Liquid preparation containing brimonidine

Abstract

To provide a liquid preparation for ophthalmic use which comprises brimonidine or a salt thereof.SOLUTION: On the basis of the finding that a liquid preparation for ophthalmic use containing low-concentration brimonidine with added vitamins has good transferability to the conjunctiva, a liquid preparation for ophthalmic use containing low-concentration brimonidine and vitamins is provided. The low-concentration brimonidine is highly compatible with vitamins and stabilizes the vitamins, which frequently cause reduction in content.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to liquid formulations containing brimonidine or a salt thereof. [Background technology]

[0002] Brimonidine and its salts are known as alpha-2 adrenergic receptor agonists. The human eye contains many alpha-2 adrenergic receptors (hereinafter sometimes abbreviated as alpha-2 receptors). Alpha-2 receptor agonists reduce intraocular pressure by inhibiting aqueous humor production and promoting aqueous humor outflow via the uveoscleral outflow pathway. Based on this effect, alpha-2 receptor agonists have traditionally been used to treat glaucoma and ocular hypertension. Alpha-2 receptor agonists also reduce the lumen size of alpha-2 receptor-rich arterioles, particularly terminal arterioles. This action results in vasoconstriction, reducing redness and increasing whiteness of the eye, thereby improving the aesthetic appearance of the eye (Patent Document 1: Japanese Patent No. 5671459; Patent Document 2: Japanese Patent No. 5738890).

[0003] Regarding formulations containing brimonidine and / or a salt thereof in combination with timolol and / or a salt thereof, formulation technologies focusing on formulation stability have also been investigated. For example, Patent Document 3 (JP 2009-533462 A) discloses that a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5 can suppress the production of degradation products and has improved stability. Furthermore, Patent Document 4 (JP 2017-222707 A) discloses that by containing an eye drop containing brimonidine and / or a salt thereof and brinzolamide and / or a salt thereof in a transparent container having a maximum transmittance of 67% or less for light with wavelengths of 360 to 460 nm and a maximum transmittance of 78% or less for light with wavelengths of 600 to 680 nm, decomposition of brimonidine and / or a salt thereof due to exposure to light can be suppressed, thereby ensuring formulation stability.

[0004] When preparing eye drops, well-known additives are added along with one or more active ingredients. When preparing a formulation, active ingredients and additives cannot be combined arbitrarily, and it is necessary to evaluate the stability, efficacy, safety, etc. of the formulation as a whole, taking into account the compatibility between the active ingredients and between the active ingredients and additives. [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 Application Publication No. 2017-222707 Summary of the Invention [Problem to be solved by the invention]

[0006] When brimonidine or its salts are formulated into a liquid ophthalmic preparation for relieving or suppressing eye redness, it is necessary to consider the compatibility of the active ingredients to be blended and to select additives that are compatible with the active ingredients. [Means for solving the problem]

[0007] The present inventors have conducted extensive research with the aim of providing a stabilized ophthalmic liquid formulation containing low concentrations of brimonidine, and have found that liquid formulations containing low concentrations of brimonidine are compatible with vitamins, and that the stability of vitamins, which are prone to content loss, against light or heat is improved.Furthermore, the present inventors have found that ophthalmic liquid formulations containing low concentrations of brimonidine to which vitamins have been added have high conjunctival penetration.

[0008] As one embodiment of the present invention, there is provided the following liquid ophthalmic formulation. [1] An ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or its salts and vitamins. [2] The ophthalmic liquid preparation according to Item 1, wherein the vitamin is at least one selected from the group consisting of vitamin A, vitamin B, and vitamin E. [3] The ophthalmic liquid formulation according to item 2, wherein the vitamin A is retinol palmitate. [4] The ophthalmic liquid formulation according to Item 2, wherein the B vitamins are at least one selected from flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine and / or a salt thereof, panthenol, and pantothenic acid and / or a salt thereof. [5] The ophthalmic liquid formulation according to Item 2, wherein the vitamin E compound is d-α-tocopherol acetate. [6] The ophthalmic liquid formulation according to Item 2, wherein the concentrations of vitamins are 0.01 to 0.05 w / v% for flavin adenine dinucleotide sodium, 0.004 to 0.02 w / v% for cyanocobalamin, 10,000 units / 100 ml to 50,000 units / 100 ml for vitamin A, 0.01 to 0.1 w / v% for pyridoxine and / or a salt thereof, 0.01 to 0.1 w / v% for panthenol and pantothenic acid and / or a salt thereof, and 0.005 to 0.05 w / v% for vitamin E.

[0009] Furthermore, as one embodiment of the present invention, there is provided a photostabilization method as described below. [7] A method for photostabilizing vitamins in an ophthalmic liquid preparation, comprising blending 0.01 to 0.05 w / v% brimonidine and / or a salt thereof in the ophthalmic liquid preparation containing vitamins.

[0010] Furthermore, as one embodiment of the present invention, there is provided the following light stabilizer. [8] A photostabilizer for vitamins in an ophthalmic liquid preparation, characterized by containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, for use in an ophthalmic liquid preparation containing vitamins.

[0011] Furthermore, as one embodiment of the present invention, there is provided a method for thermal stabilization as described below. [9] A method for thermally stabilizing vitamins in an ophthalmic liquid preparation, comprising blending 0.01 to 0.05 w / v% brimonidine and / or a salt thereof in the ophthalmic liquid preparation containing vitamins.

[0012] Furthermore, as one embodiment of the present invention, there is provided the following heat stabilizer.

[10] A thermal stabilizer for vitamins in ophthalmic liquid preparations, characterized by containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, for use in ophthalmic liquid preparations containing vitamins.

[0013] Furthermore, as one embodiment of the present invention, there is provided a method for promoting conjunctival migration as described below.

[11] A method for promoting the conjunctival transfer of brimonidine and / or a salt thereof when administered by eye drop, comprising blending a vitamin with an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof.

[0014] Furthermore, as one embodiment of the present invention, there is provided the conjunctival migration promoter shown below.

[12] A conjunctival transfer promoter for brimonidine and / or a salt thereof when administered by eye drop, characterized by incorporating vitamins into an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof. [Effects of the Invention]

[0015] According to the present invention, an ophthalmic liquid formulation containing low concentrations of brimonidine and vitamins exhibits at least one of the effects of improving the stability of the vitamins against light or heat and improving the transferability of brimonidine to the conjunctiva. DETAILED DESCRIPTION OF THE INVENTION

[0016] It is understood that the terms used in this specification are 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 those skilled in the art to which this invention belongs. The numerical range specified in this specification is intended to include its lower and upper limits.

[0017] (definition) As used herein, "brimonidine" refers to the compound with the IUPAC name 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine. Furthermore, unless otherwise specified, the concentrations of brimonidine and / or its salts are expressed in terms of brimonidine tartrate.

[0018] As used herein, "low concentration brimonidine" refers to brimonidine at a concentration of 0.05 w / v % or less.

[0019] In this specification, "vitamins" is 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 that cannot be synthesized in sufficient amounts within the body of the organism.

[0020] As used herein, the term "ophthalmic liquid preparation" refers to an aqueous liquid preparation based on water.

[0021] As used herein, "photostability" refers to the degree to which the vitamin content in a liquid ophthalmic formulation is maintained after the formulation is exposed to a certain amount of light.

[0022] As used herein, "photostabilization" refers to suppressing the decrease in vitamin content in an ophthalmic liquid formulation due to exposure to a certain amount of light, thereby maintaining a higher vitamin retention rate. For example, when an ophthalmic liquid formulation containing vitamins is filled into a colorless glass ampoule and exposed to 100,000 lx·hr of white light, photostabilization means that the vitamin content is maintained, i.e., the vitamin retention rate is higher, compared to a formulation that does not contain brimonidine.

[0023] As used herein, the term "photostabilization method" refers to a method for suppressing a decrease in the vitamin content in an ophthalmic liquid formulation due to exposure to a certain amount of light in the ophthalmic liquid formulation, and for maintaining a higher residual rate of the vitamins.

[0024] As used herein, the term "photostabilizer" refers to an agent that is incorporated to suppress the decrease in vitamin content in an ophthalmic liquid preparation due to exposure to a certain amount of light and to maintain a higher residual rate of vitamins.

[0025] As used herein, the term "thermal stability" refers to the degree to which the vitamin content in an ophthalmic liquid formulation is maintained after the formulation has been stored at a certain temperature for a certain period of time.

[0026] As used herein, "thermal stabilization" refers to suppressing the decrease in vitamin content in an ophthalmic liquid formulation due to storage at a constant temperature for a certain period of time, thereby maintaining a higher vitamin residual rate. For example, thermal stabilization means that, after an ophthalmic liquid formulation containing vitamins is filled into a colorless glass ampoule and stored at 80°C for 3 days or 1 week, or at 70°C for 1 week, the vitamin content is maintained, i.e., the vitamin residual rate is higher, compared to a formulation not containing brimonidine.

[0027] As used herein, the term "thermal stabilization method" refers to a method for suppressing the decrease in vitamin content in an ophthalmic liquid preparation due to storage at a certain temperature for a certain period of time, and for maintaining a higher residual rate of vitamins.

[0028] As used herein, the term "photostabilizer" refers to an agent that is incorporated to suppress the decrease in vitamin content in an ophthalmic liquid preparation due to storage at a certain temperature for a certain period of time, and to maintain a higher residual rate of vitamins.

[0029] As used herein, the term "conjunctival transferability" is an index showing the ease with which brimonidine in an ophthalmic liquid preparation administered by eye drop transfers to the conjunctiva, which is the site of action.

[0030] As used herein, the term "method for promoting conjunctival transfer" refers to a method carried out to increase the amount of brimonidine in an ophthalmic liquid formulation that transfers to the conjunctiva, the site of action, when administered by eye drop.

[0031] As used herein, the term "conjunctival transport promoter" refers to an agent incorporated to increase the amount of brimonidine transported to the conjunctiva, the site of action, in an ophthalmic liquid formulation administered by eye drop.

[0032] DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will be described below. The embodiments provided below are provided for a better understanding of the present invention, and it is understood 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 in consideration of the description in this specification. It is also understood that the following embodiments can be used alone or in combination.

[0033] The liquid ophthalmic formulation of the present invention contains brimonidine and / or a salt thereof. Pharmaceutically acceptable salts of brimonidine include any 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 known to those skilled in the art, preferably tartrate.

[0034] In the present invention, low-concentration brimonidine refers to brimonidine at a concentration of 0.05 w / v% or less. For example, the upper limit of the concentration may be 0.04 w / v% or 0.03 w / v% in order to prevent side effects. The lower limit of the concentration is not limited as long as brimonidine is contained, but may be 0.01 w / v%. For example, in consideration of the effects of the present drug, 0.015 w / v% or 0.02 w / v% may be used.

[0035] Additives that can be incorporated into the liquid ophthalmic preparation of the present invention include vitamins. Vitamins are broadly divided 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 approval standards for manufacturing (importing) over-the-counter drugs stipulate the vitamins that can be incorporated into eye drops, and from this perspective, vitamin A, vitamin B, and vitamin E are particularly preferred.

[0036] Examples of vitamin A include retinol and its related substances. Examples of retinol-related substances include retinal, retinoic acid, retinol palmitate, and other retinoids, such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, and bexarotene. Retinol palmitate and retinol acetate are preferred for use in eye drops. Vitamin A acts on epithelial cells to induce their proliferation, and can be incorporated into eye drops for purposes such as corneal and conjunctival protection. 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. The content of vitamin A can be expressed as vitamin A potency. When vitamin A is used, it is preferably incorporated at 1,000 to 300,000 units / 100 ml, more preferably 10,000 to 50,000 units / 100 ml. To maximize efficacy, the vitamin A compound may be used in an amount of 15,000 units or more, or 20,000 units or more. To prevent side effects, the vitamin A compound may be used in an amount of 30,000 units or less.

[0037] Examples of B vitamins 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 also include provitamins, which are derivatives, 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.

[0038] Examples of vitamin B2 include riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, and pharmaceutically acceptable salts thereof. Examples of salts include sodium and potassium salts. Flavin adenine dinucleotide sodium is preferred for use in eye drops. Vitamin B2 is directly involved in oxidation-reduction reactions. When used in eye drops, it promotes the enzymatic respiratory metabolism of corneal and conjunctival cells, thereby protecting the cornea and conjunctiva. Vitamin B2 can also be incorporated into eye drops for the treatment of keratitis suspected to be caused by vitamin B2 deficiency or metabolic disorders. When vitamin B2 is used, it is preferably incorporated at 0.001 to 0.5 w / v%, more preferably 0.01 to 0.05 w / v%. To maximize efficacy, vitamin B2 may be used at 0.015 w / v% or more, or even 0.02 w / v% or more. From the viewpoint of suppressing side effects, it may be used at 0.04 w / v % or less, 0.03 w / v % or less, or 0.02 w / v % or less.

[0039] Examples of vitamin B5 include panthenol, pantothenic acid, or derivatives or salts thereof. In addition to panthenol and pantothenic acid, examples of derivatives or salts thereof include pantethine, pantetheine, pantothenyl alcohol, pantothenyl ethyl ether, pantetheine pantothenyl alcohol, calcium pantothenate, and sodium pantothenate. For use as eye drops, panthenol, calcium pantothenate, and sodium pantothenate are preferred as vitamin B5. When vitamin B5 is used, it is preferably formulated at 0.001 to 1 w / v%, more preferably 0.01 to 0.1 w / v%. To maximize efficacy, vitamin B5 may be used at 0.02 w / v% or more, or 0.03 w / v% or more. To suppress side effects, it may be used at 0.08 w / v% or less, or 0.05 w / v% or less.

[0040] Examples of vitamin B6 include pyridoxal, pyridoxamine, pyridoxine, and pharmaceutically acceptable salts thereof. From the viewpoint of use as an eye drop, pyridoxine hydrochloride is preferred. Vitamin B6 is involved in protein metabolism as a coenzyme for amino acid decarboxylase and aminotransferase in the body, and can be incorporated into eye drops to suppress eye fatigue. When vitamin B6 is used, it is preferably incorporated at 0.001 to 1 w / v%, more preferably 0.01 to 0.1 w / v%. From the viewpoint of exerting efficacy, vitamin B6 may be used at 0.02 w / v% or more, or 0.03 w / v% or more. From the viewpoint of suppressing side effects, it may be used at 0.08 w / v% or less, or 0.07 w / v% or less.

[0041] Vitamin B12 is a compound with a structure in which cobalt is coordinated to a corrin ring. Specific examples include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate. Vitamin B12 can be incorporated into eye drops for its pharmacological effects, such as the alleviation of tired eyes and eye strain. When vitamin B12 is used, it is preferably incorporated at 0.001 to 0.1 w / v%, more preferably 0.004 to 0.02 w / v%. From the viewpoint of exerting efficacy, vitamin B12 may be used at 0.008 w / v% or more, or 0.01 w / v% or more. From the viewpoint of suppressing side effects, it may be used at 0.015 w / v% or less, or 0.01 w / v% or less.

[0042] Examples of vitamin E include tocopherol, tocotrienol, tocophersolan, and derivatives thereof. Tocopherol and tocotrienol may be α-, β-, γ-, or δ-tocopherol, and may be either d- or dl-tocopherol. For use as an eye drop, examples include d-α-tocopherol acetate and dl-α-tocopherol acetate. When vitamin E is used, it is preferably formulated at 0.0005 to 1 w / v%, more preferably 0.005 to 0.05 w / v%. From the viewpoint of efficacy, vitamin E may be used at 0.01 w / v% or more, or 0.02 w / v% or more. From the viewpoint of suppressing side effects, it may be used at 0.04 w / v% or less, 0.03 w / v% or less, or 0.02 w / v% or less.

[0043] 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).

[0044] In the present invention, the vitamins in an ophthalmic preparation exhibit the physiological effects that each component normally exhibits, while in an ophthalmic liquid preparation containing brimonidine or a salt thereof, they also exhibit the effect of improving the conjunctival transport of brimonidine or a salt thereof.

[0045] The conjunctiva is a membrane that covers the sclera (the white of the eye) and lines the inside of the eyelid, and is primarily composed of conjunctival epithelial cells. The conjunctival epithelial layer contains blood vessels, fibrous tissue, and lymphatic vessels. It 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 attack and inflammation. Even in the absence of inflammation, lack of sleep or overuse of the eyes can increase blood flow to supply oxygen and nutrients to the eyes, causing congestion. In order for brimonidine to exert its effect of reducing eye redness or whitening in the present invention, the active ingredient of the instilled formulation must reach and act on the capillaries in the conjunctiva.

[0046] Conjunctival penetration is an index of the ease with which the active ingredient of an ophthalmic liquid formulation administered via eye drop reaches the conjunctiva, the site of action. Corneal epithelial cells and conjunctival epithelial cells form tight junctions between cells, forming hydrophobic membranes due to their cell membranes. This restricts the permeation of water-soluble drugs through the cornea and conjunctiva. The intraocular penetration of an instilled drug via the cornea or conjunctiva is determined by measuring the drug concentration in the aqueous humor and conjunctival tissue after instillation. However, measuring intraocular penetration in humans is difficult, and analysis is performed using predictive models based on animal experiments. A simple method for measuring intraocular penetration is based on the octanol / water partition coefficient. The octanol / water partition coefficient can be used to evaluate not only intraocular penetration but also conjunctival penetration.

[0047] In the present invention, the ophthalmic liquid preparation is an aqueous liquid preparation mainly based on water, but may further contain any liquid base that can be used in eye drops. The ophthalmic liquid preparation of the present invention is prepared so as to have a pH and osmolality acceptable for eye drops. The pH of the ophthalmic liquid preparation can be adjusted to 5.0 to 9.0, for example, 5.5 to 8.5, using a pH adjuster. It can also be adjusted to 6.0 to 8.0. The amounts of components added to the ophthalmic liquid preparation are adjusted so that the osmolality ratio of the ophthalmic liquid preparation is preferably 0.5 to 2.5, more preferably 0.7 to 1.5, for example.

[0048] The ophthalmic liquid preparation of the present invention is preferably an eye drop. The ophthalmic liquid preparation of the present invention may be a liquid preparation that relieves or suppresses eye redness. Relieving or suppressing eye redness refers to increasing the whiteness of the white of the eye, which can also be called eye whitening.

[0049] A light-shielding container can be used for liquid preparations with low photostability. However, eye drops are used for a certain period of time after opening. When a light-shielding container is used for eye drops, it becomes difficult to check the remaining amount or any abnormalities in the contents, so it is desirable to use a transparent container for eye drops. Therefore, it is important to provide a preparation with high photostability. Alternatively, a colored transparent container can be used instead of a light-shielding container.

[0050] The ophthalmic liquid formulation of the present invention 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 tartrate, the active ingredient of the present invention, optional active ingredients and additives may be included. Examples of such ingredients include, but are not limited to, decongestants, focus-adjusting agents, anti-inflammatory and astringent agents, antihistamines, vitamins, nutrients, sulfonamides, preservatives, pH adjusters, isotonicity agents, thickeners, antioxidants, solubilizers, stabilizers, surfactants, fragrances, and refreshing agents. These active ingredients and additives may be used singly or in combination from each category.

[0051] As a decongestant, epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof may be used.

[0052] Neostigmine methylsulfate can be used as the accommodative agent.

[0053] As anti-inflammatory and astringent agents, ε-aminocaproic acid, allantoin, berberine or its salts, azulene sulfonic acid or its salts, glycyrrhizic acid or its salts, zinc sulfate, zinc lactate, and lysozyme chloride can be used.

[0054] As the antihistamine, diphenhydramine hydrochloride and chlorpheniramine maleate can be used.

[0055] Amino acids or their salts, and sodium chondroitin sulfate ester may be used as moisturizing and nutrient-retaining components. The amino acids or their salts include, in addition to amino acids, substances with a sulfate group instead of the 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. Preferred amino acids include aspartic acid, methionine, and glycine. The amino acids, excluding glycine, may be L-, D-, or DL-amino acids.

[0056] As the sulfonamide drug, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidine sodium can be used.

[0057] Examples of preservatives that can be used include 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, alkylpolyaminoethylglycine, boric acid, and borax.

[0058] Examples of pH adjusters that can be used 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.

[0059] Examples of the isotonic agent include sugars and salts, and examples of the salts that can be used include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. As the sugar, any monosaccharide or polysaccharide can be used, and examples of the sugar that can be used include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc.

[0060] As the thickener, sodium chondroitin sulfate, polyvinyl alcohol, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone, etc., or salts thereof may be used.

[0061] Examples of solubilizing agents that can be used include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, and Pluronic; and polyhydric alcohols such as glycerin and macrogol.

[0062] Examples of stabilizers that can be used include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, and tocopherol.

[0063] Examples of surfactants that can be used include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts.

[0064] As the fragrance or freshening agent, menthol, ethanol, camphor, geraniol, borneol, menthol, rhubarb, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc. may be used.

[0065] The optional ingredients mentioned above may be used for purposes other than those listed above. For example, ethanol, which is used as a cooling agent, may be added to ophthalmic solutions as a preservative.

[0066] All documents mentioned herein are incorporated by reference in their entirety.

[0067] The following examples of the present invention are for illustrative purposes only and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the claims. The present invention may be modified, for example, by adding, deleting, or substituting components of the present invention, provided that the modifications do not depart from the spirit of the present invention. [Example]

[0068] Test Example 1: Photostability test of sodium flavin adenine dinucleotide 1. Preparation of Eye Drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, brimonidine tartrate (Hinewy Pharma.Tech.Co.,Ltd.) and flavin adenine dinucleotide sodium (Alfa Aesar) were added, and the pH was adjusted to 5.5-8.5 using hydrochloric acid and aqueous sodium hydroxide to prepare solutions with the compositions shown in Tables 1 to 3, and eye drops were obtained. The values ​​in the tables are in w / v% except for pH and residual rate.

[0069] 2. Method for evaluating the photostability of flavin adenine dinucleotide sodium Five mL of the eye drops obtained above was placed in a glass ampoule and exposed to 100,000 lx·hr of white light to obtain a degraded product. The concentrations of sodium flavin adenine dinucleotide in the samples stored at room temperature for one week and in the degraded samples were measured using a high-performance liquid chromatograph system (HPLC, Shimadzu Corporation) under the conditions shown below, and the residual rate (%) of sodium flavin adenine dinucleotide was calculated using the formula shown below. The results, along with the composition of each formulation, are shown in Tables 1 to 3.

[0070] <High-performance liquid chromatography conditions> Column: 4.6 mm inner diameter x 15 cm length, octadecylsilanized silica gel ("Unicil QC18" manufactured by GL Sciences) Detector: ultraviolet absorption photometer (measurement wavelength: 350 nm) Column temperature: 40℃ Mobile phase: Potassium dihydrogen phosphate solution (1 → 500) / methanol for liquid chromatography (750 / 250) Flow rate: approx. 0.5mL / min

[0071] <Residual rate of flavin adenine dinucleotide sodium> The residual rate (%) of flavin adenine dinucleotide sodium was calculated according to the following formula.

number

[0072] [Table 1] [Table 2] [Table 3]

[0073] In Examples 1 to 8, the photostability of flavin adenine dinucleotide sodium was improved by adding brimonidine tartrate. The residual rate was improved by 4.4 to 17.4% compared to Comparative Examples 1 to 6.

[0074] Test Example 2: Thermal stability test of cyanocobalamin 1. Preparation of Eye Drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) and cyanocobalamin (Fujifilm Wako Pure Chemical Industries, Ltd.) were added, and the pH was adjusted to 5.5-8.5 using hydrochloric acid and aqueous sodium hydroxide to prepare solutions with the compositions shown in Tables 4 to 6, and eye drops were obtained. The values ​​in the tables are in w / v% except for pH and residual rate.

[0075] 2. Method for evaluating the thermal stability of cyanocobalamin Five mL of the resulting eye drops was added to a glass ampoule and stored in a thermostatic chamber at 80°C for one week to obtain a degraded product. The cyanocobalamin concentrations in the samples stored at room temperature for four weeks and in the degraded samples were measured using a high-performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual cyanocobalamin rate (%) was calculated according to the following formula. The results, along with the composition of each formulation, are shown in Tables 4 to 6.

[0076] <High-performance liquid chromatography conditions> Column: 4.6 mm inner diameter x 15 cm length, octadecylsilanized silica gel (AA12S05-1506WT, manufactured by YMC Co., Ltd.) Detector: ultraviolet absorption photometer (measurement wavelength: 278 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: approx. 1mL / min

[0077] <Residual rate of cyanocobalamin> The residual rate (%) of cyanocobalamin was calculated according to the following formula.

number

[0078] In Examples 9 to 16, the addition of brimonidine tartrate improved the thermal stability of cyanocobalamin in the pH range of 6.5 to 7.5. The residual rate was improved by 0.8 to 5.2% compared to Comparative Examples 7 to 12.

[0079] Test Example 3: Thermal stability test of d-α-tocopherol acetate 1. Preparation of Eye Drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) and d-α-tocopherol acetate (Combi-Blocks) were added. The pH was adjusted to 5.5-8.5 using hydrochloric acid and aqueous sodium hydroxide to prepare solutions with the compositions shown in Tables 7 and 8, yielding eye drops. The values ​​in the tables are in w / v %. When d-α-tocopherol acetate was added, it was added in a state where it was mixed with polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals) that had been dissolved by heating. The values ​​in the tables are in w / v % except for pH and residual percentage.

[0080] 2. Method for evaluating the thermal stability of d-α-tocopherol acetate Five mL of the resulting eye drops was added to a glass ampoule and stored in a thermostatic chamber at 70°C for one week to obtain a deteriorated product. The concentrations of d-α-tocopherol acetate in the samples stored at room temperature for four weeks and in the deteriorated samples were measured using a high-performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual percentage of d-α-tocopherol acetate (%) was calculated according to the following formula. The results, along with the composition of each formulation, are shown in Tables 7 and 8.

[0081] <High-performance liquid chromatography conditions> Column: 4.6 mm inner diameter x 15 cm length, octylsilanized silica gel ("OC12S05-1546WT" manufactured by YMC Co., Ltd.) Detector: ultraviolet absorption photometer (measurement wavelength: 284 nm) Column temperature: 40℃ Mobile phase: Liquid chromatography grade acetonitrile / water / phosphoric acid mixture (930 / 69 / 1) Flow rate: approx. 1mL / min

[0082] <Residual rate of d-α-tocopherol acetate> The residual rate (%) of d-α-tocopherol acetate was calculated according to the following formula.

number

[0083] [Table 8]

[0084] In Examples 17 to 22, the addition of brimonidine tartrate improved the thermal stability of d-α-tocopherol acetate in the pH range of 6.5 to 8.5. The residual rate was improved by 9.9 to 36.9% compared to Comparative Examples 13 to 16.

[0085] Test Example 4: Photostability test of pyridoxine hydrochloride 1. Preparation of Eye Drops Trometamol (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) and pyridoxine hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.) were added, and the pH was adjusted to 5.5-8.5 using hydrochloric acid and aqueous sodium hydroxide to prepare solutions with the compositions shown in Tables 9 to 11, and eye drops were obtained. The values ​​in the tables are in w / v% except for pH and residual rate.

[0086] 2. Method for evaluating the photostability of pyridoxine hydrochloride Five mL of the resulting eye drops was placed in a glass ampoule and exposed to 100,000 lx·hr of white light to obtain a degraded sample. The pyridoxine hydrochloride concentrations in the samples stored at room temperature for one week and in the degraded samples were measured using a high-performance liquid chromatograph (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual rate (%) of pyridoxine hydrochloride was calculated using the following formula:

[0087] <High-performance liquid chromatography conditions> Column: 4.6 mm inner diameter x 15 cm length, octadecylsilanized silica gel (AA12S05-1546WT, manufactured by YMC Co., Ltd.) Detector: ultraviolet absorption photometer (measurement wavelength: 290 nm) Column temperature: 40℃ Mobile phase: Add 400 mL of acetonitrile for liquid chromatography and 2 g of sodium lauryl sulfate to 600 mL of 0.05 mol / L potassium dihydrogen phosphate test solution, then add phosphoric acid to adjust the pH to 3.5. Flow rate: approx. 1mL / min

[0088] <Residual rate of pyridoxine hydrochloride> The residual rate (%) of pyridoxine hydrochloride was calculated according to the following formula.

number

[0089] Test Example 5: Heat stability test of panthenol 1. Preparation of Eye Drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, brimonidine tartrate (Hinewy Pharma.Tech.Co.,Ltd.) and panthenol (Fujifilm Wako Pure Chemical Industries, Ltd.) were added, and the pH was adjusted to 5.5-8.5 using hydrochloric acid and aqueous sodium hydroxide to prepare solutions with the compositions shown in Tables 12 to 14, thereby obtaining eye drops. The values ​​in the tables are in w / v% except for pH and residual rate.

[0090] 2. Evaluation method for the thermal stability of panthenol 5 mL of the eye drops obtained above was added to a glass ampoule and stored in a thermostatic chamber at 80°C for 3 days to obtain a deteriorated product. The panthenol concentrations in the product stored at room temperature for 4 weeks and the deteriorated product were measured using a high-performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual rate (%) of panthenol was calculated according to the following formula.

[0091] <High-performance liquid chromatography conditions> Column: Guard column (YMC, "AA30S05-G304CC") + 4.6 mm inner diameter x 15 cm length octadecylsilanized silica gel (YMC, "AA30S05-1546WT") Detector: ultraviolet absorption photometer (measurement wavelength: 220 nm) Column temperature: 40℃ Mobile phase: Add 100 mL of liquid chromatography grade methanol to 900 mL of 0.05 mol / L potassium dihydrogen phosphate test solution, then add phosphoric acid to adjust the pH to 3.0. Flow rate: approx. 1mL / min <Panthenol Residual Rate> The residual rate (%) of panthenol was calculated according to the following formula.

number

[0092] Test Example 6: Measurement of the amount of brimonidine tartrate distributed between the octanol layer and the water layer (Prescription) Each sample was prepared using standard methods. Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were dissolved in purified water, followed by flavin adenine dinucleotide sodium (Alfa Aesar), cyanocobalamin (Fujifilm Wako Pure Chemical Industries, Ltd.), retinol palmitate (Fujifilm Wako Pure Chemical Industries, Ltd.), d-α-tocopherol acetate (Combi-Blocks), pyridoxine hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.), or panthenol (Fujifilm Wako Pure Chemical Industries, Ltd.). The pH was adjusted with a pH adjuster and the solution was diluted with purified water. When adding retinol palmitate or d-α-tocopherol acetate, they were added in a mixture with polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals) that had been dissolved in the solution by heating. The values ​​in the table are in w / v% except for the pH and retinol palmitate columns, which are shown in activity units per 100 mL. [Table 15] [Table 16]

[0093] (Test operation) The test solution and 1-octanol (Nacalai Tesque) were mixed according to the following procedure. 1) Plastic centrifuge tubes were filled with 2.5 mL of each test solution and 1-octanol saturated with water. 2) The mixture was mixed for 30 seconds using a vortex mixer (VX100, Labnet International). 3) The mixture was shaken for 30 minutes using a shaker (MW-1, AS ONE) that stirs vertically (300 times / min). 4) The mixture was shaken for 24 hours or more using a horizontally stirring rotary shaker (Universal Shaker SHK-U4, AGC Technoglass) (120 rpm / min). 5) The mixture was mixed for 30 seconds using a vortex mixer (VX100, Labnet International). 6) The octanol layer and the aqueous layer were separated by centrifugation (LC-120, Tomy Seiko) (3,000 rpm, 10 minutes), and the aqueous layer was collected and mixed to prepare the aqueous layer sample.

[0094] (Measurement of Brimonidine Tartrate Content in Test Solution and Aqueous Layer) The brimonidine tartrate content of each test solution and the aqueous layer sample obtained after mixing each test solution with octanol was measured by high performance liquid chromatography (HPLC). Column: 4.6 mm inner diameter x 75 mm length, octadecylsilanized silica gel ("Symmetry C18 3.5" manufactured by Waters) Detector: UV-visible spectrophotometer Measurement wavelength: 264nm Mobile phase: 5.175 g of ammonium dihydrogen phosphate was dissolved in 900 mL of water, and 100 mL of acetonitrile for liquid chromatography was added.

[0095] The amount of brimonidine tartrate that migrated to the octanol layer after mixing of octanol with each sample was calculated from the difference between the amount of brimonidine tartrate in each test solution obtained by measurement and the amount of brimonidine tartrate in the aqueous layer of the sample after mixing. The increase in the amount of brimonidine tartrate that migrated to the octanol layer due to the addition of vitamins (C rate ) was calculated according to the following formula:

number

[0096] [Table 17]

[0097] [Table 18] It has been found that by incorporating at least one vitamin selected from the group consisting of flavin adenine dinucleotide sodium, cyanocobalamin, retinol palmitate, d-α-tocopherol acetate, pyridoxine hydrochloride, and panthenol into a brimonidine tartrate solution, the amount of brimonidine tartrate that migrates to the octanol layer is increased, and the lipid solubility of brimonidine tartrate is improved.

[0098] Test Example 7: Measurement of the amount of brimonidine tartrate transferred to rabbit conjunctiva (Prescription) Each sample was prepared using standard methods. Specifically, boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.), borax (Nacalai Tesque), and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were dissolved in purified water, followed by the addition of d-α-tocopherol acetate or pyridoxine hydrochloride. The pH was then adjusted with a pH adjuster and the solution was diluted with purified water. When adding d-α-tocopherol acetate, it was added in a state where it was mixed with polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals) that had been dissolved by heating. The values ​​in the table, excluding pH, are in w / v%. [Table 19]

[0099] (Test operation) 1-1) Tube 1: Four tubes for each group. The specimen was dispensed into 1 mL sample tubes (1.5 mL microtubes, Zaltostat). 1-2) Tube 2: Four sample tubes with filters (Ultrafree-MC-GV 0.45 μm, Millipore) were prepared for each group. 2) Rabbit eyeballs (Kitayama Labes) were obtained and the conjunctiva was excised. 3) The conjunctiva was washed by immersion in physiological saline (Otsuka saline injection, Otsuka Pharmaceutical Factory). 4) The moisture on the surface was gently wiped off with a Kimwipe, and the conjunctival weight was measured. 5) After measuring the conjunctival weight, the conjunctiva was placed in 1-1) Tube 1 and shaken at 1,500 rpm for 5 minutes using a shaker (Block Bath Shaker - MyBL-100CS, AS ONE). 6) The conjunctiva was removed from the centrifuge tube in 5). 7) 300 μL of the sample was taken from the centrifuge tube in 6) after removing the conjunctiva, added to 1-2) Tube 2, and centrifuged (15,000 rpm, 10 minutes, 4°C) in a tabletop high-speed microcentrifuge (CT-12RE, Hitachi Koki), and the filtrate was used as the sample.

[0100] (Determination of the amount of transfer to the conjunctiva) The brimonidine tartrate content of (i) the test solution without immersion in the conjunctiva and (ii) the specimen in 7) was measured by high-performance liquid chromatography (HPLC), and the amount transferred to the conjunctiva per specimen was calculated from the difference between (i) and (ii). Furthermore, the content of brimonidine tartrate transferred per 1 g of conjunctiva for each individual was calculated from the conjunctival weight measured in 4), and the average value of the four specimens was used as the amount transferred to the conjunctiva. Increase in the amount of brimonidine tartrate transferred to the conjunctiva by the combination of d-α-tocopherol acetate or pyridoxine hydrochloride (C rate ) was calculated according to the following formula:

number

[0101] [Table 20]

[0102] Among the combinations that showed improved transferability (lipid solubility) to the octanol layer in Test Example 6, the actual transferability to the conjunctiva was investigated using d-α-tocopherol acetate and pyridoxine hydrochloride, which are representative combinations. As a result, the amount of brimonidine transferred to the conjunctiva was improved, similar to the results of the transferability to the octanol layer. Therefore, it can be assumed that the transferability to the conjunctiva of other vitamins that showed improved transferability to the octanol layer in Test Example 6 will also be improved.

Claims

1. An ophthalmic liquid preparation containing 0.01 to 0.05 w / v % brimonidine and / or a salt thereof and vitamins.

2. 2. The ophthalmic liquid preparation according to claim 1, wherein the vitamin is at least one selected from the group consisting of vitamin A, vitamin B, and vitamin E.

3. 3. The liquid ophthalmic preparation according to claim 2, wherein the vitamin A is retinol palmitate.

4. 3. The ophthalmic liquid preparation according to claim 2, wherein the B vitamins are at least one selected from flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine and / or a salt thereof, panthenol, and pantothenic acid and / or a salt thereof.

5. 3. The ophthalmic liquid preparation according to claim 2, wherein the vitamin E is d-α-tocopherol acetate.

6. 3. The ophthalmic liquid preparation according to claim 2, wherein the concentrations of the vitamins are as follows: flavin adenine dinucleotide sodium 0.01 to 0.05 w / v %, cyanocobalamin 0.004 to 0.02 w / v %, vitamin A's 10,000 units / 100 ml to 50,000 units / 100 ml, pyridoxine and / or a salt thereof 0.01 to 0.1 w / v %, panthenol and pantothenic acid and / or a salt thereof 0.01 to 0.1 w / v %, and vitamin E's 0.005 to 0.05 w / v %.

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