KR20140139501A - Aqueous composition containing 2-amino-3-(4-bromobenzoyl)- phenylacetic acid - Google Patents

Abstract

The present invention relates to an aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally a benzalkonium chloride and / or a polyoxyethylene sorbitan fatty acid ester. By limiting the content of the benzalkonium chloride and the polyoxyethylene sorbitan fatty acid ester to a certain range, it is possible to obtain a composition in which the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt is maintained and the appearance is not changed .

Description

(4-bromobenzoyl) phenylacetic acid (AQUEOUS COMPOSITION CONTAINING 2-AMINO-3- (4-BROMOBENZOYL) -PHENYLACETIC ACID}

The present invention relates to an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof and a process for producing the same.

2-Amino-3- (4-bromobenzoyl) phenylacetic acid is a compound represented by the following formula (1):

≪ / RTI > The common name of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is bromfenac, which is known as a non-steroidal anti-inflammatory agent and is used in the ophthalmic area as an eye drop for treating inflammation of the external and anterior parts of the eye.

It is known that 2-amino-3- (4-bromobenzoyl) phenylacetic acid is insufficient in stability in an aqueous solution and generates red insoluble foreign matters during storage. For this reason, Patent Document 1 discloses an eye drop containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid in which a water-soluble polymer (polyvinylpyrrolidone) and a sulfite (such as sodium sulfite) , 2-amino-3- (4-bromobenzoyl) phenylacetic acid has been stabilized.

In Patent Document 2, it has been reported that when a combination of an antibacterial quaternary ammonium compound and boric acid is used in an ophthalmic composition of an acidic drug, a composition with stable storage is provided, and an example of an acidic agent is bromfenac.

Patent Document 3 discloses a process for producing 2-amino-3- (4-bromo-benzoyl) phenylacetic acid by adding an alkylaryl polyether alcohol type polymer or a polyethylene glycol fatty acid ester in an aqueous solution containing 2- Bromobenzoyl) phenylacetic acid can be stabilized.

Patent Document 4 discloses a stable Bromfenac aqueous liquid composition containing a low concentration of benzalkonium chloride and having a preservative effect.

However, in an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt, the content of the benzalkonium chloride and the polyoxyethylene sorbitan fatty acid ester is limited within a certain range, (4-bromobenzoyl) phenylacetic acid or a salt thereof.

On the other hand, it has been pointed out that, in the manufacturing process of eyedrops, there is a fear that iron powder is mixed into the eyedrop being manufactured from the production port.

Patent Document 1: U.S. Patent No. 4910225 Patent Document 2: International Publication No. WO96 / 14829 pamphlet Patent Document 3: U.S. Patent Application Publication No. 2005/0239895 Patent Document 4: International Publication WO2012 / 99142 pamphlet

As described above, in an aqueous composition containing conventional 2-amino-3- (4-bromobenzoyl) phenylacetic acid, no human has ever been able to determine the content of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester In the aqueous solution of 2-amino-3- (4-bromobenzoyl) phenylacetic acid by restricting the concentration of the 2-amino-3-

Disclosure of Invention An object of the present invention is to provide a 2-amino-3- (4-bromobenzoyl) phenylacetic acid which is sufficiently stable even in long-term preservation by improving the stability of 2-amino- Acetic acid. ≪ / RTI > In addition, the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in the aqueous composition is sufficiently maintained even in the presence of iron which may be incorporated from the production port in the manufacturing process.

The present inventors have found that the improvement in stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt in an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt As a result of studies on the risk, it was found that the content A (parts by mass) of the benzalkonium chloride and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester to 100 parts by mass of 2-amino-3- (4- )end,

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

The stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof is improved, and it is found that a high residual ratio is maintained even after storage for a long period of time and a red insoluble foreign matter is not generated Thus, the present invention has been completed.

The aqueous composition of the present invention was also excellent in preservative effect.

That is, the present invention relates to the following.

(1) An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, The content A (parts by mass) of the benzalkonium chloride and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester to 100 parts by mass of 3- (4-bromobenzoyl) phenylacetic acid,

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

&Lt; / RTI &gt;

(2) the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester,

0 < A < 1, 0 &lt; B &lt; 26A + 5

When A = 1, 2? B? 30

1 < A < 3, 5 < B &lt;

3? A? 5, 20 <B? 30

(1). &Lt; / RTI &gt;

(3) the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester,

1 < A < 3 and 5 < B &lt;

(1). &Lt; / RTI &gt;

(4) the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester,

1.2? A? 2.5 and 7? B? 20

(1). &Lt; / RTI &gt;

(5) An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, The concentration X (w / v%) and the concentration Y (w / v%) of the polyoxyethylene sorbitan fatty acid ester,

0? X <0.001, 0? Y <96X + 0.005

When X = 0.001, 0.001 < Y &lt; 0.1

0.001 < X < 0.003, 0.005 < Y &lt; 0.1

When 0.003? X? 0.01, 0.02 < Y? 0.1

&Lt; / RTI &gt;

(6) the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,

0? X <0.001, 0? Y <26X + 0.005

When X = 0.001, 0.002? Y? 0.03

0.001 < X < 0.003, 0.005 < Y &lt; 0.03

0.003? X? 0.005, 0.02 < Y? 0.03

(5). &Lt; / RTI &gt;

(7) the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,

0.001 < X < 0.003 and 0.005 < Y &

(5). &Lt; / RTI &gt;

(8) the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,

0.0012? X? 0.0025 and 0.008? Y? 0.02

(5). &Lt; / RTI &gt;

(9) The aqueous composition according to any one of (1) to (8), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.

(10) The aqueous composition according to any one of (1) to (9) above, wherein the concentration of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in the aqueous composition is 0.01 to 1.0% .

(11) The aqueous composition according to any one of (1) to (10), further containing 0.01 to 3.0% (w / v) of sodium chloride.

(12) The aqueous composition according to any one of (1) to (8) above, wherein the pH of the aqueous composition is more than 7.0 and not more than 9.5.

(13) The aqueous composition as described in any one of (1) to (12) above, wherein the aqueous composition is an injectable solution, a sap, a viscous solution, a viscous liquid or an eye drop.

(14) The aqueous composition according to (13), which is an ophthalmic injection.

(15) The aqueous composition according to (13), which is an eye drop.

(16) A process for producing an aqueous composition as described in any one of (1) to (15) above, which comprises reacting 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof, Wherein the benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester is dissolved in an aqueous solvent.

In each of the structures (1) to (16), two or more can be arbitrarily selected and combined.

The present invention also relates to the following.

(17) A process for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition, , And 0 to 10 parts by mass of a benzalkonium chloride (content A (parts by mass)) and a content B (parts by mass) within the following ranges are added to the aqueous medium .

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

According to the present invention, since 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in the aqueous composition is stabilized over a long period of time, An aqueous composition containing 3- (4-bromobenzoyl) phenylacetic acid or a salt thereof is provided. In addition, the aqueous composition of the present invention maintains sufficient stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt even in the presence of iron which is likely to be incorporated from the production port in the manufacturing process.

Hereinafter, the present invention will be described in detail.

As used herein, "aqueous solvent" means water or a solvent containing water (for example, a mixture of water and a water-soluble solvent such as alcohol). The aqueous solvent is not particularly limited as long as it is water or a solvent containing water, but is preferably purified water.

In a preferred embodiment, the aqueous composition of the present invention is an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, Aqueous solution containing a polyoxyethylene sorbitan fatty acid ester represented by the content B (parts by mass) within a range of 0 to 10 parts by mass of benzalkonium chloride (content A (parts by mass)) and 100 parts by mass of phenylacetic acid .

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

And, in the aqueous composition, 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt is present in a uniformly dissolved form in an aqueous solvent.

In the aqueous composition of the present invention, 2-amino-3- (4-bromobenzoyl) phenylacetic acid can be prepared by reacting 2-amino-3- (4-bromobenzoyl) (In which the carboxyl group forms a carboxylate ion and the amino group forms an ammonium ion), a positive ionic form (in which only the amino group forms an ammonium ion), a salt of a sulfonic acid group, a salt of a (4-bromobenzoyl) phenylacetic acid, May exist in dissolved form, as negative ionic bodies (only carboxyl groups form carboxylate ions).

In the aqueous composition 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 examples of the salt include salts with inorganic acids, , A quaternary ammonium salt, a salt with a halogen ion, a salt with an alkali metal, a salt with an alkaline earth metal, a metal salt, a salt with an organic amine and the like. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptanoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, But are not limited to, ethane di- sulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, Sulfonic acid, sulfosalicylic acid, and the like. Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like. Examples of the salt with a halogen ion include a salt with a chloride ion, a bromide ion, an iodide ion and the like. Examples of the salt with an alkali metal include salts with lithium, sodium and potassium, Include salts with calcium, magnesium and the like, and metal salts include salts with iron and zinc. Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, - (hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like. In the aqueous compositions of the present invention, the preferred salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is the sodium salt.

In the aqueous composition of the present invention, the concentration of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is not particularly limited as long as it is sufficient to exhibit a desired pharmaceutical effect, but 0.01 to 1.0% (w / v) , More preferably 0.03 to 0.5% (w / v), still more preferably 0.05 to 0.2% (w / v) and most preferably 0.08 to 0.1% (w / v). In addition, when these salts are used, salts of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or hydrates thereof, .

In the aqueous composition of the present invention, benzalkonium chloride (hereinafter also referred to, BAK) _{are, [C 6 H 5 CH 2} N (CH 3) 2 R] has the chemical structure represented by Cl, that R is C ₈ H ₁₇ ~C ₁₈ H ₃₇ is a one, or a mixture thereof. Preferably, R is C ₁₂ H ₂₅ the N- benzyl -N, N- dimethyl-lauryl ammonium chloride (hereinafter also referred to, BAK C12), R is C ₁₄ H ₂₉ the N- benzyl -N, N- dimethyl pre (Hereinafter also referred to as BAK C14) or N-benzyl-N-cetyldimethylammonium chloride (hereinafter also referred to as BAK C16) in which R is C ₁₆ H ₃₃ , or a mixture thereof. In the present invention, the preferred benzalkonium chloride is BAK C12.

In the aqueous composition of the present invention, the polyoxyethylene sorbitan fatty acid ester is not particularly limited, and polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40 , Polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan triolate, and polysorbate 80 is preferred.

In the aqueous composition of the present invention, the content of the benzalkonium chloride and the polyoxyethylene sorbitan fatty acid ester is preferably such that the content A of the benzalkonium chloride relative to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid (Parts by mass) and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester,

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

Lt; / RTI &gt;

0 < A < 1, 0 &lt; B &lt; 26A + 5

When A = 1, 2? B? 30

1 < A < 3, 5 < B &lt;

3? A? 5, 20 <B? 30

, And more preferably,

1 < A < 3 and 5 < B &lt;

, More preferably within the range of &lt; RTI ID = 0.0 &gt;

1.2? A? 2.5 and 7? B? 20

Is most preferable.

The upper limit of the content of the benzalkonium chloride in the aqueous composition of the present invention is preferably 10 parts by mass, more preferably 6 parts by mass, and most preferably 5 parts by mass per 100 parts by mass of 2-amino-3- (4-bromobenzoyl) More preferably 4 parts by mass, still more preferably 3 parts by mass, particularly preferably 2.5 parts by mass, most preferably 2 parts by mass. On the other hand, the lower limit of the content is more preferably 0 mass part, more preferably 0.2 mass part, still more preferably 0.5 mass part, still more preferably 0.8 mass part, still more preferably 1 mass part, most preferably 1.2 mass part, The content of the benzalkonium chloride is preferably from 0 to 10 parts by mass, more preferably from 0.2 to 5 parts by mass, still more preferably from 0.5 to 3 parts by mass, particularly preferably from 1 to 2.5% by mass and most preferably from 1.2 to 2 parts by mass The addition is most preferred.

The upper limit of the content of the polyoxyethylene sorbitan fatty acid ester in the aqueous composition of the present invention is preferably 100 parts by mass, more preferably 50 parts by mass, per 100 parts by mass of 2-amino-3- (4-bromobenzoyl) More preferably 40 parts by mass, still more preferably 30 parts by mass, still more preferably 25 parts by mass, most preferably 20 parts by mass. On the other hand, the lower limit of the content is more preferably 0 part by mass, more preferably 2 parts by mass, still more preferably 5 parts by mass, still more preferably 6 parts by mass, most preferably 7 parts by mass and most preferably 9 parts by mass. The content of the polyoxyethylene sorbitan fatty acid ester is preferably 0 to 100 parts by mass, more preferably 0 to 50 parts by mass, still more preferably 2 to 40 parts by mass, still more preferably 5 to 30 parts by mass, Particularly preferably from 7 to 25 parts by mass, and most preferably from 9 to 20 parts by mass.

The concentrations of the benzalkonium chloride and the polyoxyethylene sorbitan fatty acid ester in the aqueous composition of the present invention are such that the concentration X (w / v%) of the benzalkonium chloride and the concentration Y (w / v%) of the polyoxyethylene sorbitan fatty acid ester, end,

0? X <0.001, 0? Y <96X + 0.005

When X = 0.001, 0.001 < Y &lt; 0.1

0.001 < X < 0.003, 0.005 < Y &lt; 0.1

When 0.003? X? 0.01, 0.02 < Y? 0.1

, And more preferably,

0? X <0.001, 0? Y <26X + 0.005

When X = 0.001, 0.002? Y? 0.03

0.001 < X < 0.003, 0.005 < Y &lt; 0.03

0.003? X? 0.005, 0.02 < Y? 0.03

, More preferably within the range of &lt; RTI ID = 0.0 &gt;

0.001 < X < 0.003 and 0.005 < Y &

, More preferably within the range of &lt; RTI ID = 0.0 &gt;

0.0012? X? 0.0025 and 0.008? Y? 0.02

Is most preferable.

The upper limit of the concentration of the benzalkonium chloride in the aqueous composition of the present invention is preferably 0.01% (w / v), more preferably 0.006% (w / v), still more preferably 0.005% (w / Still more preferably 0.004% (w / v), particularly preferably 0.003% (w / v), even more preferably 0.0025% (w / v) and most preferably 0.002% (w / v). The lower limit of the concentration is preferably 0% (w / v), more preferably 0.0002% (w / v), still more preferably 0.0005% (w / v) , Still more preferably 0.001% (w / v) and most preferably 0.0012% (w / v). The concentration is preferably 0 to 0.01% (w / v), more preferably 0.0002 to 0.005% (w / v), still more preferably 0.0005 to 0.003% (w / v) % (w / v) is particularly preferred, and 0.0012 to 0.002% (w / v) is most preferred.

The upper limit of the concentration of the polyoxyethylene sorbitan fatty acid ester in the aqueous composition of the present invention is preferably 0.1% (w / v), more preferably 0.05% (w / v), still more preferably 0.04% (w / v) , Even more preferably 0.03% (w / v), most preferably 0.025% (w / v) and most preferably 0.02% (w / v) The lower limit of the concentration is preferably 0% (w / v), more preferably 0.002% (w / v), still more preferably 0.005% (w / v) , Still more preferably 0.009% (w / v), and most preferably 0.01% (w / v). The concentration is preferably 0 to 0.1% (w / v), more preferably 0 to 0.05% (w / v), still more preferably 0.002 to 0.04% (w / v) % w / v, even more preferably 0.008 to 0.025% w / v, and most preferably 0.01 to 0.02% w / v.

As an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt, an aqueous composition containing neither a benzalkonium chloride nor a polyoxyethylene sorbitan fatty acid ester is also within the scope of the present invention .

The aqueous composition of the present invention may further contain additives such as buffering agents, isotonizing agents, pH adjusting agents, stabilizers, preservatives, solubilizing agents and thickening agents, if necessary.

The aqueous composition of the present invention can be compounded with a buffer that can be used as an additive for pharmaceuticals. Examples of the buffering agent include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof,? -Aminocaproic acid or trometamol. Examples of the phosphate include sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate and the like. Examples of the borate include borax, sodium borate and potassium borate, Examples of the citric acid salt include sodium citrate and disodium citrate. Examples of the acetic acid salt include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate, sodium hydrogencarbonate and the like. Include sodium tartrate and potassium tartrate. 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 buffer in the aqueous composition of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and / or the ratio of the osmotic pressure. The total amount thereof is preferably 0.01 to 15% (w / v) More preferably 0.1 to 5% (w / v), even more preferably 0.25 to 4% (w / v), still more preferably 0.5 to 3% (w / v) Is most preferable.

To the aqueous composition of the present invention, an isotonic agent which can be used as an additive of a pharmaceutical can be appropriately compounded. Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents. Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like. Nonionic isotonic agents include glycerin, propylene glycol, sorbitol, mannitol and the like. A preferred isotonizing agent is sodium chloride, and a composition which maintains the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof and has no change in appearance can be obtained.

The aqueous composition of the present invention may contain a proper amount of a pH adjuster which can be used as an additive for pharmaceuticals. Examples of the pH adjuster 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, a preferable pH adjusting agent is hydrochloric acid or sodium hydroxide.

The pH of the aqueous composition of the present invention is preferably 7.0 to 9.5, more preferably 7.5 to 9.0, further preferably 8.0 to 8.6, most preferably 8.2 to 8.4.

The aqueous composition of the present invention can suitably contain a stabilizer usable as an additive for pharmaceuticals. Examples of the stabilizer include edetic acid, sodium edetate, sulfite, water-soluble polymer, and the like. Examples of the sulfite include sodium sulfite, potassium sulfite, magnesium sulfite and calcium sulfite. Examples of the water-soluble polymer include polyvinylpyrrolidone, polyvinyl alcohol, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium polyacrylate, and the like.

The concentration of the total stabilizer in the aqueous composition of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and / or the osmotic pressure ratio.

The water-based composition of the present invention can appropriately contain a preservative that can be used as an additive for pharmaceuticals. Examples of the preservative include benzethonium chloride, sorbic acid, potassium sorbate, methyl peroxybenzoate, propyl peroxybenzoate, and chlorobutanol.

The concentration of the preservative in the aqueous composition of the present invention can be appropriately adjusted in consideration of the effect on the drug, other additives and / or the osmotic pressure ratio, and the total amount thereof is preferably 0.00005 to 0.01% (w / v) More preferably 0.0002 to 0.004% (w / v), still more preferably 0.0005 to 0.003% (w / v), still more preferably 0.001 to 0.002% (w / v) Is most preferable.

The formulation of the aqueous composition of the present invention is not particularly limited as long as it can be used as a medicine. Examples of the formulations include injections, liquids, dots, eye drops, eye drops, and the like. Preferably, ophthalmic injections and eyedrops can be mentioned, and particularly preferable eye drops can be mentioned.

The aqueous composition of the present invention can be prepared by dissolving 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof and a benzalkonium chloride and a polyoxyethylene sorbitan fatty acid ester in an aqueous solvent have.

In the preparation of the aqueous composition of the present invention, besides 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, hydrates thereof can be used. Specific examples of such hydrates include sodium 2-amino-3- (4-bromobenzoyl) phenylacetic acid, monohydrate of 2-amino-3- (4-bromobenzoyl) phenylacetate, Sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 3/2 hydrate and the like, and 2-amino-3- (4-bromobenzoyl) phenylacetic acid sodium 3/2 .

As the aqueous solvent, the solvent described above may be used.

Accordingly, the present invention provides an aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, The content A (parts by mass) of the benzalkonium chloride and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester with respect to 100 parts by mass of the amino-3- (4-bromobenzoyl)

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

(2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof and optionally a benzalkonium chloride and / or a polyoxyethylene sorbitan fatty acid ester In an aqueous solvent.

The present invention also relates to a process for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition, (Content A (parts by mass)) of 0 to 10 parts by mass with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in the aqueous composition containing (Parts by mass) of the polyoxyethylene sorbitan fatty acid ester in the aqueous medium.

0? A < 1, 0? B < 96A + 5

When A = 1, 1 < B &amp;le; 100

1 < A < 3, 5 < B &lt;

3? A? 10, 20 <B? 100

Test results and formulation examples are shown below, but they are for better understanding of the present invention and are not intended to limit the scope of the present invention.

1. Stability evaluation test (1)

The stability of the aqueous composition of the present invention was examined.

1-1. Preparation of formulation

Example 1

0.1 g of sodium 2-amino-3- (4-bromobenzoyl) phenylacetic acid / 3/2 hydrate (hereinafter referred to as present compound), 1.25 g of boric acid, 1.0 g of borax, 0.02 g of sodium edetate g, 0.005 g of polysorbate 80 and 0.001 g of benzalkonium chloride were added and sufficiently stirred. 1 N aqueous sodium hydroxide solution and dilute hydrochloric acid (10%) were added to adjust the pH to about 8.3, and then an appropriate amount of purified water was added to make the total amount 100 mL.

The preparation of Comparative Example 1 shown in Table 1 was prepared in the same manner as in the preparation method of Example 1.

1-2. Test Methods

The content of 2-amino-3- (4-bromobenzoyl) phenylacetic acid when stored at 25 ° C and 40 ° C for 6 months was quantified using high performance liquid chromatography (HPLC) (%) Was calculated. In addition, the change in appearance was visually observed.

1-3. Test Results and Considerations

The test results are shown in Table 1.

PE: polyethylene, PP: polypropylene

- indicates that there is no change in appearance.

As is apparent from Table 1, the formulation of Example 1 maintained a high residual ratio for 6 months at 25 占 폚 and 40 占 폚 as compared with the formulation of Comparative Example 1, and maintained a clear, yellow, . From the above, it was confirmed that the formulation of Example 1 as the aqueous composition of the present invention had excellent stability.

2. Stability evaluation test (2)

The stability of the aqueous composition of the present invention when the content of benzalkonium chloride or polyoxyethylene sorbitan fatty acid ester was changed was examined.

2-1. Preparation of formulation

Preparations of Examples 2 to 15 and Comparative Examples 2 to 8 shown in Tables 2 to 4 were prepared in the same manner as in the preparation method of Example 1.

2-2. Test Methods

The content of 2-amino-3- (4-bromobenzoyl) phenylacetic acid when stored at 40 ° C for 6 months or 60 ° C for 1 month was quantified using high performance liquid chromatography , And the residual ratio (%) was calculated. In addition, the change in appearance was visually observed.

2-3. Test Results and Considerations

The test results are shown in Tables 2 to 4.

- indicates that there is no change in appearance.

- indicates that there is no change in appearance.

- indicates that there is no change in appearance.

+ Indicates a change in appearance.

As is evident from Tables 2 to 4, the preparations of Examples 2 to 15 maintained a high residual ratio at 6 占 폚 at 40 占 폚 or 1 month at 60 占 폚, and maintained the clearness, yellow color, and no precipitation. From the above, it was confirmed that the formulations of Examples 2 to 15 which are the aqueous compositions of the present invention had excellent stability.

3. Stability evaluation test (3)

The stability of the aqueous composition of the present invention when the pH was changed was examined.

3-1. Preparation of formulation

The preparations of Examples 16 to 19 shown in Table 5 were prepared in the same manner as in the preparation method of Example 1.

3-2. Test Methods

The change in appearance when the formulation was stored at 60 占 폚 for one month was visually observed.

3-3. Test Results and Considerations

The test results are shown in Table 5.

- indicates that there is no change in appearance.

As is evident from Table 5, the formulations of Examples 16 to 19 retained the texture, yellow color, and no precipitation at 60 DEG C for 1 month. From the above, it was confirmed that the formulations of Examples 16 to 19, which are the aqueous compositions of the present invention, have excellent stability.

4. Stability evaluation test (4)

The stability of the aqueous composition of the present invention in the presence of iron was studied.

4-1. Preparation of formulation

The preparations of Examples 20 to 23 and Comparative Example 9 shown in Table 6 were prepared in the same manner as in the preparation method of Example 1.

4-2. Test Methods

After preparation of the test preparation, 5 μg of each of the iron (III) chloride was added. The content of 2-amino-3- (4-bromobenzoyl) phenylacetic acid when stored at 60 占 폚 for 2 weeks was quantified by high performance liquid chromatography (HPLC), and the residual ratio (% And the moisture evaporation from the container was corrected and calculated. In addition, the change in appearance was visually observed.

4-3. Test Results and Considerations

The test results are shown in Table 6.

- indicates that there is no change in appearance.

As clearly shown in Table 6, the formulations of Examples 20 to 23 were stable for 2 weeks at 60 占 폚 as compared with the formulation of Comparative Example 9, and maintained the clearness, yellow color, and no precipitation. From the above, it was confirmed that the preparations of Examples 20 to 23 which are the aqueous compositions of the present invention had excellent stability even in the presence of iron powder.

5. Example of preparation

Representative pharmaceutical preparations using the present compounds are shown below. In the following formulation examples, the blending amount of each component is the content in 100 mL.

Formulation Example 1

0.1 g of the present compound

Polysorbate 80 0.005 g

Boric acid 1.25 g

Borax 1.0 g

0.02 g of sodium edetate

Benzalkonium chloride 0.001 g

Hydrochloric acid q.s.

Sodium hydroxide qs

Purified water quantity

pH 8.3

Formulation Example 2

0.1 g of the present compound

Polysorbate 80 0.03 g

Boric acid 1.25 g

Borax 1.0 g

0.02 g of sodium edetate

Benzalkonium chloride 0.01 g

Hydrochloric acid q.s.

Sodium hydroxide qs

Purified water quantity

pH 8.3

Formulation Example 3

0.01 g of the present compound

Polysorbate 80 0.005 g

0.05 g of sodium edetate

Benzalkonium chloride 0.001 g

Hydrochloric acid q.s.

Sodium hydroxide qs

Purified water quantity

pH 8.3

In addition, the blending amounts and blending ratios of the respective components in Formulation Examples 1 to 3, that is, the present compound, polysorbate 80, benzalkonium chloride and other additives can be appropriately adjusted.

Claims (16)

An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, The content A (parts by mass) of the benzalkonium chloride and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester with respect to 100 parts by mass of the phenoxyacetic acid (4-bromobenzoyl)
0? A < 1, 0? B < 96A + 5
When A = 1, 1 < B &amp;le; 100
1 < A < 3, 5 < B &lt;
3? A? 10, 20 <B? 100
&Lt; / RTI &gt; The method of claim 1, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester
0 < A < 1, 0 < B < 26A + 5
When A = 1, 2? B? 30
1 < A < 3, 5 &lt; B &lt;
3? A? 5, 20 <B? 30
&Lt; / RTI &gt; The method of claim 1, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester
1 < A < 3 and 5 < B &lt;
&Lt; / RTI &gt; The method of claim 1, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester
1.2? A? 2.5 and 7? B? 20
&Lt; / RTI &gt; An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, wherein the concentration X of the benzalkonium chloride w / v%) and the concentration Y (w / v%) of polyoxyethylene sorbitan fatty acid ester,
0? X <0.001, 0? Y <96X + 0.005
When X = 0.001, 0.001 < Y < 0.1
0.001 < X < 0.003, 0.005 < Y &lt; 0.1
When 0.003? X? 0.01, 0.02 &lt; Y? 0.1
&Lt; / RTI &gt; 6. The method according to claim 5, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,
0? X <0.001, 0? Y <26X + 0.005
When X = 0.001, 0.002? Y? 0.03
0.001 < X < 0.003, 0.005 < Y < 0.03
0.003? X? 0.005, 0.02 &lt; Y? 0.03
&Lt; / RTI &gt; 6. The method according to claim 5, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,
0.001 < X < 0.003 and 0.005 < Y &
&Lt; / RTI &gt; 6. The method according to claim 5, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester,
0.0012? X? 0.0025 and 0.008? Y? 0.02
&Lt; / RTI &gt; 9. The aqueous composition according to any one of claims 1 to 8, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80. 10. The aqueous composition according to any one of claims 1 to 9, wherein the concentration of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in the aqueous composition is 0.01 to 1.0% (w / v). 11. The aqueous composition according to any one of claims 1 to 10, further comprising 0.01 to 3.0% (w / v) sodium chloride. 12. The aqueous composition according to any one of claims 1 to 11, wherein the pH of the aqueous composition is greater than 7.0 and not greater than 9.5. 13. The aqueous composition according to any one of claims 1 to 12, wherein the aqueous composition is an injection, a sap, a dentifrice, a dentifrice or an eye drop. The aqueous composition according to claim 13, which is an ophthalmic injection. 14. The aqueous composition of claim 13, wherein the composition is an eye drop. 16. A process for the preparation of the aqueous composition as claimed in any one of claims 1 to 15, which comprises reacting 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof, and optionally benzalkonium chloride And / or the polyoxyethylene sorbitan fatty acid ester is dissolved in an aqueous solvent.