Aqueous liquid

Abstract

To provide a formulation technique for providing preservation efficacy to a level where at least bacteriostatic activity is observed without blending a preservative in an aqueous liquid preparation containing brimonidine and / or a salt thereof.SOLUTION: There is provided an aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof and a buffering agent, which has preservation efficacy to a level where at least bacteriostatic activity is observed even if a preservative is not substantially contained.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an aqueous solution containing brimonidine and / or its salt and having a preservation efficacy at least above the level where bacteriostatic action is recognized.

Background Art

[0002] In aqueous solutions such as eye drops and eye washes, preservatives such as benzalkonium chloride and methylparaben are usually added to prevent the growth of microorganisms. However, it is known that while preservatives can prevent the growth of bacteria, they may exhibit irritation and cytotoxicity (see Non-Patent Document 1).

[0003] Conventionally, in order to prevent the growth of bacteria during storage in aqueous solutions without preservatives, a mechanism for preventing the backflow of the aqueous solution once it has leaked outside into the container, and / or a mechanism for preventing the entry of foreign substances (such as microorganisms) into the container, is used by accommodating them in a multi-dose type container (hereinafter, sometimes referred to as a "multi-dose preservative-free 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, and have the effect of reducing intraocular pressure by suppressing the production of aqueous humor and promoting the outflow of aqueous humor through the uveoscleral outflow pathway. Conventionally, they have been used for the treatment of glaucoma and ocular hypertension.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Patent Documents

[0006]

Patent Document 1

Patent Document 2

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

[0008] The inventors have found that an aqueous solution containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent can possess preservative efficacy at a level at least sufficient to exhibit bacteriostatic activity, even if it is substantially free of preservatives. The present invention was completed by further investigation based on this finding.

[0009] In other words, the present invention provides inventions in the following embodiments. Item 1. An aqueous solution comprising brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent, substantially free of preservatives. Item 2. The aqueous solution according to Item 1, wherein the buffer is at least one selected from the group consisting of boric acid buffer, phosphate buffer, and Tris buffer. Item 3. The aqueous solution according to item 1 or 2, wherein the concentration of edetic acid and / or its salt is 0.005 to 0.5 w / v%. Item 4. An aqueous solution according to any one of items 1 to 3, wherein the concentration of brimonidine and / or its salt is 0.05 to 0.2 w / v%. Item 5. An aqueous solution according to any of items 1 to 4, having a pH of 6 to 8. Item 6. An aqueous solution, which is an eye drop, as described in any of items 1 to 5. Item 7. An aqueous liquid according to any one of items 1 to 6, contained in a multi-dose container having a mechanism for preventing backflow of an aqueous liquid that has leached out into the container, and / or a mechanism for preventing contamination of the container with foreign matter. Item 8. Brimonidine and / or its salt is brimonidine tartrate, The concentration of brimonidine and / or its salt is 0.05-0.2 w / v%, The buffering agent is at least one selected from the group consisting of borate buffering agent, phosphate buffering agent, and Tris buffering agent. The edetate and / or salt thereof is sodium edetate dihydrate. The concentration of EDTA and / or its salt is 0.005~0.5 w / v%, The pH is 6-8, and An aqueous liquid contained in a multi-dose container having a mechanism to prevent the backflow of the aqueous liquid that has leached out into the container, and / or a mechanism to prevent the incorporation of foreign matter into the container. Item 9. A method for imparting preservative efficacy to an aqueous solution containing brimonidine and / or a salt thereof, The process includes preparing an aqueous solution that is substantially free of preservatives and contains brimonidine and / or its salts, edetic acid and / or its salts, and a buffering agent. A method for imparting preservative properties. Item 10. The method of imparting according to item 9, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer. Item 11. The method of imparting according to item 9 or 10, wherein the concentration of edetic acid and / or its salt in the aqueous solution is 0.005 to 0.5 w / v%. Item 12. The method of imparting according to any one of items 9 to 11, wherein the concentration of brimonidine and / or its salt is 0.05 to 0.2 w / v%. Item 13. The method of imparting the aqueous solution according to any one of items 9 to 12, wherein the pH of the aqueous solution is 6 to 8. Item 14. The method of dispensing according to any one of items 9 to 13, wherein the aqueous solution is an eye drop solution. Item 15. The method of imparting according to any one of Items 9 to 14, which is contained in a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid that has once leaked outside into the container and / or a mechanism for preventing the entry of foreign substances into the container. Item 16. The concentration of brimonidine and / or its salt in the aqueous liquid is 0.05 to 0.2 w / v%, The buffering agent is at least one selected from the group consisting of boric acid buffer, phosphate buffer, and Tris buffer, Edetic acid and / or its salt is sodium edetate dihydrate, The concentration of edetic acid and / or its salt in the aqueous liquid is 0.005 to 0.5 w / v%, The pH of the aqueous liquid is 6 to 8, and Furthermore, a method of imparting storage efficacy, which includes a step of storing the prepared aqueous liquid in a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid that has once leaked outside into the container and / or a mechanism for preventing the entry of foreign substances into the container. Item 17. An aqueous liquid containing brimonidine and / or its salt, edetic acid and / or its salt, and a buffering agent, and substantially free of a preservative, is contained in a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid that has once leaked outside into the container and / or a mechanism for preventing the entry of foreign substances into the container, which is characterized by a pharmaceutical product.

Effects of the Invention

[0010] According to the aqueous liquid of the present invention, due to the synergistic effect of brimonidine and / or its salt and edetic acid and / or its salt, it can have a storage efficacy level above at least the level where bacteriostatic action is recognized even without substantially containing a preservative. Therefore, even when the aqueous liquid of the present invention is contained in a multi-dose type preservative-free container and used, it can prevent microbial contamination caused by liquid residue on the outer surface of the nozzle, and can more highly ensure the safety of the aqueous liquid administered by eye drops or other operations.

Modes for Carrying Out the Invention

[0011] 1.Definition In this specification, the "aqueous solution" is a preparation that contains water as a base and exhibits a liquid state.

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

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

[0014] In this specification, the "buffer" refers to a compound or mixture having the effect of alleviating fluctuations in the hydrogen ion concentration (pH) of an aqueous solution.

[0015] In this specification, the "preservative" is a component having preservative efficacy. When the relevant component is made into an aqueous solution containing only the said component at a concentration acceptable for an eye drop, the aqueous solution is judged to be "conforming" based on the criteria defined in Category "IA" in the "Preservative Efficacy Test Method" of the 17th Revised Japanese Pharmacopoeia Reference Information. However, in the present invention, the preservative does not include boric acid buffer.

[0016] In this specification, "substantially free of preservatives" means that the concentration of the preservative is a concentration at which the preservative alone cannot exhibit preservative efficacy. Specifically, when an aqueous solution containing only the preservative is made, it means that the concentration is less than the minimum concentration of the preservative at which the aqueous solution is judged to be "conforming" based on the criteria defined in Category "IC" in the "Preservative Efficacy Test Method" of the 17th Revised Japanese Pharmacopoeia Reference Information.

[0017] In this specification, "multi-dose container" refers to a container filled with multiple doses of aqueous solution for repeated use. Multi-dose containers include those having a mechanism to prevent backflow of aqueous solution that has leached out into the container or a mechanism to prevent contamination of the container with foreign matter (i.e., multi-dose preservative-free containers), and multi-dose containers that do not have such a mechanism. Multi-dose preservative-free containers typically have structures such as a backflow prevention valve, a microfilter, or a special double-walled bottle as a mechanism to prevent backflow of aqueous solution that has leached out into the container or a mechanism to prevent contamination of the container with foreign matter (for example, Patent Documents 1 to 4).

[0018] In this specification, "unit dose container" refers to a container filled with a single dose of aqueous solution, which is used up in one application.

[0019] In this specification, "pharmaceutical product" refers to a product in which an aqueous liquid is contained in any container.

[0020] In this specification, "method for imparting preservative efficacy" means a method for transforming an aqueous solution that does not meet the criteria defined for category "IC" in the Reference Information "Preservative Efficacy Test Method" of the 17th Edition of the Japanese Pharmacopoeia into an aqueous solution that meets the criteria defined for category "IC" in the same test. Furthermore, efficacy judged to be "compliant" based on the criteria defined for "IC" may be referred to as "JPIC IC compliant preservative efficacy."

[0021] In this specification, "bacteriostatic effect" refers to an effect that, in tests based on the "Preservative Efficacy Test Method" of the 17th edition of the Japanese Pharmacopoeia, does not reduce the number of viable bacteria or fungi, but also does not increase them. Furthermore, "possessing a level of preservative efficacy that at least exhibits bacteriostatic effect" is synonymous with being judged as "compliant" based on the standards defined in the aforementioned "IC".

[0022] 2. Aqueous liquid Traditionally, eye drops contained in regular multi-dose containers, which do not fall under the category of multi-dose preservative-free containers, are required to have preservative efficacy that meets the criteria for category "IA" as defined in the "Preservative Efficacy Test Method" of the 17th edition of the Japanese Pharmacopoeia. However, eye drops contained in multi-dose preservative-free containers are not required to meet the same criteria. Nevertheless, when aqueous solutions are contained in multi-dose preservative-free containers and used frequently, the aqueous solution may remain attached to the outer surface of the nozzle. The aqueous solution remaining on the outer surface of the nozzle may become contaminated with microorganisms, and if used frequently in this state, it becomes impossible to ensure the sterility of the aqueous solution administered through eye drop administration. Therefore, it is desirable that aqueous preparations contained in multi-dose preservative-free containers have preservative efficacy at least at a level that allows for bacteriostatic activity, even without the addition of preservatives.

[0023] However, conventionally, no formulation technology has been reported for enhancing the preservative efficacy of aqueous solutions containing brimonidine and / or its salts without the addition of preservatives. Furthermore, conventional technologies have not been able to eliminate concerns about microbial contamination caused by residual aqueous solution on the outer surface of the nozzle when the solution is housed in a multi-dose preservative-free container.

[0024] In contrast, the present inventors have found that an aqueous solution containing brimonidine and / or its salt, edetic acid and / or its salt, and a buffering agent, substantially free of preservatives, has improved preservative efficacy due to the synergistic effect of brimonidine and / or its salt and edetic acid and / or its salt, and that even without the use of preservatives, it has preservative efficacy that is deemed "compliant" based on the criteria for category "IC" in the "Preservative Efficacy Test Method" of the Seventeenth Edition of the Japanese Pharmacopoeia Reference Information.

[0025] In one embodiment, the present invention provides an aqueous solution comprising brimonidine and / or a salt thereof, edetate and / or a salt thereof, and a buffer, and substantially free of preservatives.

[0026] The salt of brimonidine used in this invention is not particularly limited, as long as it is pharmaceutically acceptable, but specifically, examples include organic salts such as tartrates and acetates; and inorganic salts such as hydrochlorides. Brimonidine or its salt may also be in the form of a solvate such as a hydrate. Among brimonidine or its salt, brimonidine tartrate is preferred. In the aqueous solution of the present invention, either brimonidine or a salt thereof may be used alone, or they may be used in combination.

[0027] In the aqueous solution of the present invention, the concentration of brimonidine or its salt is not particularly limited and may be set appropriately according to the use of the aqueous solution, the severity of symptoms in the target patient, the amount applied per dose, etc., but 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 its salt is the concentration converted to brimonidine tartrate.

[0028] The salt of EDTA used in this invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include sodium EDTA salts such as monosodium EDTA, disodium EDTA (EDTA), and tetrasodium EDTA. The salt of EDTA may also be in the form of a solvate, such as a hydrate. One of EDTA or its salts may be selected and used alone, or two or more may be used in combination. Among EDTA or its salts, sodium EDTA dihydrate is preferred from the viewpoint of providing even better preservative efficacy.

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

[0030] In the aqueous solution of the present invention, the concentration of edetic acid or its salt is typically 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 better preservative efficacy. In this specification, the concentration of edetic acid or its salt is the concentration converted to disodium edetate dihydrate.

[0031] The buffering agent used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartaric acid buffers, acetate buffers, amino acid buffers, and the like.

[0032] Specific examples of boric acid buffers include boric acid and / or its salts. The 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 individually or in combination of two or more. The boric acid salts 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. Furthermore, boric acid / or its salts may be in hydrate form, such as borax.

[0033] As a boric acid buffer, one type may be selected from boric acid and its salts and used alone, or two or more types may be used in combination. Among boric acid and its salts, from the viewpoint of providing better 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] Another preferred embodiment of the boric acid buffer is a combination of boric acid and borax. By using boric acid and borax in this way, it is possible to achieve even better preservation efficacy. When using boric acid and borax in combination, there are no particular restrictions on the ratio of these components, but for example, 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 40 to 60 parts by mass of borax per 100 parts by mass of boric acid.

[0035] Regarding the amount of boric acid buffer used, from the viewpoint of buffering effect, the concentration of boric acid or its salt is usually 0.1 to 2 w / v%, more preferably 0.5 to 1.5 w / v%, even more preferably 0.7 to 1.0 w / v%, and particularly preferably 0.4 to 0.6 w / v%. In this specification, the concentration of boric acid or its salt is the concentration converted to boric acid.

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

[0037] As a phosphate buffer, one type may be selected from phosphoric acid and its salts and used alone, or two or more types may be used in combination. Among phosphoric acid and its salts, from the viewpoint of providing better preservative efficacy, phosphate salts are preferred, more preferably at least one of dialkali metal hydrogen phosphate and dialkali metal dihydrogen phosphate, and particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0038] Furthermore, a preferred embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate. By using a combination of dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate in this way, it is possible to achieve even better preservation efficacy. When using a combination of dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate, there are no particular restrictions on the ratio of these salts, but 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 dialkali metal dihydrogen phosphate are used per 100 parts by mass of dialkali metal hydrogen phosphate.

[0039] Regarding the amount of phosphate buffer used, from the viewpoint of buffering effect, the concentration of phosphoric acid or its salt 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 to phosphoric acid.

[0040] Examples of Tris buffering agents include trometamol and / or its salts. While there are no particular restrictions on trometamol salts, provided they are pharmaceutically acceptable, examples include organic acid salts such as acetate; and organic acid salts such as hydrochloride and sulfonate.

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

[0042] Regarding the amount of Tris buffer used, from the viewpoint of buffering effect, it 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%. In this specification, the concentration of Tris buffer is expressed as the concentration converted to trometamol.

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

[0044] Specific examples of tartaric acid buffers include tartaric acid and / or its salts. The salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. The salts of tartaric acid may also be in the form of solvates such as hydrates. One of tartaric acid and its salts may be selected and used alone as a tartaric acid buffer, or two or more may be used in combination.

[0045] Specific examples of acetic acid buffers include acetic acid and / or its salts. The salts of acetic 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; and ammonium salts. The salts of acetic acid may also be in the form of solvates such as hydrates. One of acetic acid and its salts may be selected and used alone as an acetic acid buffer, or two or more may be used in combination.

[0046] Examples of amino acid buffers include acidic amino acids and / or their salts. Examples of acidic amino acids include aspartic acid and glutamic acid. Salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts. One type of acidic amino acid and its salt may be selected and used alone as an amino acid buffer, or two or more types may be used in combination.

[0047] These cushioning materials may be used individually or in combination of two or more types.

[0048] Among these buffering agents, boric acid buffering agents, phosphate buffering agents, and Tris buffering agents are preferred from the viewpoint of providing even better preservation effectiveness.

[0049] The aqueous solution of the present invention substantially does not contain a preservative, but if it were to be prepared as an aqueous solution containing only a preservative, it may contain an amount of preservative less than the minimum concentration of preservative required to be "compliant" under the criteria defined for category "IC" in the Reference Information "Preservative Efficacy Test Method" of the 17th edition of the Japanese Pharmacopoeia.

[0050] Examples of preservatives include sodium chlorite and other chlorite salts; 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, polyhexanides, etc.

[0051] The acceptable concentration of the preservative in the aqueous solution of the present invention varies depending on the type of preservation, but specifically, it is 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 solution of the present invention, by containing brimonidine and / or its salt, edetic acid and / or its salt, and a buffering agent, is made possible to have a preservative efficacy at a level at least that exhibits bacteriostatic activity. Therefore, the aqueous solution of the present invention does not substantially contain any other components that improve preservative efficacy in the presence of brimonidine and / or its salt.

[0053] For example, it is known that dorzolamide and / or its salts can improve preservative efficacy when present with brimonidine and / or its salts in aqueous solutions with a pH of 6.0 or higher. Therefore, one embodiment of the aqueous solution of the present invention is one that substantially does not contain dorzolamide and / or its salts. Specifically, 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, halides, etc. Furthermore, "substantially does not contain dorzolamide and / or its salts" specifically means that the concentration of dorzolamide and / or its salts is less than 0.1 w / v%, preferably 0.05 w / v%, more preferably 0.01 w / v%, and particularly preferably 0 w / v%.

[0054] In addition to the above-mentioned components, the aqueous solution of the present invention may optionally contain additives such as isotonic agents, polyhydric alcohols, surfactants, viscosity modifiers, chelating agents (other than EDTA and its salts), cooling agents, stabilizers, and pH adjusters.

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

[0056] The polyhydric alcohols are not particularly limited as long as they are pharmaceutically acceptable, but examples include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually or in combination of two or more.

[0057] The surfactants are not particularly limited as long as they are pharmaceutically acceptable, but examples include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually or in combination of two or more.

[0058] The viscosity agent is not particularly limited to the extent that it is pharmaceutically acceptable, but examples include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These viscosity agents may be used individually or in combination of two or more.

[0059] The chelating agents (other than EDTA and its salts) are not particularly limited to those that are pharmaceutically acceptable, but examples include citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphate, metaphosphate, hexametaphosphate, and their salts. The form of the salts is not particularly limited to those that are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts. These chelating agents may be used individually or in combination of two or more.

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

[0061] The stabilizers are not particularly limited as long as they are pharmaceutically acceptable, but examples include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. These stabilizers may be used individually or in combination of two or more.

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

[0063] The concentrations of these additives should be set appropriately according to the type of additive used and the characteristics that should be imparted to the aqueous solution.

[0064] Furthermore, the aqueous solution of the present invention may, as necessary, contain pharmacological components that exhibit therapeutic effects against glaucoma or ocular hypertension, in addition to brimonidine and / or its salts, to the extent that they do not interfere with the effects of the present invention.

[0065] Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathetic stimulants such as pilocarpine hydrochloride; anticholinesterases such as distigmine bromide; sympathetic stimulants such as dipivefrin hydrochloride; β1 blockers such as betaxolol hydrochloride; β-blockers such as timolol maleate; α1 and β-blockers such as nipradilol and levovunol hydrochloride; and α1 blockers such as bunazosin hydrochloride. These pharmacological components may be used individually or in combination of two or more.

[0066] The concentrations of these pharmacological components should be set appropriately according to the type of pharmacological component used and the therapeutic effect to be imparted.

[0067] The pH of the aqueous solution of the present invention is not particularly limited, but for example, pH 6 to 8 is preferred. From the viewpoint of providing even better preservation efficacy, pH 7 to 8 is preferred, and pH 7 is even more preferred.

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

[0069] The aqueous formulation of the present invention, by containing the aforementioned components, is capable of having a preservative efficacy at a level at least sufficient to demonstrate bacteriostatic activity. Specifically, the preservative efficacy of the aqueous formulation of the present invention is judged to be "compliant" based on the criteria defined for category "IC" in the "Preservative Efficacy Test Methods" of the 17th edition of the Japanese Pharmacopoeia. The JP IC compliant preservative efficacy can be determined by a test method in accordance with the "Preservative Efficacy Test Methods" of the 17th edition of the Japanese Pharmacopoeia, and the specific test method is shown in the "Test Examples" section below.

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

[0071] The aqueous solution of the present invention can be used as an ophthalmic preparation such as eye drops or eye wash. In particular, the aqueous solution of the present invention can suppress the production of aqueous humor and lower intraocular pressure through the action of brimonidine and / or its salt, and is therefore suitable for use as an aqueous solution for treating glaucoma or ocular hypertension when provided as eye drops.

[0072] The aqueous preparation of the present invention may be manufactured according to known preparation methods depending on its intended use, for example, by the method described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia.

[0073] For the container that holds the aqueous solution of the present invention, an eye drop container, an eye wash container, or the like may be used depending on the intended use of the aqueous formulation.

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

[0075] Furthermore, in the case of multi-dose containers, it is particularly preferable to use multi-dose preservative-free containers in order to maintain the sterile state of the aqueous solution contained within during storage. With conventional aqueous solutions that do not contain preservatives, even when using multi-dose preservative-free containers, there is a concern about microbial contamination of the aqueous solution remaining on the outer surface of the nozzle. However, the aqueous solution of the present invention has a preservative efficacy of at least a level in which bacteriostatic activity is observed, so even if it remains on the outer surface of the nozzle of a multi-dose preservative-free container, the aforementioned microbial contamination can be suppressed.

[0076] 3. Method for imparting preservative effect The present invention provides a method for imparting preservative efficacy to an aqueous solution containing brimonidine and / or a salt thereof, characterized by comprising the step of preparing an aqueous solution that is substantially free of preservatives and contains brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and a buffering agent.

[0077] According to the method for imparting preservative efficacy of the present invention, it becomes possible to impart Japanese Pharmacopoeia IC-compliant preservative efficacy to an aqueous solution containing brimonidine and / or a salt thereof.

[0078] In the method for imparting preservative efficacy of the present invention, the type and concentration of brimonidine and / or its salt, the type and concentration of edetic acid and / or its salt, the type and concentration of buffering agent, the types of other additives and pharmacological components incorporated into the aqueous solution, the pH of the aqueous solution, the formulation form, the use, etc., are as described in the "1. Aqueous Solution" section above. [Examples]

[0079] The present invention will be specifically described below with reference to examples, but the present invention is not limited in any way by these examples. In the following test examples, orthoboric acid was used in all cases.

[0080] Test Example 1: Evaluation of Preservative Efficacy The preservative efficacy of eye drops with the composition shown in Table 1 was evaluated in accordance with the "Preservative Efficacy Test Method" in the Reference Information of the 17th Revised Japanese Pharmacopoeia. The specific test methods are as follows.

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

[0082] 1-2. Test bacteria The following three types of bacteria and two types 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 aforementioned test fungi were inoculated onto the surface of agar slant media and pre-cultured. For pre-culture, soybean casein digest agar medium was used for bacteria, and Sabouraud glucose agar medium 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 aforementioned sample into five sterile, stoppered test tubes, and then add 1 × 10⁶ of each pre-cultured test bacterium. 5 ~1 × 10 6 The samples were inoculated to a CFU / mL level and prepared as a mixed sample. The mixed sample was stored at 20-25°C, protected from light. Note that each test bacterium was not mixed; each bacterial species was inoculated individually into the sample to prepare the mixed sample.

[0085] At the start of the experiment, and on days 7, 14, and 28 from the start of the experiment, 1 mL was sampled from each mixed sample and diluted with 9 mL of physiological saline. If necessary, the same dilution was repeated 2-3 times, and 1 mL of each dilution was dispensed into sterile petri dishes. Next, for bacteria, soybean casein digest agar medium supplemented with 0.1% lecithin and 0.7% polysorbate 80 was added and mixed in, and for fungi, Sabouraud glucose agar medium supplemented with 0.1% lecithin and 0.7% polysorbate 80 was added and mixed in. Then, for bacteria, the samples were incubated at 30-35°C for 3-5 days, and for fungi, at 20-25°C for 5-7 days. After incubation, the number of colonies produced was measured, and the number of viable cells per 1 mL of mixed sample (cfu / mL) and the logarithmic decrease in the number of viable cells (log) were calculated.

number

[0086] 1-5. Determination of preservative effectiveness The preservative efficacy of each test solution is determined according to "4. Preservative Efficacy Test Method" in the Reference Information of the 17th Edition of the Japanese Pharmacopoeia. The evaluation was conducted according to the criteria for Category 1C described in "Table 3 Criteria for Judgment by Formulation Category" of the "Judgment" section. Specifically, if all of the following conditions were met, the product was judged as "compliant" and all others were judged as "uncompliant". (1) For all three types of bacteria, the logarithmic reduction value (log) was 1.0 log or more compared to the inoculated number of bacteria after 14 days, and the number of viable bacteria after 28 days did not increase from the number after 14 days, and (2) For all two types of fungi, the number of viable bacteria after 14 days and 28 days did not increase from the number of inoculated bacteria.

[0087] 2. Test Results The results obtained are shown in Tables 1-3. An aqueous solution (Reference Example 1) that did not contain brimonidine tartrate and sodium edetate dihydrate, but contained a boric acid buffer (boric acid and borax), exhibited preservative efficacy compliant with the Japanese Pharmacopoeia (JP). However, aqueous solutions containing brimonidine tartrate or sodium edetate dihydrate along with a boric acid buffer (Comparative Examples 1 and 2) showed reduced preservative efficacy and did not meet the JP compliant standards. In contrast, an aqueous solution (Example 1) containing brimonidine tartrate and sodium edetate dihydrate along with a boric acid buffer showed improved preservative efficacy and met the JP compliant standards. Furthermore, even when using phosphate buffers and Tris buffers, aqueous solutions containing brimonidine tartrate and sodium edetate dihydrate showed improved preservative efficacy and met the JP compliant standards.

[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 5 mL colorless glass ampoules. These were placed in a tabletop constant temperature and humidity chamber (NST-80, Nagano Science Co., Ltd.) and stored at 60°C for 4 weeks under light-shielding conditions. The brimonidine tartrate content before and after storage was measured using a high-performance liquid chromatography system (Shimadzu Corporation) under the following conditions.

[0092] <Measurement conditions> Detector: UV absorbance spectrophotometer (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 aqueous phosphate solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) mixture Mobile phase B: 4.3 mM aqueous phosphate solution / methanol / acetonitrile mixture (volume ratio: 40 / 30 / 30) Flow rate: 1.0 mL / min Autosampler internal temperature: 5℃ Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was varied as shown in Table 4 to control the linear concentration gradient.

[0093] [Table 4]

[0094] The residual rate of brimonidine in the aqueous solution was calculated according to the following formula.

number

[0095] The results obtained are shown in Table 5. When sodium edetate dihydrate was not included, the aqueous solution without preservatives (Comparative Example 9) showed a lower retention rate of brimonidine compared to aqueous solutions containing preservatives commonly found in eye drops (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 preservatives, the stability of brimonidine tartrate was further improved in the aqueous solution containing sodium edetate dihydrate. In other words, these results clearly show that aqueous solutions substantially free of preservatives and containing brimonidine and / or its salt, and edetate and / or its salt, are superior in terms of the stability of brimonidine and / or its salt.

[0096] [Table 5]

Claims

1. A method for imparting preservative efficacy to an aqueous solution containing brimonidine tartrate, contained in a multi-dose container, A method for imparting preservative efficacy, 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, edetic acid and / or a salt thereof, and a buffering agent.

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

3. The method according to claim 1 or 2, wherein the concentration of edetic acid and / or its salt in the aqueous solution is 0.001 to 0.5 w / v%.

4. The method according to any one of claims 1 to 3, wherein the concentration of brimonidine tartrate in the aqueous solution is 0.05 to 0.2 w / v%.

5. The method according to any one of claims 1 to 4, wherein the pH of the aqueous solution is 6 to 8.

6. The method according to any one of claims 1 to 5, wherein the aqueous solution is an eye drop solution.

Images