Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof and a method for producing the same.
• Patent Document 2 reports that when an antibacterial polymer quaternary ammonium compound and boric acid are used in combination in an ophthalmic composition of an acidic drug, a storage-stable composition is provided.
• an acidic drug bromfenac is provided. Is listed.
• Patent Document 3 2-amino-3- (4-bromobenzoyl) phenylacetic acid-containing aqueous solution is prepared by adding an alkylaryl polyether alcohol type polymer or polyethylene glycol fatty acid ester to 2-amino-3- (4 -Bromobenzoyl) phenylacetic acid has been reported to be stabilized.
• Patent Document 4 discloses a bromfenac aqueous liquid composition containing a low concentration of benzalkonium chloride, which has a storage effect and is stable.
• an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof the content of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester should be limited to a certain range.
• iron may be mixed into the manufactured eye drops from the manufacturing pot.
• the present invention relates to the following.
• An aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and optionally benzalkonium chloride and / or polyoxyethylene sorbitan fatty acid ester, Benzalkonium chloride content A (mass part) and polyoxyethylene sorbitan fatty acid ester content B (mass part) with respect to 100 parts by mass of amino-3- (4-bromobenzoyl) phenylacetic acid, When 0 ⁇ A ⁇ 1, 0 ⁇ B ⁇ 96A + 5 When A 1, 1 ⁇ B ⁇ 100 When 1 ⁇ A ⁇ 3, 5 ⁇ B ⁇ 100 When 3 ⁇ A ⁇ 10, 20 ⁇ B ⁇ 100 An aqueous composition that is within the range of (2) Benzalkonium chloride content A and polyoxyethylene sorbitan fatty acid ester content B When 0 ⁇ A ⁇ 1, 0 ⁇ B ⁇ 26A +
• a method for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition which comprises 100 masses of 2-amino-3- (4-bromobenzoyl) phenylacetic acid 0 to 10 parts by mass of benzalkonium chloride (content A (parts by mass)) and polyoxyethylene sorbitan fatty acid ester represented by content B (parts by mass) within the following range It also relates to a method of adding to the aqueous medium.
• 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an 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.
• the aqueous composition of the present invention has sufficient stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof even in the presence of iron that may be mixed in from the production kettle in the production process. Retain sex.
• the “aqueous solvent” means water or a solvent containing water (for example, a mixture of water-soluble solvent such as alcohol and water).
• the aqueous solvent is not particularly limited as long as it is water or a solvent containing water, but is preferably purified water.
• the aqueous composition of the present invention is an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, wherein 2-amino-3- (4-bromo Benzoyl) phenyloxyacetate with respect to 100 parts by mass of polyoxyl represented by 0 to 10 parts by mass of benzalkonium chloride (content A (parts by mass)) and content B (parts by mass) within the following range
• An aqueous composition comprising ethylene sorbitan fatty acid ester.
• the salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is not particularly limited as long as it is a pharmaceutically acceptable salt.
• the salt include salts with inorganic acids, organic Examples include salts with 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.
• the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, sulfuric acid And salts with methyl, naphthalenesulfonic acid, sulfosalicylic acid and the like.
• Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
• Salts with halogen ions include salts with chloride ions, bromide ions, iodide ions, etc.
• Salts with alkali metals include salts with lithium, sodium, potassium, etc., alkaline earths
• Examples of the salt with metal include salts with calcium, magnesium and the like, and examples of the metal salt include salts with iron, zinc and the like.
• Salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
• the preferred salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is the sodium salt.
• the concentration of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is not particularly limited as long as it is an amount sufficient to achieve a desired medicinal effect. 0% (w / v) is preferable, 0.03-0.5% (w / v) is more preferable, 0.05-0.2% (w / v) is further more preferable, 0.08-0. 1% (w / v) is most preferred. These concentrations were 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.
• 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 its R Is C 8 H 17 to C 18 H 37 or a mixture thereof.
• N-benzyl-N, N-dimethyllauryl ammonium chloride (hereinafter also referred to as BAK C12) in which R is C 12 H 25 , N-benzyl-N, N-dimethyl in which R is C 14 H 29
• BAK C12 N-benzyl-N, N-dimethyllauryl ammonium chloride
• R is C 12 H 25
• BAK C14 myristylammonium chloride
• BAK C16 N-benzyl-N-cetyldimethylammonium chloride
• R is C 16 H 33
• the preferred benzalkonium chloride is BAK C12.
• the content of benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester is such that the content of benzalkonium chloride is 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid.
• the upper limit of the content of benzalkonium chloride in the aqueous composition of the present invention is preferably 10 parts by mass with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid, and 6 parts by mass. More preferred is 5 parts by mass, more preferred is 4 parts by mass, more preferred is 3 parts by mass, particularly preferred is 2.5 parts by mass, and most preferred is 2 parts by mass.
• the lower limit of the content is preferably 0 part by mass, more preferably 0.2 part by mass, further preferably 0.5 part by mass, more preferably 0.8 part by mass, particularly preferably 1 part by mass. 2 parts by mass is most preferred.
• the content range of benzalkonium chloride is preferably 0 to 10 parts by mass, more preferably 0.2 to 5 parts by mass, further preferably 0.5 to 3 parts by mass, and 1 to 2.5% by mass. Part is particularly preferred, and 1.2 to 2 parts by weight 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 with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid, and 50 parts by mass. Is more preferable, 40 parts by mass is further preferable, 30 parts by mass is more preferable, 25 parts by mass is particularly preferable, and 20 is most preferable.
• the lower limit of the content is preferably 0 part by mass, more preferably 2 parts by mass, further preferably 5 parts by mass, more preferably 6 parts by mass, particularly preferably 7 parts by mass, and most preferably 9 parts by mass.
• the range of 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, further preferably 2 to 40 parts by mass, and more preferably 5 to 30 parts by mass. -25 parts by weight is particularly preferred, and 9-20 parts by weight is most preferred.
• 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), and 0.005% (w / V) is more preferred, 0.004% (w / v) is more preferred, 0.003% (w / v) is particularly preferred, 0.025% (w / v) is more particularly preferred, 0.002 % (W / v) is most preferred.
• the lower limit of the concentration is preferably 0% (w / v), more preferably 0.0002% (w / v), further preferably 0.0005% (w / v), and 0.0008% (w / v).
• v) is more preferred, 0.001% (w / v) is particularly preferred, and 0.0012% (w / v) is most preferred.
• the concentration range is preferably 0 to 0.01% (w / v), more preferably 0.0002 to 0.005% (w / v), and 0.0005 to 0.003% (w / v). Is more preferable, 0.001 to 0.0025% (w / v) is particularly preferable, and 0.0012 to 0.002% (w / v) is most preferable.
• 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), and 0.04% ( w / v) is more preferred, 0.03% (w / v) is more preferred, 0.025% (w / v) is particularly preferred, and 0.02% (w / v) is most preferred.
• the lower limit of the concentration is preferably 0% (w / v), more preferably 0.002% (w / v), still more preferably 0.005% (w / v), and 0.008% (w / v).
• v) is more preferred, 0.009% (w / v) is particularly preferred, and 0.01% (w / v) is most preferred.
• the concentration range is preferably 0 to 0.1% (w / v), more preferably 0 to 0.05% (w / v), and further 0.002 to 0.04% (w / v).
• 0.005 to 0.03% (w / v) is more preferable, 0.008 to 0.025% (w / v) is particularly preferable, and 0.01 to 0.02% (w / v) is preferable. Most preferred.
• An aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof and containing neither benzalkonium chloride nor polyoxyethylene sorbitan fatty acid ester is also included in the present invention. Included in the range.
• a preferable buffer is boric acid or a salt thereof, for example, boric acid or borax.
• the concentration of the buffering agent 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, but the total amount is 0.01 to 15%.
• (W / v) is preferred, 0.05 to 10% (w / v) is more preferred, 0.1 to 5% (w / v) is more preferred, and 0.25 to 4% (w / v) is more preferred. Particularly preferred is 0.5 to 3% (w / v).
• an isotonic agent that can be used as a pharmaceutical additive can be appropriately blended.
• isotonic agents include ionic and nonionic tonicity agents.
• examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride
• examples of the nonionic tonicity agent include glycerin, propylene glycol, sorbitol, mannitol, and the like.
• a preferred tonicity agent is sodium chloride, and a composition in which the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof is maintained and the appearance does not change can be obtained.
• the pH of the aqueous composition of the present invention is preferably 7.0 to 9.5, more preferably 7.5 to 9.0, still more preferably 8.0 to 8.6, and 8.2 to 8.4. Most preferred.
• a stabilizer that can be used as a pharmaceutical additive can be appropriately blended.
• the stabilizer include edetic acid, sodium edetate, sulfite, water-soluble polymer and the like.
• the sulfite include sodium sulfite, potassium sulfite, magnesium sulfite, and calcium sulfite.
• the water-soluble polymer include polyvinyl pyrrolidone, polyvinyl alcohol, carboxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, 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 influence on drugs, other additives and / or osmotic pressure ratio.
• a preservative that can be used as a pharmaceutical additive can be appropriately blended.
• preservatives include benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.
• the concentration of the preservative in the aqueous composition of the present invention can be appropriately adjusted in consideration of the influence on the drug, other additives and / or the osmotic pressure ratio, and the total amount is 0.00005 to 0.005.
• 01% (w / v) is preferable, 0.0001 to 0.005% (w / v) is more preferable, 0.0002 to 0.004% (w / v) is further preferable, and 0.0005 to 0.00.
• 003% (w / v) is particularly preferable, and 0.001 to 0.002% (w / v) is most preferable.
• the aqueous composition of the present invention dissolves 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof and benzalkonium chloride and a polyoxyethylene sorbitan fatty acid ester in an aqueous solvent. Can be manufactured.
• 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof as well as a hydrate thereof can be used.
• Specific examples of such hydrates include sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 1/2 hydrate, sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, Monohydrate, sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 3/2 hydrate, and the like, such as sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, Preferable examples include 3/2 hydrate.
• the aqueous solvent the solvents described above can be used.
• the present invention is 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 benzalkonium chloride and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid, When 0 ⁇ A ⁇ 1, 0 ⁇ B ⁇ 96A + 5 When A 1, 1 ⁇ B ⁇ 100 When 1 ⁇ A ⁇ 3, 5 ⁇ B ⁇ 100 When 3 ⁇ A ⁇ 10, 20 ⁇ B ⁇ 100
• a process for the preparation of an aqueous composition which is in the range of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof and optionally a benzalkonium chloride and / or poly
• the present invention also relates to a production method characterized by dissolving oxyethylene sorbitan fatty acid ester in an aqueous solvent.
• Stability evaluation test (1) The stability of the aqueous composition of the present invention was examined. 1-1. Preparation of test preparation Example 1 To 90 mL of purified water, 0.1 g of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate 3/2 hydrate (hereinafter also referred to as this compound), 1.25 g of boric acid, and borax 1.0 g, 0.02 g of sodium edetate hydrate, 0.005 g of polysorbate 80, and 0.001 g of benzalkonium chloride were added and sufficiently stirred. A 1N aqueous sodium hydroxide solution and dilute hydrochloric acid (10%) were added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Comparative Example 1 shown in Table 1 was prepared in the same manner as the preparation method of Example 1.
• test preparation was stored at 25 ° C. and 40 ° C. for up to 6 months, the content of 2-amino-3- (4-bromobenzoyl) phenylacetic acid was quantified using high performance liquid chromatography (HPLC). The residual rate (%) was calculated. Moreover, the change of the external appearance was observed visually.
• Test results and discussion Table 1 shows the test results.
• PE polyethylene
• PP polypropylene
• 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.
• Stability evaluation test (3) The stability of the aqueous composition of the present invention when the pH was changed was examined.
• Stability evaluation test (4) The stability of the aqueous composition of the present invention in the presence of iron was investigated.

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• 2013
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