Classifications

• • 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
  • A61K31/01—Hydrocarbons
• • 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
• • 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
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • 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
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation solutions

Definitions

• the present invention relates to an aqueous ophthalmic composition containing liquid paraffin and a method for atomizing emulsion particles thereof.
• Liquid paraffin is a cold liquid hydrocarbon and is characterized by having low polarity.
• an ophthalmic composition it is widely used as a base of eye ointment.
• an aqueous ophthalmic composition it is necessary to uniformly disperse liquid paraffin in water, but liquid paraffin becomes turbid even when using a surfactant or the like because of its low polarity, and it transmits It was difficult to raise the rate.
• a preparation having a cloudy appearance has a problem that it is difficult to determine whether or not foreign matter is mixed at the time of production or use.
• the present invention has been made in view of the above problems, and it is possible to increase the permeability of the composition by making the emulsion particles in the composition into fine particles, even without high-pressure emulsification and high concentration of surfactant. It is an object of the present invention to provide an aqueous ophthalmic composition containing liquid paraffin which can suppress creaming by storage and is excellent in appearance storage stability and can stabilize a tear liquid oil layer.
• the tear fluid oil layer is composed of lipids secreted from the meibomian glands. It is known that aging of the lipid in the oil reservoir proceeds with aging and hormonal balance change. It is further known that it is facilitated by contact lens wear. The progress of lipid saturation leads to destabilization of the tear fluid oil layer, development of dry eye and further contributing to eyestrain.
• the present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing this tear oil layer.
• the present inventors contain (A) liquid paraffin and (B) a nonionic surfactant (B (C) terpenoid is added to the aqueous ophthalmic composition in which the blending mass ratio of the component (A) to the component (B) represented by (A) is 3 ⁇ (B) / (A) ⁇ 25.
• the emulsion particles are finely divided without high-pressure emulsification or blending of surfactant at a high concentration, so the permeability of the composition is increased, and creaming by long-term storage It has been found that the present invention can be achieved.
• the present invention provides the following invention.
• (A) Liquid paraffin, (B) non-ionic surfactant, and (C) terpenoid are contained, and the compounding mass of (A) component and (B) component represented by (B) / (A) An aqueous ophthalmic composition having a ratio of 3 ⁇ (B) / (A) ⁇ 25 and a blending amount of the component (C) of 0.0001 to 0.5 w / v%. [2].
• (D) Retinol palmitic acid ester, tocopherol acetate, glycerin, propylene glycol, benzododecinium bromide, 2-methacryloyloxyethyl phosphoryl choline, at least one selected from sesame oil and castor oil according to [1].
• Ophthalmic composition [3].
• the blending mass ratio of the component (A) to the component (B) containing (A) liquid paraffin and (B) a nonionic surfactant and represented by (B) / (A) is 3 ⁇
• a method for atomizing emulsion particles in an aqueous ophthalmic composition wherein the aqueous ophthalmic composition contains 0.0001 to 0.5 w / v% of (C) terpenoid in the aqueous ophthalmic composition. Method of atomizing emulsion particles.
• the transmittance of the composition is increased, and creaming due to long-term storage can be suppressed, and appearance preservation is stable. It is possible to provide an aqueous ophthalmic composition containing liquid paraffin which is excellent in sex and stabilizes a tear oil layer.
• Liquid paraffin is a component having a high effect of stabilizing the tear film formation on an unstable tear solution formation with increased saturated lipid.
• Liquid paraffin is an oil having low polarity as compared with vegetable oils and hydrocarbons composed of triglyceride and squalane having a short carbon chain length among the hydrocarbons.
• liquid paraffin is a mixture of hydrocarbons obtained from crude oil, and is liquid at normal temperature.
• the crude oil is manufactured by a method such as vacuum distillation and solvent degassing treatment using atmospheric residual oil of crude oil as a raw material, and thereafter, a method of solvent purification method or hydrocracking method treatment.
• liquid paraffin used for this invention It can be used individually by 1 type or in combination of 2 or more types suitably.
• the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used.
• limiting in particular about the presence or absence of the double bond in a hydrocarbon is used suitably.
• the hydrocarbon structure may contain any of linear, branched and cyclic structures, and liquid paraffin of any specific gravity can be used.
• liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable.
• the viscosity of liquid paraffin is correlated with its molecular weight, and the kinematic viscosity is preferably 30 to 100 mm 2 / s, preferably 37 to 88 mm in the measurement method of the 16th revised Japanese Pharmacopoeia, Method 1 (37.8 ° C). More preferable is 2 / s, and more preferable is 74 to 88 mm 2 / s. Two or more of the above viscosity ranges may be mixed. By setting it as said 30 mm ⁇ 2 > / s or more, the tear fluid oil layer stabilization effect can be acquired more.
• one having a diameter of 74 to 88 mm 2 / s is preferable. Further, by setting the thickness to 100 mm 2 / s or less, the transmittance of the appearance can be enhanced, and at the same time, the eye irritation specific to liquid paraffin can be further reduced. From the viewpoint of appearance transmittance and reduction of eye irritation, those of 37 to 88 mm 2 / s are preferable.
• the blending amount of the component (A) is 0.001 to 2 w / v% (mass / volume%) in the aqueous ophthalmic composition (hereinafter sometimes referred to as a composition) from the viewpoint of stabilization of the tear fluid oil layer.
• G / 100 mL is preferable, 0.001 to 1 w / v% is more preferable, 0.01 to 1 w / v% is more preferable, and 0.05 to 1 W / V% is most preferable.
• the nonionic surfactant (B) is not particularly limited, and nonionic surfactants used in ophthalmic compositions may be used singly or in appropriate combination of two or more. Specifically, nonionic surfactant other than (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) (B-1) and (B-2) Agents and the like.
• the component (B) preferably contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
• Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and the average addition mole number of ethylene oxide is Several different types are known.
• the average addition mole number of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified.
• 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 added mole number 35), polyoxyethylene castor oil 40 (EO average added mole number 40), polyoxyethylene castor oil 50 (EO average added mole number 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like.
• These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene castor oil 35 from the viewpoint of reducing the feeling of irritation when instilled.
• polyoxyethylene hydrogenated castor oil polyoxyethylene hydrogenated castor oil is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and the average addition of ethylene oxide Several types with different numbers of moles are known.
• the average addition mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, and 5 to 100 moles are exemplified.
• 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), Examples include polyoxyethylene hydrogenated castor oil 60 (EO average added mole number 60), polyoxyethylene cured castor oil 80 (EO average added mole number 80), polyoxyethylene cured castor oil 100 (EO average added mole number 100), etc.
• polyoxyethylene hydrogenated castor oils can be used singly or in appropriate combination of two or more. It is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 from the viewpoint of reducing the feeling of irritation when instilled.
• Nonionic surfactants other than (B-1) and (B-2) polyoxyethylene sorbitan fatty acid ester POE sorbitan represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate) Fatty acid ester), polyoxyethylene polyoxypropylene glycol (POEPOP glycol) represented by poloxamer, polyethylene glycol monostearate (10), polyethylene glycol monostearate represented by polyethylene glycol monostearate (40), etc.
• the compounding amount of the component (B) is appropriately selected by the compounding mass ratio with the component (A), and the compounding mass ratio of the component (A) to the component (B) represented by (B) / (A) is 3 ⁇ (B) / (A) ⁇ 25.
• This ratio is less than 3, the atomization of the emulsion particles is insufficient, and when it exceeds 25, the surfactant which does not form an emulsion is present in excess, and foaming tends to occur.
• the blending mass ratio is preferably 4 ⁇ (B) / (A), and more preferably 5 ⁇ (B) / (A).
• permeability of a composition will be 50% or more.
• the transmittance of the composition becomes 70% or more.
• the said ratio is w / v% ratio, it becomes the same value as mass ratio.
• the blending amount of the component (B) is not particularly limited as long as the above ratio is satisfied, but 0.0001 to 10 w / v% in the composition is preferable, and 0.0001 to 5 w / v% is more preferable.
• the terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, terpene ketone and the like. Also, depending on the carbon number, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes and tetraterpenes.
• monoterpenes such as menthol, menthol, camphor, borneol, leunow, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoid.
• diterpenes such as retinol and retinal
• tetraterpenes such as carotenoid.
• terpenoids can be used either in d form, l form or dl form.
• menthol menthol, menthol, camphor, borneol, geraniol, cineole and linalool are preferable, and menthol, camphor, borneol, geraniol, cineole and linalool are more preferable. More preferably, menthol is used because the effect of atomization of the emulsion particles is large.
• an essential oil containing the above-mentioned compound may be used as a terpenoid.
• oils examples include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, and essential oils of Dipterocarpus plants, rosmarinic oil, lavender oil and the like.
• the compounding amount of the component (C) is 0.0001 to 0.5 w / v% in the composition, and is appropriately selected from the kind of the component (C), other compounding components such as the component (B), and the compounding amount thereof Be done. Preferably, it is 0.0001 to 0.2 w / v%. In this compounding concentration range, there is little possibility that (C) terpenoid precipitates regardless of the types and compounding amounts of other compounding components. Further, from the viewpoint of making the emulsion particles fine, 0.0001 w / v% or more is preferable, and from the viewpoint of reducing the feeling of irritation, 0.075 w / v% or less is more preferable.
• menthol When menthol is blended, it is particularly preferably 0.0001 to 0.075 w / v%, most preferably 0.001 to 0.075 w / v%, when menthol is blended, from the viewpoint of remarkable increase in atomization.
• 0.001 to 0.075 w / v% in the composition is preferable, and 0.005 to 0.075 w / v% is more preferable.
• cineole, linalool or geraniol it is preferably 0.0005 to 0.075 w / v%, more preferably 0.0025 to 0.075 w / v% in the composition, from the viewpoint of increasing the fineness of the composition. .
• the compounding amount of the component (D) in the composition is preferably in the following range from the viewpoint of enhancing atomization of the composition.
• 0.001 to 5.0 w / v% is preferable, 0.01 to 3.0 w / v% is more preferable, and 0.01 to 1.0 w / v% Is more preferred.
• glycerin, propylene glycol, benzododecinium bromide, sesame oil and castor oil are blended, 0.005 to 5.0 w / v% is preferable, 0.05 to 3.0 w / v% is more preferable, and 0 1 to 1.0 w / v% is more preferable.
• blending 2-methacryloyl oxyethyl phosphoryl choline 0.01-5.0 w / v% is preferable, 0.03-2.0 w / v% is more preferable, 0.05-1.0 w / v% is More preferable.
• composition of the present invention other components to be blended in the ophthalmic composition can be blended in appropriate amounts as long as the effects of the present invention are not impaired.
• Other components include preservatives, saccharides, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs and the like. These components may be blended singly or in appropriate combination of two or more.
• the compounding quantity of the component shown below is a preferable range in the case of mix
• preservatives thimerosal, phenylethyl alcohol, alkylaminoethyl glycine, chlorhexidine gluconic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, etc. may be mentioned as preservatives having a hydrophobic moiety such as alkyl chain or benzene ring.
• 0.1 w / v% or less is preferable, 0.01 w / v% or less is more preferable, and 0.001 w / v% or less is more preferable, because paraffin is less likely to be transferred to the tear oil layer. More preferably, they are not contained in
• sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like.
• any of D body, L body, or DL body may be sufficient as these.
• the blending amount thereof 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%. More preferable.
• the buffer examples include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like.
• 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 alkali agent is mentioned.
• the inorganic acid includes (dilute) hydrochloric acid.
• the inorganic alkali agent sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like can be mentioned.
• the pH of the composition may be 3.5 to 13.0, preferably 3.5 to 8.0, more preferably 5.5 to 8 from the viewpoint of further improving various conditions caused by tear film instability. .0 is more preferred.
• the pH is measured at 25 ° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).
• tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate and the like. It can be mentioned. From the viewpoint of further improving the various conditions caused by the tear liquid layer destabilization, it is preferable that at least one of sodium chloride and potassium chloride be blended to be isotonic.
• the osmotic pressure ratio of the composition to saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and more preferably 0.83 from the viewpoint of further improving the various conditions caused by the tear fluid layer destabilization. Most preferred is 1.20.
• the osmotic pressure is measured at 25 ° C. using an automatic osmometer (A2O, Advanced Instruments).
• the stabilizer examples include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
• the blending amount thereof 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 preferred.
• polyhydric alcohols examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.
• the blending amount of the polyhydric alcohol 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.
• thickener examples include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer and the like.
• blending a viscosity agent 0.001-5.0 w / v% in a composition is preferable, 0.001-1 w / v% is more preferable, 0.001-0.1 w / v is preferable. % Is more preferred.
• oil components other than (A) liquid paraffin and (D) soybean oil, olive oil, corn oil, coconut oil, almond oil, medium-chain fatty acid triglyceride, acetic acid-d- ⁇ -tocopherol, retinol palmitate, white petrolatum , Purified lanolin, cholesterol, mixed tocopherols and the like.
• the blending amount thereof is preferably 0.001 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v%, and 0.001 to 0.25 w / v% is most preferred.
• Examples of the drug include decongestion components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride etc.), Anti-inflammatory and astringent agents (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 Salts, etc., antihistamines (eg, diphenhydramine hydrochloride, chlorphenir
• the compounding amount of the drug can be selected from the effective appropriate amount of each drug, but 0.001 to 5.0 w / v% in the composition is preferable, 0.001 to 1 w / v% Is more preferable, and 0.001 to 0.1 w / v% is more preferable.
• the method for producing the composition of the present invention is not particularly limited, and the composition can be obtained by mixing the components (A), (B) and (C) and optional components as needed.
• a mixed solution of oily components such as (A), part or all of (B) and (C) components is mixed with an aqueous solution containing an aqueous component and emulsified, and after adjusting the pH, the total volume is adjusted with water
• the mixing method of each liquid may be a general method, and is appropriately performed using a pulsator, a propeller blade, a paddle blade, a turbine blade, etc., but the number of rotations is not particularly limited. Is preferred.
• each liquid is not particularly limited, but it is preferable that both the oil component and the surfactant component be at the melting temperature or higher, and specifically, it is appropriately selected from the range of 40 to 95 ° C.
• the permeability of the composition can be increased and the creaming due to long-term storage can be suppressed by atomizing the emulsion particles in the composition.
• the composition may be further sealed by a package, and inert gas in the space formed between the container and the package may be enclosed;
• the substance may be filled in a resin container and sealed by a package together with an oxygen scavenger.
• the composition of the present invention is an "aqueous ophthalmic composition".
• the "aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water.
• the content of water is preferably 90.0 to 99.5 w / v% in the composition, from the viewpoint of facilitating mixing with tear fluid and obtaining a tear oil layer stabilization effect, and 95.0 to 97%. .5 w / v% is more preferred.
• the particle diameter of the emulsion particles (the association of the (A) component and the (B) component) contained in the composition of the present invention can be 800 nm or less, preferably 500 nm or less, and more preferably 300 nm or less.
• the lower limit is not particularly limited, but may be 1 nm.
• the particle diameter refers to the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity.
• the particle diameter is measured by a constant temperature bath at a constant temperature of 25 ° C. using a constant temperature bath by various measuring devices to which the principle of light scattering or the like is applied.
• a particle size measuring apparatus ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.
• the transmittance of the composition of the present invention is 30 to 100% at a wavelength of 600 nm measured using a spectrophotometer (for example, UV-1800, Shimadzu Corporation). 50 to 100% is preferable, and 70 to 100% is more preferable.
• a spectrophotometer for example, UV-1800, Shimadzu Corporation
• the composition of the present invention is preferably a liquid from the viewpoint of facilitating application to the eye, and the viscosity at 25 ° C. facilitates mixing with tear fluid, and from the point of achieving a tear oil layer stabilization effect, 20 mPa ⁇ s
• the following is preferable, 10 mPa ⁇ s or less is more preferable, and 5 mPa ⁇ s or less is more preferable.
• the measuring method of a viscosity is performed using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).
• composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash etc.
• tear dilution ratio is high, release of surfactant from liquid paraffin is further promoted, and liquid paraffin delivery Can be suitably used as an eye drop and an eye drop for contact lens (eye drop for contact lens wearer).
• the contact lenses include, but are not limited to, hard contact lenses, O 2 hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, and the like.
• the tear fluid oil layer stabilizing effect 1 to 3 drops of 10 to 50 ⁇ L at a time, and more preferably 1 to 6 times a day. More preferably, 1 to 3 drops of 10 to 30 ⁇ L at a time, and 1 to 6 times a day.
• the present invention contains (A) liquid paraffin and (B) a nonionic surfactant, and the blending mass ratio of the (A) component to the (B) component represented by (B) / (A) is A method for atomizing emulsion particles in an aqueous ophthalmic composition, wherein 3 ⁇ (B) / (A) ⁇ 25, wherein the aqueous ophthalmic composition comprises (C) terpenoid in an amount of 0.0001 to 0.5 w / w.
• a method for atomizing emulsion particles containing v% Preferred components and amounts are the same as described above.
• the composition can be made transparent, and the appearance storage stability can be improved.
• “Appearance storage stability” means that when the composition is stored over time, aggregation, creaming, coalescence, floating and the like of the association of the (A) component and the (B) component are suppressed. .
• the atomization effect by the component (C) can not be obtained.
• Example, Comparative Example Each aqueous component in the following table was dissolved in 90 mL of purified water, and heated and mixed at 90 ° C. for 15 minutes. Separately, a preliminary mixture of (A) liquid paraffin, (B) nonionic surfactant and (C) terpenoid was prepared, and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the pre-mixture was added to the aqueous solution, and heated and mixed at 90 ° C. for 15 minutes. After that, the reaction solution was cooled to room temperature, pH was adjusted, and purified water was added to 100 mL. The viscosity of each example was in the range of 0.5 to 2.0 mPa ⁇ s. The following evaluation was performed about the obtained composition. The results are shown in the table.
• the particle diameter of the emulsion particles in the composition immediately after production was measured using ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.). From the particle diameter obtained, atomization of emulsion particles in the composition is shown by the following evaluation criteria.
• the particle diameter is the average diameter (median diameter nm) of the volume-based particle size distribution calculated from the scattered light intensity, and the measurement was carried out under a constant temperature condition of 25 ° C.
• composition Permeability (%)] ⁇ : 70% or more and 100% or less 70: 50% or more and less than 70% ⁇ : 30% or more and less than 50% x: less than 30% “O” or more is accepted.
• compositions of the examples were all "o" in the following appearance storage stability evaluation.
• DR-1 is an apparatus capable of measuring an interference image of light reflected at the interface between the surface of the tear fluid oil layer and the tear fluid water layer. In a normal eye, a uniform gray or white interference image is observed, and when the tear fluid oil layer collapses, the interference image disappears.
• each composition was instilled in a subject, and after 10 minutes, it blinked several times, and the time from the blink to the collapse of the tear fluid oil layer (oil layer BUT) was measured.
• the subjects selected 13 eyes of 7 people who had oil reservoir BUT less than 10 seconds before instillation. The results are shown by the following evaluation criteria from the average value of 7 eyes and 13 eyes.
• the oil layer BUT which was less than 10 seconds, did not fluctuate more than 10 seconds in intraday and inter-day variations, in compositions without liquid paraffin, and improvement to 10 seconds or more was acceptable as having sufficient utility. It was judged.
• Oil layer BUT is 60 seconds or more ⁇ : Oil layer BUT is 30 seconds to 60 seconds ⁇ : Oil layer BUT is 10 seconds to 30 seconds x (not good): Oil layer BUT is less than 10 seconds " ⁇ " or more is accepted.
• the aqueous ophthalmic composition of the present invention was confirmed to have a tear oil layer stabilizing effect.
• Liquid paraffin 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 76.6 mm 2 / s (KAYDOL, manufactured by Shima Trading Co., Ltd.)
• Liquid paraffin 16th Amended Japanese Pharmacopoeia Method 1 (37.8 ° C) Dynamic viscosity 34.8 mm 2 / s (Hycor M-172, Kaneda Co., Ltd.)
• Polyoxyethylene (POE) castor oil polyoxyethylene castor oil 35: Uniox C 35, manufactured by NOF Corporation
• Polyoxyethylene (POE) hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (Polyoxyethylene hydrogenated castor oil 60: HCO60, HCO40, manufactured by Nippon Surfactant Industries Co., Ltd.) Monostearate PEG (polyethylene glycol monostearate (10): MYS 10 V,

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