TW201343197A - Aqueous composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid - Google Patents

Abstract

The present invention is about an aqueous composition which contains 2-amino-3-(4-bromobenzoyl)phenylacetic acid or its salt, and benzalkonium chloride and/or polyoxyethylene sorbitan fatty acid ester depending on the situation. The stability of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid or its salt may be maintained, and a composition with no change in appearance may be obtained by limiting the content of the benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester in a definite range.

Description

Aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetic acid

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

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

The general name for 2-amino-3-(4-bromobenridinyl)phenylacetic acid is Bromfenac, a non-steroidal anti-inflammatory agent used in ophthalmology as an eye drop. Inflammation treatment of the external eye and anterior eye.

It is known that 2-amino-3-(4-bromobenzylidene)phenylacetic acid lacks stability in an aqueous solution and produces red insoluble impurities during storage. Therefore, in Patent Document 1, a water-soluble polymer (polyvinylpyrrolidone, etc.) and a sub-group are blended in an eye drop containing 2-amino-3-(4-bromobenzylidene)phenylacetate. Sulfate (sodium sulfite, etc.) to stabilize 2-amino-3-(4-bromobenzylidene)phenylacetic acid.

In Patent Document 2, if an antibacterial polymer quaternary ammonium compound and boric acid are used in combination in an ophthalmic composition for an acidic agent, A report for the storage of stable compositions, and examples of bromfenac as an acidic agent.

In Patent Document 3, an alkyl aryl polyether alcohol type polymer or polyethylene is added by an aqueous liquid preparation containing 2-amino-3-(4-bromobenzylidene)phenylacetate. The alcohol fatty acid ester can be reported as a stabilization of 2-amino-3-(4-bromobenzylidene)phenylacetic acid.

Patent Document 4 discloses a bromfenac aqueous liquid composition containing a low concentration of benzalkonium chloride, which has a preservative effect and is stable.

However, there is no use of benzylammonium chloride and polyoxyethylene sorbitan in an aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetate or a salt thereof. The content of the fatty acid ester is limited to a certain range to investigate the stabilization of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof.

On the other hand, in the manufacturing process of the eye drop agent, there has been an indication that the iron component from the manufacturing kettle is mixed into the eyedrops produced.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] US Patent No. 4910225

[Patent Document 2] International Publication WO96/14829

[Patent Document 3] US Patent Application Publication No. 2005/0239895

[Patent Document 4] International Publication WO2012/99142 Booklet

As described above, in the aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetate, no one has hitherto been able to use benzalkonium chloride and polyoxyethylene. The content of the sorbitan fatty acid ester is limited to a certain range to achieve stabilization of 2-amino-3-(4-bromobenzylidene)phenylacetic acid in an aqueous solution.

An object of the present invention is to provide a 2-amine-containing compound which is sufficiently stable under long-term storage by enhancing the stability of 2-amino-3-(4-bromobenzylidene)phenylacetic acid in an aqueous composition. An aqueous composition of benzyl-3-(4-bromobenzylidene)phenylacetic acid. In addition, it is also in the production step that the 2-amino-3-(4-bromobenzylidene)phenyl group in the aqueous composition can be sufficiently maintained even in the presence of iron which may be mixed in the production tank. The stability of acetic acid.

The present inventors have improved 2-amino-3-(4-bromobenzylidene) in an aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetate or a salt thereof. As a result of intensive studies on the stability of phenylacetic acid or a salt thereof, it was found that benzylammonium chloride was oxidized with respect to 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid. When the content A (parts by mass) and the polyoxyethylene sorbitan fatty acid ester content B (parts by mass) are at 0≦A<1, 0≦B<96A+5 A=1, 1<B≦100 1< When A<3, 5<B≦100 3≦A≦10, when 20<B≦100, 2-amino-3-(4-bromobenzylidene)phenylacetic acid or its salt The stability is improved and the high residual rate can be maintained under long-term storage. The present invention is completed without generating red insoluble impurities.

The aqueous composition of the present invention is also excellent in antiseptic effect.

That is, the present invention relates to the following:

(1) An aqueous composition comprising 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, and optionally, benzalkonium chloride and/or polyoxyethylene An aqueous composition of sorbitan fatty acid ester, wherein A content (parts by mass) of benzalkonium chloride is relative to 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid When the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester is 0≦A<1, when 0≦B<96A+5 A=1, when 1<B≦100 1<A<3, 5<B≦100 3≦A≦10, 20<B≦100.

(2) The aqueous composition according to the above (1), wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester are 0≦A<1, 0≦B<26A +5 A=1, 2≦B≦30 1<A<3, 5<B≦30 3≦A≦5, 20<B≦30.

(3) The aqueous composition according to (1) above, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester are 1<A<3, and 5<B≦30 Within the scope.

(4) The aqueous composition according to (1) above, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester are 1.2 ≦A ≦ 2.5, and 7 ≦ B ≦ 20 Within the scope.

(5) An aqueous composition comprising 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, and optionally, benzalkonium chloride and/or polyoxyethylene An aqueous composition of sorbitan fatty acid ester wherein the concentration of benzalkonium chloride X (w/v%) and the concentration of polyoxyethylene sorbitan fatty acid ester Y (w/v%) are at 0≦X When <0.001, 0≦Y<96X+0.005 X=0.001, when 0.001<Y≦0.1 0.001<X<0.003, 0.005<Y≦0.1 0.003≦X≦0.01, and 0.02<Y≦0.1.

(6) The aqueous composition according to the above (5), wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester are at 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<Y≦0.03.

(7) The aqueous composition according to (5) above, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester are in the range of 0.001 < X < 0.003 and 0.005 < Y ≦ 0.03 Within the scope.

(8) The aqueous composition according to (5) above, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester are in the range of 0.0012 ≦ X ≦ 0.0025 and 0.008 ≦ Y ≦ 0.02 Within the scope.

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

(10) The aqueous composition according to any one of the above (1) to (8) wherein the concentration of 2-amino-3-(4-bromobenzylidene)phenylacetic acid in the aqueous composition is It is 0.01~1.0% (w/v).

(11) The aqueous composition according to any one of (1) to (8) above which further contains 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 aqueous composition has a pH of more than 7.0 and 9.5 or less.

The aqueous composition according to any one of the above (1) to (8) wherein the aqueous composition is an injection, an infusion, a nasal spray, an ear lotion or an eye drop.

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

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

(16) A method for producing an aqueous composition according to any one of the above (1) to (8), which is characterized in that 2-amino-3-(4-bromobenzhydrazide) Phenylacetic acid or a salt thereof or a hydrate thereof, and optionally a benzalkonium chloride and/or a polyoxyethylene sorbitan fatty acid ester are dissolved in an aqueous solvent.

Further, each of the configurations (1) to (16) above may be arbitrarily selected from two or more types. combination.

The invention is further related to the following.

There is also a method of (17) which is a method for stabilizing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof in an aqueous composition, wherein 100 parts by mass is relative to 100 parts by mass 2-amino-3-(4-bromobenzylidene)phenylacetic acid, 0 to 10 parts by mass of benzalkonium chloride (content A (parts by mass)), and content B in the following range ( The polyoxyethylene sorbitan fatty acid ester shown in parts by mass is added to the aforementioned aqueous medium; when 0≦A<1, 0≦B<96A+5 A=1, 1<B≦100 1<A<3 When 5<B≦100 3≦A≦10, 20<B≦100.

According to the present invention, since 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof in the aqueous composition can be stabilized for a long period of time, it is possible to provide, for example, stable storage at room temperature for 2 years. The above aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof. Further, in the production step, the aqueous composition of the present invention can maintain 2-amino-3-(4-bromobenzylidene)phenylacetic acid or its active ingredient even in the presence of iron which may be mixed in the production tank. The full stability of the salt.

[Formation of the Invention]

Hereinafter, the present invention will be described in detail.

In the present specification, the "aqueous solvent" means water or a solvent containing water (for example, a mixture of a water-soluble solvent such as an alcohol and water). The aqueous solvent is not particularly limited as long as it is water or a solvent containing water, and is preferably distilled water.

In a preferred embodiment, the aqueous composition of the present invention is an aqueous composition which is an aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, wherein 0 to 10 parts by mass of benzalkonium chloride (content A (parts by mass)), and the following range, with respect to 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid a polyoxyethylene sorbitan fatty acid ester having a content B (parts by mass); when 0 ≦ A < 1, 0 ≦ B < 96A + 5 A = 1, 1 < B ≦ 100 1 < A < 3 When 5<B≦100 3≦A≦10, 20<B≦100.

Further, in the aqueous composition, 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof is present in a form of being uniformly dissolved in an aqueous solvent.

In the aqueous composition of the present invention, 2-amino-3-(4-bromobenzylidene)phenylacetic acid can be undissociated 2-amino-3-(4-bromobenzylidene)benzene. Acetate itself, a salt of 2-amino-3-(4-bromobenzylidene)phenylacetate, a zwitterion (carboxy group forms a carboxylate ion, and an amine group forms an ammonium ion), a cation (amino group only) A form in which an ammonium ion is formed and an anion (only a carboxyl group forms a carboxylate ion) exists in a dissolved form.

In the aqueous composition of the present invention, the salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples of the salt include formation with a mineral acid. Salt, formed with organic acids a salt, a quaternary ammonium salt, a salt formed with a halogen ion, a salt formed with an alkali metal, a salt formed with an alkaline earth metal, a metal salt, a salt formed with an organic amine, or the like. The salt formed with the inorganic acid may, for example, be a salt formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like. Examples of the salt formed with an organic acid include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, dextrose heptanoic acid, glucuronic acid, and p-benzoic acid. Formic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactanoic acid, oleic acid, pamoic acid, polygalacturonic acid a salt formed of stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfinic acid or the like. The quaternary ammonium salt may, for example, be a salt formed with methyl bromide, methyl iodide or the like. Examples of the salt formed with a halogen ion include a salt formed with a chloride ion, a bromide ion, an iodide ion, and the like. Examples of the salt formed with the alkali metal include a salt formed of lithium, sodium, potassium, or the like. The salt formed of the alkaline earth metal may be a salt formed with calcium, magnesium, or the like. Examples of the metal salt include salts formed of iron, zinc, and the like. Examples of the salt formed with the organic amine include triethylenediamine, 2-aminoethanol, 2,2-imidobis(ethanol), and 1-deoxy-1-(methylamino)-2-D. -sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(phenylmethyl)-1,2-ethanediamine The salt formed. In the aqueous composition of the present invention, a preferred salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid is a sodium salt.

In the aqueous composition of the present invention, the concentration of 2-amino-3-(4-bromobenzylidene)phenylacetic acid is not particularly limited as long as it is a sufficient amount to exert a desired pharmacological effect. Good for 0.01~1.0% (w/v), better It is 0.03~0.5% (w/v), preferably 0.05~0.2% (w/v), and most preferably 0.08~0.1% (w/v). Further, when such a concentration is used as a salt of 2-amino-3-(4-bromobenzylidene)phenylacetate or a hydrate thereof, it is converted into 2-amino-3-(4). The mass of -bromobenzhydryl)phenylacetic acid was calculated.

In the aqueous composition of the present invention, benzalkonium chloride (hereinafter also referred to as "BAK") has a chemical structure represented by [C ₆ H ₅ CH ₂ N(CH ₃ ) ₂ R]Cl, and R is a C ₈ H ₁₇ ~ C ₁₈ H ₃₇ or a mixture thereof. Preferably, N is a C ₁₂ H ₂₅ N-benzyl-N,N-dimethyldodecylammonium chloride (hereinafter also referred to as "BAK C12"), and R is a C ₁₄ H ₂₉ N- Benzyl-N,N-dimethyltetradecylammonium chloride (hereinafter also referred to as "BAK C14") or R is C ₁₆ H ₃₃ N-benzyl-N-hexadecyldimethylammonium Chloride (hereinafter also referred to as "BAK C16") or a mixture of such. In the present invention, 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 examples of the polyoxyethylene sorbitan fatty acid ester include Polysorbate 80, Polysorbate 65, Polysorbate 60, Polysorbate 40, and polyoxyethylene dehydration. Sorbitol laurate, polyoxyethylene sorbitan trioleate, etc., preferably Polysorbate 80.

In the aqueous composition of the present invention, with respect to the content of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester, relative to 100 parts by mass of 2-amino-3-(4-bromobenzhydrazide) The content of phenylacetic acid, benzalkonium chloride A (parts by mass) and the content of polyoxyethylene sorbitan fatty acid ester B (parts by mass) are 0≦A<1, 0≦B<96A+ 5 When A=1, 1<B≦100 1<A<3, 5<B≦100 3≦A≦10, 20<B≦100, preferably 0≦A<1, 0 ≦B<26A+5 A=1, 2≦B≦30 1<A<3, 5<B≦30 3≦A≦5, 20<B≦30, more preferably In the case of 1<A<3, and 5<B≦30, it is preferable to be in the range of 1.2≦A≦2.5, and 7≦B≦20.

The upper limit of the content of benzalkonium chloride in the aqueous composition of the present invention is preferably 10% by mass based on 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid. The portion is more preferably 6 parts by mass, more preferably 5 parts by mass, still more preferably 4 parts by mass, particularly preferably 3 parts by mass, more preferably 2.5 parts by mass, most preferably 2 parts by mass. On the other hand, the lower limit of the content is preferably 0 parts by mass, more preferably 0.2 parts by mass, still more preferably 0.5 parts by mass, still more preferably 0.8 parts by mass, particularly preferably 1 part by mass, most preferably 1.2 parts by mass. The content of the benzalkonium chloride is preferably 0 to 10 parts by mass, more preferably 0.2 to 5 parts by mass, still more preferably 0.5 to 3 parts by mass, particularly preferably 1 to 2.5% by mass, most preferably 1.2~2 parts by mass.

The upper limit of the content of the polyoxyethylene sorbitan fatty acid ester in the aqueous composition of the present invention, relative to 100 parts by mass of the 2-amino group -3-(4-bromobenzylidene)phenylacetic acid, preferably 100 parts by mass, more preferably 50 parts by mass, still more preferably 40 parts by mass, still more preferably 30 parts by mass, particularly preferably 25 parts by mass The portion is preferably 20 parts by mass. On the other hand, the lower limit of the content is preferably 0 parts by mass, more preferably 2 parts by mass, still more preferably 5 parts by mass, still more preferably 6 parts by mass, particularly preferably 7 parts by mass, 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. It is preferably 7 to 25 parts by mass, and most preferably 9 to 20 parts by mass.

For the concentration of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester in the aqueous composition of the present invention, the concentration of benzalkonium chloride X (w/v%) and polyoxyethylene sorbitan The concentration Y (w/v%) of the fatty acid ester is preferably 0≦X<0.001, 0≦Y<96X+0.005 X=0.001, 0.001<Y≦0.1 0.001<X<0.003, 0.005<Y ≦0.1 0.003≦X≦0.01, in the range of 0.02<Y≦0.1, more preferably 0≦X<0.001, 0≦Y<26X+0.005 X=0.001, 0.002≦Y≦0.03 0.001< When X<0.003, 0.005<Y≦0.03 0.003≦X≦0.005, and in the range of 0.02<Y≦0.03, it is preferably in the range of 0.001<X<0.003 and 0.005<Y≦0.03. The best is at 0.0012≦X≦0.0025, and 0.008 ≦Y≦0.02 The situation within the scope.

The upper limit of the concentration of 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/v), More preferably, it is 0.004% (w/v), particularly preferably 0.003% (w/v), more preferably 0.025% (w/v), and most preferably 0.002% (w/v). On the other hand, 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 0.0008% (w/v). ), particularly preferably 0.001% (w/v), most preferably 0.0012% (w/v). The concentration range is preferably 0 to 0.01% (w/v), more preferably 0.0002 to 0.005% (w/v), more preferably 0.0005 to 0.003% (w/v), and particularly preferably 0.001 to 0.0025%. (w/v), the best is 0.0012~0.002% (w/v).

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). More preferably, it is 0.03% (w/v), particularly preferably 0.025% (w/v), and most preferably 0.02% (w/v). On the other hand, 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. () 08% (w/v), particularly preferably 0.009% (w/v), and most preferably 0.01% (w/v). The concentration range is preferably 0 to 0.1% (w/v), more preferably 0 to 0.05% (w/v), more preferably 0.002 to 0.04% (w/v), and even more preferably 0.005 to 0.03. %(w/v), particularly preferably 0.008 to 0.025% (w/v), and most preferably 0.01 to 0.02% (w/v).

Is an aqueous composition containing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, and does not contain any of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester. Aqueous compositions of the present invention are also included in the scope of the present invention.

In the aqueous composition of the present invention, additives such as a buffering agent, a tonicity agent, a pH adjuster, a stabilizer, a preservative, a solubilizing agent, and a tackifier may be added as needed.

The aqueous composition of the present invention can be blended with a buffer which 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, ε-aminohexanoic acid, and tromethamine (Trometamol) and so on. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of the borate include borax, sodium borate, potassium borate, and the like. Examples of the acid salt include sodium citrate and disodium citrate. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium hydrogencarbonate. Examples of the tartrate include tartaric acid. Sodium, potassium tartrate, etc. In the present invention, a preferred buffering agent is boric acid or a salt thereof such as 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 influence on the drug, other additives, and/or osmotic pressure ratio, and is preferably 0.01 to 15% (w/v) in terms of the total amount thereof. More preferably, it is 0.05~10% (w/v), preferably 0.1~5% (w/v), especially preferably 0.25~4% (w/v), and most preferably 0.5~3% (w/ v).

An isotonizing agent which can be used as an additive for pharmaceuticals can be appropriately blended in the aqueous composition of the present invention. Examples of the isotonizing agent include an ionic isotropic agent, a nonionic isotropic agent, and the like. Examples of the ionic isotropic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Examples of the nonionic isomerizing agent include glycerin and propylene glycol. Sorbitol, mannitol, and the like. A preferred isotonic agent is sodium chloride, and a composition which retains stability of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof without change in appearance can be obtained.

The aqueous composition of the present invention can be appropriately blended with 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 hydrogencarbonate, and the like. In the present invention, preferred pH adjusting agents are hydrochloric acid and sodium hydroxide.

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

A stabilizer which can be used as an additive to a pharmaceutical product can be appropriately blended in the aqueous composition of the present invention. Examples of the stabilizer include ethylenediaminetetraacetic acid (EDTA), sodium ethylenediaminetetraacetate, sulfite, and a water-soluble polymer. Examples of the sulfite include sodium sulfite, potassium sulfite, magnesium sulfite, and calcium sulfite. Examples of the water-soluble polymer include polyvinylpyrrolidone, polyvinyl alcohol, carboxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sodium polyacrylate.

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

The aqueous composition of the present invention can be suitably blended with a preservative which can be used as an additive for pharmaceuticals. Examples of the preservative include positive soap (benzethonium chloride), sorbic acid, potassium sorbate, methyl paraben, propyl paraben, chlorobutanol and the like.

The concentration of the preservative in the aqueous composition of the present invention can be tested The amount of the drug is appropriately adjusted for the influence of the drug, other additives, and/or the osmotic pressure ratio, and is preferably 0.00005 to 0.01% (w/v), more preferably 0.0001 to 0.005% (w/v). Preferably, it is 0.0002~0.004% (w/v), especially preferably 0.0005~0.003% (w/v), and most preferably 0.001~0.002% (w/v).

The dosage form of the aqueous composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical user. Examples of the dosage form include an injection, an infusion, a nasal spray, an ear lotion, an eye drop, and the like. An ophthalmic injection or an eye drop is preferred, and an eye drop is particularly preferred.

The aqueous composition of the present invention can be obtained by dispersing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof or a hydrate thereof with benzalkonium chloride and polyoxyethylene dehydrated pear The alcohol fatty acid ester is dissolved in an aqueous solvent to produce.

When the aqueous composition of the present invention is prepared, a hydrate thereof may be used in addition to 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof. Specific examples of the hydrate include sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. 1/2 hydrate, sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. 1 hydrate, sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. As the 3/2 hydrate or the like, sodium 2-amino-3-(4-bromobenzylidene)phenylacetate is preferred. 3/2 hydrate.

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

Accordingly, the present invention also relates to a process for the preparation of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, and optionally a benzalkonium chloride and/or An aqueous composition of a polyoxyethylene sorbitan fatty acid ester, that is, a content A of benzylammonium chloride relative to 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid ( Parts by mass) with polyoxyethylene When the content B (parts by mass) of sorbitan fatty acid ester is 0≦A<1, when 0≦B<96A+5 A=1, when 1<B≦100 1<A<3, 5<B≦100 3≦A≦10, a method for producing an aqueous composition in the range of 20<B≦100, characterized in that 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof or The hydrates thereof, and optionally the benzalkonium chloride and/or the polyoxyethylene sorbitan fatty acid ester, are dissolved in an aqueous solvent.

The present invention still further relates to a process for stabilizing 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof in an aqueous composition, wherein a 2-amine is contained An aqueous composition of -3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, based on 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid 0 to 10 parts by mass of benzalkonium chloride (content A (part by mass)), and polyoxyethylene sorbitan fatty acid ester represented by the content B (parts by mass) in the following range are added to the aforementioned aqueous medium. When 0≦A<1, 0≦B<96A+5 A=1, 1<B≦100 1<A<3, when 5<B≦100 3≦A≦10, 20<B≦100.

The test results and the formulation examples are shown below, but are provided to provide a clearer understanding of the invention and are not intended to limit the scope of the invention.

1. Stability assessment test (1)

The stability of the aqueous composition of the present invention is discussed.

1-1. Preparation of test preparation

Example 1

0.1 g of sodium 2-amino-3-(4-bromobenzylidene)phenylacetate was added to 90 mL of distilled water. 3/2 hydrate (hereinafter also referred to as "the present compound"), 1.25 g of boric acid, 1.0 g of borax, 0.02 g of sodium ethylenediaminetetraacetate hydrate, 0.005 g of Polysorbate 80, and 0.001 g of benzyl chloride Alkanlamide, stir well. After adding a 1 N aqueous sodium hydroxide solution and dilute hydrochloric acid (10%) to bring the pH to around 8.3, an appropriate amount of distilled 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 method

The content of 2-amino-3-(4-bromobenzylidene)phenylacetic acid was determined by high performance liquid chromatography (HPLC) after storage at 25 ° C and 40 ° C for 6 months. Its residual rate (%). Further, the change in appearance was visually observed.

1-3. Test results and investigation

The test results are shown in Table 1.

It can be understood from Table 1 that the preparation of Example 1 is compared with Comparative Example 1 The preparation can maintain a high residual rate at 25 ° C and 40 ° C for 6 months, maintaining a clear, yellow, and no precipitation state. From the above, it was confirmed that the preparation of Example 1 which is an aqueous composition of the present invention has excellent stability.

2. Stability assessment test (2)

The stability of the aqueous composition of the present invention when changing the content of benzalkonium chloride or polyoxyethylene sorbitan fatty acid ester is discussed.

2-1. Modulation of test preparations

The 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 method

Determination of 2-amino-3-(4-bromobenzidine) by high performance liquid chromatography (HPLC) after storage at 40 ° C for 6 months or 60 ° C for 1 month The content of phenylacetic acid was calculated, and the residual ratio (%) was calculated. Further, the change in appearance was visually observed.

2-3. Test results and investigation

The test results are shown in Tables 2 to 4.

As can be seen from Tables 2 to 4, the preparations of Examples 2 to 15 can maintain a high residual ratio at 40 ° C for 6 months or at 60 ° C for 1 month, and remain in a state of being clear, yellow, and containing no precipitate. From the above, it was confirmed that the preparations of Examples 2 to 15 which belong to the aqueous composition of the present invention have excellent stability.

2. Stability assessment test (3)

The stability of the aqueous composition of the present invention when pH is changed is discussed.

3-1. Modulation of test preparations

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 method

The change in appearance of the test preparation after storage at 60 ° C for one month was visually observed.

3-3. Test results and investigation

The test results are shown in Table 5.

As is clear from Table 5, the preparations of Examples 16 to 19 were kept clear, yellow, and contained no precipitate at 60 ° C for 1 month. From the above, it was confirmed that the preparations of Examples 16 to 19 which are aqueous compositions of the present invention have excellent stability.

4. Stability assessment test (4)

The stability of the aqueous composition of the present invention in the presence of iron is discussed.

4-1. Modulation of test preparations

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 method

After preparing the test preparation, 5 μg of each of iron (III) chloride was added. The content of 2-amino-3-(4-bromobenzylidene)phenylacetic acid stored at 60 ° C for 2 weeks was quantified by high performance liquid chromatography (HPLC), and the amount of water evaporation from the container was corrected. The residual ratio (%) of the present compound was calculated. Further, the change in appearance was visually observed.

4-3. Test results and investigation

The test results are shown in Table 6.

As is clear from Table 6, the preparations of Examples 20 to 23 were stable at 60 ° C for 2 weeks as compared with the preparation of Comparative Example 9, and remained clear, yellow, and free from precipitation. From the above, the preparations of Examples 20 to 23 which are confirmed to belong to the aqueous composition of the present invention have excellent stability even in the presence of iron.

3. Formulation examples

Representative examples of the use of the present compounds are shown below. Further, in the following formulation examples, the blending amount of each component was 100 mL.

Formulation Example 1

This compound 0.1g

Polysorbate 80 0.005g

Boric acid 1.25g

Borax 1.0g

Sodium edetate 0.02g

Benzyl ammonium chloride 0.001g

Hydrochloric acid

Sodium hydroxide

Distilled water

pH 8.3

Formulation Example 2

This compound 0.1g

Polysorbate 80 0.03g

Boric acid 1.25g

Borax 1.0g

Sodium edetate 0.02g

Benzyl ammonium chloride 0.01g

Hydrochloric acid

Sodium hydroxide

Distilled water

pH 8.3

Formulation Example 3

The present compound 0.01g

Polysorbate 80 0.005g

Sodium EDTA 0.05g

Benzyl ammonium chloride 0.001g

Hydrochloric acid

Sodium hydroxide

Distilled water

pH 8.3

Further, the blending amount or blending ratio of each component in the above 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-bromobenzylidene)phenylacetic acid or a salt thereof, and optionally containing benzalkonium chloride and/or polyoxygen An aqueous composition of an ethylene sorbitan fatty acid ester, wherein the content of the benzalkonium chloride is A (parts by mass) relative to 100 parts by mass of 2-amino-3-(4-bromobenzylidene)phenylacetic acid When the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester is 0≦A<1, 0≦B<96A+5 A=1, 1<B≦100 1<A<3 , 5<B≦100 3≦A≦10, 20<B≦100. The aqueous composition of claim 1, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester are at 0≦A<1, 0≦B<26A+5 When A=1, 2≦B≦30 1<A<3, 5<B≦30 3≦A≦5, and 20<B≦30. The aqueous composition of claim 1, wherein the content A of the benzalkonium chloride and the content B of the polyoxyethylene sorbitan fatty acid ester are 1<A<3, and 5<B≦30 Within the scope. The aqueous composition of claim 1, wherein the content of the benzalkonium chloride and the content of the polyoxyethylene sorbitan fatty acid ester B are in the range of 1.2≦A≦2.5, and 7≦B≦20. Inside. An aqueous composition comprising 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, and optionally, benzalkonium chloride and/or polyoxyethylene sorbitan An aqueous composition of a fatty acid ester wherein the concentration X (w/v%) of benzalkonium chloride and the concentration Y (w/v%) of the polyoxyethylene sorbitan fatty acid ester are at 0≦X<0.001 When 0≦Y<96X+0.005 X=0.001, when 0.001<Y≦0.1 0.001<X<0.003, 0.005<Y≦0.1 0.003≦X≦0.01, 0.02<Y≦0.1. The aqueous composition of claim 5, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester are at 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, and 0.02<Y≦0.03. An aqueous composition according to claim 5, wherein benzalkonium chloride The concentration X of the polyoxyethylene sorbitan fatty acid ester is in the range of 0.001 < X < 0.003 and 0.005 < Y ≦ 0.03. The aqueous composition of claim 5, wherein the concentration X of the benzalkonium chloride and the concentration Y of the polyoxyethylene sorbitan fatty acid ester are in the range of 0.0012 ≦ X ≦ 0.0025 and 0.008 ≦ Y ≦ 0.02. Inside. The aqueous composition according to any one of claims 1 to 8, wherein the polyoxyethylene sorbitan fatty acid ester is Polysorbate 80. The aqueous composition according to any one of claims 1 to 8, wherein the concentration of 2-amino-3-(4-bromobenzylidene)phenylacetic acid in the aqueous composition is 0.01 to 1.0%. (w/v). The aqueous composition according to any one of claims 1 to 8, which further contains 0.01 to 3.0% (w/v) of sodium chloride. The aqueous composition according to any one of claims 1 to 8, wherein the aqueous composition has a pH of more than 7.0 and 9.5 or less. The aqueous composition according to any one of claims 1 to 8, wherein the aqueous composition is an injection, an infusion, a nasal spray, an ear lotion or an eye drop. An aqueous composition according to claim 13 of the patent application, which is an ophthalmic injection. An aqueous composition according to claim 13 of the patent application, which is an eye drop. A manufacturing method, such as any one of claims 1 to 8 of the patent application scope A method for producing an aqueous composition comprising 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof or a hydrate thereof, and optionally benzyl chloride The ammonium and/or polyoxyethylene sorbitan fatty acid ester is dissolved in an aqueous solvent.