[go: up one dir, main page]

HK1220393A1 - Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid - Google Patents

Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid Download PDF

Info

Publication number
HK1220393A1
HK1220393A1 HK16108544.6A HK16108544A HK1220393A1 HK 1220393 A1 HK1220393 A1 HK 1220393A1 HK 16108544 A HK16108544 A HK 16108544A HK 1220393 A1 HK1220393 A1 HK 1220393A1
Authority
HK
Hong Kong
Prior art keywords
equal
less
aqueous composition
amino
bromobenzoyl
Prior art date
Application number
HK16108544.6A
Other languages
Chinese (zh)
Other versions
HK1220393B (en
Inventor
岡本智之
冈本智之
山口真生
Original Assignee
参天制药株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 参天制药株式会社 filed Critical 参天制药株式会社
Publication of HK1220393A1 publication Critical patent/HK1220393A1/en
Publication of HK1220393B publication Critical patent/HK1220393B/en

Links

Classifications

    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/0046—Ear
    • 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]
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

　An aqueous composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, benzalkonium bromide, and polyoxyethylene sorbitan fatty acid ester wherein the stability of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid in the aqueous composition is improved by limiting the content of benzalkonium bromide and polyoxyethylene sorbitan fatty acid ester to a certain range.

Description

Aqueous compositions containing stabilized 2-amino-3- (4-bromobenzoyl) phenylacetic acid
Technical Field
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.
Background
2-amino-3- (4-bromobenzoyl) phenylacetic acid is a compound represented by the following formula (1):
the common name for 2-amino-3- (4-bromobenzoyl) phenylacetic acid is Bromfenac (Bromfenac), a known non-steroidal anti-inflammatory drug, which is used in the field of ophthalmology as eye drops for the treatment of inflammation of the outer eye and the anterior segment of the eye (antiaoreyement).
It is known that 2-amino-3- (4-bromobenzoyl) phenylacetic acid lacks stability in aqueous solution and produces red insoluble foreign matter during preservation. Therefore, in patent document 1, 2-amino-3- (4-bromobenzoyl) phenylacetic acid is stabilized by adding a water-soluble polymer (such as polyvinylpyrrolidone) and a sulfite (such as sodium sulfite) to an eye drop containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid.
Patent document 2 reports that when an antibacterial polymeric quaternary ammonium compound and boric acid are used in combination in an ophthalmic composition for an acidic drug, a composition stable in storage is provided, and bromfenac is given as an example of the acidic drug.
Patent document 3 reports that 2-amino-3- (4-bromobenzoyl) phenylacetic acid is stabilized by adding an alkylaryl polyether alcohol type polymer or a polyethylene glycol fatty acid ester to an aqueous liquid containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid.
Patent document 4 discloses a stable bromfenac aqueous liquid composition containing benzalkonium chloride at a low concentration and having a storage potency.
However, patent document 4 merely shows usefulness in terms of preservation efficacy, that is, efficacy of inhibiting the proliferation of bacteria mixed in an aqueous liquid composition.
Patent document 1: specification of U.S. Pat. No. 4910225
Patent document 2: WO96/14829
Patent document 3: U.S. patent application publication No. 2005/0239895 specification
Patent document 4: WO2012/99142 pamphlet
Disclosure of Invention
As described above, no one has so far achieved the technical effect of improving the storage stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in an aqueous solution by adding benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester to a conventional aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid and limiting the content thereof to a certain range.
The present invention addresses the problem of providing an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid that is sufficiently stable even during long-term storage by improving the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid in the aqueous composition.
As a result of intensive studies by the inventors of the present application to improve the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, it was found that if the content a (parts by mass) of benzalkonium bromide and the content B (parts by mass) of polyoxyethylene sorbitan fatty acid ester are within the following ranges with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100;
the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof can be improved, a high retention rate can be maintained even after long-term storage, and red insoluble foreign matter is not produced, thereby completing the present invention.
The aqueous composition of the present invention can maintain a clear, yellow, precipitate-free state for a long period of time, and is also excellent in preservative efficacy.
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, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester, wherein the content A (parts by mass) of benzalkonium bromide and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester are within the following ranges, based on 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
(2) The aqueous composition according to the above (1), wherein the content A of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 50;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 50.
(3) The aqueous composition according to the above (1), wherein the content A of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
when A is more than or equal to 0.5 and less than or equal to 2.4, B is more than or equal to 5 and less than or equal to 30;
when A is more than or equal to 2.4 and less than or equal to 3, B is more than 5 and less than or equal to 30.
(4) The aqueous composition according to the above (1), wherein the content A of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
a is more than or equal to 0.8 and less than or equal to 2, and B is more than or equal to 5 and less than or equal to 20.
(5) An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester, wherein the concentration X (w/v%) of benzalkonium bromide and the concentration Y (w/v%) of the polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.1;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.1.
(6) The aqueous composition according to the above (5), wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.05;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.05.
(7) The aqueous composition according to the above (5), wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
when X is more than or equal to 0.0005 and less than or equal to 0.0024, Y is more than or equal to 0.005 and less than or equal to 0.03;
when X is more than or equal to 0.0024 and less than or equal to 0.003, Y is more than 0.005 and less than or equal to 0.03.
(8) The aqueous composition according to the above (5), wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are in the following ranges:
x is more than or equal to 0.0008 and less than or equal to 0.002, and Y is more than or equal to 0.005 and less than or equal to 0.02.
(9) The aqueous composition according to any one of the above (1) to (8), wherein the polyoxyethylene sorbitan fatty acid ester is Polysorbate80 (Polysorbate 80).
(10) The aqueous composition according to any one of the above (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 the above (1) to (10), which comprises 1.0% (w/v) of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate 3/2 hydrate.
(12) The aqueous composition according to any one of the above (1) to (11), further comprising 0.5 to 5% (w/v) of boric acid and/or borax.
(13) The aqueous composition according to any one of the above (1) to (12), further comprising 0.005 to 0.2% (w/v) of sodium edetate hydrate.
(14) The aqueous composition according to any one of the above (1) to (13), further comprising 0.01 to 3.0% (w/v) of sodium chloride.
(15) The aqueous composition according to any one of the above (1) to (14), wherein the pH of the aqueous composition is more than 7.0 and not more than 9.5.
(16) The aqueous composition according to any one of the above (1) to (15), wherein the aqueous composition is an injection, an infusion solution, a nasal drop, an ear drop or an eye drop.
(17) The aqueous composition according to the above (16), wherein the aqueous composition is an ophthalmic injection.
(18) The aqueous composition according to the above (16), wherein the aqueous composition is an eye drop.
(19) A method for producing the aqueous composition according to any one of the above (1) to (18), wherein 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate of the same, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester are dissolved in an aqueous solvent.
The present invention still further relates to the following.
(20) A method for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition, wherein a polyoxyethylene sorbitan fatty acid ester represented by benzalkonium bromide 0 to 5 parts by mass (content A (parts by mass)) and a content B (parts by mass) within the following range is blended in the aqueous composition per 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid,
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
The respective configurations of (1) to (20) above may be combined by selecting 2 or more items arbitrarily.
The present invention provides an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, which can be stably stored at room temperature for 2 years or longer, for example, because the 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in the aqueous composition is stable over a long period of time.
Detailed Description
The present invention will be described in detail below.
In the present specification, the term "aqueous solvent" refers to water or a solvent containing water (for example, a mixture of a 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, and 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, which contains more than 0 part by mass and less than 5 parts by mass of benzalkonium bromide (content A (parts by mass)) and a polyoxyethylene sorbitan fatty acid ester represented by content B (parts by mass) within the following range, relative to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid,
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
In the aqueous composition, 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt 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-bromobenzoyl) phenylacetic acid may be present in a dissolved form in the form of undissociated 2-amino-3- (4-bromobenzoyl) phenylacetic acid itself, a salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid, zwitterions (carboxyl groups form carboxylate ions and amino groups form ammonium ions), cations (only amino groups form ammonium ions), anions (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 a salt with an inorganic acid, a salt with an organic acid, 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 the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of the salt with an organic acid include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1, 2-ethanedisulfonic acid (1, 2-ethanedisulfonic acid), isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid. Examples of the quaternary ammonium salt include salts with methyl bromide, methyl iodide, and the like. Examples of the salt with a halogen ion include salts 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, potassium, and the like; examples of the salt with an alkaline earth metal include salts with calcium, magnesium, and the like; examples of the metal salt include salts with iron, zinc, and the like. Examples of the salt with an organic amine include salts with triethylenediamine, 2-aminoethanol, 2-iminobisethanol, 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, procaine, and N, N-bis (benzyl) -1, 2-ethylenediamine. In the aqueous composition of the present invention, 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 in the aqueous composition of the present invention is not particularly limited as long as it is a sufficient amount necessary to obtain the desired pharmaceutical effect, but is preferably 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). When a salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a hydrate thereof is used, these concentrations are calculated by mass conversion to 2-amino-3- (4-bromobenzoyl) phenylacetic acid.
In the aqueous composition of the present invention, benzalkonium bromide (hereinafter, also referred to as BABr) has [ C6H5CH2N(CH3)2R]A chemical structure represented by Br, wherein R is C8H17～C18H37Or a mixture thereof. Preferably, R is C12H25N-benzyl-N, N-dimethyl ammonium lauryl bromide (hereinafter, also referred to as BABrC12), R is C14H29N-benzyl-N, N-dimethyltetradecylammonium bromide (hereinafter, also referred to as BABrC14) or R is C16H33Or N-benzyl-N-hexadecyldimethylammonium bromide (hereinafter, also referred to as BABrC16), or a mixture thereof. In the present invention, the preferred benzalkonium bromide is BABrC 12.
In the aqueous composition of the present invention, polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan fatty acid ester) is not particularly limited, and as the polyoxyethylene sorbitan fatty acid ester, polysorbate80 (polysorbate80), polysorbate65 (polysorbate65), polysorbate60 (polysorbate60), polysorbate40 (polysorbate40), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and the like can be cited, and polysorbate80 (polysorbate80) is preferred.
In the aqueous composition of the present invention, the content a (parts by mass) of benzalkonium bromide and the content B (parts by mass) of polyoxyethylene sorbitan fatty acid ester are within the following ranges with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100,
preferably within the following ranges:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 50;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 50,
more preferably in the following ranges:
when A is more than or equal to 0.5 and less than or equal to 2.4, B is more than or equal to 5 and less than or equal to 30;
when A is more than or equal to 2.4 and less than or equal to 3, B is more than 5 and less than or equal to 30,
most preferably in the following ranges:
a is more than or equal to 0.8 and less than or equal to 2, and B is more than or equal to 5 and less than or equal to 20.
The upper limit of the content of benzalkonium bromide in the aqueous composition of the present invention is preferably less than 5 parts by mass, more preferably 4 parts by mass, still more preferably 3 parts by mass, particularly preferably 2.5 parts by mass, and most preferably 2 parts by mass, per 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid. On the other hand, the lower limit of the content is preferably more than 0 part by mass, more preferably 0.2 part by mass, further preferably 0.5 part by mass, and most preferably 0.8 part by mass. The content of benzalkonium bromide is preferably in a range of more than 0 part by mass and less than 5 parts by mass, more preferably in a range of 0.2 part by mass and less than 5 parts by mass, still more preferably in a range of 0.2 part by mass and less than 4 parts by mass, further preferably in a range of 0.5 part by mass and 3 parts by mass or less, particularly preferably in a range of 0.8 part by mass and 2.5 parts by mass or less, and most preferably in a range of 0.8 part by mass and 2 parts by mass or less.
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, still more preferably 40 parts by mass, still more preferably 30 parts by mass, particularly preferably 25 parts by mass, and most preferably 20 parts by mass, relative to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid. On the other hand, the lower limit of the content is preferably more than 0 part by mass, more preferably 2 parts by mass, still more preferably 3 parts by mass, and most preferably 5 parts by mass. The content of the polyoxyethylene sorbitan fatty acid ester is preferably more than 0 part by mass and 100 parts by mass or less, more preferably more than 0 part by mass and 50 parts by mass or less, still more preferably 2 parts by mass or more and 40 parts by mass or less, still more preferably 5 parts by mass or more and 30 parts by mass or less, particularly preferably 5 parts by mass or more and 25 parts by mass or less, and most preferably 9 parts by mass or more and 20 parts by mass or less.
The concentration of benzalkonium bromide and the concentration of polyoxyethylene sorbitan fatty acid ester Y (w/v%) in the aqueous composition of the present invention are preferably in the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.1;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.1,
more preferably in the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.05;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.05,
further preferred is within the following range:
when X is more than or equal to 0.0005 and less than or equal to 0.0024, Y is more than or equal to 0.005 and less than or equal to 0.03;
when X is more than or equal to 0.0024 and less than or equal to 0.003 and Y is more than 0.005 and less than or equal to 0.03,
most preferably in the following ranges:
x is more than or equal to 0.0008 and less than or equal to 0.002, and Y is more than or equal to 0.005 and less than or equal to 0.02.
The upper limit of the concentration of benzalkonium bromide in the aqueous composition of the present invention is preferably less than 0.005% (w/v), more preferably 0.004% (w/v), still more preferably 0.003% (w/v), particularly preferably 0.025% (w/v), and most preferably 0.002% (w/v). On the other hand, the lower limit of the concentration is preferably more than 0% (w/v), more preferably 0.0002% (w/v), still more preferably 0.0005% (w/v), and most preferably 0.0008% (w/v). The concentration range is preferably greater than 0% (w/v) and less than 0.005% (w/v), more preferably 0.0002% (w/v) and less than 0.005% (w/v), still more preferably 0.0002% (w/v) and less than 0.004% (w/v), still more preferably 0.0005% (w/v) and less than 0.003% (w/v), particularly preferably 0.0008% (w/v) and less than 0.0025% (w/v), and most preferably 0.0008% (w/v) and less than 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), even more preferably 0.04% (w/v), even more preferably 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 more than 0% (w/v), more preferably 0.002% (w/v), particularly preferably 0.003% (w/v), and most preferably 0.005% (w/v). The concentration range is preferably greater than 0% (w/v) and 0.1% (w/v) or less, more preferably 0% (w/v) or more and 0.05% (w/v) or less, still more preferably 0.002% (w/v) or more and 0.04% (w/v) or less, still more preferably 0.005% (w/v) or more and 0.03% (w/v) or less, particularly preferably 0.005% (w/v) or more and 0.025% (w/v) or less, and most preferably 0.009% (w/v) or more and 0.02% (w/v) or less.
Also included within the scope of the present invention is an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, and not containing any one of benzalkonium bromide and polyoxyethylene sorbitan fatty acid esters.
In addition, additives such as a buffer, an isotonic agent, a pH adjuster, a stabilizer, a preservative, a solubilizer, and a thickener may be added to the aqueous composition of the present invention as necessary.
The aqueous composition of the present invention may contain a buffer that can be used as a pharmaceutical additive. Examples of the buffer 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, tromethamine, and the like. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; examples of the borate include borax, sodium borate, potassium borate, and the like; examples of the citrate include sodium citrate and disodium citrate; examples of the acetate include sodium acetate, potassium acetate, and the like; examples of the carbonate include sodium carbonate and sodium hydrogen carbonate; examples of the tartrate salt include sodium tartrate and potassium tartrate. In the present invention, the preferred buffering agent is boric acid or a salt thereof, for example, boric acid, borax.
The concentration of the buffer in the aqueous composition of the present invention may be appropriately adjusted in consideration of the influence on the drug, other additives and/or osmotic pressure ratio, and the total amount thereof is preferably 0.01 to 15% (w/v), more preferably 0.05 to 10% (w/v), still more preferably 0.1 to 6% (w/v), particularly preferably 0.5 to 5% (w/v), and most preferably 2 to 4% (w/v). More specifically, it is preferable to add 0.85% (w/v) boric acid and 1% (w/v) borax.
In the aqueous composition of the present invention, an isotonic agent which can be used as a pharmaceutical additive may be appropriately blended. Examples of the isotonic agent include ionic isotonic agents, nonionic isotonic agents, and the like. Examples of the ionic isotonizing agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like; examples of the nonionic isotonic agent include glycerin, propylene glycol, sorbitol, mannitol, and the like. A preferable isotonic agent is sodium chloride, and a composition which can maintain the stability of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt and does not change in appearance can be obtained.
The concentration of the isotonic agent in the aqueous composition of the present invention may be appropriately adjusted in consideration of the influence on the drug, other additives and/or osmotic pressure ratio, and the total amount thereof is preferably 0.01 to 3% (w/v), more preferably 0.02 to 2.5% (w/v), still more preferably 0.03 to 2% (w/v), particularly preferably 0.05 to 1% (w/v), and most preferably 0.1 to 0.5% (w/v). More specifically, it is preferable to add 0.23% (w/v) of sodium chloride.
In the aqueous composition of the present invention, a pH adjuster which can be used as a pharmaceutical additive may be blended in an appropriate amount. Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate. In the present invention, hydrochloric acid and sodium hydroxide are preferred as the pH adjuster.
The pH of the aqueous composition of the present invention is preferably 7.0 to 9.5, more preferably 7.5 to 9.0, even more preferably 8.0 to 8.6, and most preferably 8.2 to 8.4.
The aqueous composition of the present invention may contain a stabilizer which can be used as a pharmaceutical additive. Examples of the stabilizer include ethylenediaminetetraacetic acid, sodium ethylenediaminetetraacetate hydrate, sodium citrate, 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, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sodium polyacrylate.
The concentration of the stabilizer in the aqueous composition of the present invention may be appropriately adjusted in consideration of the influence on the drug, other additives and/or osmotic pressure ratio, and the total amount thereof is preferably 0.001 to 5% (w/v), more preferably 0.002 to 1% (w/v), still more preferably 0.003 to 0.5% (w/v), particularly preferably 0.005 to 0.2% (w/v), and most preferably 0.01 to 0.1% (w/v). More specifically, 0.02% (w/v) of sodium edetate hydrate is preferably blended.
The concentration of the total stabilizer in the aqueous composition of the present invention may be appropriately adjusted in consideration of the influence thereof on the drug, other additives and/or osmotic pressure ratio.
The aqueous composition of the present invention may contain a preservative which can be used as a pharmaceutical additive. Examples of the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, methylparaben, propylparaben, and chlorobutanol.
The concentration of the preservative in the aqueous composition of the present invention may be appropriately adjusted in consideration of the influence on the drug, other additives and/or osmotic pressure ratio, and the total amount thereof is preferably 0.00005 to 0.01% (w/v), more preferably 0.0001 to 0.005% (w/v), still more preferably 0.0002 to 0.004% (w/v), particularly preferably 0.0005 to 0.003% (w/v), and most preferably 0.001 to 0.002% (w/v).
The formulation of the aqueous composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical product. Examples of the dosage form include injections, infusion solutions, nasal drops, ear drops, and eye drops. Ophthalmic injections and eye drops are preferred, and eye drops are particularly preferred.
The aqueous composition of the present invention can be produced by dissolving 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate of the same, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester in an aqueous solvent.
In addition to 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt, a hydrate thereof may be used in the preparation of the aqueous composition of the present invention. Specific examples of such hydrates include 1/2 hydrate of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 1 hydrate of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 3/2 hydrate of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate, 3/2 hydrate, and the like, and preferred examples thereof include 3/2 hydrate of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate.
As the aqueous solvent, the solvents described above can be used.
Accordingly, the present invention also relates to a method for producing an aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester, wherein the content a (parts by mass) of benzalkonium bromide and the content B (parts by mass) of the polyoxyethylene sorbitan fatty acid ester are within the following ranges, relative to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100,
the method for producing an aqueous composition is characterized by dissolving 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate of the same, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester in an aqueous solvent.
The present invention further relates to a method for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition, wherein benzalkonium bromide (more than 0 part by mass and less than 5 parts by mass, content a (parts by mass)) and a polyoxyethylene sorbitan fatty acid ester represented by content B (parts by mass) within the following range are blended in the aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof with respect to 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid,
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
Hereinafter, test results and formulation examples are given for better understanding of the present invention, and do not limit the scope of the present invention.
1. Stability evaluation test
The stability of the aqueous composition of the present invention was investigated.
1-1. Preparation of test formulations
Example 1
To 90mL of purified water were added 0.1g of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate 3/2 hydrate (hereinafter also referred to as this compound), 0.85g of boric acid, 1.0g of borax, 0.02g of sodium edetate hydrate, 0.005g of polysorbate80, 0.0012g of benzalkonium bromide and 0.23g of sodium chloride, and the mixture was sufficiently stirred. A1N aqueous solution of sodium hydroxide 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 to 100 mL.
The formulations shown in tables 1 and 2 were prepared in the same manner as in example 1.
1-2. Test method
The content of 2-amino-3- (4-bromobenzoyl) phenylacetic acid after the test preparation was stored at 60 ℃ for 1 week or 1 month was quantified by High Performance Liquid Chromatography (HPLC), and the retention (%) thereof was calculated. Further, the change in appearance was visually observed, and the sample was judged to be clear, yellow and free of precipitates, and was judged to be + if the change in the above state was confirmed.
1-3. Test results and investigation
The test results are shown in tables 1 and 2.
[ Table 1]
-means no change in appearance was found.
-means no change in appearance was found. + indicates that a change in appearance was found.
[ Table 2]
-means no change in appearance was found.
-means no change in appearance was found.
+ indicates that a change in appearance was found.
-means no change in appearance was found.
+ indicates that a change in appearance was found.
As is clear from tables 1 and 2, the formulations of examples 1 to 20 maintained a high retention rate at 60 ℃ for 1 week or 1 month, and remained clear, yellow, and free of precipitates. From the above results, it was confirmed that the formulations of examples 1 to 20, which are the aqueous compositions of the present invention, have excellent stability.
2. Preparation examples
Hereinafter, typical preparation examples using the compound are given. In the following formulation examples, the amount of each component added was 100 mL.
Formulation example 1
Preparation example 2
Preparation example 3
The amounts and ratios of the components in preparation examples 1 to 3, i.e., the compound, polysorbate80, benzalkonium bromide and other additives, may be appropriately adjusted.

Claims (20)

1. An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester, wherein the content A of benzalkonium bromide in parts by mass and the content B of the polyoxyethylene sorbitan fatty acid ester in parts by mass are within the following ranges relative to 100 parts by mass of the 2-amino-3- (4-bromobenzoyl) phenylacetic acid:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
2. The aqueous composition according to claim 1, wherein the content a of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 50;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 50.
3. The aqueous composition according to claim 1, wherein the content a of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when A is more than or equal to 0.5 and less than or equal to 2.4, B is more than or equal to 5 and less than or equal to 30;
when A is more than or equal to 2.4 and less than or equal to 3, B is more than 5 and less than or equal to 30.
4. The aqueous composition according to claim 1, wherein the content a of benzalkonium bromide and the content B of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
a is more than or equal to 0.8 and less than or equal to 2, and B is more than or equal to 5 and less than or equal to 20.
5. An aqueous composition comprising 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester, wherein the concentration X (w/v%) of benzalkonium bromide and the concentration Y (w/v%) of the polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.1;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.1.
6. The aqueous composition according to claim 5, wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when X is more than 0 and less than 0.0024, Y is more than 0 and less than or equal to 0.05;
when X is more than or equal to 0.0024 and less than 0.005, Y is more than 0.005 and less than or equal to 0.05.
7. The aqueous composition according to claim 5, wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
when X is more than or equal to 0.0005 and less than or equal to 0.0024, Y is more than or equal to 0.005 and less than or equal to 0.03;
when X is more than or equal to 0.0024 and less than or equal to 0.003, Y is more than 0.005 and less than or equal to 0.03.
8. The aqueous composition according to claim 5, wherein the concentration X of benzalkonium bromide and the concentration Y of polyoxyethylene sorbitan fatty acid ester are within the following ranges:
x is more than or equal to 0.0008 and less than or equal to 0.002, and Y is more than or equal to 0.005 and less than or equal to 0.02.
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, which comprises 1.0% (w/v) of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate 3/2 hydrate.
12. The aqueous composition of any one of claims 1 to 11, further comprising 0.5 to 5% (w/v) of boric acid and/or borax.
13. The aqueous composition according to any one of claims 1 to 12, further comprising 0.005 to 0.2% (w/v) of sodium edetate hydrate.
14. The aqueous composition according to any one of claims 1 to 13, further comprising 0.01 to 3.0% (w/v) of sodium chloride.
15. The aqueous composition according to any one of claims 1 to 14, wherein the aqueous composition has a pH of more than 7.0 and 9.5 or less.
16. The aqueous composition according to any one of claims 1 to 15, wherein the aqueous composition is an injection, an infusion solution, a nasal drop, an ear drop or an eye drop.
17. The aqueous composition of claim 16, wherein the aqueous composition is an ophthalmic injection.
18. The aqueous composition of claim 16, wherein the aqueous composition is an eye drop.
19. A method for producing the aqueous composition according to any one of claims 1 to 18, characterized by dissolving 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof or a hydrate thereof, benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester in an aqueous solvent.
20. A method for stabilizing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof in an aqueous composition, wherein 0 to 5 parts by mass of benzalkonium bromide and a polyoxyethylene sorbitan fatty acid ester are blended in the aqueous composition within the following range, based on 100 parts by mass of 2-amino-3- (4-bromobenzoyl) phenylacetic acid, the content of benzalkonium bromide is represented by content A, the content of the polyoxyethylene sorbitan fatty acid ester is represented by content B, and the content A and the content B are both represented by parts by mass,
when A is more than 0 and less than 2.4, B is more than 0 and less than or equal to 100;
when A is more than or equal to 2.4 and less than or equal to 5, B is more than 5 and less than or equal to 100.
HK16108544.6A 2013-09-26 2014-09-25 Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid HK1220393B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2013-199442 2013-09-26
JP2013199442 2013-09-26
PCT/JP2014/075342 WO2015046281A1 (en) 2013-09-26 2014-09-25 Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid

Publications (2)

Publication Number Publication Date
HK1220393A1 true HK1220393A1 (en) 2017-05-05
HK1220393B HK1220393B (en) 2019-11-08

Family

ID=

Also Published As

Publication number Publication date
TW201601717A (en) 2016-01-16
CN105451731B (en) 2019-01-18
CN105451731A (en) 2016-03-30
JP2015086222A (en) 2015-05-07
WO2015046281A1 (en) 2015-04-02

Similar Documents

Publication Publication Date Title
US11439652B2 (en) Ophthalmic aqueous composition
TWI757799B (en) Manufacturing method of aqueous ophthalmic solution
JP6716293B2 (en) Ophthalmic composition
MX2020008173A (en) Combination of an antimuscarinic or an anticholinergic agent and lipoic acid and uses thereof.
JPWO2005046700A1 (en) Aqueous preparation containing aminoglycoside antibiotic and bromfenac
JP2017514924A5 (en)
JP5922609B2 (en) Aqueous composition containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid
AR085273A1 (en) PROPELLENT FREE LIQUID FORMULATION THAT INCLUDES AN ANTIMUSCARINIC DRUG
CN114630669B (en) Stable pharmaceutical composition
CN103608000B (en) Eye drops containing hyaluronic acid or its salts and propylene glycol
HK1220393A1 (en) Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid
HK1220393B (en) Aqueous composition containing stabilized 2-amino-3-(4-bromobenzoyl)phenylacetic acid
JP5253775B2 (en) Latanoprost eye drops
HK40074840B (en) Stable pharmaceutical composition
HK40074840A (en) Stable pharmaceutical composition
HK1235711A1 (en) Ophthalmic aqueous composition
JP4832015B2 (en) Oxyglutathione-containing aqueous solution
HK1235711B (en) Ophthalmic aqueous composition
HK1238174A1 (en) Ophthalmic aqueous composition
WO2017091165A1 (en) Liquid formulation of levodropropizine and method for preparation thereof

Legal Events

Date Code Title Description
PC Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee)

Effective date: 20230924