Brimonidine liquid formulation

Abstract

To provide an ophthalmologic liquid formulation that contains brimonidine and / or a salt thereof and a preservative, where the liquid formulation is less prone to reduced transition to the conjunctiva.SOLUTION: It has been found out that adding an amino acid can prevent reduced transition to the conjunctiva. Thus, there are provide an ophthalmologic liquid formulation that contains brimonidine and / or a salt thereof, a preservative, and an amino acid.SELECTED DRAWING: None

Description

Technical Field

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

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 Initiative] [Problems that the invention aims to solve]

[0006] For brimonidine and / or its salts to be formulated as an ophthalmic liquid formulation to alleviate or suppress eye redness, high stability is required, as is the ability to transfer to the conjunctiva, which is the site of action of brimonidine and / or its salts. Furthermore, multi-dose ophthalmic liquid formulations typically contain preservatives for quality preservation. However, when preservatives are added to ophthalmic liquid formulations containing brimonidine and / or its salts, a problem arises in that the amount of brimonidine and / or its salts that transfer to the oil layer, which is an indicator of conjunctival transfer, decreases. [Means for solving the problem]

[0007] Therefore, the present inventors searched for compounds that suppress the decrease in the amount of brimonidine and / or its salt transferred to the oil layer, and found that amino acids have the effect of suppressing the decrease in the amount of brimonidine and / or its salt transferred to the oil layer caused by preservatives. Furthermore, they found that the photostability of ophthalmic liquid formulations containing brimonidine and / or its salt with selected amino acids added was also improved.

[0008] As one embodiment of the present invention, the following ophthalmic liquid formulation is provided. [1] An ophthalmic liquid preparation containing 0.01-0.05 w / v% brimonidine and / or its salts, a preservative, and amino acids. [2] The ophthalmic liquid formulation described in item 1, wherein the preservative is a bactericidal surfactant. [3] The ophthalmic liquid formulation according to item 2, wherein the bactericidal surfactant is selected from the group consisting of benzalkonium salt, alkyldiaminoethylglycine salt, and polyhexamethylene biguanide salt. [4] An ophthalmic liquid preparation according to any one of items 1 to 3, wherein the amino acids are at least one selected from aspartic acid and / or its salts, and taurine. [5] An ophthalmic liquid preparation as described in any one of items 1 to 4, wherein the concentration of amino acids is 0.01 to 10 w / v%.

[0009] Furthermore, as an embodiment of the present invention, the following method for promoting conjunctival migration is provided. [6] A method for promoting the conjunctival penetration of brimonidine and / or its salts in ophthalmic administration, characterized by adding amino acids to an ophthalmic liquid preparation containing 0.01-0.05 w / v% brimonidine and / or its salts and a preservative.

[0010] Furthermore, as an embodiment of the present invention, the following conjunctival migration promoter is provided. [7] A conjunctival penetration enhancer for brimonidine and / or its salts, used in an ophthalmic liquid formulation containing 0.01-0.05 w / v% brimonidine and / or its salts and a preservative, the enhancer containing amino acids.

[0011] 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 thereof in an ophthalmic liquid formulation, characterized by incorporating amino acids in an ophthalmic liquid formulation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof and a preservative.

[0012] Furthermore, as an embodiment of the present invention, the following light stabilizer is provided. [9] A light stabilizer for brimonidine and / or a salt thereof, used in an ophthalmic liquid formulation containing 0.01-0.05 w / v% brimonidine and / or a salt thereof and a preservative, wherein the light stabilizer contains amino acids. [Effects of the Invention]

[0013] According to the present invention, by adding amino acids to an ophthalmic liquid preparation containing a preservative and brimonidine and / or a salt thereof, an effect of improving conjunctival migration is exerted. Further, an ophthalmic liquid preparation containing brimonidine and / or a salt thereof, a preservative, and amino acids has improved photo stability.

Embodiments for Carrying Out the Invention

[0014] It is understood that the terms used in this specification are used in the meanings 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 the present invention pertains. The numerical ranges specified in this specification include their lower and upper limits.

[0015] (Definition) In this specification, "brimonidine" refers to a compound with the IUPAC name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine. Further, in this specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

[0016] In this specification, "low-concentration brimonidine" refers to brimonidine at a concentration of 0.05 w / v% or less.

[0017] In this specification, an "ophthalmic liquid preparation" is an aqueous liquid preparation based on water and refers to an ophthalmic preparation, particularly a preparation used for eye drops.

[0018] In this specification, "photo stability" refers to the degree to which the content of brimonidine and / or a salt thereof in the preparation is maintained after the ophthalmic liquid preparation is exposed to a certain amount of light.

[0019] In this specification, "photostabilization" means suppressing the decrease in the content of brimonidine and / or its salts in an ophthalmic liquid formulation due to exposure to a certain amount of light, and maintaining a higher retention rate of brimonidine and / or its salts. As an example, when an ophthalmic liquid formulation containing brimonidine and / or its salts is filled into a colorless glass ampoule and exposed to 600,000 lx·hr of white light, the content of brimonidine and / or its salts is maintained compared to a case without preservatives and amino acids, meaning that the retention rate of brimonidine and / or its salts is higher.

[0020] In this specification, "light stabilization method" means a method performed to suppress the decrease in the content of brimonidine and / or its salts in an ophthalmic liquid formulation due to exposure to a certain amount of light, and to maintain a higher retention rate of brimonidine and / or its salts.

[0021] In this specification, "light stabilizer" means an agent formulated to suppress the decrease in the content of brimonidine and / or its salts in an ophthalmic liquid formulation due to exposure to a certain amount of light, and to maintain a higher residual rate of brimonidine and / or its salts.

[0022] In this specification, "conjunctival penetration" is an indicator of how easily brimonidine and / or its salts in an ophthalmic liquid preparation administered by eye drops penetrate the conjunctiva, which is the site of action.

[0023] In this specification, "method for promoting conjunctival penetration" means a method performed to increase the amount of brimonidine and / or its salts in an ophthalmic liquid preparation administered by eye drops that penetrates to the conjunctiva, which is the site of action.

[0024] In this specification, "conjunctival penetration enhancer" means an agent added to an ophthalmic liquid preparation administered by eye drops to increase the amount of brimonidine and / or its salts that are transferred to the conjunctiva, which is the site of action.

[0025] (Description of preferred embodiments) Preferred embodiments of the present invention are 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 invention should not be limited to the following description. Therefore, it is clear to those skilled in the art that modifications can be made within the scope of the invention, taking into consideration the description herein. Furthermore, it is understood that the following embodiments can be used individually or in combination.

[0026] The ophthalmic liquid formulation of the present invention contains brimonidine and / or a salt thereof, and further contains a preservative and amino acids.

[0027] Any salt of brimonidine that is pharmaceutically acceptable can be used. Examples of pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, 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, with tartrate being preferred.

[0028] In this 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% 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 for example, considering the effect of this drug, 0.015 w / v% or 0.02 w / v% may be used.

[0029] In this invention, preservatives are added from the viewpoint of maintaining the quality of ophthalmic liquid formulations. Any component that can be used in eye drops, such as a surfactant, can be used as a preservative. Surfactants are thought to act on the cell membranes of bacteria and exert a bactericidal effect. Surfactants are classified into ionic surfactants (anionic, cationic, and amphoteric) and nonionic surfactants, and some of these are known to exhibit high bactericidal activity. Surfactants that have bactericidal activity can be specifically called bactericidal surfactants. Examples of bactericidal surfactants include cationic surfactants, anionic surfactants, and amphoteric surfactants, with cationic surfactants and amphoteric surfactants exhibiting particularly high bactericidal activity. Examples of cationic surfactants with high bactericidal activity include benzalkonium salt, benzethonium salt, dialkyldimethylammonium salt, and polyhexamethylene biguanide salt. An example of an amphoteric surfactant with high bactericidal activity is alkylpolyaminoethylglycine salt. As for the surfactant salt, it can be selected as appropriate, and examples include hydrochloride salt, chloride salt, and sulfate salt. The concentration of the preservative can be appropriately determined from the standpoint of use in ophthalmic liquid formulations. For example, it can be used at a concentration of 0.001 w / v% to 0.1 w / v%, preferably at a concentration of 0.005 w / v% to 0.05 w / v%.

[0030] On the other hand, when preservatives are added to ophthalmic liquid formulations containing brimonidine and / or its salts, the conjunctival penetration of brimonidine and / or its salts may decrease. Bactericidal surfactants are examples of preservatives that can reduce the conjunctival penetration of brimonidine and / or its salts.

[0031] Additives that can be incorporated into the ophthalmic liquid formulation of the present invention include amino acids or salts thereof. Amino acids include amino acids and substances other than amino acids that have a sulfonic acid group instead of a carboxyl group, such as taurine. Examples of amino acids include protein-constituting amino acids, such as glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine, and serine. Acidic amino acids, such as glutamic acid or aspartic acid, are preferred, and aspartic acid is even more preferred. For acidic amino acids, alkali metal salts, such as sodium salts or potassium salts, can be used. For example, potassium aspartate can be incorporated into the ophthalmic liquid formulation of the present invention. The amino acids used in the present invention, excluding glycine, may be L-form amino acids, D-form amino acids, or both. Only one type of amino acid may be used, or multiple types may be used in combination. Furthermore, amino acids may be used in combination with taurine. When amino acids, particularly potassium aspartate and / or taurine, are added to ophthalmic liquid formulations containing brimonidine and / or its salts, the conjunctival penetration of brimonidine and / or its salts, which is reduced by the addition of preservatives, is improved, and a photostabilization effect is also exhibited.

[0032] The concentration of amino acids can be appropriately selected depending on their type, and as an example, they can be formulated at concentrations from 0.01 w / v% to 10.0 w / v%. From the viewpoint of safety for the eyes, it is preferable to use 5 w / v% as the upper limit of the amino acid concentration, more preferably 2.5 w / v%, and even more preferably 1.0 w / v%. From the viewpoint of exhibiting a conjunctival migration promoting effect or a photostabilizing effect, it is possible to use 0.05 w / v% as the lower limit of the amino acid concentration, and more preferably 0.1 w / v%.

[0033] 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.

[0034] Corneal and conjunctival epithelial cells form tight junctions between cells, creating a hydrophobic membrane derived from the cell membrane. This restricts the permeability of water-soluble drugs across the cornea and conjunctiva. The intraocular penetration of instilled eye drops across the cornea and conjunctiva is determined by measuring the drug concentration in the aqueous humor and conjunctiva after instillation. However, this measurement is difficult in humans, and analysis is performed using predictive models based on animal experiments. A simple method for measuring the intraocular penetration of drugs is the octanol / water partition coefficient method. The octanol / water partition coefficient can be used to evaluate not only intraocular penetration but also conjunctival penetration. Specifically, the eye drop solution is mixed with octanol saturated with water, and the amount of drug present in the octanol layer (also called the oil layer) after mixing is defined as the amount of drug transferred. A higher amount of transferred drug indicates higher conjunctival penetration.

[0035] 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 as 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, for example, 5.5 to 8.5. For example, it can also be adjusted to 6.0 to 8.0. As an example of the osmotic pressure ratio of the ophthalmic liquid formulation, the amount of components 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.

[0036] 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.

[0037] 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.

[0038] 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 these active ingredients and additives may be used from each category, or multiple types may be used in combination. The optional components are described below, 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. The amino acids and preservatives used in this invention are listed as examples of optional components, but this does not mean that these components are used arbitrarily; rather, it means that the same or different components may be included for other purposes.

[0039] 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 approval standards for the manufacture (import) of over-the-counter drugs specify the vitamins that can be included in eye drops, and from this perspective, vitamin A, vitamin B, and vitamin E are particularly preferred.

[0040] 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 perspective of formulation as eye drops, retinol palmitate and retinol acetate are 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.

[0041] Vitamin B compounds can 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 pharmacovigilant salts. Among the vitamin B compounds, vitamins B2, B5, B6, and B12 are particularly preferred from the standpoint of being included in eye drops.

[0042] 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.

[0043] 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 such derivatives or salts. From the perspective of use as eye drops, panthenol, calcium pantothenate, and sodium pantothenate are preferred as vitamin B5.

[0044] 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.

[0045] Vitamin B12 is a compound with a cobalt group coordinated to a 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.

[0046] 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 perspective of use as eye drops, examples include d-α-tocopherol acetate and dl-α-tocopherol acetate.

[0047] 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).

[0048] Epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof may be used as decongestants.

[0049] Neostigmine methylsulfate can be used as an agent to improve the focusing ability.

[0050] 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, lysozyme chloride, or its salts may be used.

[0051] Diphenhydramine hydrochloride, chlorpheniramine maleate, or salts thereof may be used as antihistamines.

[0052] 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 ophthalmic liquid formulations 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. Regarding amino acids or their salts, the term "amino acids" refers not only to amino acids but also to substances that have a sulfate group instead of a carboxyl group, 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.

[0053] Sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidine sodium can be used as sulfonamides.

[0054] 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, alkyl polyaminoethylglycine hydrochloride, polyhexamethylene biguanide, boric acid, and borax.

[0055] 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.

[0056] Examples of isotonic agents include sugars and salts. Salts such as 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 can be used. As sugars, any monosaccharide or polysaccharide can be used; for example, glucose, cyclodextrin, xylitol, sorbitol, and mannitol can be used.

[0057] 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.

[0058] Nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyroxapol, and pluronic acid; and polyhydric alcohols such as glycerin and macrogol may be used as solubilizers.

[0059] Examples of stabilizers that can be used include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, EDTA, taurine, and tocopherol.

[0060] 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; and cationic surfactants such as alkylpyridinium salt, alkylamine salt, benzalkonium salt, and polyhexamethylene biguanide salt. In particular, benzalkonium salt, alkyldiaminoethylglycine salt, and polyhexamethylene biguanide salt can be used as bactericidal surfactants.

[0061] 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, rose oil, etc. may be used.

[0062] All references made herein are incorporated herein by citation in their entirety.

[0063] 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]

[0064] [Test Example 1] Measurement of the distribution of brimonidine tartrate into the octanol layer / aqueous layer 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. Potassium L-aspartate (Tokyo Chemical Industries, Ltd.) and / or taurine (Fujifilm Wako Pure Chemical Industries, Ltd.) were then added and dissolved as appropriate. Subsequently, benzalkonium chloride (Fujifilm Wako Pure Chemical Industries, Ltd.), alkyldiaminoethylglycine hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.), or polyhexamethylene biguanide (Carbosynth Limited) were added and dissolved. After dissolution, the pH was adjusted with a pH adjusting agent (1 mol / L hydrochloric acid or 0.1N NaOH), and the solution was made up with purified water to prepare solutions with the compositions shown in Tables 1 to 5, thereby obtaining the test eye drops for Comparative Examples 1 to 7 and Examples 1 to 17. Note that the values ​​in the tables are w / v%, except for pH and the rate of increase.

[0065] 2. Procedure for the Octanol Transfer Test The test eye drops prepared in step 1 and 1-octanol (Nacalai Tesque Co., Ltd.) were mixed according to the following procedure to obtain the aqueous layer sample: 1) Each plastic centrifuge tube was filled with 2.5 mL of each test eye drop 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 agitates in an up-and-down direction (300 times / minute). 4) The mixture was shaken for more than 24 hours using a rotary shaker (Universal Shaker SHK-U4, AGC Technoglass) that agitates horizontally (120 pm / min). 5) Mixed for 30 seconds using a vortex mixer (VX100, Labnet International). 6) The octanol layer and aqueous layer were separated by centrifugation (LC-120, Tommy Seikou) (3000 rpm, 10 minutes). The aqueous layer was then collected and used as the aqueous layer sample after mixing.

[0066] 3. Measurement of brimonidine tartrate content The brimonidine tartrate content was measured for each test eye drop prepared in 1. and the aqueous layer sample obtained after mixing in 2. using high-performance liquid chromatography (HPLC) under the conditions shown below. Column: 4.6mm inner diameter x 75mm length, octadecylsilylated silica gel ("SymmetryC18 3.5", Waters Corporation) Detector: UV-Vis absorbance spectrophotometer Measurement wavelength: 264nm Mobile phase: Ammonium dihydrogen phosphate (5.175 g) was dissolved in 900 mL of water, and 100 mL of acetonitrile for liquid chromatography was added.

[0067] The amount of brimonidine tartrate that migrated to the octanol layer by mixing octanol with each test eye drop was determined from the difference between the brimonidine tartrate content in each test eye drop obtained by measurement and the brimonidine tartrate content in the aqueous layer sample after mixing. The rate of increase in the amount of brimonidine tartrate transferred to the octanol layer due to the inclusion of amino acids (C rate The following formula was used to calculate ).

number

[0068] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0069] When the preservatives benzalkonium chloride, alkyldiaminoethylglycine hydrochloride, or polyhexamethylene biguanide were added to the test eye drops containing brimonidine tartrate, the amount of brimonidine tartrate transferred to the octanol layer decreased. On the other hand, it was shown that the decrease in the amount of brimonidine tartrate transferred to the octanol layer could be suppressed by further adding potassium L-aspartate or taurine.

[0070] [Test Example 2] 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. Potassium L-aspartate (Tokyo Chemical Industries, Ltd.) or taurine (Fujifilm Wako Pure Chemical Industries, Ltd.) were then added as appropriate amino acids and dissolved. Next, benzalkonium chloride (Fujifilm Wako Pure Chemical Industries, Ltd.), alkyldiaminoethylglycine hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.), or polyhexamethylene biguanide (Carbosynth Limited) were added as preservatives and dissolved. After dissolution, the pH was adjusted with a pH adjusting agent (1 mol / L hydrochloric acid or 0.1N NaOH) to prepare solutions with the compositions shown in Tables 6-8, thereby obtaining the test eye drops for Comparative Examples 1, 3, and 8, and Examples 2-4, 7-21. Note that the values ​​in the tables, except for pH and residual rate, are in w / v%.

[0071] 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

[0072] 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: approx. 1mL / min

[0073] [Table 6] [Table 7] [Table 8]

[0074] By adding a preservative such as benzalkonium chloride, alkyldiaminoethylglycine hydrochloride, or polyhexamethylene biguanide, along with an amino acid such as potassium L-aspartate or taurine, to a test eye drop solution containing brimonidine tartrate, the photostability of brimonidine tartrate was improved.

[0075] [Test Example 3] Measurement of the amount of brimonidine tartrate transferred to the conjunctiva of rabbits 1. Preparation of test eye drops Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.), borax (Nacalai Tesque Corporation), and brimonidine tartrate (Hinewy Pharma.Tech.Co.,Ltd) were added to purified water and dissolved. Benzalkonium chloride (Fujifilm Wako Pure Chemical Industries, Ltd.) and taurine (Fujifilm Wako Pure Chemical Industries, Ltd.) were then added and dissolved as appropriate. After dissolution, the pH was adjusted in all formulations using a pH adjuster (1 mol / L hydrochloric acid or 0.1N NaOH) to prepare the solutions listed in Table 9, obtaining the test eye drops for Comparative Example 9, Comparative Example 10, and Example 22. Note that the values ​​in the table, except for pH, are in w / v%. [Table 9]

[0076] 2. Conjunctival migration test The test eye drops prepared in step 1 were subjected to a conjunctival penetration test in 4 cases from each group, following the procedure below: 1-1) Tube 1: Four test eye drops were dispensed from each group into 1 mL sample tubes (1.5 mL microtubes, Zaltostat). 1-2) Tube2: Four filtered sample tubes (Ultrafree-MC-GV 0.45μm, Millipore) were prepared for each group. 2) We obtained extracted rabbit eyeballs (Kitayama Labes) and cut out the conjunctiva. 3) The conjunctiva was washed by immersion in physiological saline solution (Otsuka Saline Solution, Otsuka Pharmaceutical Co., Ltd.). 4) The surface moisture was lightly wiped off with a Kimwipe, and the conjunctival weight was measured. 5) After measuring the conjunctival weight, the conjunctiva was placed in Tube 1 (1-1) and shaken for 5 minutes at 1,500 rpm using a shaker (Block Bath Shaker - MyBL-100CS, AS ONE). 6)5) The conjunctiva was removed from Tube1. 7) 300 μL of the sample was taken from Tube 1 of 6) after removing the conjunctiva, added to Tube 2 of 1-2), and centrifuged using a benchtop micro-high-speed centrifuge (CT-12RE, Hitachi Koki) (15,000 rpm, 10 minutes, 4℃), and the filtrate was used as the sample.

[0077] 3. Determining the amount of conjunctival transfer (i) The brimonidine tartrate content of the test eye drops that did not immerse the conjunctiva and (ii) the brimonidine tartrate content of the samples obtained in 2. Conjunctival Transfer Test 7) ​​was measured by high-performance liquid chromatography (HPLC). The amount transferred to the conjunctiva per sample was determined from the difference between (i) and (ii). Furthermore, the amount of brimonidine tartrate transferred per gram of conjunctiva for each individual was determined from the conjunctival weight measured in 2. Conjunctival Transfer Test 4), and the average value of the four cases was taken as the amount transferred to the conjunctiva. Increased rate of brimonidine tartrate transfer to the conjunctiva due to taurine formulation (C rate The following formula was used to calculate ).

number

[0078] [Table 10]

[0079] In Test Example 1, the transferability (lipid-soluble) of preservatives and amino acids to the octanol layer was investigated. For the representative combination of taurine and benzalkonium chloride, we examined its actual transferability to the conjunctiva. Similar to the results for transfer to the octanol layer, the addition of benzalkonium chloride reduced the amount of brimonidine tartrate transferred to the conjunctiva. However, the addition of taurine further suppressed this decrease. Therefore, it can be inferred that the combination of preservatives and amino acids that showed improved transferability to the octanol layer in Test Example 1 also shows improved transferability to the rabbit conjunctiva.

Claims

1. An ophthalmic liquid formulation containing 0.01 w / v% to 0.05 w / v% brimonidine and / or a salt thereof, a preservative, and amino acids, wherein the amino acids are at least one selected from the group consisting of aspartic acid and / or a salt thereof and taurine, and the preservative is a cationic surfactant or an amphoteric surfactant.

2. The ophthalmic liquid formulation according to claim 1, wherein the preservative is selected from the group consisting of benzalkonium salt, alkyldiaminoethylglycine salt, and polyhexamethylene biguanide salt.

3. The ophthalmic liquid formulation according to claim 1, wherein the preservative is selected from the group consisting of benzalkonium chloride, alkyldiaminoethylglycine hydrochloride, and polyhexamethylene biguanide.

4. An ophthalmic liquid formulation according to any one of claims 1 to 3, wherein the concentration of amino acids is 0.01 w / v% to 10 w / v%.

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