JP6621955B2 - Aqueous liquid - Google Patents

Description

  The present invention relates to an aqueous liquid preparation containing brimonidine and / or a salt thereof and having excellent storage efficacy.

  In order to prevent the growth of microorganisms, aqueous solutions such as eye drops and eye wash solutions usually contain preservatives such as benzalkonium chloride and methylparaben. However, it is known that preservatives can prevent bacterial growth while exhibiting irritation and cytotoxicity (see Non-Patent Document 1).

  Conventionally, in order to prevent bacterial growth during storage in an aqueous solution containing no preservative, a mechanism for preventing the backflow of the aqueous solution once leached to the outside into the container and / or a container for foreign matters (microorganisms, etc.) Used in a multi-dose type container (hereinafter sometimes referred to as “multi-dose type preservative-free container”) having a mechanism for preventing intrusion (for example, Patent Documents 1 to 4) reference).

  Brimonidine and its salts, known as adrenergic α2 receptor agonists, reduce intraocular pressure by promoting aqueous humor outflow through the uveal sclera outflow tract along with suppression of aqueous humor production. It has been used to treat glaucoma and ocular hypertension.

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

Japanese Patent Laid-Open No. 2006-132465 JP 2005-343549 A JP 2004-51170 A Japanese Patent Laid-Open No. 2002-80055

  An object of the present invention is to provide a preparation technique relating to an aqueous liquid preparation containing brimonidine and / or a salt thereof.

  The inventor of the present invention provides excellent preservation even when an aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and boric acid and / or a salt thereof substantially does not contain a preservative. It was found to have efficacy. The present invention has been completed by further studies based on this finding.

That is, this invention provides the invention of the aspect hung up below.
Item 1. An aqueous liquid preparation containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, boric acid and / or a salt thereof, and substantially free of a preservative.
Item 2. Item 2. The aqueous liquid preparation according to Item 1, wherein the concentration of boric acid and / or a salt thereof is 0.5 to 1.5 w / v%.
Item 3. Item 3. The aqueous solution according to Item 1 or 2, wherein the concentration of edetic acid and / or a salt thereof is 0.001 to 0.5 w / v%.
Item 4. 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. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, wherein the pH is 6 to 8.
Item 6. Item 6. The aqueous liquid preparation according to any one of Items 1 to 5, which is an ophthalmic solution.
Item 7. Item 1-6, which is accommodated in a multi-dose type container that does not have a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container. The aqueous liquid preparation in any one.
Item 8. Boric acid and / or salt thereof is boric acid and / or borax,
The concentration of boric acid and / or its salt is 0.5-1.5 w / v%,
Edetic acid and / or its salt is sodium edetate dihydrate,
The concentration of edetic acid and / or its salt is 0.001 to 0.5 w / v%,
Brimonidine and / or its salt is brimonidine tartrate;
The concentration of brimonidine and / or its salt is 0.05-0.2 w / v%,
Housed in a multi-dose type container that has a pH of 6 to 8 and does not have a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container. Item 8. The aqueous liquid preparation according to any one of Items 1 to 7.
Item 9. A method for imparting storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof,
A method for imparting preservative efficacy, comprising a step of preparing an aqueous solution containing substantially no preservative and containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and boric acid and / or a salt thereof. .
Item 10. Item 10. The application method according to Item 9, wherein the concentration of boric acid and / or a salt thereof is 0.5 to 1.5 w / v%.
Item 11. Item 11. The application method according to Item 9 or 10, wherein the concentration of edetic acid and / or a salt thereof in the aqueous liquid is 0.001 to 0.5 w / v%.
Item 12. Item 12. The application method according to any one of Items 9 to 11, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid is 0.05 to 0.2 w / v%.
Item 13. Item 13. The application method according to any one of Items 9 to 12, wherein the pH of the aqueous liquid preparation is 6 to 8.
Item 14. Item 14. The application method according to any one of Items 9 to 13, wherein the aqueous liquid preparation is an ophthalmic solution.
Item 15. Furthermore, the prepared aqueous liquid agent is accommodated in a multi-dose type container that does not have a mechanism for preventing the backflow of the aqueous liquid agent once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container. Item 15. The application method according to any one of Items 9 to 14, comprising a step.
Item 16. Boric acid and / or salt thereof is boric acid and / or borax,
The concentration of boric acid and / or salt thereof in the aqueous liquid is 0.5 to 1.5 w / v%,
Edetic acid and / or its salt is sodium edetate dihydrate,
The concentration of edetic acid and / or salt thereof in the aqueous liquid is 0.001 to 0.5 w / v%,
Brimonidine and / or its salt is brimonidine tartrate;
The concentration of brimonidine and / or its salt in the aqueous liquid is 0.05 to 0.2 w / v%,
A mechanism in which the pH of the aqueous liquid is 6 to 8, and the prepared aqueous liquid is prevented from flowing back into the container once the aqueous liquid has been leached to the outside, or a mechanism for preventing foreign substances from entering the container. Item 16. The application method according to any one of Items 9 to 15, further comprising a step of accommodating in a multi-dose type container that does not have a gas.
Item 17. An aqueous solution containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, boric acid and / or a salt thereof, and substantially free of a preservative,
It is accommodated in a multi-dose type container that does not have a mechanism for preventing the backflow of the aqueous liquid agent that has been leached to the outside into the container, or a mechanism for preventing foreign substances from entering the container.
A pharmaceutical product characterized by that.

  According to the aqueous liquid preparation of the present invention, the brimonidine and / or salt thereof, edetic acid and / or salt thereof, and boric acid and / or borate can be used without synthesizing a preservative. , Can have excellent storage efficacy. Therefore, the aqueous liquid preparation of the present invention is a multi-dose type container that does not have a mechanism for preventing the backflow of the aqueous liquid agent once leached to the outside into the container or a mechanism for preventing foreign substances from entering the container (that is, The multi-dose type preservative-free container can be provided using a multi-dose type container that does not correspond to the multi-dose type preservative-free container.

1. Definitions In the present specification, an “aqueous liquid agent” is a preparation that contains water as a base and exhibits a liquid state.

  As used herein, “brimonidine” is a compound known as an adrenergic α2 receptor agonist and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.

  In the present specification, “edetic acid” is a known compound that is also called “ethylenediaminetetraacetic acid”.

  In this specification, “preservative” is a component having a preservative effect, and when the aqueous solution containing only the relevant component at a concentration allowed by eye drops, the aqueous solution is the 17th revised Japanese Pharmacopoeia. Refers to information judged to be “conforming” based on the criteria defined in the category “IA” in the reference information “Preservation Efficacy Test”. However, in the present invention, the preservative does not include boric acid and salts thereof.

  In the present specification, “substantially free of preservative” means that the concentration of the preservative is a concentration that cannot exert the preservative effect only by the preservative, specifically, only the preservative. When the aqueous solution contains a preservative that is “conforming” based on the criteria defined in the category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information Point to less.

  In the present specification, the “multi-dose container” refers to a container that is filled with a plurality of use amounts of an aqueous liquid and is used repeatedly. The multi-dose type container includes a multi-dose type container (that is, a multi-dose type container having a mechanism for preventing the backflow of the aqueous liquid once leached to the outside into the container and / or a mechanism for preventing foreign substances from entering the container. Preservative-free containers) and multi-dose containers that do not have the mechanism. Multi-dose type preservative-free containers are usually used as a mechanism to prevent the backflow of aqueous liquids that have been leached to the outside into the container or to prevent foreign substances from entering the container. It has a structure such as a simple double structure bottle (for example, Patent Documents 1 to 4).

  In the present specification, the “unit dose container” refers to a container that is filled with a single use amount of an aqueous liquid agent and is used up after a single instillation.

  As used herein, “pharmaceutical product” refers to a product in which an aqueous liquid is contained in an arbitrary container.

  In this specification, the “method for imparting preservative efficacy” refers to an aqueous solution that does not become “conforming” based on the criteria set forth in the category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. It means a method in which a liquid is made an aqueous liquid that is “conforming” based on the criteria defined in category “IA” in the same test. Further, in this specification, “conformity” determined based on the criteria defined in “IA” may be referred to as “JPA IA conformity preservation effect”.

2. Regarding ophthalmic solutions contained in aqueous liquid multi-dose containers, in Japan, it is judged as “conforming” based on the criteria set forth in category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law” Usually, a preservative is blended because it is required to have a preservative effect. However, while preservatives can prevent bacterial growth, they may exhibit irritation and cytotoxicity.

  On the other hand, the multi-dose type preservative-free container requires a complicated structure such as a backflow prevention valve, a microfilter, a special double structure bottle, and has a problem of increasing the manufacturing cost. For this reason, there is a strong demand for the development of a formulation technique that provides an excellent antiseptic effect in an aqueous liquid preparation containing no preservative, without using a multi-dose type preservative-free container. Further, conventionally, in an aqueous liquid preparation containing brimonidine and / or a salt thereof, it can be said that sufficient studies have been made on a technique for providing an excellent antiseptic effect without blending a preservative from the viewpoint of formulation. There is no current situation.

The present inventor believes that an aqueous liquid preparation containing boric acid and / or a salt thereof can have a preservative effect depending on its concentration, but boric acid and / or a salt thereof and brimonidine and / or a salt thereof in combination, In addition, it has been found that the combined use of boric acid and / or a salt thereof and edetic acid and / or a salt thereof reduces the inherent storage efficacy of boric acid and / or a salt thereof. On the other hand, the present inventor blended three components of brimonidine and / or a salt thereof, boric acid and / or a salt thereof, and edetic acid and / or a salt thereof into an aqueous solution. Preservation efficacy is improved by the synergistic action of the pharmacopoeia, and it has preservation efficacy judged as “conformity” based on the criteria defined in category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law” Found to get.

  In one aspect, the present invention provides an aqueous solution comprising brimonidine and / or salt thereof, edetic acid and / or salt thereof, boric acid and / or borate, and substantially free of preservatives. To do.

  The salt of brimonidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specifically, an organic acid salt such as tartrate or acetate; an inorganic acid salt such as hydrochloride Etc. Brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or its salt, brimonidine tartrate is preferable.

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

  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 set depending on the use of the aqueous liquid preparation, the degree of symptoms of the patient to be applied, the amount applied per time, and the like. For example, 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, particularly preferably 0.1 w / v% can be mentioned. In this specification, the concentration of brimonidine or a salt thereof is a concentration converted to brimonidine tartrate.

  The salt of edetic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, edetic acid such as monosodium edetate, disodium edetate (EDTA), tetrasodium edetate, An acid sodium salt is mentioned. The salt of edetic acid may be in the form of a solvate such as a hydrate. Among the edetic acids or salts thereof, edetic acid disodium dihydrate is preferably used from the viewpoint of providing more excellent storage efficacy.

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

  In the aqueous liquid preparation of the present invention, the concentration of edetic acid or a salt thereof is, for example, 0.001 to 0.5 w / v%, preferably 0.001 to 0.3 w / v% w / v%, more preferably 0. 0.005 to 0.2 w / v% w / v%, particularly preferably 0.01 to 0.1 w / v%. In the present specification, the concentration of edetic acid or a salt thereof is a concentration converted to disodium edetate dihydrate.

  Conventionally, boric acid and / or a salt thereof is a component that is used as a buffering agent. However, in the aqueous liquid preparation of the present invention, boric acid and / or a salt thereof not only provides a buffering action but also has an excellent effect. It is also an element that provides preservation efficacy.

  The boric acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferable. These boric acids may be used alone or in combination of two or more.

  The boric acid salt used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts Metal salts; Aluminum salts; Organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. These boric acid salts may be used alone or in combination of two or more.

  The boric acid and / or salt thereof used in the present invention may be in the form of a hydrate such as borax.

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

  Among the boric acids and salts thereof, at least one of boric acid and borax is preferable, and at least one of orthoboric acid and borax is preferable, from the viewpoint of imparting further excellent preservation effect.

  Moreover, the combination of boric acid and borax is mentioned as a suitable one aspect | mode of the boric acid and / or its salt used by this invention. Thus, by using a combination of boric acid and borax, it is possible to provide an appropriate buffer action while providing a further excellent antiseptic effect. When boric acid and borax are used in combination, these ratios are not particularly limited. For example, per 100 parts by mass of boric acid, borax is 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably. Is 40 to 60 parts by mass.

In the aqueous liquid preparation of the present invention, the concentration of boric acid or a salt thereof is not particularly limited, and examples thereof include 0.1 to 2 w / v%. From the viewpoint of providing even better storage efficacy, the concentration of boric acid or a salt thereof is preferably 0.5 to 1.5 w / v%, more preferably 0.
. 7-1.0 w / v% is mentioned. In this specification, the concentration of boric acid or a salt thereof is a concentration converted to boric acid.

  The aqueous liquid preparation of the present invention does not substantially contain a preservative, but when the aqueous solution contains only the preservative, the aqueous solution is classified in category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Method”. An amount of preservative may be included that is less than the minimum concentration of preservative that is “fit” based on the criteria defined in

  Specific examples of preservatives include chlorite such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid such as sorbic acid and potassium sorbate and salts thereof; Paraoxybenzoic acid esters such as methyl paraben and propyl paraoxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide and the like.

  The concentration of the preservative allowed in the aqueous liquid preparation of the present invention varies depending on the type of storage, etc., but specifically, less than 0.001 w / v%, preferably 0.0005 w / v% or less, Preferably it is 0.0001 w / v% or less, Most preferably, it is 0 w / v%.

  In the aqueous liquid preparation of the present invention, it is possible to provide excellent preservation efficacy by containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and boric acid and / or a salt thereof. . Therefore, in the aqueous liquid preparation of the present invention, in addition to the above-described components, components that improve the storage efficacy in the presence of brimonidine and / or a salt thereof may not be substantially contained.

  For example, it is known that dorzolamide and / or a salt thereof can improve storage efficacy when coexisting with brimonidine and / or a salt thereof in an aqueous solution having a pH of 6.0 or more. As one aspect, dorzolamide and / or a salt thereof is substantially free. Specific examples of the salt of dorzolamide include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid And salts with organic acids such as malic acid, citric acid and tartaric acid; salts with alkali metals, salts with alkaline earth metals, salts with organic amines, halides and the like. Further, “substantially free of dorzolamide and / or a salt thereof” specifically means that the concentration of dorzolamide and / or a salt thereof is less than 0.1 w / v%, preferably 0.05 w / v%. Hereinafter, it is more preferably 0.01 w / v% or less, particularly preferably 0 w / v%.

  In the aqueous liquid preparation of the present invention, in addition to the above components, an isotonic agent, a polyhydric alcohol, a surfactant, a thickener, a chelating agent (other than edetic acid and its salts), a buffering agent (if necessary) You may contain additives, such as a boric acid and its salt), a refreshing agent, a stabilizer, a pH adjuster.

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

  The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

  The surfactant is not particularly limited as long as it is pharmaceutically acceptable. For example, tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Nonionic surfactants such as diols; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls Anionic surfactants such as ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, water-soluble Molecule: Celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like. These thickeners may be used alone or in combination of two or more.

  The chelating agent (other than edetic acid and its salt) is not particularly limited as long as it is pharmaceutically acceptable. For example, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1- Examples thereof include hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.

  The buffer (other than boric acid and its salts) is not particularly limited as long as it is pharmaceutically acceptable. For example, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer Agents, amino acid buffers and the like. These buffering agents may be used alone or in combination of two or more.

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

  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 and the like. Can be mentioned. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.

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

  What is necessary is just to set the density | concentration of these additives suitably according to the characteristic etc. which should be provided to the kind of additive to be used, or an aqueous liquid agent.

  Furthermore, the aqueous liquid preparation of the present invention contains, in addition to brimonidine and / or a salt thereof, a pharmacological component exhibiting a therapeutic effect on glaucoma or ocular hypertension as necessary, as long as the effects of the present invention are not hindered. It may be.

Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic drugs such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; and sympathetic nerves such as dipivefrin hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α ₁ / β blockers such as nipradilol and levobanolol hydrochloride; α ₁ blockers such as bunazosin hydrochloride . These pharmacological components may be used alone or in combination of two or more.

  What is necessary is just to set the density | concentration of these pharmacological components suitably according to the kind of pharmacological component to be used, the medicinal effect which should be provided, etc.

  Although it does not restrict | limit especially about pH of the aqueous liquid preparation of this invention, For example, pH 6-8 is mentioned. The pH of the aqueous liquid preparation of the present invention is preferably 7 to 8 and more preferably pH 7 from the viewpoint of providing further excellent storage efficacy.

  Although it does not restrict | limit especially about the osmotic pressure ratio of the aqueous liquid preparation of this invention, For example, 0.5-4, Preferably it is 0.7-1.3, More preferably, it is 0.9-1.1. The osmotic pressure ratio is a ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is in accordance with the “osmotic pressure method (osmolarity measurement method)” defined in the 17th revision Japanese Pharmacopoeia. Measured.

  The aqueous liquid preparation of the present invention can have excellent storage efficacy by including the above-described components. Specifically, the preservative efficacy of the aqueous preparation of the present invention is determined to be “conforming” based on the criteria defined in the category “IA” in the 17th revised Japanese Pharmacopoeia Reference Information “Preservation Efficacy Test Law”. Is. The JP IA conforming storage efficacy can be determined by a test method in accordance with the 17th revised Japanese Pharmacopoeia reference information “Preservation Efficacy Test Method”, and the specific test method is as shown in the column of Test Examples described later.

  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., preferably an aqueous solution.

  The aqueous liquid preparation of the present invention can be used as ophthalmic preparations such as eye drops and eyewashes. In particular, the aqueous liquid preparation of the present invention is provided as an ophthalmic solution because it can suppress the production of aqueous humor and reduce intraocular pressure by the action of brimonidine and / or a salt thereof. It can be suitably used for the therapeutic use.

  The aqueous liquid preparation of the present invention may be produced according to a known preparation method depending on its use, and for example, it can be produced using the method described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations.

  About the container which accommodates the aqueous liquid preparation of this invention, what is necessary is just to use an eye drop container, an eyewash container, etc. according to the use of the said aqueous formulation.

  The aqueous liquid preparation of the present invention may be a multi-dose type container or a unit dose type container that can be used after one eye drop. In particular, a multi-dose type container that does not have a mechanism for preventing backflow of an aqueous liquid agent that has been leached to the outside into the container or a mechanism for preventing foreign substances from entering the container is excellent in the aqueous liquid agent itself to be contained. Since it is required to have a preservative effect, it is suitable as a container for containing the aqueous liquid preparation of the present invention.

3. The present invention relates to a method for imparting preservation efficacy to an aqueous liquid preparation containing brimonidine and / or a salt thereof, which is substantially free of preservatives, brimonidine and / or a salt thereof, edetic acid and There is provided a method for imparting preservative efficacy, comprising the step of preparing an aqueous liquid preparation comprising / or a salt thereof and boric acid and / or a salt thereof.

  According to the method for imparting storage efficacy of the present invention, it is possible to impart JP-IA compatible storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof.

  In the method for imparting preservation efficacy of the present invention, the type and concentration of brimonidine and / or its salt used, the type and concentration of edetic acid and / or its salt, the type and concentration of boric acid and / or its salt, and an aqueous solution The types of other additives and pharmacological components to be blended, the pH of the aqueous liquid, the preparation form, the use, and the like are as described in the column of “2. Aqueous liquid”.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In the following test examples, all boric acid was orthoboric acid.

Test Example 1: Evaluation of Preservative Efficacy According to the 17th revision Japanese Pharmacopoeia Reference Information "Preservation Efficacy Test Method", the preservative efficacy of eye drops having the composition shown in Table 1 was evaluated. Specific test methods and the like are as shown below.

1. Test material and test method
1-1. Preparation of specimen An aqueous solution (ophthalmic solution) having the composition shown in Tables 1 and 2 was prepared and filtered through a 0.22 µm filter. In the aqueous liquid preparation of Example 1, the total amount of boric acid and borax is 0.95 g (concentration: 0.95 w / v%) in terms of boric acid. The total amount of sand is 0.72 g (concentration: 0.72 w / v%) in terms of boric acid.

1-2. 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)
(fungus)
・ Candida (Candida albicans, C. albicans / ATCC 10231)
Black mold (Aspergillus brasiliensis, A. brasiliensis / ATCC 16404)

1-3. Pre-culture Each of the test bacteria was inoculated on the surface of an agar slant medium and pre-cultured. As the agar medium for preculture, a soy bean / casein / digest agar medium was used in the case of bacteria, and a Sabouraud dextrose agar medium was used in the case of fungi. In the case of bacteria, the preculture was performed at 30 to 35 ° C. for 18 to 24 hours, Candida was cultured at 20 to 25 ° C. for 44 to 52 hours, and Black mold was cultured at 20 to 25 ° C. for 6 to 10 days.

1-4. Preparation of mixed sample and measurement of the number of bacteria 10 mL each of the specimens were dispensed into 5 sterilized test tubes with a stopper, and each precultured test bacteria was 1 × 10 ⁵ to 1 × 10 ⁶ CFU / mL. These were used as mixed samples. The mixed sample was stored at 20 to 25 ° C. in the dark. In addition, each test microbe was not mixed, but each specimen was inoculated into each specimen individually to prepare a mixed sample.

At the start of the test and on days 7, 14, and 28 after the start of the test, 1 mL was sampled from each mixed sample, and the solution was diluted with 9 mL of physiological saline. If necessary, the same dilution was further performed 2-3 times, and 1 mL of each diluted solution was dispensed into a sterile petri dish. Next, for bacteria, add soybean casein digest agar medium with 0.1% lecithin and 0.7% polysorbate 80. For fungi, add 0.1% lecithin and 0.7% polysorbate 80. The Sabouraud glucose agar medium was added and mixed. Then, after culturing at 30 to 35 ° C. for 3 to 5 days in the case of bacteria and 5 to 7 days at 20 to 25 ° C. in the case of fungi, the number of generated colonies is measured, and the number of viable bacteria per 1 mL of the mixed sample (cfu / mL) and the logarithmic decrease value (log) of the viable cell count.

1-5. Judgment of preservation efficacy The preservation efficacy of each test solution is determined according to Category 1A described in "Table 3. Judgment Criteria by Formulation" in "4. Evaluation was made according to criteria. Specifically, (1) in all three types of bacteria, the log reduction value (log) is 1.0 log or more compared to the number of inoculated bacteria after 7 days, 3.0 logs or more after 14 days, and viable bacteria after 28 days If the number does not increase after 14 days, and (2) in all two fungi, the number of viable bacteria after 7, 7, and 28 days does not increase from the number of inoculated bacteria is satisfied. Judgment was made, and the others were judged as “nonconforming”.

2. Test results The results obtained are shown in Tables 1 and 2. An aqueous solution with a total concentration of boric acid and borax (as boric acid) of 0.95 w / v% (as boric acid) has excellent storage efficacy even without brimonidine tartrate and sodium edetate dihydrate. And had a JP IA compatible storage effect (Reference Example 1). On the other hand, when only one of brimonidine tartrate or sodium edetate dihydrate is blended in an aqueous solution having a total concentration of boric acid and boric acid of 0.95 w / v% (as boric acid), the preservative efficacy Decrease was observed, and it did not have JP IA compatible storage efficacy. On the other hand, in the case of blending both brimonidine tartrate and sodium edetate dihydrate in an aqueous solution having a total concentration of boric acid and boric acid of 0.95 w / v% (as boric acid), It had excellent storage efficacy and had JP IA compatible storage efficacy (Example 1).

In addition, in the case of an aqueous solution having a total concentration of boric acid and borax of 0.72 w / v% (as boric acid), it does not contain brimonidine tartrate and sodium edetate dihydrate. It did not have a preservative effect (Reference Example 2). In addition, when only one of brimonidine tartrate or sodium edetate dihydrate is blended in an aqueous solution having a total concentration of boric acid and borax of 0.72 w / v% (as boric acid), the preservative efficacy Was observed (Comparative Examples 3 to 5). On the other hand, in the case of blending both brimonidine tartrate and sodium edetate dihydrate in an aqueous solution having a total concentration of boric acid and borax of 0.72 w / v% (as boric acid), Excellent storage efficacy was observed, and it had JP IA compatible storage efficacy (Examples 2 and 3).

  From the above results, it was revealed that the storage efficacy was synergistically enhanced by blending brimonidine tartrate and sodium edetate dihydrate together with boric acid and borax.

Test Example 2: Evaluation of thermal stability An aqueous solution (ophthalmic solution) having the composition shown in Table 4 was prepared. After filtration with 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 desktop thermostat (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 according to the following conditions using a high performance liquid chromatograph system (Shimadzu Corporation).

<Measurement conditions>
Detector: UV absorptiometer (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) Mixed mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio) : 40/30/30) Mixed liquid Flow rate: 1.0 mL / min
Autosampler internal temperature: 5 ℃
Mobile phase liquid feed: The linear concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 3.

According to the following calculation formula, the residual rate of brimonidine in the aqueous liquid was calculated.

  Table 4 shows the obtained results. In the case where sodium edetate dihydrate is not blended, an aqueous solution containing no preservative and containing boric acid and borax (Comparative Example 8) is combined with a preservative that is generally blended into eye drops. The residual rate of brimonidine was lower than that of an aqueous liquid containing boric acid and borax (Comparative Examples 6 and 7). The stability of brimonidine can be improved by blending preservatives such as sodium bisulfite and benzalkonium chloride. However, the stability of brimonidine tartrate was further improved in an aqueous liquid preparation containing sodium edetate dihydrate, boric acid and borax without blending a preservative. That is, from this result, the aqueous solution containing substantially no preservative and containing brimonidine and / or a salt thereof, edetic acid and / or a salt thereof, and boric acid and / or a salt thereof is used as brimonidine and / or It was revealed that the salt was also excellent in terms of stability.

Claims (7)

Aqueous solution containing brimonidine and / or salt thereof, edetic acid and / or salt thereof, boric acid and / or salt thereof, substantially free of preservatives and free of dorzolamide and / or salt thereof .   The aqueous liquid preparation according to claim 1, wherein the concentration of boric acid and / or a salt thereof is 0.5 to 1.5 w / v%.   The aqueous liquid agent of Claim 1 or 2 whose density | concentration of edetic acid and / or its salt is 0.001-0.5 w / v%.   The aqueous liquid preparation according to any one of claims 1 to 3, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.   The aqueous liquid preparation according to any one of claims 1 to 4, wherein the pH is 6-8.   The aqueous liquid preparation according to any one of claims 1 to 5, which is an ophthalmic solution. A method for imparting storage efficacy to an aqueous solution containing brimonidine and / or a salt thereof,
Free of preservatives substantially, and free of dorzolamide and / or a salt thereof, and brimonidine and / or its salts, and edetic acid and / or salts thereof, the aqueous solution containing boric acid and / or salts thereof Including the step of preparing,
How to give preservation efficacy.