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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61K47/02—Inorganic compounds
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions

Definitions

• the present invention relates to an eye drop and a method for maintaining the preservative effect of the eye drop.
• Bromfenac sodium has the action of suppressing the biosynthesis of prostaglandin (PG), has a therapeutic effect on conjunctivitis, allergic conjunctivitis, blepharitis with eye inflammation, etc., and is widely used as eye drops Yes.
• PG prostaglandin
• cationic antiseptics such as benzalkonium chloride have been widely known for eye drops (for example, Patent Document 1 and Patent Document 2). Further, in the eye drop, a nonionic surfactant that does not exhibit ionic properties even when dissolved in water is generally used.
• the surface tension of the eye drop is lowered by adding a nonionic surfactant to the eye drop.
• problems such as dripping of the ophthalmic solution and cracking of the ophthalmic container arise.
• the use concentration of the nonionic surfactant it is preferable to reduce the use concentration of the nonionic surfactant as much as possible, and it is more preferable not to use the nonionic surfactant at all.
• the present invention relates to an eye drop that can maintain an excellent preservative effect for a long period of time without substantially containing a cationic preservative and a nonionic surfactant, and a method for maintaining the preservative effect of the eye drop
• the purpose is to provide.
• the present inventors substantially contain a cationic preservative and a nonionic surfactant when a specific concentration range of borate ion and sodium edetate is contained.
• the inventors have found that an excellent antiseptic effect can be maintained for a long period of time, and have reached the present invention. That is, the present invention relates to the following.
• the first aspect of the present invention is that 0.01-1.0% (w / v) 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, 215-360 mM boric acid Ophthalmic solution containing ions and 0.001 to 0.15% (w / v) sodium edetate, substantially free of cationic preservatives and nonionic surfactants, An ophthalmic solution having an osmotic pressure ratio of 0.8 to 1.3.
• the second aspect of the present invention is that 0.01-1.0% (w / v) 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, 215-360 mM boric acid Ophthalmic solution containing ions and 0.001 to 0.15% (w / v) sodium edetate, substantially free of cationic preservatives and nonionic surfactants, It is an eye drop that conforms to the criteria in the 16th revision Japanese Pharmacopoeia Preservation Efficacy Test Act.
• bromfenac eye drops containing a specific concentration range of borate ions and sodium edetate, and substantially free of cationic preservatives and nonionic surfactants are excellent antiseptics over a long period of time. It can be effective. Furthermore, the bromfenac ophthalmic solution of the present invention contains substantially no cationic preservative such as benzalkonium chloride and a nonionic surfactant, so there is no need to worry about the damage to corneal cells, and In addition, no dripping of eye drops or cracking of the eye drops container occurs.
• the eye drop of the present invention comprises 0.01 to 1.0% (w / v) 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, 215 to 360 mM borate ion and 0.001.
• Bromfenac or a salt thereof contains 2-amino-3- (4-bromobenzoyl) phenylacetic acid (also referred to as “bromfenac”) or a salt thereof as a medicinal ingredient, preferably as a medicinal ingredient. Contains only 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof.
• 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof is non-dissociated 2-amino-3- (4-bromobenzoyl) phenylacetic acid itself, 2-amino- 3- (4-Bromobenzoyl) phenylacetic acid salt, zwitterion (carboxy group forms carboxylate ion and amino group forms ammonium ion), positive ion body (only amino group contains ammonium ion) And at least one selected from the group consisting of a negative ionic form (only the carboxy group forms a carboxylate ion) can exist in dissolved form, but 2-amino-3- (4 -Bromobenzoyl) phenylacetic acid salts are preferred.
• 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, Examples thereof include salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, metal salts, salts with organic amines, and the like.
• 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.
• a preferred salt of 2-amino-3- (4-bromobenzoyl) phenylacetic acid is a sodium salt.
• the concentration of 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve a desired medicinal effect. -1.0% (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.
• Borate ions can be contained in the eye drop of the present embodiment by blending a compound that dissolves in water to generate borate ions. Although it does not specifically limit as this compound, A boric acid and / or a borate are preferable, and it is more preferable to use both a boric acid and a borate. Examples of the borate include borax, sodium borate, potassium borate and the like, and borax is preferable.
• the eye drop of this embodiment is excellent in preservative effect, and when it is 360 mM or less, no boric acid crystals are precipitated.
• the borate ion concentration in the eye drop of the present embodiment is preferably 217 mM as the lower limit, more preferably 219 mM, preferably 340 mM, more preferably 310 mM, and still more preferably 307 mM.
• edetate sodium (ethylenediaminetetraacetic acid sodium salt) in the eye drop of the present embodiment may be in the form of a hydrate.
• edetate sodium include edetate monosodium, edetate disodium, and edetate tetrasodium.
• hydrates include edetate disodium dihydrate.
• the ophthalmic solution of this embodiment is excellent in antiseptic effect when the sodium edetate concentration is 0.001% (w / v) or more.
• E. coli and / or Pseudomonas aeruginosa has an antiseptic effect, and if it is 0.15% (w / v) or less, no irritation occurs.
• the borate ion concentration in the eye drop of the present embodiment is preferably 0.005% (w / v), more preferably 0.01% (w / v) as a lower limit, and 0.02% (w / v).
• the upper limit is preferably 0.13% (w / v), more preferably 0.1% (w / v), and still more preferably 0.08% (w / v).
• the ophthalmic solution of the present embodiment contains sodium edetate and borate ions at concentrations within the above-mentioned numerical ranges, and thus can exhibit synergistically excellent antiseptic effects.
• the eye drop of the present embodiment contains substantially no cationic preservative and nonionic surfactant.
• “substantially does not contain a cationic preservative” means that the concentration of the cationic preservative in the eye drop is 0.003% (w / v) or less, preferably 0.8. It is 001% (w / v) or less, and more preferably indicates that no cationic preservative is contained.
• “substantially does not contain a nonionic surfactant” means that the concentration of the nonionic surfactant in the eye drop is 0.003% (w / v) or less. Yes, preferably 0.001% (w / v) or less, more preferably no nonionic surfactant.
• the eye drop of this embodiment does not substantially contain a cationic preservative such as chlorhexidine, benzethonium chloride, cetylpyridinium chloride, and cetrimide, and is also polyoxyethylene hydrogenated castor oil 20, polyoxyethylene.
• a cationic preservative such as chlorhexidine, benzethonium chloride, cetylpyridinium chloride, and cetrimide
• polyoxyethylene hydrogenated castor oil polyoxyethylene.
• Contains substantially no nonionic surfactants such as polyoxyethylene hydrogenated castor oil such as hydrogenated castor oil 60, polyoxyethylene sorbitan such as polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate .
• the eye drop of the present embodiment does not substantially contain these cationic antiseptics, so there is no need to worry about damaging to corneal cells, and substantially contains these nonionic surfactants. Therefore, the dripping of the ophthalmic solution and the cracking of the ophthalmic container do not occur, and the generation of fine particles in the ophthalmic solution can be suppressed.
• the concentration is preferably 0.01% (w / v), more preferably 0.05% (w / v), 0.1% (w / v) is more preferable, and the upper limit is preferably 0.5% (w / v), more preferably 0.3% (w / v).
• the ophthalmic solution of the present embodiment is easy to adjust the osmotic pressure ratio of the eye drop to the above numerical range, although boric acid is precipitated. It is hard to do and it is easy to show the superior antiseptic effect.
• the eye drop of the present embodiment preferably further contains a pH adjuster in order to adjust the pH to the preferred range described below.
• the pH adjusting agent is not particularly limited as long as it can adjust the pH of the eye drop of the present embodiment, and specific examples include dilute hydrochloric acid, sodium hydroxide and the like.
• the addition amount (concentration) of the pH adjusting agent is not particularly limited as long as the pH of the eye drop of the present embodiment can be adjusted to a preferable range described later.
• the eye drop of the present embodiment may further contain a buffering agent in order to adjust the pH to a preferable range described later.
• a buffering agent examples include epsilon-aminocaproic acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate and the like.
• the addition amount (concentration) of the buffering agent is not particularly limited as long as the pH of the eye drop of the present embodiment can be adjusted to a preferable range described later.
• the eye drop of the present embodiment does not substantially contain a cationic preservative, but may be contained as long as it is a preservative other than the cationic preservative and can be used as a pharmaceutical additive. For example, 0.002% (w / v) or less is preferable, and 0.0015% (w / v) or less is more preferable. However, since the ophthalmic solution of this embodiment contains borate ions and sodium edetate in a specific concentration range as described above, it is not necessary to contain a preservative other than the cationic preservative, and other than the cationic preservative. It is preferable that no preservative is contained.
• the eye drop of the present embodiment also contains a nonionic surfactant substantially, but is a surfactant other than the nonionic surfactant and can be used as an additive for pharmaceuticals. If it is, it may contain, for example, you may contain a cationic surfactant and anionic surfactant.
• cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- Examples thereof include 2-alkyl imidazoline, 1-hydroxylethyl-2-alkyl imidazoline and the like.
• anionic surfactants include phospholipids, and examples of phospholipids include lecithin.
• phospholipids include lecithin.
• the ophthalmic solution of the present embodiment contains borate ions and sodium edetate in a specific concentration range as described above, it is not necessary to contain a surfactant other than the nonionic surfactant. It is preferable that no surfactant other than the surfactant is contained.
• the eye drop of the present embodiment is preferably an aqueous composition.
• the “aqueous composition” means a composition based on water.
• the eye drop of the present embodiment is preferably an aqueous solution containing at least the above-mentioned 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, borate ion and sodium edetate as an aqueous composition.
• an ophthalmic solution can be used as an eye drop described later.
• a pharmaceutically acceptable additive can be added as necessary.
• the pH of the ophthalmic solution of this embodiment is preferably 7.8, more preferably 8.0, as the lower limit in terms of sufficiently dissociating the salt when bromfenac salt is used as the medicinal component.
• the pH of the eye drop is preferably 8.6, more preferably 8.3, as the upper limit of the eye irritation.
• a pH within the above numerical range is preferred.
• the eye drop of this embodiment has an osmotic pressure ratio of 0.8 to 1.3.
• the eye drop of the present embodiment is less likely to precipitate boric acid and easily exhibits excellent antiseptic effect.
• the lower limit of the osmotic pressure ratio in the eye drop of the present embodiment is preferably 0.80, more preferably 0.86, still more preferably 1.05, and the upper limit is preferably 1.25, more preferably 1.23. Preferably, 1.21 is more preferable, and 1.20 is even more preferable.
• the osmotic pressure ratio is preferably in the above numerical range. In the ophthalmic solution of the present embodiment, the osmotic pressure ratio is considered to depend on the balance of the salt concentration such as sodium chloride and potassium chloride, the borate ion concentration and the added amount of pH adjusting agent and buffering agent.
• the ophthalmic solution of the present embodiment conforms to the criteria in the 16th revised Japanese Pharmacopoeia preservation efficacy test method.
• the criteria used in the examples described later are applied as the judgment criteria.
• the eye drop of the second aspect of the present embodiment is not limited to Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis, as well as Escherichia coli and Pseudomonas aeruginosa, which generally require stronger storage efficacy. Storage efficacy that meets the criteria can be exhibited in 2 weeks and 4 weeks of storage.
• the preservative effect determined by the above preservative effect test method is also referred to as antiseptic effect.
• the eye drop in the first aspect of the present embodiment can also preferably have a preservative efficacy that meets the above criteria.
• the eye drop of this embodiment can be prepared, for example, by a conventional method.
• 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof, borate ion and sodium edetate and as necessary It can be obtained by dissolving sodium chloride, potassium chloride, a buffering agent or the like to be blended accordingly in water and adjusting the pH by adding a pH adjusting agent if necessary.
• 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 eye drop of the present invention is stable over a long period of time, can suppress the generation of precipitates due to the coexistence of bromfenac and other components, and can maintain the concentration of bromfenac high over a long period of time. Therefore, the eye drop of the present invention can stably exhibit effects such as medicinal effects as a therapeutic agent for symptoms associated with eye inflammation such as conjunctivitis, allergic conjunctivitis, blepharitis.
• the eye drop of the present invention can exhibit an excellent antiseptic or storage effect over a long period of time, and there is no dripping of the eye drop and no cracking occurs in the eye drop container.
• the eye drop can be stored in a multi-dose type container. It is suitable for.
• the present invention relates to a method for maintaining antiseptic efficacy of eye drops, comprising 0.01-1.0% (w / v) 2-amino-3- (4-bromobenzoyl) phenylacetic acid or a salt thereof,
• a method for maintaining the preservative effect of an eye drop substantially free of a nonionic surfactant also referred to as “a method for maintaining preservative effect of eye drop”.
• the eye drop contains 215 to 360 mM borate ions and 0.001 to 0.15% (w / v) sodium edetate, and the osmotic pressure ratio of the eye drop is 0.8.
• Including -1.3 According to this method, even an eye drop that does not substantially contain a cationic preservative and a nonionic surfactant can exhibit an excellent antiseptic effect over a long period of time. In addition, the preservation effect can be exerted.
• the description of these components in the eye drops of the present invention described above can be applied to borate ions, sodium edetate, and the osmotic pressure ratio, including preferred values thereof. Moreover, the description about the eye drop of the above-mentioned this invention is applicable as an eye drop with which antiseptic effect is maintained by this method.
• Example 1 0.9 g of boric acid, 0.7 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride / 0.1% sodium edetate aqueous solution were added and stirred well. To this solution, 0.1 g of sodium 2-amino-3- (4-bromobenzoyl) phenylacetate.3 / 2 hydrate (hereinafter also referred to as compound A) was added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to around 8.0, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 2 0.9 g of boric acid, 0.7 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride / 0.1% sodium edetate aqueous solution were added and stirred well. To this solution, 0.08 g of sodium edetate hydrate and 0.1 g of compound A were added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to around 8.0, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 3 A beaker containing 85 mL of 2.2% boric acid / 2.2% borax aqueous solution, 50 mL of 0.6% sodium chloride / 0.4% potassium chloride aqueous solution, and 4.25 mL of 0.8% sodium edetate hydrate aqueous solution In addition, it was well stirred. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to about 8.0, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 4 A beaker containing 85 mL of 2.2% boric acid / 2.2% borax aqueous solution, 50 mL of 0.6% sodium chloride / 0.4% potassium chloride aqueous solution, and 4.25 mL of 0.8% sodium edetate hydrate aqueous solution In addition, it was well stirred. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to around 8.6, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 5 1.1 g boric acid, 0.9 g borax, 60 mL purified water, 20 mL 0.5% sodium chloride / 0.1% sodium edetate aqueous solution were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to around 8.0, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 6 1.1 g boric acid, 0.9 g borax, 60 mL purified water, 20 mL 0.5% sodium chloride / 0.1% sodium edetate aqueous solution were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to bring the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 7 160 mL of an aqueous solution of 1.4% boric acid, 1.4% borax, 0.13% sodium chloride, 0.03% sodium edetate hydrate was added to a beaker. 0.3 g of sodium chloride and 0.2 g of potassium chloride were added and stirred well. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid and sodium hydroxide test solution 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 200 mL.
• Example 8 1.3 g boric acid, 1.0 g borax, 60 mL purified water, 20 mL 0.5% sodium chloride / 0.1% sodium edetate aqueous solution were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to adjust the pH to around 8.0, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 9 80 mL of a solution of 1.6% boric acid, 1.3% borax, 0.03% sodium edetate hydrate, 0.13% sodium chloride and 0.13% compound A was added to the beaker. Dilute hydrochloric acid and sodium hydroxide test solution were added to bring the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 100 mL.
• Example 10 After adding 160 mL of purified water to the beaker, 2.2 g of boric acid, 2.2 g of borax, 0.4 g of sodium chloride, and 0.04 g of sodium edetate hydrate were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 11 After adding 160 mL of purified water to the beaker, 2.2 g of boric acid, 2.2 g of borax, 0.4 g of sodium chloride, and 0.01 g of sodium edetate hydrate were added and stirred well. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 12 After adding 160 mL of purified water to a beaker, 2.2 g of boric acid, 2.2 g of borax, and 0.04 g of sodium edetate hydrate were added and stirred well. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 13 After adding 160 mL of purified water to a beaker, 2.4 g of boric acid, 2.0 g of borax, 0.4 g of sodium chloride, and 0.04 g of sodium edetate hydrate were added and stirred well. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 7.8, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 14 After adding 160 mL of purified water to the beaker, 2.6 g of boric acid, 2.8 g of borax, and 0.1 g of sodium edetate hydrate were added and stirred well. 0.2g of compound A was added to this liquid, and it fully stirred. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Comparative Example 1 After adding 50 mL of purified water to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added and stirred well. To this solution, 2 mL of a 1.0% sodium edetate hydrate solution and 0.1 g of Compound A were added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to bring 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 2 After adding 50 mL of purified water to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added and stirred well. To this solution, 5 mL of a 1.0% sodium edetate hydrate solution and 0.1 g of Compound A were added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to bring 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 3 After adding 50 mL of purified water to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid and sodium hydroxide test solution were added to bring 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 4 After 160 mL of purified water was added to the beaker, 1.6 g of boric acid, 2.0 g of borax, and 0.4 g of sodium chloride were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Comparative Example 5 After 160 mL of purified water was added to the beaker, 1.8 g of boric acid, 1.8 g of borax, and 0.4 g of sodium chloride were added and stirred well. To this solution, 0.1 g of Compound A was added and stirred sufficiently. Dilute hydrochloric acid or sodium hydroxide test solution was added to adjust the pH to around 8.3, and then an appropriate amount of purified water was added to make the total volume 200 mL.
• Example 1 to 9 and Comparative Examples 1 to 3 were dispensed into five sterilized PE containers, and the precultured test bacteria shown in Tables 5 to 7 below were 10 5 to 10 6 cells / mL. After preparing the mixed sample so inoculated, it was stored at 20-25 ° C. in the dark. In addition, each test specimen was inoculated independently without mixing the test bacteria. After storage for 2 weeks and 4 weeks from the start of storage, 1 mL of each mixed sample was sampled, and the number of viable bacteria was measured. Test strains are listed below.
• the mobile phase was measured for 8 minutes in a gradient mode using acetonitrile and 0.01% phosphoric acid solution adjusted to pH 3.5 at a flow rate of 0.47 mL.
• As a sample 2 ⁇ L of 10-fold diluted water was injected and detected at a wavelength of 230 nm.
• the osmotic pressure ratio was measured by the method described above. The solution state was observed visually. The results are shown in Table 8.

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• 2016
  • 2016-06-09 KR KR1020187000016A patent/KR20180016469A/ko unknown
  • 2016-06-09 JP JP2016115280A patent/JP2017002042A/ja active Pending
  • 2016-06-09 WO PCT/JP2016/067220 patent/WO2016199854A1/ja active Application Filing
  • 2016-06-13 TW TW105118302A patent/TW201713325A/zh unknown

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