JP2026020360A - Water-based liquid - Google Patents

Abstract

[Problem] 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 has a bacteriostatic effect, even if it is substantially free of preservatives.
[Selection diagram] None

Description

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.

Aqueous liquid preparations such as eye drops and eyewashes typically contain preservatives such as benzalkonium chloride and methylparaben to prevent microbial growth. However, while preservatives can prevent bacterial growth, they are also known to be irritating and cytotoxic (see Non-Patent Document 1).

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

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.

Japanese Ophthalmology, Vol. 58, No. 10, pp. 945-950, 1987

Japanese Patent Application Laid-Open No. 2016-132465 Japanese Patent Application Laid-Open No. 2005-343549 Japanese Patent Application Laid-Open No. 2004-51170 Japanese Patent Application Laid-Open No. 2002-80055

The object of the present invention is to provide a formulation technology for an aqueous liquid preparation containing brimonidine and/or a salt thereof.

The 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 can have preservative effectiveness at least at a level at which bacteriostatic activity is observed, even if it is substantially free of preservatives. The present invention was completed based on this finding and through further investigation.

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 a salt thereof 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 %,
An aqueous liquid preparation having a pH of 6 to 8 and contained in a multi-dose container having a mechanism for preventing the aqueous liquid preparation once exuded to the outside from flowing back 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 applying 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 preparation 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 %,
A method for imparting preservative effectiveness, comprising the step of: storing the aqueous liquid preparation in a multi-dose container having a pH of 6 to 8; and further having a mechanism for preventing backflow of the aqueous liquid preparation once exuded to the outside into the container, and/or a mechanism for preventing intrusion of foreign matter into 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 exuded to the outside into the container and/or a mechanism for preventing foreign matter from entering the container.
A pharmaceutical product characterized by:

The aqueous liquid preparation of the present invention, due to the synergistic effect of brimonidine and/or a salt thereof and edetic acid and/or a salt thereof, can provide preservative effectiveness at least at a level at which bacteriostatic activity is recognized, 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, it can prevent microbial contamination that may occur due to residual liquid on the outer surface of the nozzle, thereby ensuring a higher level of safety for aqueous liquid preparations administered by eye drop administration, etc.

1. Definition In this specification, the term "aqueous liquid preparation" refers to a preparation that contains water as a base and is in a liquid state.

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.

In this specification, "edetic acid" refers to a known compound also known as ethylenediaminetetraacetic acid.

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.

As used herein, the term "preservative" refers to a component having preservative properties, which, when prepared into an aqueous solution containing only the component in question at a concentration acceptable for eye drops, is judged to be "compliant" based on the criteria set forth in Category "IA" of the "Preservative Effectiveness Test Method" in the Reference Information for the Japanese Pharmacopoeia, 17th Edition. However, in the present invention, the term "preservative" does not include boric acid buffer.

As used herein, "substantially free of preservatives" refers to a concentration of preservatives at which the preservative alone is ineffective; specifically, when made into an aqueous solution containing only the preservative, the concentration of preservative is lower than the minimum concentration required for the solution to 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.

In this specification, the term "multi-dose container" refers to a container filled with an amount of aqueous liquid medicine sufficient for multiple uses and used repeatedly. Multi-dose containers include those that have a mechanism to prevent the aqueous liquid medicine that has seeped out from flowing back into the container or a mechanism to prevent 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 structures such as a backflow prevention valve, a microfilter, or a special double-walled bottle as a mechanism to prevent the aqueous liquid medicine that has seeped out from flowing back into the container or a mechanism to prevent foreign matter from entering the container (e.g., Patent Documents 1 to 4).

As used herein, the term "unit-dose container" refers to a container filled with a single dose of aqueous liquid preparation that can be used up after one instillation.

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

As used herein, "method of imparting preservative effectiveness" refers to a method of converting an aqueous liquid formulation that does not "comply" with the criteria set forth in Category "IC" in the "Preservative Effectiveness Test Method" of the Japanese Pharmacopoeia, 17th Edition, into an aqueous liquid formulation that "complies" with the criteria set forth in Category "IC" in the same test. Furthermore, efficacy that is judged to "comply" with the criteria set forth in "IC" is sometimes referred to as "JP IC-compliant preservative effectiveness."

In this specification, "bacteriostatic effect" refers to an effect that does not reduce, but at least does not increase, the number of viable bacteria or fungi in a test based on the "Preservative Effectiveness Test Method" in the Reference Information for the 17th Edition of the Japanese Pharmacopoeia. 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 standards set forth in the aforementioned "IC."

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

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

In contrast, the present inventors have discovered that an aqueous liquid formulation 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 "compliant" based on the criteria set forth in Category "IC" in the Reference Information for "Preservative Effectiveness Testing Methods" of the 17th Edition of the Japanese Pharmacopoeia, even without the use of preservatives.

In one aspect, the present invention provides an aqueous liquid formulation comprising brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer, and which is substantially free of preservatives.

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.In addition, brimonidine or its salt may be in the form of a solvate such as a hydrate.Among brimonidine or its salt, 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.

In the aqueous liquid preparation of the present invention, the concentration of brimonidine or a salt thereof is not particularly limited and may be set appropriately depending on the intended use of the aqueous liquid preparation, the severity of the patient's symptoms, the amount administered per dose, etc., but examples include 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.

The salt of edetic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples 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 greater preservative effectiveness.

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

In the aqueous liquid preparation of the present invention, the concentration of edetic acid or a salt thereof 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 more excellent preservative effectiveness. In this specification, the concentration of edetic acid or a salt thereof is the concentration converted into edetate disodium dihydrate.

The buffers used in the present invention are not particularly limited, as long as they are pharmaceutically acceptable, but examples include borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartrate buffers, acetate buffers, amino acid buffers, etc.

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. Of 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.

As the 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, at least one of boric acid and borax is preferred, and at least one of orthoboric acid and borax is even more preferred, from the perspective of providing superior preservative effectiveness.

A suitable embodiment of the boric acid buffer is a combination of boric acid and borax. Using a combination of boric acid and borax in this way makes it possible to provide even better preservative effectiveness. When using a combination of boric acid and borax, there are no particular restrictions on the ratio, but examples include 0 to 100 parts by weight, preferably 20 to 80 parts by weight, and more preferably 40 to 60 parts by weight of borax per 100 parts by weight of boric acid.

From the standpoint of buffering action, the amount of boric acid buffer used is typically 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 terms of the concentration of boric acid or its salts. In this specification, the concentration of boric acid or its salts is the concentration converted into boric acid.

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.

As the phosphate buffer, one selected from phosphoric acid and its salts may be used alone, or two or more may be used in combination. Among phosphoric acid and its salts, from the viewpoint of providing superior preservative effectiveness, preferred are phosphate salts, more preferred are at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferred are at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

A suitable embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate. Using a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate in this manner makes it possible to provide even better preservative effectiveness. When a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate is used, the ratio between them is not particularly limited, but examples include 1 to 120 parts by weight, preferably 5 to 80 parts by weight, and more preferably 10 to 40 parts by weight of the alkali metal dihydrogen phosphate per 100 parts by weight of the dialkali metal hydrogen phosphate.

In terms of buffering action, the amount of phosphate buffer used is typically 0.1 to 5 w/v%, preferably 1 to 3 w/v%, and more preferably 1.5 to 2.0 w/v% phosphoric acid or a salt thereof. In this specification, the concentration of the phosphate buffer is expressed in terms of phosphoric acid.

Specific examples of Tris buffers include trometamol and/or its salts. There are no particular limitations on the salts of trometamol, as long as they are pharmaceutically acceptable, but examples include organic acid salts such as acetate salts, and organic acid salts such as hydrochloride and sulfonate salts.

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

From the standpoint of buffering action, the amount of Tris buffer used is typically 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 in terms of trometamol.

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

Specific examples of tartaric acid buffers include tartaric acid and/or its salts. 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; and alkaline earth metal salts such as calcium salts and magnesium salts. Tartaric acid salts may also be in the form of solvates such as hydrates. Tartaric acid and its salts may be selected and used alone or in combination as the tartaric acid buffer.

Specific examples of acetate buffers include acetic acid and/or salts thereof. 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. Acetic acid salts may also be in the form of solvates such as hydrates. Acetic acid and its salts may be selected and used alone or in combination as the acetate buffer.

Specific examples of amino acid buffers include acidic amino acids and/or their salts. Specific 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, and examples include alkali metal salts such as sodium salts and potassium salts. As an amino acid buffer, one type may be selected from acidic amino acids and their salts and used alone, or two or more types may be used in combination.

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

Among these buffers, borate buffer, phosphate buffer, and Tris buffer are preferred from the viewpoint of providing even better preservative effectiveness.

The aqueous liquid formulation of the present invention is substantially free of preservatives, but may contain a preservative in an amount less than the minimum concentration of preservative that would be "compliant" based on the criteria set forth in Category "IC" of the Reference Information for "Preservative Effectiveness Testing Methods" in the 17th Edition of the Japanese Pharmacopoeia, when the aqueous solution contains only preservatives.

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.

The acceptable concentration of preservatives 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%.

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 providing a preservative effect at least at a level at which bacteriostatic activity is observed. Therefore, the aqueous liquid preparation of the present invention does not necessarily need to contain substantially any components other than the above components that improve preservative effect in the presence of brimonidine and/or a salt thereof.

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%.

In addition to the above-mentioned ingredients, 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.

The tonicity 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 tonicity agents may be used alone or in combination of two or more.

There are no particular limitations on polyhydric alcohols, so long as they are pharmaceutically acceptable, but examples include propylene glycol, butylene glycol, polyethylene glycol, glycerin, etc. These polyhydric alcohols may be used alone or in combination of two or more.

The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples include nonionic surfactants such as tyloxapol, 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-acyltaurine 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 alone or in combination of two or more.

Thickening agents are not particularly limited as long as they are 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 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.

Chelating agents (other than edetic acid and its salts) are not particularly limited as long as they are pharmaceutically acceptable, but examples 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, but examples 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.

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

Stabilizers are not particularly limited as long as they are pharmaceutically acceptable, but examples include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

There are no particular limitations on pH adjusters, so long as they are pharmaceutically acceptable. 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 alone or in combination of two or more.

The concentrations of these additives can be set appropriately depending on the type of additive used and the properties to be imparted to the aqueous liquid.

Furthermore, the aqueous liquid preparation of the present invention may contain, in addition to brimonidine and/or its salt, pharmacological ingredients that exhibit therapeutic effects against glaucoma or ocular hypertension, as needed, to the extent that the effects of the present invention are not impaired.

Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone, etc.; parasympathomimetics such as pilocarpine hydrochloride, etc.; anticholinesterase drugs 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.

The concentrations of these pharmacological ingredients can be set appropriately depending on the type of pharmacological ingredient used and the medicinal effect to be achieved.

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

The osmotic pressure ratio of the aqueous liquid preparation of the present invention is not particularly limited, but 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.

By containing the aforementioned ingredients, the aqueous liquid formulation of the present invention is able to have preservative effectiveness at least at a level at which bacteriostatic activity is recognized. Specifically, the preservative effectiveness of the aqueous formulation of the present invention is judged to be "compliant" based on the standards set forth in the "Preservative Effectiveness Test Method" in the Reference Information for the Japanese Pharmacopoeia, 17th Edition, for Category "IC." JP IC-compliant preservative effectiveness can be determined using a test method in accordance with the "Preservative Effectiveness Test Method" in the Reference Information for the Japanese Pharmacopoeia, 17th Edition, and the specific test method is as described in the "Test Examples" section below.

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

The aqueous solution of the present invention can be used as ophthalmic preparations such as eye drops and eyewashes. In particular, the aqueous solution of the present invention can suppress the production of aqueous humor and reduce intraocular pressure through the action of brimonidine and/or its salts, and therefore is provided as eye drops and can be suitably used as an aqueous solution for treating glaucoma or ocular hypertension.

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

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

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

Furthermore, in the case of multi-dose containers, 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 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 bacteriostatic activity is recognized, and therefore can suppress such microbial contamination even if it remains on the outer surface of the nozzle of a multi-dose preservative-free container.

3. Method for imparting 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.

The method of imparting preservative effectiveness of the present invention makes it possible to impart preservative effectiveness conforming to the Japanese Pharmacopoeia IC standard to aqueous liquid preparations containing brimonidine and/or its salts.

In the method of imparting preservative effectiveness of the present invention, the type and concentration of brimonidine and/or its salts, the type and concentration of edetic acid and/or its salts, the type and concentration of buffering agent, the types of other additives and pharmacological ingredients to be blended in the aqueous liquid, the pH of the aqueous liquid, the formulation, uses, etc. are as described above in the section "1. Aqueous Liquid."

The present invention will be explained in detail below using examples, but the present invention is not limited to these examples. In the following test examples, orthoboric acid was used as the boric acid.

Test Example 1: Evaluation of preservative effectiveness In accordance with the "Test method for preservative effectiveness" in the reference information of the Japanese Pharmacopoeia, 17th Edition, the preservative effectiveness of the ophthalmic solution having the composition shown in Table 1 was evaluated. The specific test method etc. are as follows.

1. Test materials and test methods
1-1. Preparation of Samples 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.

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 (Pseudomonas aeruginosa, P.aeruginosa / ATCC 9027)
(fungi)
- Candida albicans (C. albicans / ATCC 10231)
- Black koji mold (Aspergillus brasiliensis, A. brasiliensis / ATCC 16404)

1-3. Pre-culture : Each of the test bacteria was inoculated onto the surface of an agar slant and pre-cultured. Soybean casein digest agar was used for bacteria, and Sabouraud glucose agar was used for fungi. Pre-culture was carried out 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 Kuro-koji mold.

1-4. Preparation of mixed samples and bacterial count measurement The specimen was dispensed into five sterilized test tubes with stoppers, each 10 mL, and each pre-cultured test bacterium was inoculated to a concentration of 1 x 10 ⁵ to 1 x 10 ⁶ CFU/mL to prepare mixed samples. The mixed samples were stored at 20 to 25°C, protected from light. The test bacterium species were not mixed, but each bacterium species was inoculated into a test specimen individually to prepare the mixed samples.

At the start of the test and on days 7, 14, and 28 after the start of the test, 1 mL of each mixed sample was sampled and 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, for bacteria, soybean casein digest agar medium supplemented with 0.1% lecithin and 0.7% polysorbate 80 was added, and for fungi, Sabouraud dextrose agar medium supplemented with 0.1% lecithin and 0.7% polysorbate 80 was added and mixed. 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 (cfu/mL) per mL of the mixed sample and the logarithmic reduction in viable cell count (log) were calculated.

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."

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 and 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.

Test Example 2: Evaluation of Thermal Stability Aqueous solutions (ophthalmic solutions) were prepared with the compositions shown in Table 5. 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.

<Measurement conditions>
Detector: UV absorption photometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6mm ID x 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) mixture Mobile phase B: 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 40/30/30) mixture Flow rate: 1.0 mL/min
Autosampler internal temperature: 5°C
Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 4 to control the linear concentration gradient.

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

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.

Claims (1)

An aqueous liquid formulation containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer, and substantially free of preservatives.