Water-based liquid

Abstract

An object of the present invention is to provide a formulation technology that provides an aqueous liquid preparation containing brimonidine and / or a salt thereof with preservative effectiveness at least at a level at which a bacteriostatic effect is observed without the addition of a preservative. [Solution] An aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer can have a preservative effectiveness at a level that at least exhibits bacteriostatic activity, even if it is substantially free of preservatives.

Description

[Technical Field]

[0001] The present invention relates to an aqueous liquid preparation containing brimonidine and / or a salt thereof, which has a preservative effect at least at a level at which a bacteriostatic effect is observed. [Background technology]

[0002] Aqueous liquid preparations such as eye drops and eyewashes usually contain preservatives such as benzalkonium chloride and methylparaben to prevent the growth of microorganisms. However, while preservatives can prevent the growth of bacteria, they are known to be irritating and cytotoxic (see Non-Patent Document 1).

[0003] Conventionally, in order to prevent bacterial growth during storage of preservative-free aqueous liquid preparations, they have been contained in multi-dose containers (hereinafter sometimes referred to as "multi-dose preservative-free containers") that have a mechanism for preventing the aqueous liquid preparation that has once seeped out from flowing back into the container, and / or a mechanism for preventing foreign matter (such as microorganisms) from entering the container (see, for example, Patent Documents 1 to 4, etc.).

[0004] On the other hand, brimonidine and its salts are known as adrenergic α2 receptor agonists, which have the effect of reducing intraocular pressure by inhibiting aqueous humor production and promoting the outflow of aqueous humor via the uveoscleral outflow pathway, and have traditionally been used to treat glaucoma and ocular hypertension. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Japanese Ophthalmology, Vol. 58, No. 10, pp. 945-950, 1987 [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-132465 [Patent Document 2] Japanese Patent Application Laid-Open No. 2005-343549 [Patent Document 3] Japanese Patent Application Laid-Open No. 2004-51170 [Patent Document 4] Japanese Patent Application Laid-Open No. 2002-80055 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a formulation technology relating to an aqueous liquid preparation containing brimonidine and / or a salt thereof. [Means for solving the problem]

[0008] The present inventors have found that an aqueous liquid preparation comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer can have preservative effectiveness at least at a level at which a bacteriostatic effect is observed, even if the aqueous liquid preparation does not substantially contain a preservative. The present invention was completed based on this finding and through further investigation.

[0009] That is, the present invention provides the following aspects. Item 1. An aqueous liquid preparation comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of preservatives. Item 2. The aqueous liquid preparation according to Item 1, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer. Item 3. The aqueous liquid preparation according to Item 1 or 2, wherein the concentration of edetic acid and / or a salt thereof is 0.005 to 0.5 w / v %. Item 4. The aqueous liquid preparation according to any one of Items 1 to 3, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v %. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, which has a pH of 6 to 8. Item 6. The aqueous liquid preparation according to any one of Items 1 to 5, which is an eye drop. Item 7. The aqueous liquid preparation according to any one of Items 1 to 6, which is contained in a multi-dose container having a mechanism for preventing backflow of the aqueous liquid preparation once it has seeped out into the container, and / or a mechanism for preventing foreign matter from entering the container. Item 8. Brimonidine and / or its salt is brimonidine tartrate, the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%, the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer; edetic acid and / or a salt thereof is sodium edetate dihydrate, the concentration of edetic acid and / or a salt thereof is 0.005 to 0.5 w / v%, pH is 6 to 8, and An aqueous liquid preparation contained in a multi-dose container having a mechanism for preventing backflow of the aqueous liquid preparation once it has seeped out into the container, and / or a mechanism for preventing foreign matter from entering the container. Item 9. A method for imparting preservative effect to an aqueous liquid formulation containing brimonidine and / or a salt thereof, comprising: The method includes the step of preparing an aqueous liquid formulation that is substantially free of preservatives and contains brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer; Method of imparting preservative effect. Item 10. The method of applying according to Item 9, wherein the buffer is at least one selected from the group consisting of borate buffers, phosphate buffers, and Tris buffers. Item 11. The method of administering according to Item 9 or 10, wherein the concentration of edetic acid and / or a salt thereof in the aqueous liquid preparation is 0.005 to 0.5 w / v %. Item 12. The method of administering according to any one of Items 9 to 11, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v %. Item 13. The method of applying according to any one of Items 9 to 12, wherein the aqueous liquid preparation has a pH of 6 to 8. Item 14. The method of applying according to any one of Items 9 to 13, wherein the aqueous liquid preparation is an eye drop. Item 15. The method of application according to any one of Items 9 to 14, wherein the aqueous liquid preparation is contained in a multi-dose container having a mechanism for preventing backflow of the aqueous liquid preparation once it has seeped out into the container, and / or a mechanism for preventing foreign matter from entering the container. Item 16. The concentration of brimonidine and / or a salt thereof in the aqueous liquid is 0.05 to 0.2 w / v%, the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, and a Tris buffer; edetic acid and / or a salt thereof is sodium edetate dihydrate, the concentration of edetic acid and / or a salt thereof in the aqueous liquid preparation is 0.005 to 0.5 w / v%, The pH of the aqueous solution is 6 to 8, and The method for imparting preservative efficacy further comprises a step of storing the prepared aqueous liquid in a multi-dose container having a mechanism for preventing backflow of the aqueous liquid once it has seeped out into the container, and / or a mechanism for preventing foreign matter from entering the container. Item 17. An aqueous liquid preparation comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, and substantially free of preservatives, The aqueous liquid preparation is contained in a multi-dose container having a mechanism for preventing backflow of the aqueous liquid preparation once it has seeped out into the container, and / or a mechanism for preventing foreign matter from entering the container. A pharmaceutical product characterized by: [Effects of the Invention]

[0010] According to the aqueous liquid preparation of the present invention, the synergistic effect of brimonidine and / or a salt thereof and edetic acid and / or a salt thereof can provide a preservative effect at least at a level at which a bacteriostatic effect is observed, even without substantially containing a preservative. Therefore, even when the aqueous liquid preparation of the present invention is contained in a multi-dose preservative-free container and used, it can prevent microbial contamination that may occur due to residual liquid on the outer surface of the nozzle, and can more highly ensure the safety of the aqueous liquid preparation administered by eye drop administration, etc. DETAILED DESCRIPTION OF THE INVENTION

[0011] 1.Definition As used herein, the term "aqueous liquid preparation" refers to a preparation that contains water as a base and is in a liquid form.

[0012] As used herein, "brimonidine" refers to 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine, a compound known as an adrenergic α2 receptor agonist.

[0013] In this specification, "edetic acid" is a known compound also known as ethylenediaminetetraacetic acid.

[0014] As used herein, the term "buffer" refers to a compound or mixture that acts to moderate fluctuations in the hydrogen ion concentration (pH) of an aqueous liquid preparation.

[0015] In this specification, the term "preservative" refers to an ingredient that has preservative effect, and when the aqueous solution contains only the ingredient in question at a concentration acceptable for eye drops, the aqueous solution satisfies the criteria for category "IA" in the "Preservative Effectiveness Test Method" of the Reference Information for the Japanese Pharmacopoeia, 17th Edition. However, in the present invention, the preservative does not include borate buffer.

[0016] In this specification, "substantially free of preservatives" refers to a concentration of preservatives at which the preservative alone is unable to exert its preservative effect, and specifically refers to a concentration of preservatives at which, when an aqueous solution containing only the preservative is prepared, the aqueous solution is "compliant" based on the criteria set forth in Category "IC" in the Reference Information for "Preservative Effectiveness Testing Methods" in the 17th Edition of the Japanese Pharmacopoeia.

[0017] As used herein, the term "multi-dose container" refers to a container filled with an amount of aqueous liquid preparation sufficient for multiple uses and used repeatedly. Multi-dose containers include those that have a mechanism for preventing the aqueous liquid preparation once seeped out from flowing back into the container or a mechanism for preventing foreign matter from entering the container (i.e., multi-dose preservative-free containers), and those that do not have such mechanisms. Multi-dose preservative-free containers typically have a structure such as a backflow prevention valve, a microfilter, or a special double-walled bottle as a mechanism for preventing the aqueous liquid preparation once seeped out from flowing back into the container or a mechanism for preventing foreign matter from entering the container (e.g., Patent Documents 1 to 4).

[0018] As used herein, the term "unit-dose container" refers to a container filled with a single dose of aqueous liquid preparation and used up after one instillation.

[0019] As used herein, the term "pharmaceutical product" refers to a product in which an aqueous liquid formulation is contained in any container.

[0020] As used herein, the term "method of imparting preservative effectiveness" refers to a method of converting an aqueous liquid formulation that does not meet the criteria for Category "IC" in the "Preservative Effectiveness Test Method" of the Japanese Pharmacopoeia, 17th Edition, into an aqueous liquid formulation that meets the criteria for Category "IC" in the same test. Furthermore, efficacy that is judged to be "compliant" based on the criteria for "IC" is sometimes referred to as "JP IC-compliant preservative effectiveness."

[0021] In this specification, "bacteriostatic effect" refers to an effect that does not reduce, but at least does not increase, the number of live bacteria or fungi in a test based on the "Preservative Effectiveness Test Method" in the Reference Information of the Japanese Pharmacopoeia, 17th Edition. Furthermore, "having a preservative effectiveness at least at a level at which bacteriostatic effect is recognized" is synonymous with being judged to be "compliant" based on the criteria set forth in the above-mentioned "IC."

[0022] 2. Water-based liquid Previously, ophthalmic solutions packaged in standard multi-dose containers (those not classified as preservative-free multi-dose containers) were required to have a preservative effectiveness that meets the criteria for Category IA in the Japanese Pharmacopoeia, 17th Edition, Reference Information, "Preservative Effectiveness Test Method." However, ophthalmic solutions packaged in preservative-free multi-dose containers are not required to meet the same criteria. However, when aqueous solutions are packaged in preservative-free multi-dose containers and used frequently, some of the solution may remain on the outer surface of the nozzle. This residual solution may become contaminated with microorganisms, and frequent use in this state could result in the inability to ensure the sterility of the aqueous solution administered by instillation. Therefore, it is desirable for aqueous formulations packaged in preservative-free multi-dose containers to have a preservative effectiveness at least at a level that is recognized as bacteriostatic, even if they do not contain preservatives.

[0023] However, no formulation technology has been reported to date that enhances the preservative effectiveness of an aqueous liquid preparation containing brimonidine and / or a salt thereof without incorporating a preservative, and conventional technology has not been able to eliminate concerns about microbial contamination caused by the aqueous liquid remaining on the outer surface of the nozzle when the preparation is contained in a multi-dose preservative-free container.

[0024] In contrast, the present inventors have discovered that an aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, but substantially free of preservatives, has improved preservative effectiveness due to the synergistic effect of brimonidine and / or a salt thereof, and edetic acid and / or a salt thereof, and has preservative effectiveness that is deemed to be "compliant" based on the criteria set forth in Category "IC" in the Reference Information for "Preservative Effectiveness Test Method" of the 17th Edition of the Japanese Pharmacopoeia, even without the use of a preservative.

[0025] In one embodiment, the present invention provides an aqueous liquid formulation comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent, and which is substantially free of preservatives.

[0026] The brimonidine salt used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specifically includes organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride. Brimonidine or its salts may also be in the form of a solvate such as a hydrate. Among brimonidine or its salts, brimonidine tartrate is preferred. In the aqueous liquid preparation of the present invention, either brimonidine or a salt thereof may be used alone, or these may be used in combination.

[0027] In the aqueous liquid preparation of the present invention, the concentration of brimonidine or a salt thereof is not particularly limited and may be appropriately determined depending on the intended use of the aqueous liquid preparation, the severity of symptoms in the patient to whom the preparation is to be administered, the amount administered per administration, etc., and may be, for example, 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, and particularly preferably 0.1 w / v%. In this specification, the concentration of brimonidine or a salt thereof is the concentration converted into brimonidine tartrate.

[0028] The salt of edetic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sodium salts of edetate such as monosodium edetate, disodium edetate (EDTA), and tetrasodium edetate. The salt of edetic acid may also be in the form of a solvate such as a hydrate. One type of edetic acid or a salt thereof may be selected and used alone, or two or more types may be used in combination. Among edetic acid or a salt thereof, sodium edetate dihydrate is preferred from the viewpoint of providing even more excellent preservative effectiveness.

[0029] In the aqueous liquid preparation of the present invention, either edetic acid or a salt thereof may be used alone, or these may be used in combination.

[0030] In the aqueous liquid preparation of the present invention, the concentration of edetic acid or a salt thereof is usually 0.001 to 0.5 w / v%, preferably 0.005 to 0.05 w / v%, more preferably 0.003 to 0.02 w / v%, and particularly preferably 0.005 to 0.01 w / v%, from the viewpoint of providing even more excellent preservative effectiveness. In this specification, the concentration of edetic acid or a salt thereof is the concentration converted into edetate disodium dihydrate.

[0031] The buffer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc.

[0032] Specific examples of boric acid buffers include boric acid and / or salts thereof. Boric acid is not particularly limited as long as it is pharmaceutically acceptable, but examples include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used alone or in combination of two or more. Salts of boric acid are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid and / or its salts may also be in the form of a hydrate, such as borax.

[0033] As the boric acid buffer, one selected from boric acid and its salts may be used alone or in combination of two or more. Among boric acid and its salts, from the viewpoint of providing a more excellent preservative effect, at least one of boric acid and borax is preferred, and at least one of orthoboric acid and borax is more preferred.

[0034] In addition, a preferred embodiment of the boric acid buffer is a combination of boric acid and borax. By using boric acid and borax in combination in this way, it is possible to provide even more excellent preservative effect. When using boric acid and borax in combination, the ratio thereof is not particularly limited, but for example, 0 to 100 parts by mass of borax per 100 parts by mass of boric acid, preferably 20 to 80 parts by mass, more preferably 40 to 60 parts by mass, can be mentioned.

[0035] The amount of boric acid buffer used is, from the viewpoint of buffering action, typically 0.1 to 2 w / v%, more preferably 0.5 to 1.5 w / v%, still more preferably 0.7 to 1.0 w / v%, and particularly preferably 0.4 to 0.6 w / v% in terms of the concentration of boric acid or a salt thereof. In this specification, the concentration of boric acid or a salt thereof is the concentration converted into boric acid.

[0036] Specific examples of phosphate buffers include phosphoric acid and / or salts thereof. Phosphate salts are not particularly limited as long as they are pharmaceutically acceptable, and examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates, for example, disodium hydrogen phosphate may be in the form of a dodecahydrate, and sodium dihydrogen phosphate may be in the form of a dihydrate.

[0037] The phosphate buffer may be one selected from phosphoric acid and its salts and used alone or in combination of two or more. Among phosphoric acid and its salts, from the viewpoint of providing a more excellent preservative effect, preferred is a phosphate, more preferred is at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferred is at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0038] Another preferred embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate. Using a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate in combination in this manner makes it possible to provide even more excellent preservative effectiveness. When a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate are used in combination, the ratio between them is not particularly limited, but may be, for example, 1 to 120 parts by mass, preferably 5 to 80 parts by mass, and more preferably 10 to 40 parts by mass of the alkali metal dihydrogen phosphate per 100 parts by mass of the dialkali metal hydrogen phosphate.

[0039] Regarding the amount of the phosphate buffer used, from the viewpoint of buffering action, the concentration of phosphoric acid or a salt thereof is usually 0.1 to 5 w / v%, preferably 1 to 3 w / v%, and more preferably 1.5 to 2.0 w / v%. In this specification, the concentration of the phosphate buffer is the concentration converted into phosphoric acid.

[0040] Specific examples of Tris buffers include trometamol and / or its salts. The salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and examples include organic acid salts such as acetate salts, and organic acid salts such as hydrochloride and sulfonate salts.

[0041] As the Tris acid buffer, one selected from trometamol and its salts may be used alone or in combination of two or more. Among trometamol and its salts, trometamol is preferred from the viewpoint of providing superior preservative effectiveness.

[0042] The amount of Tris buffer used is usually 0.1 to 2 w / v%, preferably 0.3 to 1.75 w / v%, and more preferably 0.5 to 1.5 w / v%, from the viewpoint of buffering action. In this specification, the concentration of Tris buffer is the concentration converted to trometamol.

[0043] Specific examples of citrate buffers include citric acid and / or salts thereof. The salts of citric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. Furthermore, the salts of citric acid may be in the form of solvates such as hydrates. As the citrate buffer, one selected from citric acid and its salts may be used alone, or two or more may be used in combination.

[0044] Specific examples of tartaric acid buffers include tartaric acid and / or salts thereof. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. Furthermore, the salts of tartaric acid may be in the form of solvates such as hydrates. As the tartaric acid buffer, one selected from tartaric acid and its salts may be used alone, or two or more may be used in combination.

[0045] Specific examples of acetate buffers include acetic acid and / or salts thereof. The salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the salts of acetic acid may be in the form of a solvate such as a hydrate. As the acetate buffer, one selected from acetic acid and its salts may be used alone, or two or more may be used in combination.

[0046] Specific examples of the amino acid buffer include acidic amino acids and / or their salts. Specific examples of the acidic amino acids include aspartic acid and glutamic acid. The salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one selected from acidic amino acids and salts thereof may be used alone, or two or more may be used in combination.

[0047] These buffers may be used alone or in combination of two or more.

[0048] Among these buffers, borate buffer, phosphate buffer and Tris buffer are preferred from the viewpoint of providing even more excellent preservative effect.

[0049] The aqueous liquid preparation of the present invention is substantially free of preservatives, but may contain a preservative in an amount that is less than the minimum concentration of preservative that, when made into an aqueous solution containing only a preservative, will be "compliant" based on the criteria set forth in Category "IC" in the "Preservative Effectiveness Test Method" in the Reference Information for the 17th Edition of the Japanese Pharmacopoeia.

[0050] Specific examples of preservatives include chlorites such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid and its salts such as sorbic acid and potassium sorbate; parahydroxybenzoic acid esters such as methylparaben and propyl parahydroxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, etc.

[0051] The acceptable concentration of the preservative in the aqueous liquid preparation of the present invention varies depending on the type of preservation, etc., but specifically includes less than 0.001 w / v%, preferably 0.0005 w / v% or less, more preferably 0.0001 w / v% or less, and particularly preferably 0 w / v%.

[0052] The aqueous liquid preparation of the present invention contains brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer, thereby achieving a preservative effect at least at a level at which a bacteriostatic effect is observed. Therefore, the aqueous liquid preparation of the present invention may be substantially free of components that improve the preservative effect in the presence of brimonidine and / or a salt thereof, in addition to the above components.

[0053] For example, it is known that dorzolamide and / or its salts can improve preservative effectiveness when coexisting with brimonidine and / or its salts in an aqueous liquid preparation having a pH of 6.0 or higher. Therefore, one embodiment of the aqueous liquid preparation of the present invention is one that is substantially free of dorzolamide and / or its salts. Specific examples of dorzolamide salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, and tartaric acid; salts with alkali metals, salts with alkaline earth metals, salts with organic amines, and halides. Furthermore, "substantially free of dorzolamide and / or its salts" specifically refers to a dorzolamide and / or its salt concentration of less than 0.1 w / v%, preferably 0.05 w / v% or less, more preferably 0.01 w / v% or less, and particularly preferably 0 w / v%.

[0054] In addition to the above-mentioned components, the aqueous liquid preparation of the present invention may contain additives such as an isotonic agent, a polyhydric alcohol, a surfactant, a thickening agent, a chelating agent (other than edetic acid and its salts), a cooling agent, a stabilizer, and a pH adjuster, as needed.

[0055] The isotonicity agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; metal salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; etc. These isotonicity agents may be used alone or in combination of two or more.

[0056] The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, glycerin, etc. These polyhydric alcohols may be used alone or in combination of two or more.

[0057] The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol, etc.; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine, etc.; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, etc.; cationic surfactants such as alkylpyridinium salts, alkylamine salts, etc. These surfactants may be used alone or in combination of two or more.

[0058] The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

[0059] The chelating agent (other than edetic acid and its salts) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof. The salt form is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts. These chelating agents may be used alone or in combination of two or more.

[0060] The cooling agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 1-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

[0061] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

[0062] The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

[0063] The concentrations of these additives may be appropriately set depending on the types of additives used and the properties to be imparted to the aqueous liquid preparation.

[0064] Furthermore, the aqueous liquid preparation of the present invention may contain, in addition to brimonidine and / or a salt thereof, a pharmacological ingredient that exhibits a therapeutic effect on glaucoma or ocular hypertension, as needed, within a range that does not impair the effects of the present invention.

[0065] Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone, etc.; parasympathomimetics such as pilocarpine hydrochloride, etc.; anticholinesterase agents such as distigmine bromide, etc.; sympathomimetics such as dipivefrine hydrochloride, etc.; β1-blockers such as betaxolol hydrochloride, etc.; β-blockers such as timolol maleate, etc.; α1-β-blockers such as nipradilol, levobunolol hydrochloride, etc.; α1-blockers such as bunazosin hydrochloride, etc. These pharmacological ingredients may be used alone or in combination of two or more.

[0066] The concentrations of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used, the medicinal effect to be imparted, and the like.

[0067] The pH of the aqueous liquid preparation of the present invention is not particularly limited, and may be, for example, pH 6 to 8. From the viewpoint of providing even more excellent preservative effectiveness, the pH of the aqueous liquid preparation of the present invention is preferably pH 7 to 8, and more preferably pH 7.

[0068] The osmotic pressure ratio of the aqueous liquid preparation of the present invention is not particularly limited, and may be, for example, 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w / v% aqueous sodium chloride solution, and the osmotic pressure is measured in accordance with the "osmotic pressure method (osmolality measurement method)" specified in the 17th Edition of the Japanese Pharmacopoeia.

[0069] By including the above-mentioned components, the aqueous liquid preparation of the present invention is able to have a preservative effectiveness at least at a level at which bacteriostatic activity is recognized. Specifically, the preservative effectiveness of the aqueous preparation of the present invention is judged to be "compliant" based on the criteria set forth in the "Preservative Effectiveness Test Method" of the Japanese Pharmacopoeia, 17th Edition, Reference Information, Category "IC." JP IC-compliant preservative effectiveness can be determined by a test method in accordance with the "Preservative Effectiveness Test Method" of the Japanese Pharmacopoeia, 17th Edition, Reference Information, and the specific test method is as shown in the Test Examples section below.

[0070] The formulation form of the aqueous liquid preparation of the present invention is not particularly limited, and may be any of an aqueous solution, a suspension, an emulsion, etc., but is preferably an aqueous solution.

[0071] The aqueous liquid preparation of the present invention can be used as an ophthalmic preparation such as eye drops, eyewash, etc. In particular, since the aqueous liquid preparation of the present invention can suppress the production of aqueous humor and reduce intraocular pressure by the action of brimonidine and / or a salt thereof, it is provided as eye drops and can be suitably used as an aqueous liquid preparation for treating glaucoma or ocular hypertension.

[0072] The aqueous liquid preparation of the present invention may be prepared according to a known preparation method depending on the intended use, for example, by the method described in the General Provisions for Preparations in the 17th Edition of the Japanese Pharmacopoeia.

[0073] The container for storing the aqueous liquid preparation of the present invention may be an eye dropper, an eyewash container, or the like, depending on the intended use of the aqueous preparation.

[0074] The aqueous liquid preparation of the present invention may be in a multi-dose container or a unit-dose container.

[0075] Furthermore, in the case of a multi-dose container, it is particularly preferable to use a multi-dose preservative-free container in order to maintain the sterility of the aqueous liquid formulation contained therein during storage. With conventional aqueous liquid formulations that do not contain preservatives, even when a multi-dose preservative-free container is used, there is a concern about microbial contamination of the aqueous liquid formulation remaining on the outer surface of the nozzle. However, the aqueous liquid formulation of the present invention has a preservative effectiveness at least at a level at which a bacteriostatic effect is recognized, and therefore can suppress such microbial contamination even if the aqueous liquid formulation remains on the outer surface of the nozzle of a multi-dose preservative-free container.

[0076] 3. How to provide preservative effect The present invention provides a method for imparting preservative effect to an aqueous liquid preparation containing brimonidine and / or a salt thereof, the method comprising the step of preparing an aqueous liquid preparation that is substantially free of preservatives and contains brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffer.

[0077] According to the method of the present invention for imparting a preservative effect, it is possible to impart a preservative effect conforming to the Japanese Pharmacopoeia IC standard to an aqueous liquid preparation containing brimonidine and / or a salt thereof.

[0078] In the method of imparting preservative effectiveness of the present invention, the type and concentration of brimonidine and / or a salt thereof, the type and concentration of edetic acid and / or a salt thereof, the type and concentration of a buffer, the types of other additives and pharmacological ingredients to be blended in the aqueous liquid, the pH of the aqueous liquid, the formulation form, uses, etc. are as described in the section "1. Aqueous liquid" above. [Example]

[0079] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the following test examples, orthoboric acid was used as the boric acid.

[0080] Test Example 1: Evaluation of preservative effectiveness In accordance with the "Preservative Effectiveness Test Method" in the Reference Information of the Japanese Pharmacopoeia, 17th Edition, the preservative effectiveness of the eye drops having the composition shown in Table 1 was evaluated. The specific test method etc. are as follows.

[0081] 1. Test materials and test methods 1-1. Sample preparation Aqueous liquid preparations (eye drops) having the compositions shown in Tables 1 to 3 were prepared and filtered through a 0.22 μm filter to serve as samples. The total amount of boric acid and borax in Example 1 was 0.72 g (concentration: 0.72 w / v%) converted to boric acid, and the total amount of disodium hydrogen phosphate hydrate and sodium dihydrogen phosphate in Example 2 was 1.8 g (concentration: 1.8 w / v%) converted to phosphoric acid.

[0082] 1-2. Test bacteria The following three species of bacteria and two species of fungi were used: (bacteria) ·Staphylococcus aureus, S. aureus / ATCC 6538 ·Escherichia coli (E.coli / ATCC 8739) ·Pseudomonas aeruginosa, P.aeruginosa / ATCC 9027 (fungi) Candida albicans (C. albicans / ATCC 10231) Black koji mold (Aspergillus brasiliensis, A. brasiliensis / ATCC 16404)

[0083] 1-3. Preculture The test bacteria were inoculated onto the surface of an agar slant and pre-cultured. Soybean-casein-digest agar was used for bacteria, and Sabouraud-dextrose agar was used for fungi. Pre-culture was performed at 30-35°C for 18-24 hours for bacteria, at 20-25°C for 44-52 hours for Candida, and at 20-25°C for 6-10 days for Aspergillus oryzae.

[0084] 1-4. Preparation of mixed samples and measurement of bacterial count Dispense 10 mL of the sample into five sterilized test tubes with stoppers, and add 1 × 10 5 ~1×10 6 The test bacteria were inoculated so that the concentration of CFU / mL was reached, and these were used as mixed samples. The mixed samples were stored at 20-25°C, shielded from light. The test bacteria were not mixed, but each species was inoculated into a specimen individually to prepare mixed samples.

[0085] At the start of the test and on days 7, 14, and 28, 1 mL of each mixed sample was diluted with 9 mL of saline. Similar dilutions were repeated two or three times as necessary, and 1 mL of each diluted solution was dispensed into sterile Petri dishes. Next, the samples were mixed with soybean casein digest agar supplemented with 0.1% lecithin and 0.7% polysorbate 80 for bacteria, or Sabouraud dextrose agar supplemented with 0.1% lecithin and 0.7% polysorbate 80 for fungi. After incubation at 30-35°C for 3-5 days for bacteria and at 20-25°C for 5-7 days for fungi, the number of colonies formed was counted, and the viable cell count per mL of mixed sample (cfu / mL) and the logarithmic reduction in viable cell count (log) were calculated.

number

[0086] 1-5. Determining preservative effectiveness The preservative effectiveness of each test solution was evaluated according to the criteria for Category 1C described in "Table 3: Judgment Criteria by Formulation Category" in "4. Judgment" of the Reference Information for "Preservative Effectiveness Testing Methods" in the 17th Edition of the Japanese Pharmacopoeia. Specifically, a test solution was judged to be "compliant" if it met all of the following criteria: (1) for all three types of bacteria, the logarithmic reduction (log) was 1.0 log or more after 14 days compared to the inoculated number of bacteria, and the viable number after 28 days did not increase from 14 days, and (2) for all two types of fungi, the viable number after 14 days and 28 days did not increase from the inoculated number of bacteria. Otherwise, it was judged to be "non-compliant."

[0087] 2. Test Results The results are shown in Tables 1 to 3. The aqueous liquid preparation (Reference Example 1) that did not contain brimonidine tartrate or sodium edetate dihydrate but contained a borate buffer (boric acid and borax) had a preservative effectiveness conforming to the Japanese Pharmacopoeia IC standard. However, the aqueous liquid preparations (Comparative Examples 1 and 2) that contained brimonidine tartrate or sodium edetate dihydrate together with a borate buffer had reduced preservative effectiveness and did not have the preservative effectiveness conforming to the Japanese Pharmacopoeia IC standard. In contrast, the aqueous liquid preparation (Example 1) that contained brimonidine tartrate and sodium edetate dihydrate together with a borate buffer had improved preservative effectiveness and had the preservative effectiveness conforming to the Japanese Pharmacopoeia IC standard. Furthermore, even when a phosphate buffer and a Tris buffer were used, the aqueous liquid preparations containing brimonidine tartrate and sodium edetate dihydrate had improved preservative effectiveness and were able to have the preservative effectiveness conforming to the Japanese Pharmacopoeia IC standard.

[0088] [Table 1]

[0089] [Table 2]

[0090] [Table 3]

[0091] Test Example 2: Evaluation of thermal stability Aqueous solutions (eye drops) with the compositions shown in Table 5 were prepared. After filtration through a 0.22 μm filter, 5 mL of each aqueous solution was filled into a 5 mL colorless glass ampoule. These were placed in a tabletop thermo-hygrostat (NST-80, Nagano Science Co., Ltd.) and stored at 60°C under light-shielded conditions for 4 weeks. The brimonidine tartrate content before and after storage was measured using a high-performance liquid chromatograph system (Shimadzu Corporation) under the following conditions.

[0092] <Measurement conditions> Detector: UV absorption photometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6mm ID×150mm, 3.5μm, Waters Column temperature: constant temperature around 40°C Mobile phase A: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Flow rate: 1.0 mL / min Autosampler temperature: 5℃ Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 4 to control the linear concentration gradient.

[0093] [Table 4]

[0094] The residual rate of brimonidine in the aqueous liquid preparation was calculated according to the following formula:

number

[0095] The results are shown in Table 5. When sodium edetate dihydrate was not added, the aqueous solution containing no preservative (Comparative Example 9) had a lower residual rate of brimonidine than the aqueous solutions containing preservatives commonly used in ophthalmic solutions (Comparative Examples 7 and 8). The stability of brimonidine can be improved by adding preservatives such as sodium bisulfite and benzalkonium chloride. However, even without adding a preservative, the stability of brimonidine tartrate was further improved in the aqueous solution containing sodium edetate dihydrate. In other words, these results demonstrate that aqueous solutions containing brimonidine and / or a salt thereof and edetic acid and / or a salt thereof, which are substantially free of preservatives, are also superior in terms of the stability of brimonidine and / or a salt thereof.

[0096] [Table 5]

Claims

1. A method for improving the stability of brimonidine tartrate in an aqueous liquid preparation containing brimonidine tartrate and contained in a multi-dose container, A method for improving stability, comprising the step of preparing an aqueous solution (excluding cases where betaxolol or a salt thereof is included) that does not contain dorzolamide and / or a salt thereof, but contains brimonidine tartrate, edetate and / or a salt thereof, and a buffering agent.

2. The method according to claim 1, wherein the aqueous solution has a remaining brimonidine content of 98.2% or more, as measured under the following conditions. <Measurement conditions for the remaining brimonidine percentage> Fill a 5 mL colorless glass ampoule with 5 mL of aqueous solution and store it at 60°C for 4 weeks under light-shielding conditions. Measure the brimonidine tartrate content before and after storage using a high-performance liquid chromatography system, and calculate the remaining brimonidine percentage according to the following formula. [Math 1]

3. The method according to claim 1 or 2, wherein the buffer is at least one selected from the group consisting of boric acid buffer, phosphate buffer, and Tris buffer.

4. The method according to any one of claims 1 to 3, wherein the concentration of edetic acid and / or its salt in the aqueous solution is 0.001 to 0.5 w / v%.

5. The method according to any one of claims 1 to 4, wherein the concentration of brimonidine tartrate in the aqueous solution is 0.05 to 0.2 w / v%.

6. The method according to any one of claims 1 to 5, wherein the pH of the aqueous solution is 6 to 8.

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