WO2021221074A1

WO2021221074A1 - Liquid preparation containing brimonidine

Info

Publication number: WO2021221074A1
Application number: PCT/JP2021/016851
Authority: WO
Inventors: 敬一松久; 涼蒲原
Original assignee: 千寿製薬株式会社
Priority date: 2020-04-27
Filing date: 2021-04-27
Publication date: 2021-11-04
Also published as: JP2021175739A

Abstract

The purpose of the present invention is to provide a liquid preparation for ophthalmic use which comprises brimonidine or a salt thereof. On the basis of the finding that a liquid preparation for ophthalmic use which contains brimonidine at a low concentration and to which vitamins are added has good transferability to the conjunctiva, provided is a liquid preparation for ophthalmic use which contains brimonidine at a low concentration and vitamins. Brimonidine at a low concentration is highly compatible with vitamins and stabilizes the vitamins which frequently cause reduction in the content thereof.

Description

Liquid formulation containing brimonidine

The present invention relates to a liquid preparation containing brimonidine or a salt thereof.

Brimonidine and its salts are known as α-2 adrenergic receptor agonists. The human eye has many α-2 adrenaline receptors (hereinafter, may be abbreviated as α-2 receptors), and α-2 receptor agonists suppress the production of aqueous humor and the uveal tract. It has the effect of lowering intraocular pressure by promoting the outflow of aqueous humor through the scleral outflow tract. Based on this effect, α-2 receptor agonists have conventionally been used in the treatment of glaucoma and ocular hypertension. In addition, α-2 receptor agonists have the effect of causing a reduction in the lumen size of α-2 receptor concentrated arterioles, especially terminal arterioles. By this action, vasoconstriction can occur, the redness of the eye can be reduced, the whiteness can be increased, and the aesthetic appearance of the eye can be improved (Patent Document 1: Patent No. 5671459; Patent Document 2: Patent No. 2: 5738890).

For a formulation in which brimonidine and / or a salt thereof and timolol and / or a salt thereof are used in combination, a formulation technique focusing on the stability of the formulation is also being studied. For example, in Patent Document 3 (Japanese Patent Laid-Open No. 2009-533462), 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 is described. It is disclosed that the formation of decomposition products can be suppressed and the stability is improved. Further, in Patent Document 4 (Japanese Unexamined Patent Publication No. 2017-222707), an eye drop containing brimonidine and / or a salt thereof, and brinzolamide and / or a salt thereof, has a maximum transmittance of light having a wavelength of 360 to 460 nm of 67%. By accommodating in a transparent container having the following and a maximum transmittance of light having a wavelength of 600 to 680 nm of 78% or less, decomposition of brimonidine and / or a salt thereof due to light exposure can be suppressed, and formulation stability is ensured. It is disclosed that it can be done.

When formulated as an eye drop, a well-known additive is added together with one or more active ingredients. It is not possible to arbitrarily combine active ingredients and additives in the formulation, and considering the compatibility between the active ingredients and the compatibility between the active ingredients and the additives, the stability, efficacy, safety, etc. of the entire formulation, etc. Need to be evaluated.

Patent No. 5671459 Patent No. 5738890 Special Table 2009-533462 JP-A-2017-222707

When formulating brimonidine or a salt thereof as an ophthalmic liquid preparation that relieves or suppresses red eye, it is necessary to select an additive that is compatible with the active ingredients to be blended.

The present inventors conducted intensive studies for the purpose of providing a stabilized liquid preparation for ophthalmology containing a low concentration of brimonidine, and found that the liquid preparation containing a low concentration of brimonidine is compatible with vitamins. It was often found that the stability of vitamins, which are prone to decrease in content, to light or heat is increased. It was also found that an ophthalmic liquid preparation containing a low concentration of brimonidine to which vitamins were added has high conjunctival transferability.

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

Further, as an embodiment of the present invention, the following photostabilization method is provided.
[7] Light of vitamins in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof in the ophthalmic liquid preparation containing vitamins. Stabilization method.

Further, as an embodiment of the present invention, the following light stabilizer is provided.
[8] Vitamin in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, which is used in an ophthalmic liquid preparation containing vitamins. Kind of light stabilizer.

Further, as an embodiment of the present invention, the following thermal stabilization method is provided.
[9] Heat of vitamins in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof in the ophthalmic liquid preparation containing vitamins. Stabilization method.

Further, as an embodiment of the present invention, the following thermal stabilizer is provided.
[10] A vitamin in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, which is used in an ophthalmic liquid preparation containing vitamins. Kind of heat stabilizer.

Further, as an embodiment of the present invention, the following method for promoting conjunctival migration is provided.
[11] Brimonidine and / or a salt thereof in eye drop administration, which comprises adding vitamins to an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% of brimonidine and / or a salt thereof. Method for promoting conjunctival migration.

Further, as an embodiment of the present invention, the following conjunctival transfer promoter is provided.
[12] Brimonidine and / or a salt thereof in eye drop administration, which comprises adding vitamins to an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% of brimonidine and / or a salt thereof. Conjunctival transfer promoter.

According to the present invention, an ophthalmic liquid preparation containing a low concentration of brimonidine and vitamins exerts at least one effect of improving the stability of vitamins to light or heat and improving the conjunctival transferability of brimonidine. ..

It is understood that the terms used in the present specification are used in the meanings commonly used in the art unless otherwise specified. Thus, unless otherwise defined, all terminology and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The numerical range specified herein shall include its lower and upper limits.

(Definition)
As used herein, "brimonidine" is referred to as IUPAC name: 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine (5-Bromo-N- (4,5). -Dihydro-1H-imidazole-2-yl) quinoxaline-6-amine) compound. Further, in the present specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

In the present specification, "low concentration brimonidine" refers to brimonidine having a concentration of 0.05 w / v% or less.

As used herein, the term "vitamins" is a general term for organic compounds other than carbohydrates, proteins, and lipids that cannot synthesize a sufficient amount of nutrients necessary for the survival or growth of an organism in the body. ..

In the present specification, the "liquid preparation for ophthalmology" is an aqueous liquid preparation based on water.

In the present specification, "photostability" refers to the degree to which the content of vitamins in the preparation after exposing the liquid ophthalmic preparation to a certain amount of light is maintained.

As used herein, "light stabilization" refers to suppressing a decrease in the content of vitamins in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, and maintaining a higher residual rate of vitamins. To do. For photostabilization, as an example, vitamins are compared with the case where a liquid preparation for ophthalmology containing vitamins is filled in a colorless glass ampoule, exposed to white light of 100,000 lx · hr, and then does not contain brimonidine. It means that the content of vitamins is maintained, that is, the residual rate of vitamins is higher.

As used herein, the term "light stabilization method" refers to suppressing a decrease in the content of vitamins in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, and increasing the residual rate of vitamins. Means the method performed to maintain.

In the present specification, the "light stabilizer" is formulated to suppress a decrease in the content of vitamins in an ophthalmic liquid preparation due to exposure to a certain amount of light and to maintain a higher residual rate of vitamins. Means an agent.

In the present specification, "heat stability" refers to the degree to which the content of vitamins in the preparation is maintained after the liquid preparation for ophthalmology is stored at a constant temperature for a certain period of time.

In the present specification, "heat stabilization" means suppressing a decrease in the content of vitamins in an ophthalmic liquid preparation due to storage at a constant temperature for a certain period of time, and maintaining a higher residual rate of vitamins. For heat stabilization, for example, a colorless glass ampoule is filled with an ophthalmic liquid preparation containing vitamins and stored at 80 ° C. for 3 days or 1 week, or at 70 ° C. for 1 week, and then does not contain brimonidine. It means that the content of vitamins is maintained, that is, the residual rate of vitamins is higher than in the case.

In the present specification, the "heat stabilization method" is performed in order to suppress a decrease in the content of vitamins in an ophthalmic liquid preparation due to storage at a constant temperature for a certain period of time and to maintain a higher residual rate of vitamins. Means the method.

In the present specification, the "light stabilizer" is formulated to suppress a decrease in the content of vitamins in an ophthalmic liquid preparation due to storage at a constant temperature for a certain period of time and to maintain a higher residual rate of vitamins. Means an agent.

In the present specification, "conjunctival transferability" is an index indicating the ease of transfer of brimonidine in an ophthalmic liquid preparation administered by eye drops to the conjunctiva, which is the site of action.

In the present specification, the "conjunctival migration promoting method" means a method performed to increase the amount of brimonidine transferred to the conjunctiva, which is the site of action, in an ophthalmic liquid preparation administered by eye drops.

As used herein, the term "conjunctival transfer promoter" means an agent formulated to increase the amount of brimonidine transferred to the conjunctiva, which is the site of action, in an ophthalmic liquid preparation administered by eye drops.

(Explanation of Preferred Embodiment)
A preferred embodiment of the present invention will be described below. It is understood that the embodiments provided below are provided for a better understanding of the invention and the scope of the invention should not be limited to the following description. Therefore, it is clear that a person skilled in the art can appropriately make modifications within the scope of the present invention in consideration of the description in the present specification. It is also understood that the following embodiments may be used alone or in combination.

The liquid preparation for ophthalmology of the present invention contains brimonidine and / or a salt thereof. The pharmaceutically acceptable salt of brimonidine includes any salt. Pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, Examples thereof include ascorbate, maleate, methanesulfonate, tartrate and other inorganic carboxylates well known to those skilled in the art, preferably tartrate.

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

Examples of the additive to be blended in the liquid preparation for ophthalmology of the present invention include vitamins. Vitamins are roughly classified into water-soluble vitamins and fat-soluble vitamins. Examples of water-soluble vitamins include vitamin Bs and vitamin C (ascorbic acid). Examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, and vitamin K. The over-the-counter drug manufacturing (import) approval criteria stipulate the vitamins to be added to eye drops, and from this point of view, vitamin A, vitamin B, and vitamin E are particularly preferable.

Examples of vitamin A include retinol and related substances. Retinol-related substances also include retinal, retinoic acid, retinol palmitate and other retinoids such as isotretinoin, alitretinoin, acitretin, etretinate, adaparene, tazarotene, bexarotene and the like. Retinol palmitate and retinol acetate are preferable from the viewpoint of blending as eye drops. Since vitamin A acts on epithelial cells and induces proliferation, it can be added to eye drops for the purpose of protecting the cornea and conjunctiva. It can also be added to 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, and when vitamin A is used, it is preferably blended in an amount of 1 to 300,000 units / 100 ml, more preferably 10,000 to 50,000 units / 100 ml. sell. From the viewpoint of exerting the effect, the vitamin A to be blended in the eye drops may be used in an amount of 15,000 units or more, or may be used in an amount of 20,000 units or more. From the viewpoint of suppressing side effects, vitamin A to be added to eye drops may be used in an amount of 30,000 units or less.

Examples of B vitamins include vitamin B1 (thiamin, 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 derivative provitamins and pharmaceutically acceptable salts. Among the B vitamins, vitamins B2, B5, B6 and B12 are particularly preferable from the viewpoint of being blended in eye drops.

Examples of vitamin B2 include riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, and pharmaceutically acceptable salts thereof. Examples of the salt include sodium salt and potassium salt. Flavin adenine dinucleotide sodium is preferable from the viewpoint of being formulated as an eye drop. Vitamin B2 is directly involved in oxidative reduction, and when used as an eye drop, promotes enzymatic respiratory metabolism of corneal and conjunctival cells, and has a protective effect on the cornea and conjunctiva. Vitamin B2 can also be added to eye drops for the treatment of keratitis presumed to be associated with vitamin B2 deficiency or metabolic disorders. When vitamin B2 is used, it can be preferably blended at 0.001 to 0.5 w / v%, more preferably 0.01 to 0.05 w / v%. From the viewpoint of exerting efficacy, vitamin B2 may be used at 0.015 w / v% or more, or may be used at 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.

Examples of vitamin B5 include panthenol, pantothenic acid, derivatives thereof, or salts thereof. As an example, in addition to panthenol and pantothenic acid, derivatives or salts thereof include pantetheine, pantetheine, pantotheneal alcohol, pantotheneyl ethyl ether, pantetheine pantothenic acid, calcium pantothenate, sodium pantothenate and the like. From the viewpoint of being used as an eye drop, panthenol, calcium pantothenate, and sodium pantothenate are preferable as vitamin B5. When vitamin B5 is used, it can be preferably blended at 0.001 to 1 w / v%, more preferably 0.01 to 0.1 w / v%. From the viewpoint of exerting efficacy, vitamin B5 may be used at 0.02 w / v% or more, or may be used at 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 may be used at 0.05 w / v% or less.

Examples of vitamin B6 include pyridoxal, pyridoxamine, pyridoxine, and pharmaceutically acceptable salts thereof. Pyridoxine hydrochloride is preferable from the viewpoint of being used as an eye drop. Vitamin B6 is involved in protein metabolism as a coenzyme of amino acid decarboxylase and transaminase in vivo, and can be added to eye drops to suppress eye fatigue. When vitamin B6 is used, it can be preferably blended 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 may be used at 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 may be used at 0.07 w / v% or less.

Vitamin B12 is a compound having a structure in which cobalt is coordinated to the choline ring. Specifically, cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc. are used. Can be done. Vitamin B12 can be added to eye drops for pharmacological actions such as improvement of tired eyes and eyestrain. When vitamin B12 is used, it can be preferably blended 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 may be used at 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 it may be used at 0.01 w / v% or less.

Examples of vitamin E include tocopherol, tocotrienol, tocophersolan, and derivatives thereof. The tocopherol and tocotrienol may be any of α-, β-, γ-, and δ-, and may be any of d-form and dl-form. From the viewpoint of being used as eye drops, examples thereof include d-α-tocopherol acetate and dl-α-tocopherol acetate. When Vitamin E is used, it can be preferably blended at 0.0005 to 1 w / v%, more preferably 0.005 to 0.05 w / v%. From the viewpoint of exerting efficacy, vitamin Es may be used at 0.01 w / v% or more, or may be used at 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.

Examples of vitamin C include ascorbic acid or a salt thereof. Vitamin Ds include vitamin D2 (ergosterol, ergocalciferol), D3 (7-dehydrocholesterol), previtamin D3 (cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalcifer)). Ferrol), calcitronic acid), vitamin D4 (dihydroergocalciferol), vitamin D5 (dihydrotaxterol, calcitriol, tacalcitol, paricalsitol) and the like. Examples of vitamin Ks include phylloquinone (K1), menaquinone (K2), and menadione (K3).

In the present invention, vitamins exert the physiological action normally exhibited by each component as an ophthalmic preparation, while improving the conjunctival transferability of brimonidine or a salt thereof in an ophthalmic liquid preparation containing brimonidine or a salt thereof. Demonstrate.

The conjunctiva is a membrane that covers the sclera, which is the white of the eye, and the inside of the eyelids, and is mainly composed of conjunctival epithelial cells. The epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatic vessels. It is in contact with the cornea at the boundary between the white and black eyes, and the cornea and conjunctiva form the outermost layer of the eye exposed to the outside world. Since the conjunctiva is exposed to the outside world, it is easily attacked by bacteria and viruses, and inflammation is likely to occur. Even when there is no inflammation, lack of sleep and overuse of the eyes increase blood flow to supply oxygen and nutrients to the eyes, resulting in hyperemia. In the present invention, in order for brimonidine to exert an action of reducing or whitening the redness of the eye, it is necessary that the active ingredient of the drug administered by eye drops reaches the capillaries in the conjunctiva and acts.

Conjunctival transferability is an index showing the ease with which the active ingredient of an ophthalmic liquid preparation administered by eye drops can be transferred to the conjunctiva, which is the site of action. Corneal epithelial cells and conjunctival epithelial cells each form tight junctions between cells to form a hydrophobic membrane resulting from the cell membrane. This limits the permeation of water-soluble drugs through the cornea and conjunctiva. The transferability of the instilled drug through the cornea and conjunctiva is determined by measuring the drug concentration in the aqueous humor and the drug concentration in the conjunctival tissue after instillation. However, it is difficult to measure intraocular transferability in humans, and analysis using a predictive model through animal experiments has been performed. As a simple method for measuring intraocular transferability, a method based on the octanol / water partition coefficient is known. The octanol / water partition coefficient can be used to evaluate not only intraocular transferability but also conjunctival transferability.

In the present invention, the liquid preparation for ophthalmology is an aqueous liquid preparation mainly based on water, but may further contain any liquid base that can be used as an eye drop. The liquid preparation for ophthalmology of the present invention is prepared so as to have a pH and an osmotic pressure acceptable as an eye drop. The pH of the liquid preparation for ophthalmology can be adjusted to 5.0 to 9.0 using a pH adjuster, and is 5.5 to 8.5 as an example. As an example, it can be adjusted to 6.0 to 8.0. As an example of the osmotic pressure ratio of the liquid preparation for ophthalmology, the amount of the component added to the liquid preparation for ophthalmology is adjusted so as to be preferably 0.5 to 2.5, more preferably 0.7 to 1.5.

The liquid preparation for ophthalmology of the present invention is preferably an eye drop. The liquid preparation for ophthalmology of the present invention may be a liquid preparation that relieves or suppresses red eye. Relieving or suppressing red eye refers to increasing the whiteness of the white part of the eye, and can also be referred to as eye whitening.

For liquid formulations with low photostability, a light-shielding container can be used. However, eye drops are used for a certain period of time after opening. If a light-shielding container is used as the eye drop, it is difficult to confirm the residual amount and changes in the contents. Therefore, it is desired to use a transparent container for the eye drop. Therefore, it is important to provide a highly photostable preparation. Further, a colored transparent container can be used instead of the light-shielding container.

The liquid preparation for ophthalmology of the present invention can contain any component that can be used for eye drops as long as the effect of the present invention is not impaired. In addition to brimonidine tartrate, which is the active ingredient of the present invention, any active ingredient and an ingredient such as an additive may be contained. Such ingredients include decongestants, focus control function improvers, anti-inflammatory / astringent agents, antihistamines, vitamins, nutritional ingredients, sulfa drugs, preservatives, pH adjusters, isotonic agents, thickeners, antioxidants. Agents, solubilizers, stabilizers, surfactants, fragrances or refreshing agents, etc. are included, but are not intended to be limited thereto. Only one kind of these active ingredients and additives may be used from each category, or a plurality of kinds may be used in combination.

As the decongestant, epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof can be used.

Neostigmine methylsulfate can be used as a focus adjustment function improving agent.

As the anti-inflammatory / astringent agent, ε-aminocaproic acid, allantin, velverine or a salt thereof, azulene sulfonic acid or a salt thereof, glycyrrhizinic acid or a salt thereof, zinc sulfate, zinc lactate, and lysozyme chloride can be used.

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

Amino acids or salts thereof and sodium chondroitin sulfate can be used as water retention / nutritional components. As the amino acids or salts thereof, the amino acids are not only amino acids but also substances having a sulfate group instead of the carboxyl group of the amino acid, for example, taurine. Examples of amino acids include glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, aspartic acid, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine and serine. .. Amino acids preferably include aspartic acid, methionine and glycine. The amino acids other than glycine may be L-form amino acids, D-form amino acids, or DL-form amino acids.

As the sulfa agent, sulfamethoxazole, sodium suffamethoxazole, sfluisoxazole, and sodium sulfisomidin can be used.

Preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, benzalconium chloride, chlorobutanol, sodium chlorite, benzododecinium bromide, chlorhexidine. Gluconate, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, alkylpolyaminoethylglycine, boric acid, boar sand and the like can be used.

Examples of the pH adjuster include buffers such as citric acid buffer, acetate buffer, carbon dioxide buffer, borate buffer, and phosphoric acid buffer, as well as hydrochloric acid, acetic acid, boric acid, carbonic acid, sulfuric acid, and phosphoric acid. Acids such as citric acid and tartrate, and bases such as sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, triethanolamine and monoethanolamine can be used.

Examples of the tonicity agent include sugars and salts, and examples of salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, etc. Sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like can be used. As the saccharide, any monosaccharide or polysaccharide can be used, and as an example, glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like can be used.

As the thickener, sodium chondroitin sulfate, polyvinyl alcohol, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone, etc. or salts thereof can be used.

As the solubilizing agent, nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyroxapol, and pluronic; polyhydric alcohols such as glycerin and macrogol can be used.

As the stabilizer, for example, polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, tocopherol and the like can be used.

Examples of the surfactant include nonionic surfactants such as tyroxalol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxinol; alkyldiaminoethylglycine, Amphoteric surfactants such as lauryldimethylaminoacetate betaine; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; alkylpyridinium salts, Cationic surfactants such as alkylamine salts can be used.

Examples of fragrances or refreshing agents include menthol, ethanol, camphor, geraniol, borneol, menthol, ryunou, uikyo oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc. Can be used.

The above-mentioned optional components may be used for the purpose of actions other than those listed above. For example, ethanol used as a refreshing agent may be added to an ophthalmic solution as a preservative.

All documents referred to herein are incorporated herein by reference in their entirety.

The examples of the present invention described below are for illustration 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 description of the claims. Modifications of the present invention, for example, addition, deletion and replacement of the constituent elements of the present invention, can be made on condition that the gist of the present invention is not deviated.

Test Example 1: Photostability test of flavin adenine dinucleotide sodium 1. Preparation of eye drops Add purified water to boric acid (Fujifilm Wako Pure Chemical Industries) to dissolve it, add brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd), flavin adenine dinucleotide sodium (Alfa Aesar), and hydrochloric acid. The pH was adjusted to 5.5 to 8.5 using an aqueous sodium hydroxide solution, and solutions having the compositions shown in Tables 1 to 3 were prepared to obtain eye drops. The values in the table are w / v% excluding pH and residual rate.

2. Evaluation Method of Photostability of Flavin Adenine Dinucleotide Sodium 5 mL of the ophthalmic solution obtained above was added to a glass ampoule and exposed to white light of 100,000 lux · hr to obtain a deteriorated product. The flavin adenine dinucleotide sodium concentration in the product stored at room temperature for 1 week and the deteriorated product was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the flavin adenine dinucleotide was measured according to the formula shown below. The residual rate (%) of sodium was calculated. The results are shown in Tables 1 to 3 together with the composition of each formulation.

<High Performance Liquid Chromatograph Conditions>
Column: Inner diameter 4.6 mm x Length 15 cm Octadecyl silylated silica gel ("Unicil QC18" manufactured by GL Sciences)
Detector: Ultraviolet absorptiometer (measurement wavelength: 350 nm)
Column temperature: 40 ° C
Mobile phase: Potassium dihydrogen phosphate solution (1 → 500) / Methanol mixture for liquid chromatography (750/250)
Flow velocity: Approximately 0.5 mL / min

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

In Examples 1 to 8 above, the photostability of flavin adenine dinucleotide sodium was improved by the addition of brimonidine tartrate. The residual rate was improved by 4.4 to 17.4% as compared with Comparative Examples 1 to 6.

Test Example 2: Thermal stability test of cyanocobalamin 1. Preparation of eye drops Add purified water to boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) to dissolve it, add brimonidine tartrate (Hinewy Pharma.Tech.Co., Ltd), cyanokobalamine (Fujifilm Wako Pure Chemical Industries, Ltd.), and add hydrochloric acid. The pH was adjusted to 5.5 to 8.5 using an aqueous sodium hydroxide solution, and solutions having the compositions shown in Tables 4 to 6 were prepared to obtain eye drops. The values in the table are w / v% excluding pH and residual rate.

2. Evaluation Method of Thermal Stability of Cyanocobalamin 5 mL of the ophthalmic solution obtained above was added to a glass ampoule and stored in a constant temperature bath at 80 ° C. for 1 week to obtain a deteriorated product. The cyanocobalamin concentration in the product stored at room temperature for 4 weeks and the deteriorated product was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual rate (%) of cyanocobalamin was determined according to the formula shown below. Calculated. The results are shown in Tables 4 to 6 together with the composition of each formulation.

<High Performance Liquid Chromatograph Conditions>
Column: Inner diameter 4.6 mm x Length 15 cm Octadecylsilylated silica gel ("AA12S05-1506WT" manufactured by YMC Co., Ltd.)
Detector: Ultraviolet absorptiometer (measurement wavelength: 278 nm)
Column temperature: 40 ° C
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 velocity: Approximately 1 mL / min

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

In Examples 9 to 16 above, the addition of brimonidine tartaric acid 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% as compared with Comparative Examples 7 to 12.

Test Example 3: Thermal stability test of d-α-tocopherol acetate 1. Preparation of eye drops Add purified water to boric acid (Fujifilm Wako Pure Chemical Industries) to dissolve it, and add brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd) and d-α-tocopherol acetate (Combi-Blocks). The pH was adjusted to 5.5 to 8.5 using hydrochloric acid and an aqueous solution of sodium hydroxide, and solutions having the compositions shown in Tables 7 to 8 were prepared to obtain eye drops. The numerical value in the table is w / v%. When d-α-tocopherol acetate was added, it was added in a state of being mixed with heat-dissolved polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals). The values in the table are w / v% excluding pH and residual rate.

2. Evaluation Method of Thermal Stability of d-α-Tocopherol Acetate 5 mL of the ophthalmic solution obtained above was added to a glass ampoule and stored in a constant temperature bath at 70 ° C. for 1 week to obtain a deteriorated product. The concentration of d-α-tocopherol acetate in the products stored at room temperature for 4 weeks and the deteriorated products was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and d-acetic acid was measured according to the formula shown below. The residual rate (%) of α-tocopherol was calculated. The results are shown in Tables 7-8 together with the composition of each formulation.

<High Performance Liquid Chromatograph Conditions>
Column: Inner diameter 4.6 mm x length 15 cm Octylsilylated silica gel ("OC12S05-1546WT" manufactured by YMC)
Detector: Ultraviolet absorptiometer (measurement wavelength: 284 nm)
Column temperature: 40 ° C
Mobile phase: Acetonitrile / water / phosphoric acid mixed solution for liquid chromatography (930/69/1)
Flow velocity: Approximately 1 mL / min

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

In Examples 17 to 22, the addition of brimonidine tartaric acid improved the thermal stability of d-α-tocopherol acetate in the pH range of 6.5 to 8.5. The survival rate was improved by 9.9 to 36.9% as compared with Comparative Examples 13 to 16.

Test Example 4: Photostability test of pyridoxine hydrochloride 1. Preparation of eye drops Add purified water to trometamole (Fujifilm Wako Pure Chemical Industries, Ltd.) to dissolve it, add brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd), pyridoxin hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.), and hydrochloric acid. The pH was adjusted to 5.5 to 8.5 using the aqueous sodium hydroxide solution, and solutions having the compositions shown in Tables 9 to 11 were prepared to obtain eye drops. The values in the table are w / v% excluding pH and residual rate.

2. Evaluation Method of Photostability of Pyridoxine Hydrochloride 5 mL of the ophthalmic solution obtained above was added to a glass ampoule and exposed to white light of 100,000 lux · hr to obtain a deteriorated product. The pyridoxine hydrochloride concentration in the products stored at room temperature for 1 week and the deteriorated products was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual rate of pyridoxine hydrochloride was measured according to the formula shown below. (%) Was calculated.

<High Performance Liquid Chromatograph Conditions>
Column: Inner diameter 4.6 mm x length 15 cm Octadecylsilylated silica gel ("AA12S05-1546WT" manufactured by YMC Co., Ltd.)
Detector: Ultraviolet absorptiometer (measurement wavelength: 290 nm)
Column temperature: 40 ° C
Mobile phase: After adding 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, phosphoric acid is added to adjust the pH to 3.5.
Flow velocity: Approximately 1 mL / min

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

In Examples 23 to 30, the addition of brimonidine tartaric acid improved the photostability of pyridoxine hydrochloride in the pH range of 5.5 to 7.5. The residual rate was improved by 0.7 to 5.4% as compared with Comparative Examples 17 to 22.

Test Example 5: Thermal stability test of panthenol 1. Preparation of eye drops Add purified water to boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) to dissolve it, add brimonidine tartrate (Hinewy Pharma.Tech.Co., Ltd), pantenol (Fujifilm Wako Pure Chemical Industries, Ltd.), and hydrochloric acid. The pH was adjusted to 5.5 to 8.5 using the aqueous sodium hydroxide solution, and solutions having the compositions shown in Tables 12 to 14 were prepared to obtain eye drops. The values in the table are w / v% excluding pH and residual rate.

2. Evaluation Method of Thermal Stability of Panthenol 5 mL of the ophthalmic solution obtained above was added to a glass ampoule and stored in a constant temperature bath at 80 ° C. for 3 days to obtain a deteriorated product. The panthenol concentration in the products stored at room temperature for 4 weeks and the deteriorated products was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below, and the residual rate of panthenol (%) was measured according to the formula shown below. ) Was calculated.

<High Performance Liquid Chromatograph Conditions>
Column: Guard column ("AA30S05-G304CC" manufactured by YMC) + inner diameter 4.6 mm x length 15 cm octadecylsilylated silica gel ("AA30S05-1546WT" manufactured by YMC)
Detector: Ultraviolet absorptiometer (measurement wavelength: 220 nm)
Column temperature: 40 ° C
Mobile phase: After adding 100 mL of methanol for liquid chromatography to 900 mL of 0.05 mol / L potassium dihydrogen phosphate TS, the pH is adjusted to 3.0 by adding phosphoric acid.
Flow velocity: Approximately 1 mL / min
<Residual rate of panthenol>
The residual rate (%) of panthenol was calculated according to the following formula.

In Examples 31 to 38, the addition of brimonidine tartaric acid improved the thermal stability of panthenol in the pH range of 5.5 to 7.5. The residual rate was improved by 0.7 to 3.9% as compared with Comparative Examples 23 to 28.

Test Example 6: Measurement of the amount of brimonidine tartrate distributed to the octanol layer / aqueous layer (prescription) Each sample was prepared by a conventional method. That is, boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd) are added and dissolved in purified water to dissolve them, and flavin adenindinucleotide sodium (Alfa Aesar) and cyanocobalamine (Fujifilm). Wako Pure Chemical Industries, Ltd.), retinol palmitate (Fuji Film Wako Pure Chemical Industries, Ltd.), d-α-tocopherol acetate (Combi-Blocks), pyridoxin hydrochloride (Fuji Film Wako Pure Chemical Industries, Ltd.) or panthenol (Wako Pure Chemical Industries, Ltd.) After being added and dissolved, the pH was adjusted with a pH adjuster, and the mixture was mixed with purified water. When retinol palmitate and d-α-tocopherol acetate were added, they were added in a state of being mixed with polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals) dissolved by heating. The values in the table are w / v% except for the columns of pH and retinol palmitate. Retinol palmitate is shown in active units per 100 mL.

(Test operation)
The test solution and 1-octanol (Nacalai Tesque) were mixed based on the following operations.
1) A plastic centrifuge tube was filled with 2.5 mL each of 1-octanol saturated with each test solution and water.
2) Mixing was performed with a vortex mixer (VX100, Labnet International) for 30 seconds.
3) Shaking was performed for 30 minutes with a shaker (MW-1, AS ONE) (300 times / minute) that stirs in the vertical direction.
4) Shaker was shaken in a horizontal shaker (Universal Shaker SHK-U4, AGC technoglass) (120 rpm / min) for 24 hours or more.
5) Mixing was performed with a vortex mixer (VX100, Labnet International) for 30 seconds.
6) After separating the octanol layer and the aqueous layer by centrifugation (LC-120, Tomy Seiko) (3,000 rpm, 10 minutes), the aqueous layer was collected and mixed to prepare an aqueous layer sample.

(Measurement of brimonidine tartrate content in test solution and aqueous layer)
The brimonidine tartrate content of each test solution and the aqueous layer sample after mixing octanol and each test solution was measured by high performance liquid chromatography (HPLC) method.
Column: Inner diameter 4.6 mm x Length 75 mm Octadecylsilylated silica gel ("Symmetery C18 3.5" manufactured by Waters)
Detector: Ultraviolet-visible absorptiometer Measurement wavelength: 264 nm
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.

The brimonidine tartrate content transferred to the octanol layer from the mixture of octanol and each sample was determined from the difference between the brimonidine tartrate content in each test solution obtained by measurement and the brimonidine tartrate content in the sample aqueous layer after mixing. The rate of increase in the amount of brimonidine tartrate transferred to the octanol layer (C _rate ) due to the combination of vitamins was calculated according to the following formula.

[In the formula, C _sample was defined as the brimonidine tartrate content in the octanol layer of the sample after mixing, and C _{comparative example} was defined as the brimonidine tartrate content in the octanol layer of the comparative example after mixing. As C _Sample and C _{Comparative Example,} those having the same brimonidine tartrate concentration were used. ]

The brimonidine tartrate solution contains brimonidine tartrate by blending at least one vitamin among flavin adenine dinucleotide sodium, cyanocobalamin, retinol palmitate, d-α-tocopherol acetate, pyridoxin hydrochloride and panthenol. It was found that the amount transferred to the octanol layer was increased and the lipophilicity of brimonidine tartrate was improved.

Test Example 7: Measurement of Rabbit Conjunctival Transfer of Brimonidine Tartrate (Prescription) Each sample was prepared by a conventional method. That is, boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.), borax (Nacalai Tesque), and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd) are added and dissolved in purified water to dissolve them, and then d-α-tocopherol acetate or After adding and dissolving pyridoxine hydrochloride, the pH was adjusted with a pH adjuster, and the mixture was prepared with purified water. When d-α-tocopherol acetate was added, it was added in a state of being mixed with heat-dissolved polyoxyethylene hydrogenated castor oil 60 (Nikko Chemicals). The values in the table are w / v% excluding pH.

(Test operation)
1-1) Tube1: Four samples in each group were dispensed into 1 mL sample tubes (1.5 mL microtubes, Zartstat).
1-2) Tube2: Four samples in each group and a sample tube with a filter (Ultrafree-MC-GV 0.45 μm, millipore) were prepared.
2) A rabbit-extracted eyeball (Kitayama Labes) was obtained, and the conjunctiva was cut out.
3) The conjunctiva was washed by immersing it in physiological saline (Otsuka Raw Food Injection, Otsuka Pharmaceutical Factory).
4) Moisture on the surface was lightly wiped off with a Kimwipe, and the weight of the conjunctiva was measured.
5) After measuring the weight of the conjunctiva, 1-1) it was put into Tube1 and shaken at 1,500 rpm with a shaker (block bath shaker-MyBL-100CS, AS ONE) for 5 minutes.
6) The conjunctiva was taken out from the centrifuge tube of 5).
7) Take 300 μL of the sample from the centrifuge tube of 6) excluding the conjunctiva, add it to 1-2) Tube2, and centrifuge it with a desktop micro high-speed centrifuge (CT-12RE, Hitachi Koki) (15,000 rpm, 10). Minutes, 4 ° C.), and the filtrate was used as a sample.

(Determination of conjunctival transfer amount)
The brimonidine tartrate content of (i) the test solution without immersing the conjunctiva and the sample of (ii) 7) was measured by high performance liquid chromatography (HPLC), and the difference between (i) and (ii) was used to measure the content per sample. The amount of conjunctival transfer was determined, and from the conjunctival weight measured in 4), the content of brimonidine tartrate transferred per 1 g of conjunctiva was determined for each individual, and the average value of the four cases was taken as the amount of conjunctiva transfer.
The rate of increase in the amount of brimonidine tartrate transferred to the conjunctiva (C _rate ) due to the combination of d-α-tocopherol acetate or pyridoxine hydrochloride was calculated according to the following formula.

[In the formula, C _sample was the amount of brimonidine tartrate conjunctival transfer of _{Example, and C Comparative Example 35} was the amount of brimonidine tartrate conjunctiva transfer of Comparative Example 35. ]

Among the combinations in which the transferability to the octanol layer (lipophilicity) was improved in Test Example 6, the transferability to the actual conjunctiva was investigated using typical d-α-tocopherol acetate and pyridoxin hydrochloride. The amount of brimonidine transferred to the conjunctiva was improved as well as the result of transferability to the octanol layer. Therefore, it can be presumed that other vitamins having improved transferability to the octanol layer in Test Example 6 also have improved transferability to the conjunctiva.

Claims

An ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof and vitamins.
The liquid preparation for ophthalmology according to claim 1, wherein the vitamins are at least one selected from the group consisting of vitamin A, vitamin B, and vitamin E.
The liquid preparation for ophthalmology according to claim 2, wherein the vitamin A is a retinol palmitate ester.
The liquid preparation for ophthalmology 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. ..
The liquid preparation for ophthalmology according to claim 2, wherein the vitamin E is d-α-tocopherol acetate.
The concentration of vitamins is 0.01 to 0.05 w / v% for flavin adenine dinucleotide sodium, 0.004 to 0.02 w / v% for cyanocobalamin, and 10,000 units / 100 ml to 50,000 units for vitamin A. 100 ml, pyridoxin and / or its salt 0.01-0.1 w / v%, panthenol and pantothenic acid and / or its salt 0.01-0.1 w / v%, vitamin E 0.005 The liquid preparation for ophthalmology according to claim 2, which is ~ 0.05 w / v%.