improve the focusing ability.

[0043] As anti-inflammatory and astringent agents, ε-aminocaproic acid or its salts, allantoin, azulene sulfonic acid or its salts, glycyrrhizic acid or its salts, or lysozyme chloride may be used.

[0044] Diphenhydramine hydrochloride or chlorpheniramine maleate may be used as antihistamines.

[0045] As water-retaining and nutritional components, amino acids or their salts, and chondroitin sulfate sodium ester may be used. In the present invention, amino acids are incorporated into the ophthalmic liquid formulation for the purpose of improving stability and conjunctival penetration, but the same or different amino acids may also be incorporated as water-retaining and nutritional components. Amino acids refer not only to amino acids but also to substances that have a sulfate group instead of a carboxyl group of an amino acid, such as taurine. Examples of amino acids include glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine, and serine. Preferably, aspartic acid, methionine, and glycine are used as amino acids. Amino acids other than glycine may be L-forms, D-forms, or DL-forms.

[0046] Sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, or sulfisomidine sodium may be used as sulfonamides.

[0047] As preservatives, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, benzalkonium chloride, chlorobutanol, sodium chlorite, benzododecinium bromide, chlorhexidine gluconate, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, alkyl polyaminoethylglycine hydrochloride, polyhexamethylene biguanide, boric acid, or borax may be used.

[0048] pH adjusters may include buffers such as citrate buffers, acetate buffers, carbonate buffers, borate buffers, and phosphate buffers, as well as 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.

[0049] Examples of isotonic agents include sugars and salts. 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, disodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. As sugars, any monosaccharide or polysaccharide can be used; for example, glucose, cyclodextrin, xylitol, sorbitol, or mannitol can be used.

[0050] Thickening agents that may be used include sodium chondroitin sulfate, polyvinyl alcohol, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone, or salts thereof.

[0051] Nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyroxapol, and pluronic acid; glycerin, or polyhydric alcohols such as macrogol may be used as solubilizers.

[0052] Examples of stabilizers that can be used include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, EDTA, taurine, or tocopherol.

[0053] Examples of surfactants that can be used include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine salt and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfate, N-acyl taurine salt, polyoxyethylene alkyl ether phosphate, and polyoxyethylene alkyl ether sulfate; or cationic surfactants such as alkylpyridinium salt, alkylamine salt, benzalkonium salt, benzethonium salt, dialkyldimethylammonium salt, and polyhexamethylene biguanide salt. In particular, benzalkonium salt, alkyldiaminoethylglycine salt, polyhexamethylene biguanide salt, benzethonium salt, or dialkyldimethylammonium salt can be used as bactericidal surfactants.

[0054] As fragrances or cooling agents, menthol, ethanol, camphor, geraniol, borneol, menthol, bonito flakes, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, or rose oil may be used.

[0055] All references made herein are incorporated herein by citation in their entirety.

[0056] The embodiments of the present invention described below are for illustrative purposes only and do not limit the technical scope of the invention. The technical scope of the invention is limited solely by the claims. Modifications to the invention, such as additions, deletions, and substitutions of constituent elements of the invention, can be made without departing from the spirit of the invention. [Examples]

[0057] [Test Example 1] Measurement of the stability of brimonidine tartrate 1. Preparation of test eye drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were added to purified water and dissolved. Berberine chloride hydrate (Tokyo Chemical Industries, Ltd.) or zinc sulfate hydrate (Fujifilm Wako Pure Chemical Industries, Ltd.) were then added and dissolved as appropriate. After dissolution, the pH was adjusted with a pH adjuster (hydrochloric acid or sodium hydroxide aqueous solution) to prepare solutions with the compositions shown in Tables 1-5, thereby obtaining the test eye drops for Comparative Examples 1-6 and Examples 1-22. Note that the values ​​in the tables are w / v%, except for pH and residual percentage.

[0058] 2. Photostability Test 5 mL of the test eye drop solution prepared in step 1 was sealed in a glass ampoule and placed in a photostability tester (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.), exposed to 600,000 lx·hr of white light to obtain a degraded product. The brimonidine tartrate content of the degraded and pre-degraded products of each test eye drop solution in the comparative example and examples was measured using a high-performance liquid chromatography system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below. The remaining percentage (%) of brimonidine tartrate was calculated according to the calculation formula shown below.

number

[0059] 3. Measurement of brimonidine tartrate content The brimonidine tartrate content of each test eye drop was measured using high-performance liquid chromatography (HPLC) under the following conditions, both before and after degradation. Column: 4.6mm inner diameter x 15cm length, octadecylsilylated silica gel ("AA12S05-1506WT", manufactured by YMC Corporation) Detector: UV absorbance spectrophotometer (measurement wavelength: 264 nm) Column temperature: 40℃ Mobile phase: Dissolve 5.175 g of ammonium dihydrogen phosphate in 900 mL of water and add 100 mL of acetonitrile for liquid chromatography. Flow rate: about 1mL / min

[0060] [Table 1] By adding 0.025 w / v% berberine chloride hydrate or 0.25 w / v% zinc sulfate hydrate to test eye drops containing brimonidine tartrate at a concentration of 0.01-0.05 w / v%, the photostability of brimonidine tartrate was improved.

[0061] [Table 2] By adding 0.005-0.025 w / v% berberine chloride hydrate or 0.05-0.25 w / v% zinc sulfate hydrate to a test eye drop solution containing 0.025 w / v% brimonidine tartrate, the photostability of brimonidine tartrate was improved.

[0062] [Table 3] By adding 0.005-0.025 w / v% berberine chloride hydrate to test eye drops containing brimonidine tartrate at a concentration of 0.01 w / v% or 0.05 w / v%, the photostability of brimonidine tartrate was improved.

[0063] [Table 4] By adding 0.05-0.25 w / v% zinc sulfate hydrate to test eye drops containing brimonidine tartrate at a concentration of 0.01 w / v% or 0.05 w / v%, the photostability of brimonidine tartrate was improved.

[0064] [Table 5] The pH of test eye drops containing 0.025 w / v% brimonidine tartrate and 0.025 w / v% berberine chloride hydrate or 0.25 w / v% zinc sulfate hydrate was varied. When berberine chloride hydrate was added, the photostability of brimonidine tartrate improved at pH 5.5 to 8.5. When zinc sulfate hydrate was added, the photostability of brimonidine tartrate improved at pH 5.5 to 6.5. On the other hand, when zinc sulfate hydrate was added and the pH was increased, precipitation occurred.

Claims

1. An ophthalmic liquid formulation containing 0.01 w / v% to 0.05 w / v% brimonidine and / or its salts, and at least one anti-inflammatory and astringent agent selected from the group consisting of berberine, its salts and / or their hydrates, and zinc sulfate and / or its hydrate, wherein the pH is 5.0 to 9.0 when berberine, its salts and / or their hydrates are present, and the pH is 5.0 to 7.0 when zinc sulfate and / or its hydrate are present.

2. The ophthalmic liquid formulation according to claim 1, wherein the salt of berberine is berberine sulfate.

3. The ophthalmic liquid formulation according to claim 1, wherein the concentration of berberine, its salt, and / or its hydrate is 0.005 to 0.025 w / v%.

4. The ophthalmic liquid formulation according to claim 1, wherein the concentration of the zinc sulfate and / or its hydrate is 0.05 to 0.25 w / v%.

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