KR20200099547A - Eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or salt thereof - Google Patents

Abstract

An object of the present invention is to provide an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof capable of maintaining a preservative effect over a long period of time. The eye drop of the present invention is an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof contained in an eye drop container, and the eye drop container is also sealed packaged.

Description

Eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or salt thereof

The present invention relates to eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof.

2-amino-3-(4-bromobenzoyl)phenylacetic acid is the following formula (1):

It is a compound represented by. The common name of 2-amino-3-(4-bromobenzoyl)phenylacetic acid is bromfenac, which is known as a nonsteroidal anti-inflammatory agent, and is used in the ophthalmic area as an eye drop for the treatment of inflammation of the external and anterior eye areas.

In general, there are two types of eye drops (eye drops) that are used several times over a certain period after opening (multi-dose type eye drops) and one-time use type (unit dose type eye drops). In particular, a preservative such as benzalkonium chloride is generally included in the multi-dose ophthalmic solution in order to prevent spoilage of the product due to microbial contamination or the like during use.

In Patent Document 1, in an aqueous liquid composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid, an aqueous liquid composition having a preservation effect and excellent stability was prepared by combining bromfenac and benzalkonium chloride. Has been reported. However, the preservation effect when the aqueous liquid composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid is stored for a long period of time has not been studied at all. In addition, neither description nor suggestion is made to examine the packaging form.

Patent Document 1: International Publication No. WO2012/99142 pamphlet

Until now, there has been no example of examining the preservation effect in the case of long-term storage of eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof. In addition, there is no example in which the package form was examined for an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof.

The present inventors examined the preservation effect in the case of long-term storage of an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, and as a result, the preservation effect of the eye drop decreased with time. And, when stored for a long period of time, the preservation effect was not maintained. An object of the present invention is to provide an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof capable of maintaining a preservative effect over a long period of time.

The present inventors conducted intensive studies to maintain the preservative effect of eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof over a long period of time, as a result, 2-amino-3-(4- It was found that the preservation effect of this eye drop was maintained over a long period of time by accommodating an eye drop containing bromobenzoyl) phenyl acetic acid or a salt thereof in an eye drop container and sealingly packaged and further sealed with an oxygen scavenger. And completed the present invention.

That is, the present invention relates to the following.

(1) An eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof contained in an eye drop container, wherein the eye drop container is further sealed and packaged.

(2) The eye drop according to (1) above, which is sealed and packaged together with an oxygen scavenger.

(3) The eye drop according to (1) or (2), wherein the content of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is 0.05 to 0.2% (w/v).

(4) The eye drop according to any one of the above (1) to (3), further containing a benzalkonium salt.

(5) The eye drop according to the above (4), wherein the benzalkonium salt is benzalkonium chloride.

(6) The eye drop according to (4) or (5), wherein the content of the benzalkonium salt is 0.0001 to 0.01% (w/v).

(7) The eye drop according to any one of (1) to (6), further containing a sulfite.

(8) The eye drop according to (7), wherein the sulfite is sodium sulfite.

(9) The eye drop according to (7) or (8), wherein the content of sulfite is 0.01 to 0.5% (w/v).

(10)-(a) The eye drop according to any one of (1) to (9), further containing boric acid, borax, sodium edetate hydrate, povidone, and polysorbate 80.

(10)-(b) The eye drop according to any one of (1) to (9), further containing boric acid, borax, sodium edetate hydrate, povidone, and tyloxapol.

(11) The eye drop according to any one of (1) to (10)-(a) and (10)-(b), wherein the pH is 7.0 to 9.0.

(12) The eye drop according to any one of the above (1) to (11), which is hermetically packaged in a pillow bag.

(13) The eye drop according to (12), wherein the pillow bag is made of an aluminum film.

(14) The eye drop according to (12) or (13), wherein the pillow bag has an oxygen permeability of 20 ml/m 2 ·atm·24 h or less.

(15) The eye drop according to any one of (2) to (14), wherein the oxygen scavenger is an iron-based oxygen scavenger.

The present invention also relates to the following.

(16) An ophthalmic pharmaceutical product comprising an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, an eye drop container containing the eye drop agent, and a package in which the eye drop container is sealed. .

(17) The ophthalmic pharmaceutical product according to (16), wherein the packaging further seals the oxygen scavenger.

The present invention also relates to the following.

(18) 2-amino-3- (4-bromobenzoyl) phenyl acetic acid or a salt thereof, containing an eye drop in an eye drop container, the eye drop container is also sealed packaging of the ophthalmic pharmaceutical product Manufacturing method.

(19) The method for producing an ophthalmic pharmaceutical product according to (18) above, which is sealed and packaged together with an oxygen scavenger.

The present invention also relates to the following.

(20) A package in which an eye drop container containing an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is contained.

(21) The packaging according to (20), wherein the oxygen scavenger is further sealed.

The present invention also relates to the following.

(22) A method for preserving an eye drop, comprising accommodating an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof in an eye drop container, and sealing the eye drop container further.

(23) The method for preserving the eye drops according to (22) above, which is sealed and packaged together with an oxygen scavenger.

On the other hand, each of the components described in the above (1) to (23) can be arbitrarily selected and combined with two or more.

According to the present invention, it is possible to provide an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof capable of maintaining a preservative effect over a long period of time.

1 is a graph showing the results of a reference test.

Hereinafter, the present invention will be described in detail.

In this specification, unless otherwise noted, the unit "%" of the content means "w/v%", and has the same meaning as "g/100 mL".

In the present specification, the term "eyedrop container" means that an eye drop (aqueous composition) containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is put in a pharmaceutically acceptable state, that is, It means containing an eye drop (aqueous composition).

In the present specification, "packaging" means to accommodate (storage) the eye drop container in the present invention, and is distinguished from the eye drop container described above.

In addition, in this specification, ``packaging'' means to accommodate (storage) the object inside the packaging, and for example, by wrapping the object with a film, the object is accommodated (stored) inside the bag made of film. Also includes. In addition, ``closely packed'' means sealing the object inside the packaging (to make it airtight). For example, after wrapping the object with a film, the opening of the bag made of film is closed, and the inside of the bag It also includes sealing the object (making it airtight). On the other hand, the sealed state here includes the airtight state and the sealed state.

In the present specification, the term "preservation effect" means the antiseptic effect of the eye drops, and the term "maintenance of the preservation effect" means that the attenuation of the preservation effect over time of the eye drops is suppressed. The preservation effect of the eye drops may be determined by whether or not it satisfies the standard "category IA" in the "preservation efficacy test method", for example, the 17th revised Japanese pharmacy store reference information.

<Eye drops>

The eye drop of the present invention contains 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof (hereinafter referred to as the present compound), is accommodated in an eye drop container, and is placed inside the eye drop container. It is sealed and packaged. Furthermore, the eye drops of the present invention are hermetically packaged inside the package together with, for example, a deoxidant. The eye drops containing the present compound are accommodated in an eye drop container and sealed inside the package, and further, by being hermetically packaged inside the package together with a deoxidant, the preservation effect is maintained over a long period of time. In addition, the ophthalmic agent of the present invention suppresses the formation of a related substance of the present compound over a long period of time and is pharmaceutically stable. The eye drops of the present invention are preferably in a state in which the amount of dissolved oxygen is reduced as much as possible, and in particular, it is preferable that the dissolved oxygen is not substantially contained.

In addition, the eye drops of the present invention may be, for example, eye drops that retain their preservation effect after storage (preservation) for a pharmaceutically acceptable period, for example, for 3 to 36 months under conditions of 1 to 30°C and 75% RH or less. After storage of, preferably, eye drops that maintain the preservation effect after storage for 6 months under conditions of 40°C and 75% RH or less and/or storage for 12 months under conditions of 25°C and 60% RH or less. In addition, the eye drops of the present invention may be, for example, pharmaceutically stable eye drops after storage (storage) for a pharmaceutically acceptable period, for example, for 12 to 36 months under conditions of 1 to 30°C and 40% RH or less. After storage, preferably, a pharmaceutically stable eye drop may be used for 6 months under conditions of 40°C and 25% RH or less and/or after storage for 12 months under conditions of 25°C and 60% RH or less.

(Eyedrops containing this compound (aqueous composition))

The ophthalmic composition of the present invention contains 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof as an active ingredient (pharmaceutical ingredient), and optionally contains a pharmaceutically acceptable additive And it is preferable that it is an aqueous composition. Its properties may be, for example, a liquid such as a solution or a suspension, and an aqueous solution is preferable. In addition, when the ophthalmic agent of the present invention is an aqueous composition, the aqueous solvent that can be used is not particularly limited as long as it contains water, and may be, for example, water or a mixture of a water-soluble solvent such as alcohol and water, preferably Is purified water.

In the present invention, the eye drops and the aqueous composition, or the aqueous solvent for preparing them, are preferably used by reducing the amount of dissolved oxygen as much as possible, particularly preferably in a state that does not contain dissolved oxygen substantially. There is no limitation on the means, and the amount of dissolved oxygen thereof can be reduced by removing the dissolved oxygen in the eye drops and the aqueous composition or the aqueous solvent for preparing them by substitution with an inert gas such as nitrogen or argon.

In the eye drop of the present invention, 2-amino-3-(4-bromobenzoyl)phenylacetic acid is undissolved 2-amino-3-(4-bromobenzoyl)phenylacetic acid itself, 2-amino-3-( Salts of 4-bromobenzoyl)phenylacetic acid, zwitterionic (carboxyl groups form carboxylate ions, and amino groups form ammonium ions), amphoteric ions (only amino groups form ammonium ions), negative As an ionic body (only carboxyl groups form carboxylate ions), they may exist in dissolved form.

In the eye drops of the present invention, the salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and as salts, salts with inorganic acids, salts with organic acids, Quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, metal salts, salts with organic amines, and the like. As a salt with an inorganic acid, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are mentioned. As salts with organic acids, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, manoic acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate , Methyl sulfate, naphthalenesulfonic acid, and salts with sulfosalicylic acid. Examples of the quaternary ammonium salt include salts such as methyl bromide and methyl iodide. As a salt with a halogen ion, a salt with a chloride ion, a bromide ion, an iodide ion, etc. are mentioned, as a salt with an alkali metal, a salt with lithium, sodium, potassium, etc. is mentioned, and a salt with an alkaline earth metal Examples of the salt include salts with calcium, magnesium, and the like, and examples of the metal salt include salts with iron and zinc. As a salt with an organic amine, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2- Salts such as (hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine. In the eye drop of the present invention, a preferred salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid is a sodium salt.

In the eye drops of the present invention, the concentration of 2-amino-3-(4-bromobenzoyl)phenylacetic acid is not particularly limited as long as it is an amount sufficient to exert a desired drug effect, but 0.01 to 1.0% (w/v) is It is preferable, 0.03 to 0.5% (w/v) is more preferable, 0.05 to 0.2% (w/v) is still more preferable, and 0.08 to 0.1% (w/v) is most preferable. On the other hand, these concentrations are converted to 2-amino-3-(4-bromobenzoyl)phenylacetic acid when using a salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a hydrate thereof. Calculate using mass.

In the eye drop of the present invention, a benzalkonium salt that can be used as an additive for pharmaceuticals can also be blended. Examples of the benzalkonium salt include benzalkonium chloride (BAK), benzalkonium bromide, and the like, preferably benzalkonium chloride.

The upper limit of the concentration of the benzalkonium salt in the eye drops of the present invention is not particularly limited, but 0.01% (w/v) is preferred, 0.008% (w/v) is more preferred, and 0.006% (w/v) is particularly It is preferred, and 0.005% (w/v) is most preferred. On the other hand, the lower limit of the concentration is not particularly limited, but 0.0001% (w/v) is preferable, 0.0005% (w/v) is more preferable, 0.0008% (w/v) is particularly preferable, and 0.001% ( w/v) is most preferred. The concentration range is not particularly limited, but is preferably 0.0001% (w/v) or more and 0.01% (w/v) or less, more preferably 0.0005% (w/v) or more and 0.0008% (w/v) or less, and , 0.001% (w/v) or more and 0.006% (w/v) or less are particularly preferred, and 0.001% (w/v) or 0.005% (w/v) is most preferred.

In the ophthalmic preparation of the present invention, a sulfite salt that can be used as an additive for pharmaceuticals can be blended. Examples of the sulfite salt include sodium sulfite, potassium sulfite, magnesium sulfite, calcium sulfite, and the like, preferably sodium sulfite. As sodium sulfite, dry sodium sulfite can be used, for example.

The upper limit of the concentration of sulfite in the eye drop of the present invention is not particularly limited, but 0.5% (w/v) is preferred, 0.3% (w/v) is more preferred, and 0.25% (w/v) is particularly preferred. Do. On the other hand, the lower limit of the concentration is not particularly limited, but 0.01% (w/v) is preferable, 0.03% (w/v) is more preferable, and 0.04% (w/v) is particularly preferable. The range of concentration is not particularly limited, but 0.01% (w/v) or more and 0.5% (w/v) or less are preferred, and 0.03% (w/v) or more and 0.3% (w/v) or less are more preferred, and , 0.04% (w/v) or more and 0.25% (w/v) or less are particularly preferable.

In addition to these, additives such as a buffering agent, an isotonic agent, a pH adjusting agent, a stabilizer, a preservative, a dissolution aid, and a thickening agent may be further added to the eye drop of the present invention, if necessary.

In the ophthalmic preparation of the present invention, a buffering agent that can be used as an additive for pharmaceuticals can be blended. Examples of the buffering agent include phosphoric acid or its salt, boric acid or its salt, citric acid or its salt, acetic acid or its salt, carbonic acid or its salt, tartaric acid or its salt, ε-aminocaproic acid, tromethamol, and the like. Examples of the phosphate salt include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and examples of the borate include borax, sodium borate, potassium borate, and the like, and citrate As examples, sodium citrate, disodium citrate, etc. can be mentioned, examples of the acetate salt include sodium acetate, potassium acetate, etc., examples of the carbonate include sodium carbonate and sodium hydrogen carbonate, and examples of the tartrate include sodium tartrate, Potassium tartrate, etc. are mentioned. In the present invention, a preferred buffering agent is boric acid or a salt thereof, for example, boric acid or borax.

The concentration of the buffering agent in the eye drop of the present invention can be appropriately adjusted in consideration of the effect of drugs, other additives and/or the osmotic pressure ratio, but the total amount is preferably 0.01 to 15% (w/v), and 0.05 to 10% (w/v) is more preferable, 0.1 to 6% (w/v) is more preferable, 0.5 to 5% (w/v) is particularly preferable, and 2 to 4% (w/v) is most preferable Do.

To the eye drops of the present invention, an isotonic agent that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the tonicity agent include an ionic tonicity agent and a nonionic tonicity agent. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, and examples of the nonionic tonicity agent include glycerin, propylene glycol, sorbitol, and mannitol. In the present invention, a preferred tonicity agent is sodium chloride.

The concentration of the tonicity agent in the eye drops of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and/or the osmotic pressure ratio, but the total amount is preferably 0.01 to 3% (w/v), and 0.02 to 2.5 % (w/v) is more preferable, 0.03 to 2% (w/v) is more preferable, 0.05 to 1% (w/v) is particularly preferable, and 0.1 to 0.5% (w/v) is the most desirable.

In the eye drop of the present invention, an appropriate amount of a pH adjuster that can be used as an additive for pharmaceuticals can be blended. Examples of the pH adjusting agent include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, and the like. In the present invention, preferred pH adjusters are hydrochloric acid and sodium hydroxide.

The pH of the eye drop of the present invention is preferably 7.0 to 9.5, more preferably 7.5 to 9.0, even more preferably 8.0 to 8.6, and most preferably 8.2 to 8.4.

In the eye drop of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the stabilizer include edetic acid, sodium edetate, sodium edetate hydrate, sodium citrate, water-soluble polymer, and the like. Examples of the water-soluble polymer include povidone (polyvinylpyrrolidone), polyvinyl alcohol, carboxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sodium polyacrylate. In the present invention, preferred stabilizers are sodium edetate hydrate and povidone (preferably povidone (K-30)).

The concentration of the stabilizer in the eye drops of the present invention can be appropriately adjusted in consideration of the effect of drugs, other additives and/or the osmotic pressure ratio, but the total amount is preferably 0.001 to 5% (w/v), and 0.002 to 4% (w/v) is more preferable, 0.003 to 3.5% (w/v) is more preferable, 0.005 to 3.0% (w/v) is particularly preferable, and 0.01 to 2.2% (w/v) is most preferable Do.

Preservatives that can be used as additives for pharmaceuticals can be appropriately blended into the eye drops of the present invention. Examples of the preservative include benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like.

The concentration of the preservative in the eye drops of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and/or the penetration pressure ratio, but the total amount is preferably 0.00005 to 0.01% (w/v), and 0.0001 to 0.005% (w/v) is more preferable, 0.0002 to 0.004% (w/v) is more preferable, 0.0005 to 0.003% (w/v) is particularly preferable, and 0.001 to 0.002% (w/v) is most preferable Do.

To the eye drop of the present invention, a dissolution aid that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the dissolution aid include polysorbate 80, tyloxapol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene castor oil 35, poloxamer 188, poloxamer 407, macrogol 4000, etc. And preferred dissolution aids are polysorbate 80 or tyloxapol.

The concentration of the dissolution aid in the eye drops of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and/or the osmotic pressure ratio, but the total amount is preferably 0.001 to 1.0% (w/v), and 0.005 to 0.5 % (w/v) is more preferable, 0.01 to 0.3% (w/v) is more preferable, 0.01 to 0.2% (w/v) is particularly preferable, and 0.02 to 0.18% (w/v) is the most desirable.

To the eye drop of the present invention, a thickener that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the viscous agent include polyvinyl alcohol, sodium carmellose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, glucose, glycerin, polyethylene glycol, and dextran.

The concentration of the consistency agent in the eye drops of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and/or the osmotic pressure ratio, but the total amount is preferably 0.001 to 5.0% (w/v), and 0.01 to 2.0% (w/v) is more preferable, 0.05 to 1.0% (w/v) is more preferable, 0.1 to 0.75% (w/v) is particularly preferable, and 0.2 to 0.5% (w/v) is Most preferred.

(Eye drop container)

In the present invention, the eye drop container is not particularly limited as long as it can hold an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, and is pharmaceutically acceptable. The eye drop container may be formed of one member or a plurality of members, and may be, for example, a one-piece eye drop container, a two piece eye drop container, or a three piece eye drop container. Here, for example, in the case of a three-piece eye drop container, if it is an integrally molded container that is formed of three members: a container body for accommodating the eye drops, an inner cap, and a cap. Fit into the eye drop container. In addition, when the eye drop container is formed of a plurality of members, it may be formed of a member made of the same material or may be formed of a member made of different materials. Further, the material may constitute part or all of the member, or may be coated.

As a material of the eye drop container, for example, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, etc. It can be used, preferably, polyethylene can be used.

In the present invention, it is preferable that the amount of oxygen in the eye drop container containing the eye drop agent is reduced as much as possible, and it is particularly preferable that oxygen is not substantially contained. There is no restriction on the means, for example, by removing oxygen in the eye drop container by a substitution operation with an inert gas such as nitrogen or argon, the amount of oxygen in the eye drop container can be reduced.

(Packing)

In the present invention, the packaging is not particularly limited as long as it is pharmaceutically acceptable, and may be a shaped container such as a bottle, a can, or a box, or an irregular container such as a bag. In the present invention, the preferred packaging is a bag. As a bag, a three-way seal bag, a four-way seal bag, a gusset bag, and a pillow bag are mentioned, for example, Preferably, it is a pillow bag. In addition, the packaging is not limited to a single layer structure, and may be a multilayer structure such as a multilayer film.

In addition, in the present invention, the packaging may be, for example, a sealed container, an airtight container, or a sealed container. Here, the sealed container refers to a container capable of preventing solid foreign matters from being mixed in during normal handling, transportation, or storage, thereby preventing loss of the internal ones. The airtight container refers to a container capable of preventing the loss, wind damage, defrosting, or evaporation of the contents by preventing solid or liquid foreign substances from entering under normal handling, transportation, or storage conditions. The sealed container refers to a container in which gas does not enter during normal handling, transportation, or storage conditions.

In the present invention, it is preferable that the amount of oxygen is reduced as much as possible in the package, at the time of airtight packaging or over a certain period after airtight packaging, and it is particularly preferable that oxygen is not substantially contained. There is no limitation on the means, for example, by sealing a deoxidant inside the package, or by removing oxygen in the package by a substitution operation with an inert gas such as nitrogen or argon before sealing, thereby reducing the amount of oxygen in the package. I can do it in a state.

On the other hand, in this specification, ``substantially free of oxygen'' in the packaging (container) means that the oxygen concentration in the gas in the packaging (container) is 0 or very low, and in the gas in the packaging (container) It means that the oxygen concentration is, for example, 5 vol% or less, 1 vol% or less, 0.1 vol% or less, 0.01 vol% or less, 0.001 vol% or less, 0.0001 vol% or less, and 0.00001 vol% or less. And, in this specification, the term "substantially no dissolved oxygen" in the solution means that the oxygen concentration in the solution is 0 or very low, and the oxygen in the solution and the oxygen present in the gas reach equilibrium, When present, it means that the oxygen concentration in the gas is, for example, 5 vol% or less, 1 vol% or less, 0.1 vol% or less, 0.01 vol% or less, 0.001 vol% or less, 0.0001 vol% or less, and 0.00001 vol% or less.

Here, the method of measuring the oxygen concentration in the gas in the packaging (container) and the dissolved oxygen concentration in the solution is not particularly limited, and can be measured by a general known method, for example, using a commercially available measuring device. It can be measured according to. Specifically, the oxygen concentration in the gas in the package (container) can be measured using an oxygen concentration meter of a method such as a diaphragm electrode type, magnetic type, zirconia type, and the dissolved oxygen concentration in the solution is determined by a titration method, a diaphragm electrode method, etc. It can be measured by a measuring method of.

The material of the packaging is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include paper, glass, resin and resin films, metal and metal films, and a combination of these may be used. Further, as the material of the packaging, for example, only paper may be excluded. Specifically, aluminum films, such as an aluminum foil, an aluminum vapor deposition film, and an aluminum laminate film, are mentioned. Further, the packaging may be transparent, translucent or opaque.

In addition, the material of the packaging is preferably a material having a low oxygen permeability, and specifically, an oxygen permeability of 20 ml/m 2 ·atm ·24 h or less in order to suppress the inflow of oxygen into the interior of the packaging. It is preferably 5 ml/m 2 ·atm·24 h or less, and most preferably 1.5 ml/m 2 ·atm·24 h or less.

In the present invention, in the packaging, an eye drop container containing the present compound and an optional oxygen scavenger are sealed inside, and other things may be sealed inside. For example, other pharmaceuticals/medical products, drying agents such as silica gel, Antioxidants, insect repellents, etc. may be sealed inside.

(Deoxidant)

In the present invention, the oxygen scavenger is not particularly limited as long as it can reduce the oxygen concentration of the surrounding by absorbing or reacting with oxygen. For example, a metal-based oxygen scavenger such as an iron-based oxygen scavenger, an organic oxygen scavenger, etc. Can be used, preferably, an iron-based oxygen scavenger can be used. As a specific iron-based oxygen scavenger, for example, WonderKeep product number, RP-30 (registered trademark: Powder Tech Co., Ltd.), Ageless product number, ZP-32RY (registered trademark: Mitsubishi Gas Chemical Co., Ltd.), Everfresh Part No., Q-30 (registered trademark: Torishige Sangyo Co., Ltd.) and the like.

On the other hand, in the present invention, the oxygen scavenger, for example, is sealed inside the packaging together with an eye drop container containing the present compound. In this case, the oxygen scavenger may be disposed inside the packaging and away from the packaging, It may be placed in contact. Here, the case where the package is placed in contact with the package includes the case where the package and the oxygen scavenger are integrated. For example, when the oxygen scavenger is applied to the inner surface of the package, the package has a multilayer structure, and the inner layer Or the case where the intermediate layer is made of an oxygen scavenger.

<Ophthalmic medicine product and its manufacturing method>

The ophthalmic pharmaceutical product of the present invention includes an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, an eye drop container containing the eye drop agent, and a package in which the eye drop container is sealed. It is an ophthalmic pharmaceutical product, and more preferably, an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, an eye drop container containing the eye drop agent, a deoxidant, and the above It is an ophthalmic pharmaceutical product comprising an eye drop container and a package in which the oxygen scavenger is sealed. In addition, the production method of the present invention comprises storing an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof in an eye drop container, and further sealing the eye drop container. It is a manufacturing method, and more preferably, an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is accommodated in an eye drop container, and the eye drop container is further sealed together with a deoxidant. It is a manufacturing method including that. The ophthalmic pharmaceutical product of the present invention provides an ophthalmic pharmaceutical product comprising an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof capable of maintaining a preservative effect over a long period of time. The production method of the present invention provides an ophthalmic pharmaceutical product comprising an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof capable of maintaining a preservative effect over a long period of time. Can be manufactured. In these ophthalmic pharmaceutical products and the manufacturing method thereof, the description of the above-described eye drops can be used as it is.

<packing>

The packaging of the present invention is a packaging in which an eye drop container containing an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is sealed, and more preferably, 2-amino-3-( It is an eye drop container containing an eye drop containing 4-bromobenzoyl) phenyl acetic acid or a salt thereof and a sealed package of an oxygen scavenger. The packaging of the present invention can provide a packaging that seals an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, which can maintain a preservation effect over a long period of time. In this packaging, the technology related to the eye drops described above can be used as it is.

<How to save>

The preservation method of the present invention is a method of accommodating an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof in an eye drop container, and sealing the eye drop container further, more preferably Specifically, an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is accommodated in an eye drop container, and the eye drop container is also hermetically packaged together with a deoxidant. By this method, the preservation effect of the eye drops is maintained after storage (preservation) for a pharmaceutically acceptable period. Further, the preservation method of the present invention is also a method of suppressing attenuation of the preservation effect of the eye drops, and a method of maintaining the preservation effect of the eye drops. In the preservation method of the present invention, the technology relating to the eye drops described above can be used as it is.

Example

Test examples and preparation examples are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

1. Preparation of test sample

(Example 1)

To 90 mL of purified water, 0.1 g of 2-amino-3-(4-bromobenzoyl) phenylacetate sodium 3/2 hydrate (hereinafter also referred to as this compound), 1.1 g of boric acid, 1.1 g of borax, and edetic acid 0.02 g of sodium hydrate, 2 g of povidone (K-30), 0.2 g of dry sodium sulfite, 0.15 g of polysorbate 80, and 1 mL of 0.5% benzalkonium chloride solution were added, followed by sufficiently stirring. After adding 1N aqueous sodium hydroxide solution and adjusting the pH to around 8.3, an appropriate amount of purified water was added to make the total amount 100 mL, to prepare an aqueous composition (eye drop). On the other hand, the permeation pressure of this aqueous composition was about 300 mOsm.

Next, after filling this aqueous composition into an eye drop container made of polyethylene (Petrosene 175K (registered trademark: Tosoh)), the five eye drop containers were placed in the iron-based oxygen scavenger Ageless ZP-32RY (registered trademark: Mitsubishi Gas). Kagaku Co., Ltd.) 1 piece, and pillow-packed with an aluminum laminate film (manufactured by Sun-Ei Kaken) with an oxygen permeability of 1.5 ml/m 2 ·atm ·24 h or less (manufactured by Sun Ei Kaken), and 5 eye drop containers and 1 deoxidant Was sealed inside the packaging. In addition, this was put in a paper box to obtain a test sample of Example 1.

(Comparative Example 1)

In the same manner as in Example 1, an aqueous composition containing the present compound was prepared and filled into an eye drop container. This was put in a paper box as it was without pillow packaging together with Ageless (registered trademark) to obtain a test sample of Comparative Example 1.

2. Preservation effect test

The test samples of Example 1 and Comparative Example 1 were subjected to an accelerated test that was stored for 6 months under conditions of 40°C and 25% RH or less, and Example 1 at the start and end of the accelerated test (after 6 months) And the preservation effect of the aqueous composition in Comparative Example 1 was examined. In addition, for the test sample of Example 1, a long-term storage test was also conducted under conditions of 25°C and 40% RH or less for 12 months, and Example 1 at the start and end of the long-term storage test (when 12 months elapsed). The preservation effect of the aqueous composition was also examined. Specifically, the preservation effect of each aqueous composition was examined by performing the following preservation efficacy test.

(Preservation effect test method)

The preservation efficacy test was performed in accordance with the preservation efficacy test method of the 17th revised Japanese pharmacy room. In this test, the following strains were used as inoculum.

Germ:

E. coli, Escherichia Coli ATCC 8739 (also known as E. coli )

Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 9027 (also known as P. aeruginosa )

Staphylococcus aureus ATCC 6538 (also known as S. aureus )

Yeast fungi and fungi:

Candida, Candida albicans ATCC 10231 (also known as C. albicans )

Black yeast fungus, Aspergillus brasiliensis ATCC 16404 (also known as A. brasiliensis )

The aqueous composition in Example 1 and Comparative Example 1 at the start and end of the accelerated test (at the time of 6 months), and at the start and end of the long-term storage test (at the time of 12 months) in Example 1 The aqueous composition was used as a test sample. Then, the inoculated bacterial solution was inoculated into the test sample so that the concentration of the bacterial solution in each test sample was 10 ⁵ to 10 ⁶ cells/mL (all 5 species). Specifically, each inoculated bacterial solution was prepared so as to be 10 ^{7-10 8} cfu/mL, and this inoculated bacterial solution was inoculated into the test sample so that it might be 10 ^{5-10 6} cfu/mL, and mixed uniformly. Next, the test sample after the inoculation of the bacterial solution is stored at 20 to 25°C under shading, and at each sampling point (7 days after the inoculation of the bacterial solution, 14 days or 28 days after inoculation), 1 mL from each test sample is taken with a micropipette. It was collected and the number of viable cells was measured.

(Test results and discussion)

The test results are shown in Tables 1 and 2. The test results in Tables 1 and 2 represent the ratio (B/A) of the number of bacteria at the time of inoculation (B) to the number of viable cells at the time of inspection (A) for each inoculum as a common logarithmic value (logarithmic decrease value). And, for example, in the case of "1", it shows that the number of viable cells at the time of examination has decreased to 10% of the number of inoculated bacteria. In addition, it was determined whether or not it satisfies the criteria of the standard "Category IA" according to the 17th revised Japanese pharmacy store reference information "Preservation Effect Test Method".

As shown in Tables 1 and 2, the test sample of Example 1 in which the aqueous composition (eye drop) was pillow-packed and, more specifically, pillow-packed with a deoxidant, was not only at the start of the accelerated test, but also at the end of the accelerated test. Also, it exhibited an antiseptic effect on all five kinds of bacteria, and was suitable to the standard of "Category IA" according to the "Preservation Efficacy Test Method" of the 17th revised Japanese pharmacy store reference information. On the other hand, the test sample of Comparative Example 1, in which the aqueous composition (eye drop) was not wrapped in a pillow together with a deoxidant, satisfies the same standard at the start of the accelerated test, but at the end of the accelerated test, the antiseptic effect attenuates Yes, it did not meet the criteria. From these results, it was found that the preservative effect, that is, the preservation effect, is better maintained by pillow-packing the aqueous composition (eye drop) containing the present compound, more preferably, by pillow-packing with a deoxidant. In addition, it was found that the test sample of Example 1 in which the aqueous composition (eye drop) was wrapped with a pillow with a deoxidant met the same standard at the start and end of a long-term storage test, and that the preservation effect was maintained over a long period of time. Could

3. Quantitative Analysis

The test samples of Example 1 and Comparative Example 1 were subjected to the above-described accelerated test or long-term storage test to examine changes in the content of sodium bromfenac hydrate and dry sodium sulfite in the aqueous composition during the test. Specifically, bromfenac sodium hydrate and dry sodium sulfite contained in the aqueous compositions in Example 1 and Comparative Example 1 at the start of the accelerated test and at the time of 3 months and 6 months after the start of the test, respectively, under the following conditions: Was quantified by high performance liquid chromatography (HPLC). In addition, benzalkonium chloride and dry sodium sulfite contained in the aqueous compositions in Example 1 and Comparative Example 1 at the start of the long-term storage test and at the time of 3 months, 6 months and 9 months after the start of the test were similarly used as high-speed liquids. It was quantified by chromatography (HPLC). On the other hand, the HPLC apparatus used an apparatus manufactured by Waters Corporation.

(Dried sodium sulfite quantification conditions)

Detector: electric conductivity meter

Column: Shodex IC I-524A (12 μm, 4.6 mm×100 mm, manufactured by Showa Denko Corporation)

Column temperature: constant temperature around 50°C

Mobile phase: 0.25 mM p-hydroxybenzoic acid/1.2 mM diethylaminoethanol/aqueous solution

Flow: approx. 1.5 mL/min.

Analysis time: 20 minutes

(Conditions for quantification of sodium bromfenac hydrate)

Detector: ultraviolet absorbance photometer (measurement wavelength: 266 nm)

Column: XBridge C18 (5 μm, 4.6×250 mm, manufactured by Waters)

Column temperature: constant temperature around 40℃

Mobile phase A: 20 mM phosphate buffer pH 7.3/acetonitrile (75/25)

Mobile phase B: 20 mM phosphate buffer pH 7.3/acetonitrile (30/70)

Gradient condition: 0%B(0 min)-0%B(30 min)-90%B(60 min)

Flow: approx. 1.0 mL/min.

Analysis time: 70 minutes

(Results and Discussion)

The results of the quantitative analysis are shown in Tables 3 and 4. Table 3 shows the analysis results of dry sodium sulfite, and Table 4 shows sodium bromfenac hydrate. In the analysis results in Tables 3 and 4, the content of each compound at the start of the accelerated test or the long-term storage test is set to 100%, and the content of each compound is expressed in% after a predetermined period has elapsed after the start of the test. On the other hand, this analysis result is an average value of each of the three analysis results.

As shown in Table 3, the test sample of Example 1 in which the aqueous composition (eye drops) was wrapped in a pillow, and more specifically, wrapped in a pillow together with a deoxidant, was dried during an accelerated test and a long-term storage test. There was no significant change in the sodium sulfate content. On the other hand, in the test sample of Comparative Example 1 in which the aqueous composition (eye drop) was not packaged in a pillow, the content of dry sodium sulfite was significantly decreased during the accelerated test and long-term storage test. From these results, it was found that the content of dry sodium sulfite in the aqueous composition (eye drop) was better maintained by pillow-packing the aqueous composition (eye drop) containing the present compound, more preferably, by pillow packing with a deoxidant. Could On the other hand, similarly, benzalkonium chloride in the aqueous composition (eye drop) in the test sample of Example 1 and the test sample of Comparative Example 1 was quantified, but both the test sample of Example 1 and the test sample of Comparative Example 1 were benzalkonium. There was no significant change in the content of (data not shown).

In addition, as shown in Table 4, the test sample of Example 1 in which the aqueous composition (eye drops) was wrapped in a pillow, and more specifically, a pillow-packed with a deoxidant, and the aqueous composition (eye drop) was not wrapped in a pillow. In all of the test samples of 1, no significant change occurred in the content of sodium bromfenac hydrate in the aqueous composition during the accelerated test. In addition, 6 months after the start of the accelerated test, in the aqueous composition in Example 1, two types of bromfenac analogs (existing 0.05% or more relative to sodium bromfenac hydrate) were generated. In the aqueous composition in the above, five types of bromfenac related substances (0.05% or more with respect to sodium bromfenac hydrate) were generated (shown in Table 5 below). From these results, it was found that the formation of bromfenac-related substances in the aqueous composition (eye drop) was suppressed by pillow-packing the aqueous composition (eye drop) containing the present compound, more preferably by pillow packing with an oxygen scavenger. .

4. Reference test

The relationship between the content of dry sodium sulfite in the aqueous composition (eye drop) and the preservation effect of the aqueous composition was examined by the following test.

(Test Methods)

The aqueous composition in Example 1 was stored for a certain period under the conditions of 40°C/25% RH or less or 25°C/40% RH to obtain 7 types of aqueous compositions having different contents of dry sodium sulfite. Next, about these aqueous compositions, a preservation efficacy test for S. aureus was conducted in the same manner as the preservation efficacy test described above. In addition, the content of dry sodium sulfite was quantified in the same manner as in the aforementioned quantitative analysis.

(Test results and discussion)

Fig. 1 shows the results of the test. Fig. 1 shows the content of dry sodium sulfite in the aqueous composition (the content is 0.2 g as 100%, expressed as %) on the X-axis, and the storage effect of the aqueous composition (the logarithmic decrease value 7 days after S. aureus inoculation) on the Y-axis. It is a graph plotted in.

As shown in Fig. 1, a positive correlation was observed between the content of dry sodium sulfite in the aqueous composition and the preservation effect of the aqueous composition (R ² =0.9831). From this result, it was found that in the aqueous composition containing the present compound, the preservation effect can be maintained by maintaining the content of dry sodium sulfite.

<Preparation Example>

Representative examples of formulations using this compound are shown below. On the other hand, in the following formulation examples, the blending amount of each component is the content in 100 mL.

Formulation Example 1

This compound 0.1 g

Boric acid 1.1 g

borax 1.1 g

Sodium edetate hydrate 0.02 g

Povidone (K-30) 2 g

Dry sodium sulfite 0.2 g

Polysorbate 80 0.15 g

Benzalkonium chloride 0.005 g

Sodium hydroxide Appropriate amount

Purified water Appropriate amount

pH 8.3

Formulation Example 2

This compound 0.1 g

Polysorbate 80 0.02 g

Boric acid 1.25 g

borax 1.0 g

Sodium edetate hydrate 0.02 g

Benzalkonium bromide 0.0016 g

Hydrochloric acid Appropriate amount

Sodium hydroxide Appropriate amount

Purified water Appropriate amount

pH 8.3

Formulation Example 3

This compound 0.1 g

Boric acid 1.1 g

borax 1.1 g

Sodium edetate hydrate 0.02 g

Povidone (K-30) 2 g

Dry sodium sulfite 0.2 g

Polysorbate 80 0.15 g

Benzalkonium chloride 0.001 g

Sodium hydroxide Appropriate amount

Purified water Appropriate amount

pH 8.3

Formulation Example 4

This compound 0.1 g

Boric acid 1.1 g

borax 1.1 g

Sodium edetate hydrate 0.02 g

Povidone (K-30) 2 g

Dry sodium sulfite 0.2 g

Tyloxapol 0.02 g

Benzalkonium chloride 0.005 g

Sodium hydroxide Appropriate amount

Purified water Appropriate amount

pH 8.3

On the other hand, each component in Formulation Examples 1 to 4, that is, the compounding amount and mixing ratio of the present compound and other additives can be appropriately adjusted.

Claims (23)

An eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof contained in an eye drop container, wherein the eye drop container is further hermetically packaged. The eye drop according to claim 1, which is sealed and packaged together with an oxygen scavenger. The eye drop according to claim 1 or 2, wherein the content of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is 0.05 to 0.2% (w/v). The eye drop according to any one of claims 1 to 3, further containing a benzalkonium salt. The eye drop according to claim 4, wherein the benzalkonium salt is benzalkonium chloride. The eye drop according to claim 4 or 5, wherein the content of the benzalkonium salt is 0.0001 to 0.01% (w/v). The eye drop according to any one of claims 1 to 6, further containing a sulfite. The eye drop according to claim 7, wherein the sulfite is sodium sulfite. The eye drop according to claim 7 or 8, wherein the sulfite content is 0.01 to 0.5% (w/v). The eye drop according to any one of claims 1 to 9, further containing boric acid, borax, sodium edetate hydrate, povidone, and polysorbate 80. The ophthalmic preparation according to any one of claims 1 to 10, wherein the pH is 7.0 to 9.0. The eye drop according to any one of claims 1 to 11, which is hermetically packaged in a pillow bag. The eye drop according to claim 12, wherein the pillow bag is made of an aluminum film. The eye drop according to claim 12 or 13, wherein the pillow bag has an oxygen permeability of 20 ml/m 2 ·atm·24 h or less. The eye drop according to any one of claims 2 to 14, wherein the oxygen scavenger is an iron-based oxygen scavenger. Eye drops containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof,
An eye drop container in which the eye drops are accommodated,
Sealed packaging of the eye drop container
Ophthalmic medicine product comprising a. The ophthalmic pharmaceutical product according to claim 16, wherein the packaging further seals the oxygen scavenger. A method for producing an ophthalmic pharmaceutical product comprising receiving an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof in an eye drop container, and sealing the eye drop container further. 19. The method for manufacturing an ophthalmic pharmaceutical product according to claim 18, which is sealed and packaged together with a deoxidant. An eye drop container containing an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof is sealed and packaged. The packaging according to claim 20, further comprising a deoxidant. A method for preserving an eye drop comprising storing an eye drop containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof in an eye drop container, and further sealing the eye drop container. The method for preserving the eye drops according to claim 22, wherein the eye drops are sealed and packaged together with an oxygen scavenger.

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