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
  • A61K47/02—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
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

• the present invention relates to an aqueous ophthalmic composition and a method for improving the preservation effect.
• aqueous ophthalmic composition Since it is expected that the aqueous ophthalmic composition will be used continuously after opening, it is desirable to prevent the product from spoiling due to microbial contamination. Therefore, in order to prevent spoilage, it is necessary to add a component having a bactericidal action or antibacterial action such as a preservative. Sulfite and thiosulfate are known to be one of the additives having an antibacterial action. However, sulfite and thiosulfate have not been used as preservatives for ophthalmic compositions.
• ophthalmic compositions contain various components, a nonionic surfactant is often added to prevent precipitation.
• the present invention has been made in view of the above problems, and an object thereof is to provide a composition having excellent storage effect and a method for improving the storage effect, which contains a sulfite or a thiosulfate and a nonionic surfactant. To do.
• the present inventors have found that sulfite and thiosulfate, when used as preservatives for ophthalmic compositions, have an insufficient preservation effect, and further that nonionic surfactants have the antibacterial effect of sulfite. It was found that it has a reducing effect.
• the present inventors have added one or more kinds selected from liquid paraffin and petrolatum to a composition containing a sulfite or thiosulfate and a nonionic surfactant. The present inventors have completed the present invention by finding that the desired preservation effect can be obtained.
• the present invention provides the following aqueous ophthalmic composition and a method for improving the preservation effect.
• A one or more selected from sulfites and thiosulfates, An aqueous ophthalmic composition containing (B) a nonionic surfactant, and (C) one or more selected from liquid paraffin and petrolatum.
• B a nonionic surfactant
• C one or more selected from liquid paraffin and petrolatum.
• An aqueous ophthalmic composition containing (A) one or more kinds selected from sulfites and thiosulfates, and (B) a nonionic surfactant, (C) A method for improving the preservation effect of the above aqueous ophthalmic composition, which comprises blending one or more selected from liquid paraffin and petrolatum.
• an aqueous ophthalmic composition containing a sulfite or thiosulfate and a nonionic surfactant, which is excellent in preservation effect.
• the component (A) of the present invention is one or more selected from sulfites and thiosulfates, and can be used alone or in combination of two or more.
• the sulfite of the present invention include pharmaceutically acceptable sulfites.
• sodium sulfite, potassium sulfite, dry sodium sulfite (anhydrous sodium sulfite), sodium pyrosulfite, potassium pyrosulfite, sodium hydrogen sulfite, potassium hydrogen sulfite and the like can be mentioned.
• Examples of the thiosulfate of the present invention include sodium thiosulfate and ammonium thiosulfate. Of these, dry sodium sulfite, sodium pyrosulfite, sodium hydrogen sulfite, and sodium thiosulfate are preferable from the viewpoint of good storage effect. In particular, those listed in the Japanese Pharmacopoeia are suitable.
• the blending amount of the component (A) is 0.005 w / v% (mass / volume%, g / 100 mL) in the aqueous ophthalmic composition (hereinafter, sometimes referred to as composition) from the viewpoint of storage effect.
• composition aqueous ophthalmic composition
• the above is preferable, and 0.5 w / v% or less is preferable from the viewpoint of eye irritation. 0.01 to 0.4 w / v% is more preferable, and 0.02 to 0.2 w / v% is further preferable.
• the content of the component (A) is preferably 0.01 w / v% or more in the composition, and as described above, it is preferably 0.5 w / v% or less from the viewpoint of eye irritation. 0.02 to 0.4 w / v% is more preferable, and 0.05 to 0.2 w / v% is further preferable.
• the component (B) of the present invention is a nonionic surfactant and can be used alone or in combination of two or more kinds.
• polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol), polyethylene glycol monostearate, etc. Can be mentioned.
• polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol are preferable.
• Polyoxyethylene castor oil is a compound obtained by addition-polymerizing ethylene oxide (EO) to castor oil, and several types of ethylene oxide having different average addition mole numbers are known. .
• the average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but is preferably 3 to 60 moles.
• polyoxyethylene castor oil 3 (EO average addition mole number 3), polyoxyethylene castor oil 10 (EO average addition mole number 10), polyoxyethylene castor oil 20 (EO average addition mole number 20), poly Oxyethylene castor oil 35 (EO average addition mole number 35), polyoxyethylene castor oil 40 (EO average addition mole number 40), polyoxyethylene castor oil 50 (EO average addition mole number 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like.
• polyoxyethylene castor oil 35 is preferable.
• Polyoxyethylene hydrogenated castor oil is a compound obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and several types with different average number of added moles of ethylene oxide are known. ing.
• the average number of moles of added ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is preferably 5 to 100 moles.
• polyoxyethylene hydrogenated castor oil 5 (EO average addition mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average addition mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average addition mole number 20) ), Polyoxyethylene hydrogenated castor oil 30 (EO average addition mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average addition mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average addition mole number 50), Polyoxyethylene hydrogenated castor oil 60 (EO average addition mole number 60), polyoxyethylene hydrogenated castor oil 80 (EO average addition mole number 80), polyoxyethylene hydrogenated castor oil 100 (EO average addition mole number 100), and the like. To be Among them, polyoxyethylene hydrogenated castor oil 60 is preferable.
• polyoxyethylene sorbitan fatty acid ester examples include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), and polyoxyethylene monostearate.
• polyoxyethylene (20) sorbitan monooleate (polysorbate 80) is preferable.
• Polyoxyethylene polyoxypropylene glycol is a block copolymer composed of polyoxyethylene chain (POE) and polyoxypropylene chain (POP), and is an average of ethylene oxide (EO) and propylene oxide (PO).
• POE polyoxyethylene chain
• POP polyoxypropylene chain
• EO ethylene oxide
• PO propylene oxide
• Several types with different numbers of added moles are known.
• the average addition mole number of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol is not particularly limited, but an average addition mole number of 5 to 200 moles is exemplified.
• Polyethylene glycol monostearate is a compound obtained by addition-polymerizing ethylene oxide with stearic acid, and several types are known that differ in the average number of moles of ethylene oxide added.
• the average number of moles of ethylene oxide added to polyethylene glycol monostearate is not particularly limited, but is preferably 5 to 100 moles.
• polyethylene glycol monostearate 10 (EO average addition mole number 10), polyethylene glycol monostearate 25 (EO average addition mole number 25), polyethylene glycol monostearate 40 (EO average addition mole number 40), mono Examples thereof include polyethylene glycol stearate 45 (EO average addition mole number 45), polyethylene glycol monostearate 55 (EO average addition mole number 55), and polyethylene glycol monostearate 100 (EO average addition mole number 100).
• polyethylene glycol stearate 40 is preferable.
• the content of the component (B) in the composition is preferably 0.001 to 10 w / v%, more preferably 0.01 to 5 w / v%, still more preferably 0.1 to 1 w / v%.
• the blending amount thereof is preferably 0.001 to 10 w / v% in the composition, more preferably 0.01 to 5 w / v%, and even more preferably 0. 1 to 1 w / v% is more preferable.
• the blending amount thereof in the composition is preferably 0.005 to 10 w / v%, more preferably 0.05 to 5 w / v%, and 0.5 to 1 w / v%. Is more preferable.
• the blending amount thereof is preferably 0.002 to 10 w / v% in the composition, more preferably 0.02 to 5 w / v%, and 0.2 to 1 w / v. % Is more preferable.
• the component (C) of the present invention is one or more selected from liquid paraffin and petrolatum, and can be used alone or in combination of two or more.
• the component (C) improves the storage efficacy of a composition containing (A) sulfite or thiosulfate and (B) a nonionic surfactant.
• Liquid paraffin is a component that has a high tear oil layer stabilizing effect on the unstable tear oil layer with increased saturated lipids.
• Liquid paraffin is an oil component having a lower polarity than vegetable oil consisting of triglycerides or squalane having a short carbon chain length among hydrocarbons.
• Liquid paraffin is a mixture of hydrocarbons obtained from crude oil and is liquid at room temperature. For example, it is produced by a method such as vacuum distillation of a crude oil as a raw material, vacuum distillation, solvent dehisting treatment, and then solvent refining method or hydrocracking method.
• the liquid paraffin used in the present invention is not particularly limited and may be used alone or in combination of two or more.
• the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used.
• the presence or absence of double bonds in the hydrocarbon is not particularly limited, but those containing a large amount of saturated hydrocarbon are preferably used.
• the structure of the hydrocarbon may include any of a straight chain, a branched chain and a cyclic structure, and liquid paraffin having any specific gravity can be used.
• liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable.
• a suitable type of tocopherol may be contained as a stabilizer.
• the viscosity of liquid paraffin correlates with its molecular weight. According to the 17th revised Japanese Pharmacopoeia Method 1 (37.8 ° C.), the viscosity is preferably 30 to 100 mm 2 / s, and the viscosity is 37 to 88 mm 2. / S is more preferable, and 74 to 88 mm 2 / s is even more preferable.
• Vaseline is a semi-solid oily substance that remains when distilled and refined from petroleum, and is composed of solid hydrocarbons and liquid hydrocarbons. It is semi-solid at room temperature, and solid and liquid coexist. Any specific gravity of petrolatum can be used, and the petrolatum used in the present invention is not particularly limited, and can be used alone or in combination of two or more kinds.
• the carbon chain length of the above hydrocarbon is not particularly limited, but those having 15 or more are preferably used.
• the presence or absence of double bonds in the hydrocarbon is not particularly limited, but those containing a large amount of saturated hydrocarbon are preferably used.
• the carbon chain may be linear, branched or cyclic, but most are paraffins having a branched chain (isoparaffin).
• vaseline white vaseline and yellow vaseline listed in the Japanese Pharmacopoeia are suitable.
• a suitable type of tocopherol may be contained as a stabilizer.
• the blending amount of the component (C) is preferably 0.0001 to 1 w / v% in the composition, more preferably 0.005 to 0.5 w / v%, and further preferably 0.01 to 0.2 w / v%. .
• 0.001 to 1 w / v% is preferable, 0.005 to 0.5 w / v% is more preferable, 0.01 to 0.2 w / v% is further preferable, and 0.02 to 0.2 w / v% is particularly preferred.
• petrolatum 0.0001 to 0.1 w / v% is preferable, 0.001 to 0.05 w / v% is more preferable, and 0.001 to 0.01 w / v% is further preferable.
• the blending mass ratios of the respective components shown below are as follows.
• the above ratio is the w / v% ratio, but it is the same value as the mass ratio.
• it is less than 1.5 there is a high possibility that the sulfite will cause a sensation of irritation when instilled, and from the viewpoint of the preservation effect and the decomposition product suppressing effect of the component (B), 100 or less is preferable.
• composition of the present invention can be added in appropriate amounts within a range that does not impair the effects of the present invention.
• Other components include oil components, preservatives, sugars, buffers, pH adjusters, isotonic agents, stabilizers, cooling agents, polyhydric alcohols, thickeners, drugs and the like. These components may be blended alone or in an appropriate combination of two or more. The blending amounts of the components shown below are preferable ranges when blended.
• oil component examples include castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, mixed tocopherol, wax ester, sterol ester and the like.
• the blending amount thereof is preferably 0.001 to 1.0 w / v% in the composition, more preferably 0.001 to 0.5 w / v%, and 0.001 to 0.25 w / v. % Is more preferable, and 0.1 w / v% or less is the most preferable.
• composition of the present invention obtains a preservation effect by the components (A), (B) and (C), but a preservative can be added.
• preservatives include benzalkonium chloride, benzethonium chloride, sorbic acid, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like.
• compositions can be blended in the composition at 0.1 w / v% or less, preferably 0.01 w / v% or less, more preferably 0.001 w / v% or less, still more preferably 0.0001 w / v% or less, and blended. Most preferably not.
• sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be a d-form, an l-form, or a dl-form.
• the blending amount thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and further 0.001 to 0.1 w / v%. preferable.
• the buffer examples include boric acid or a salt thereof (borax etc.), trometamol, citric acid or a salt thereof (sodium citrate etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate etc.). , Tartaric acid or its salt (sodium tartrate etc.), gluconic acid or its salt (sodium gluconate etc.), acetic acid or its salt (sodium acetate etc.), carbonic acid or its salt (sodium hydrogen carbonate etc.), various amino acids (epsilon- Aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate) and the like.
• boric acid or a salt thereof boric acid or a salt thereof (borax etc.)
• trometamol citric acid or a salt thereof (sodium citrate etc.)
• phosphoric acid or a salt thereof sodium hydrogen phosphate, sodium di
• the blending amount thereof is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 2 w / v%, and further preferably 0.001 to 1 w / v% in the composition. preferable.
• an inorganic acid or an inorganic alkaline agent can be mentioned.
• the inorganic acid may be (dilute) hydrochloric acid.
• the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
• the pH of the composition is preferably 3.5 to 8.0, more preferably 5.5 to 8.0. The pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).
• the isotonicity agent examples include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like. Can be mentioned. From the viewpoint of further improving various symptoms caused by destabilization of the tear oil layer, it is preferable to add sodium chloride or potassium chloride and to make it isotonic.
• the osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments Co.).
• the stabilizer examples include ethylenediaminetetraacetic acid (EDTA), sodium edetate, sodium edetate hydrate, cyclodextrin, dibutylhydroxytoluene and the like. Among them, ethylenediaminetetraacetic acid (EDTA) is preferable from the viewpoint of the preservation effect and the decomposition product suppressing effect of the component (B).
• the blending amount thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v%. Is more preferable.
• cooling agent examples include menthol, camphor, borneol, geraniol, cineol, linalool and the like. Any of d-form, l-form and dl-form may be used.
• the blending amount thereof is preferably 0.0001 to 0.2 w / v% in the composition.
• polyhydric alcohol examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
• the blending amount thereof in the composition is preferably 0.001 to 5.0 w / v%, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v%. Is more preferable.
• the thickener examples include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like.
• a thickening agent When a thickening agent is added, its content is preferably 0.001 to 5.0 w / v% in the composition, more preferably 0.001 to 1 w / v%, and 0.001 to 0.1 w / v%. Is more preferable.
• Examples of the drug include decongestant components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), Anti-inflammatory / astringent (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt, etc.), antihistamine (for example, diphenhydramine hydrochloride, chlorpheni
• the compounding amount of the drug can be selected as an effective appropriate amount of each drug, but 0.001 to 5 w / v% is preferable in the composition, and 0.001 to 1 w / v% is more preferable. Preferably, 0.001 to 0.1 w / v% is more preferable.
• the method for producing the composition of the present invention is not particularly limited, but for example, a mixed solution of an oil component such as the component (C) and a surfactant component such as the component (B), and an aqueous component such as the component (A) may be used. It can be obtained by mixing with an aqueous solution containing the mixture, mixing and emulsifying, adjusting the pH, and then adjusting the total volume with water.
• the mixing method of each liquid may be a general method, and may be appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the number of revolutions is not particularly limited, and it should be set to such a degree that no vigorous bubbling occurs. Is preferred.
• the mixing temperature of each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component have melting temperatures or higher, and specifically, they are appropriately selected from the range of 40 to 95 ° C.
• the injection pressure is preferably 100 to 245 MPa, more preferably 200 to 245 MPa.
• the back pressure is preferably 3 to 10 MPa, more preferably 3 to 5 MPa.
• the number of passes is preferably 1 to 10 times, more preferably 1 to 5 times.
• the obtained composition after filling the obtained composition in a resin container, it may be further sealed with a package, and an inert gas in the space formed between the container and the package may be sealed therein.
• the product may be filled in a resin container and sealed with a package together with an oxygen absorber.
• the composition of the present invention is an "aqueous ophthalmic composition".
• the "aqueous ophthalmic composition” refers to an ophthalmic composition whose medium is water.
• the water content in the composition is preferably 90.0 to 99.3 w / v%, more preferably 93.0 to 99.0 w / v%, and further preferably 95.0 to 97.5 w / v%. preferable.
• the average particle diameter of the emulsion particles (the association of the component (B) and the component (C)) contained in the composition of the present invention is preferably 100 nm or less, more preferably 10 to 50 nm, even more preferably 20 to 40 nm. With such a particle size, the preservation effect is further improved.
• the average particle size refers to the average particle size (median size) calculated by the cumulant method from the autocorrelation function obtained by the photon correlation method.
• the particle diameter is measured under a constant temperature condition of 25 ° C. using a thermostatic chamber by various measuring devices applying the principle of dynamic light scattering and the like. For example, it can be measured with a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.).
• the transmittance of the composition of the present invention is preferably 10 to 100%, more preferably 80 to 100%.
• the transmittance of the present invention refers to the transmittance at a wavelength of 600 nm measured by using a spectrophotometer (for example, UV-1800, Shimadzu Corporation).
• the composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eyes, preferably 20 mPa ⁇ s or less, more preferably 10 mPa ⁇ s or less, even more preferably 5 mPa ⁇ s or less.
• the viscosity is measured by using a cone-plate type viscometer (DV2T, Eiko Seiki Co., Ltd.).
• the composition of the present invention may be used as a liquid formulation as it is, or may be prepared as a gel formulation or the like.
• eye drops for example, general eye drops, eye drops for contact lenses, etc.
• eye washes generally eye wash, eye drops to be used after removing contact lenses, etc.
• contact lenses Examples include mounting liquid and contact removal liquid.
• it is suitable as an ophthalmic composition for contact lenses such as an eye drop for contact lenses, an eye wash used after removing a contact lens, a contact lens mounting solution, and a contact removing solution.
• the contact lens is not particularly limited, such as a hard contact lens, an O 2 hard contact lens, a soft contact lens and a silicone hydrogel contact lens.
• composition of the present invention When the composition of the present invention is used as an eye drop or an eye drop for contact lenses, it is preferable to apply 1 to 3 drops of 10 to 100 ⁇ L each time, and 1 to 6 times per day, preferably 10 to 10 times per time. 1 to 3 drops of 50 ⁇ L, more preferably 1 to 6 times a day, is more preferable. More preferably, 1 to 3 drops of 10 to 30 ⁇ L each time and 1 to 6 times per day. When used as an eye wash, it is preferable to wash 3 to 6 mL once and wash 3 to 6 times per day.
• the present invention provides a composition containing a sulfite or thiosulfate and a nonionic surfactant with one or more selected from liquid paraffin and petrolatum to obtain a desired preservation effect. Therefore, the following inventions are provided. (A) for blending an aqueous ophthalmic composition containing at least one selected from sulfites and thiosulfates and (B) a nonionic surfactant, and (C) selected from liquid paraffin and vaseline. A preservative composition containing one or more species. Suitable components and blending amounts are the same as above.
• the present invention is An aqueous ophthalmic composition containing (A) one or more kinds selected from sulfites and thiosulfates, and (B) a nonionic surfactant, (C) A method for improving the preservation effect of an aqueous ophthalmic composition, which comprises one or more selected from liquid paraffin and petrolatum. Suitable components and blending amounts are the same as above.
• % Of the composition indicates w / v% (g / 100 mL), and the ratio indicates a mass ratio (the same value as the w / v% ratio).
• Examples and comparative examples described as having high-pressure emulsification in the table The component (A) and each aqueous component were dissolved in 90 mL of water, and heated and mixed at 90 ° C. for 15 minutes to obtain an aqueous component aqueous solution. At the same time, a premix of an oil component such as (C) and a nonionic surfactant (B) was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the above aqueous component aqueous solution, and the mixture was further heated and mixed at 90 ° C. for 15 minutes.
• an oil component such as (C) and a nonionic surfactant (B)
• the obtained product was treated with a high-pressure emulsifier (Starburst Mini, Sugino Machine Ltd.) at an injection pressure of 200 MPa and a back pressure of 3 MPa five times to prepare an aqueous ophthalmic composition.
• a high-pressure emulsifier Starburst Mini, Sugino Machine Ltd.
• the following evaluation was performed on the obtained aqueous ophthalmic composition.
• Example 1 and Comparative Example 1 shown in Table 1 a storage efficacy test was carried out in accordance with the storage efficacy test method of the 17th revised Japanese Pharmacopoeia / reference information.
• Five strains of bacteria and fungi shown below were used as test strains, and the bacteria were added so that 1 mL of the sample of each example would be 10 5 cells and allowed to stand at 25 ° C.
• 1 mL of each sample was cultured in agar medium for 5 days, and the viable cell count was measured.
• the residual rate (%) with respect to the initial number of bacteria (10 5 cells / mL) was calculated.
• the operation was performed aseptically. Those satisfying the criteria in Table 2 were regarded as conforming, and those not satisfying the criteria were disqualified.
• Example 1 the criteria were met for all bacterial species. In Comparative Example 1, four strains met the criteria, but S. aureus did not. From the above, Staphylococcus aureus is the most suitable for the determination of the preservation effect of the composition containing (A) one or more kinds selected from sulfites and thiosulfates and (B) a nonionic surfactant. The examples and comparative examples having the compositions shown in the table below were evaluated and evaluated using only Staphylococcus aureus.
• the amount of decomposed products after storage was evaluated by the following method.
• Each aqueous ophthalmic composition was prepared, filled into a 20 mL glass ampoule, sealed, and stored at 70 ° C. for 6 days.
• the amount of formaldehyde after storage was quantified according to the following method.
• ⁇ Formaldehyde determination method> The formaldehyde content of the aqueous ophthalmic composition after storage was determined by high performance liquid chromatography (column: stainless steel tube having an inner diameter of about 4.6 mm and a length of about 15 cm and octadecylsilylated silicone polymer-coated silica gel of about 5 ⁇ m for liquid chromatography).
• the mobile phase water / acetonitrile mixed solution (4: 1)
• Liquid paraffin 17th revision Japanese Pharmacopoeia first hand (37.8 °C) viscosity 76.6mm 2 / s (74 ⁇ 88mm 2 / s) (KAYDOL, made island Trade Co., Ltd.) White Vaseline (Japanese Pharmacopoeia White Vaseline, Kenei Pharmaceutical Co., Ltd.) Purified Lanolin (Japanese Pharmacopoeia Purified Lanolin, Kenei Pharmaceutical Co., Ltd.) Retinol palmitate (retinol palmitate, DSM) Polyoxyethylene hydrogenated castor oil: Polyoxyethylene hydrogenated castor oil 60 (HCO60 (medicinal), manufactured by Nippon Surfactant Industry Co., Ltd.) POE Castor oil: Polyoxyethylene castor oil 35 (UNIOX C35, NOF Corporation) POE sorbitan fatty acid este

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