WO2018117014A1 - Ophthalmic composition and method for manufacturing same - Google Patents
Ophthalmic composition and method for manufacturing same Download PDFInfo
- Publication number
- WO2018117014A1 WO2018117014A1 PCT/JP2017/045278 JP2017045278W WO2018117014A1 WO 2018117014 A1 WO2018117014 A1 WO 2018117014A1 JP 2017045278 W JP2017045278 W JP 2017045278W WO 2018117014 A1 WO2018117014 A1 WO 2018117014A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- component
- castor oil
- oil
- ophthalmic composition
- Prior art date
Links
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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K9/08—Solutions
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Definitions
- the present invention relates to an ophthalmic composition containing one or more selected from vitamin A and vitamin E.
- the tear fluid layer is essential for maintaining the function of the eye in order to prevent evaporation of water from tears and to remove foreign substances, and it must be stable on the surface of the eye to fulfill its role. is necessary.
- This tear oil layer is composed of lipids (meibum) secreted from the meibomian glands, and the main components are wax esters, cholesterol esters, phospholipids and the like. On the other hand, these components increase the percentage of saturated lipids due to aging and hormonal changes, affect the stabilization of the tear fluid layer, increase the evaporation of the tear fluid layer, and cause dry eye symptoms. Furthermore, it is said to have a deep relationship with eye fatigue.
- lipid saturation proceeds excessively and the above symptoms worsen.
- the generation of lipid peroxide from the tear fluid layer also induces eye discomfort.
- the cause of the generation of lipid peroxide from the tear oil layer includes oxidation by light having a short wavelength such as ultraviolet light or blue light. In recent years, it has been considered that the risk of oxidation is increasing because the working time in the VDT equipment, which is the source of blue light, has been prolonged.
- an antioxidant component In order to suppress the generation of lipid peroxide in the tear fluid layer, it is conceivable to supply an antioxidant component to the tear fluid layer with an ophthalmic composition such as eye drops.
- an ophthalmic composition such as eye drops.
- the antioxidant component is not sufficiently transferred to the tear fluid layer and is discharged from the conjunctival sac, and the effect of suppressing lipid peroxide generation is insufficient.
- the present invention has been made in view of the above circumstances, and vitamin A and vitamin E, which are fat-soluble antioxidant components, are released from the composition by dilution of tears (hereinafter referred to as the release property of the component (A) from the composition). It is an object of the present invention to provide a composition that can be supplied to the tear oil layer, can suppress the generation of lipid peroxide, and can prevent discomfort caused by lipid peroxide.
- the present inventors have made vitamin A and / or dilute into tears after instillation by using a composition in which the type and ratio of the nonionic surfactant are limited.
- vitamin E can be released (separated / floated) from the composition and supplied to the tear oil layer.
- the composition of the present invention can suppress the generation of lipid peroxides, and further, eye fatigue, blurred and blurred eyes caused by lipid peroxides, dry eyes, foreign body sensation, eye pain, and dazzling eyes
- eye discomfort can be prevented such as heavy eyes, itchy eyes, eye discomfort, eye grease, lacrimation, and hyperemia.
- the present invention provides the following ophthalmic composition and method for producing the same. [1].
- A one or more selected from (A-1) vitamin A and (A-2) vitamin E;
- These blending mass ratios are (A-1) / [(A-1) + (A-2)] ⁇ 0.1, 0.05 ⁇ [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)], [(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] / [(A-1) + (A-2)] ⁇ (A-1) / [(A-1) + (A-2)] + [(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] / [(A-1) + (A-
- Vitamin A, vitamin E, etc. are released by dilution of tears, they can be sufficiently supplied to the tear oil layer, the generation of lipid peroxide can be suppressed, and further, eye discomfort caused by lipid peroxide can be prevented.
- An object is to provide an ophthalmic composition and a method for producing the same.
- vitamin A (A-1) vitamin A and (A-2) vitamin E. These are ingredients known as fat-soluble vitamins.
- A-1) Vitamin A examples include, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, etc., alone or in combination of two or more Can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.
- Vitamin E As vitamin E, for example, tocopherol, tocotrienol, their salts, and derivatives (esters) are used as a generic term. Specifically, for example, there are d- ⁇ -tocopherol, dl- ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol and the like, and examples of these derivatives include vitamin E acetate (tocopherol acetate). , Vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like can be mentioned, and these can be used singly or in appropriate combination of two or more. Of these, tocopherol acetate (d- ⁇ -tocopherol acetate, dl- ⁇ -tocopherol acetate, etc.) is preferable. As the component (A), (A-2) vitamin E is preferable.
- the total amount of the component (A-1) and the component (A-2) is preferably 0.0001 to 1 W / V% (mass / volume%, g / 100 mL, the same shall apply hereinafter) in the ophthalmic composition.
- 001 to 0.5 W / V% is more preferable, and 0.01 to 0.1 W / V% is particularly preferable.
- the antioxidant effect is more exhibited, and when it is 1 W / V% or more, it becomes easy to feel eye irritation.
- the amount of the component (A-1) is not particularly limited as long as the above ratio is satisfied from the viewpoint of release from the composition, but is preferably 0 to 0.1 W / V% in the composition, / V% may be sufficient. On the other hand, it is preferable to contain 0.005 W / V% or more from a viewpoint of lipid peroxide suppression.
- the amount of the component (A-2) is not particularly limited as long as it satisfies the above ratio, but is preferably 0.00009 to 1 W / V%, more preferably 0.001 to 0.5 W / V%, and More preferred is 01 to 0.1 W / V%.
- the (B) nonionic surfactant of the present invention includes (B-1) polyoxyethylene castor oil (may be described as POE castor oil), (B-2) polyoxy It is classified into ethylene hardened castor oil (may be described as POE hardened castor oil), (B-3) other nonionic surfactants, and is one or more nonionic surfactants selected from these.
- component (B) since the release from the composition can be maintained even when blended at a relatively high concentration, (B-1) the polyoxyethylene castor oil and (B -2) It is preferable to use at least one selected from polyoxyethylene hydrogenated castor oil. Furthermore, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of composition stability.
- Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil. The type of is known. The average added mole number of ethylene oxide in the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified. Specifically, polyoxyethylene castor oil 3 (the number is the average number of moles of ethylene oxide added, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor Examples include oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene castor oil 35.
- the blending amount when blending the component (B-1) is not particularly limited as long as the following ratio is satisfied, but is preferably 0.000001 W / V% or more, more preferably 0.00001 W / V% or more in the composition. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.
- Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. Several types with different numbers of moles are known. The average added mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified by 5 to 100 moles.
- polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100.
- These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.
- the blending amount when blending the component (B-2) is not particularly limited as long as the following ratio is satisfied, but is preferably 0.000001 W / V% or more, more preferably 0.00001 W / V% or more in the composition. . By setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 1.0 W / V% or less is preferable.
- Nonionic surfactants other than (B-1) and (B-2) include polysorbate 80 (polyoxyethylene (20) sorbitan monolaurate) (inside) The values are the average number of moles of ethylene oxide added, the same shall apply hereinafter), polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), mono Examples include polyethylene glycol monostearate typified by polyethylene glycol stearate (10), and these can be used alone or in combination of two or more.
- polysorbate 80 polyoxyethylene (20) sorbitan monolaurate
- POE sorbitan fatty acid ester polyoxyethylene sorbitan fatty acid ester
- poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer POEPOP glycol
- mono Examples include polyethylene glycol monostearate typified by polyethylene glycol stearate
- lecithin, hydrogenated lecithin, and phospholipids such as phosphatidylcholine and phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from vitamin A or / and vitamin E by tear dilution, and are hardly transferred to the tear oil layer. It is preferable not to be included.
- the blending amount in the case of blending the component (B-3) is not particularly limited as long as the following ratio is satisfied, but is preferably 0.000001 W / V% or more, more preferably 0.00001 W / V% or more in the composition. And by setting it as the above or more, a composition becomes more uniform. From the viewpoint of safety, 0.5 W / V% or less is preferable.
- the nonionic surfactant of a component is mix
- the following ratio is W / V% ratio, it becomes the same value as mass ratio.
- [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is the blending lower limit of the component (B),
- B) Defines the amount of nonionic surfactant. Unless 0.05 ⁇ [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is satisfied, a uniform composition cannot be obtained. The desired transmittance cannot be obtained.
- the ratio is more preferably 0.1 ⁇ , and further preferably 0.5 ⁇ .
- the upper limit of [(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)] is not particularly limited, but the composition of component (A) 2.0 or less is preferable from the viewpoint of releasability from water.
- the above formula for determining the blending conditions defines the amounts of (B-1), (B-2), and (B-3) relative to (A-1) and (A-2).
- B Since the blending conditions of (A) differ depending on the type of nonionic surfactant, each is divided by a specific coefficient for the type of component (B). For example, when comparing (B-1) /0.25 and (B-3) /0.1, the intrinsic coefficient of (B-1) is 2.5 times higher than (B-3). It means that.
- [(B-1) /0.25+ (B-2) /0.01+ (B-3) / 0 .1] represents a formula regarding the upper limit of the amount of each component (B) relative to (A-1)
- [(B-1) /0.1+ (B-2) /0.2+ (B-3) / 0 .05] represents a formula relating to the upper limit of the amount of each component (B) relative to (A-2). They are divided by the sum of components (A) (A-1) + (A-2).
- component (A-2) 1.0 W / V%, if (B-1) alone, more than 0.05 W / V%, 1.0 W / V% or less, (B-2) alone If it exists, it is necessary to be more than 0.05 W / V% and not more than 2.0 W / V%, and if it is (B-3) alone, it needs to be more than 0.05 W / V% and 0.5 W / V% or less.
- Cationic surfactants typified by benzalkonium chloride and benzethonium chloride, anionic surfactants typified by sodium lauryl sulfate and sorbic acid or salts thereof, and amphoteric surfactants typified by lauramine oxide.
- the agent inhibits separation of the component (A) and the surfactant by dilution of the tears, and the component (A) is less likely to be transferred to the tear fluid layer, so that the content is preferably 0.1 W / V% or less in the composition. , 0.01 W / V% or less is more preferable, and it is particularly preferable that the content is not substantially contained.
- the ophthalmic composition of the present invention may further contain (C) a terpenoid.
- a terpenoid By blending the terpenoid, release properties such as enhancing the release properties of the component (A) from the composition can be adjusted, and further, the effect of suppressing the generation of lipid peroxide can be enhanced.
- the terpenoid in the present invention has a structure having an isoprene unit as a structural unit, and examples thereof include terpene hydrocarbon, terpene alcohol, terpene aldehyde, and terpene ketone. Also, depending on the number of carbons, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes.
- monoterpenes such as menthol, menthone, camphor, borneol, rünou, geraniol, cineole, linalool, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids.
- diterpenes such as retinol and retinal
- tetraterpenes such as carotenoids.
- terpenoids can be used in any of d-form, l-form or dl-form.
- an essential oil containing the above compound may be used as the terpenoid.
- essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, mint oil, peppermint oil, spearmint oil, and essential oils of dipterocarpaceae, rosmarin oil, and lavender oil.
- Bergamot oil and eucalyptus oil are preferable from the viewpoint of enhancing the release from the composition of the component.
- the blending amount of the component (C) is 0.0001 to 0.2 W / V% in the composition, and is appropriately selected from the other blending components such as the type of the component (C), the component (B) and the blending amount thereof. 0.001 to 0.1 W / V% is preferable. In this blending concentration range, there is little risk of precipitation of (C) terpenoids regardless of the types and blending amounts of other blending components. Moreover, 0.005 W / V% or more is more preferable from a viewpoint of lipid peroxide generation
- composition of the present invention An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired.
- other components include oil components, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can be blended singly or in appropriate combination of two or more.
- the compounding amount of the components shown below is a preferable range when blending.
- Oil components include castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, white petrolatum, purified lanolin, cholesterol, mixed tocopherol, liquid paraffin, and the like.
- the blending amount of the oil component is preferably 0.001 to 1.0 W / V% in the composition, more preferably 0.001 to 0.5 W / V%, and most preferably 0.001 to 0.25 W / V%.
- examples of the preservative having a hydrophobic portion such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconic acid, methyl paraoxybenzoate, ethyl paraoxybenzoate, and the like ( Since the component A) is less likely to be transferred to the tear oil layer, the composition preferably has a content of 0.1 W / V% or less, more preferably 0.01 W / V% or less, and even more preferably does not contain substantially.
- sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be any of d-form, l-form, or dl-form.
- the blending amount of the saccharide is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and further preferably 0.001 to 0.1 W / V%.
- 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 of the buffer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 2 W / V%, and still more preferably 0.001 to 1 W / V%.
- an inorganic acid or an inorganic alkali agent can be used as the pH adjusting agent.
- (diluted) hydrochloric acid is mentioned as an inorganic 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).
- tonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. And 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 using an automatic osmometer (A2O, Advanced Instruments) at 25 ° C.
- the stabilizer examples include sodium edetate, sodium edetate hydrate, cyclodextrin, sulfite, and dibutylhydroxytoluene.
- the blending amount of the stabilizer is preferably 0.001 to 5.0 W / V% in the composition, more preferably 0.001 to 1 W / V%, and still more preferably 0.001 to 0.1 W / V%.
- Dibutylhydroxytoluene inhibits the separation of the component (A) and the surfactant due to dilution of tears, and the component (A) is less likely to be supplied to the tear fluid layer.
- the polyhydric alcohol examples include glycerin, propylene glycol, butylene glycol, and polyethylene glycol.
- 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 0.00. 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.
- the blending amount 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.
- drugs pharmaceutical active ingredients
- decongestants 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 azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt
- antihistamines eg, diphenhydramine hydrochloride, chlorpheniramine maleate
- the effective content of each drug can be selected as the drug content, but 0.001 to 5.0 W / V% in the composition is preferable, and 0.001 to 1 W / V% Is more preferable, and 0.001 to 0.1 W / V% is still more preferable.
- the production method of the composition of the present invention is not particularly limited.
- a mixed solution of an oil component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component.
- the total volume can be obtained 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 rotation speed is not particularly limited and should be set to a level that does not cause intense foaming. Is preferred.
- the mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are equal to or higher than the melting temperature, and specifically, appropriately selected from the range of 40 to 95 ° C. More preferably, a miniaturization step by high-pressure emulsification is performed. From the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes at a high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes at a low pressure, and the injection pressure is 100. To 245 MPa is preferable, 150 to 245 MPa is more preferable, and 200 to 245 MPa is more preferable.
- a back pressure preferably 1 to 10 MPa, more preferably 2 to 5 MPa.
- the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times.
- the temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.
- composition After filling the obtained composition into a resin container, it is further sealed with a package, and an inert gas concentration may be sealed in a space formed between the container and the package.
- the composition may be filled in a resin container and sealed with a package together with an oxygen scavenger.
- the composition of the present invention is preferably an “aqueous ophthalmic composition”.
- the “aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water.
- the amount of water is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tears and facilitating transfer of the component (A) to tears. It is more preferably 0.0 to 98.0 W / V%.
- the composition of the present invention is preferably a liquid in terms of facilitating adaptation to the eyes, and the viscosity at 25 ° C. facilitates mixing with tear fluid and facilitates transfer of component (A) to tear fluid. It is preferably 20 mPa ⁇ s or less, more preferably 10 mPa ⁇ s or less, further preferably 5 mPa ⁇ s or less, and particularly preferably 2 mPa ⁇ s or less.
- the viscosity is measured using a cone plate viscometer (DV2T, Eihiro Seiki Co., Ltd.).
- the composition of the present invention is preferably clear from the viewpoint of facilitating discovery when foreign matter is mixed.
- the transmittance at a wavelength of 600 nm measured using a spectrophotometer is 70% or more, preferably 70 to 100%, more preferably 75 to 100%, 90 to 100% is more preferable.
- the median diameter of the aggregate of the surfactant and the component (A) contained in the composition of the present invention is measured with a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.) to stabilize the composition. From the viewpoint of properties, it is preferably 1 to 200 nm, more preferably 1 to 100 nm, still more preferably 1 to 60 nm, and particularly preferably 1 to 40 nm.
- the composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eye wash, etc., but the tear dilution ratio is high, and the release of the surfactant from the component (A) is further promoted. Since the release of the component A) from the composition is improved, and the supply of the component (A) to the tear fluid layer is performed efficiently, eye drops for eye drops and eye drops for contact lenses (eye drops for contact lens wearers) It can be suitably used as an eye drop such as an agent.
- the contact lens is not particularly limited, such as a hard contact lens or a soft contact lens.
- the composition of the present invention prevents tear lipid oxidation due to VDT work or ultraviolet rays, etc., and causes eye discomfort due to lipid peroxide (eye fatigue, blurred vision, blurred vision, dry eyes, foreign body sensation, eye pain, (Dazzling eyes, heavy eyes, itchy eyes, eye discomfort, eye oil, lacrimation, hyperemia, etc.) It is effective for preventing unpleasant symptoms, and particularly effective for improving symptoms of eye fatigue, foreign body sensation, eye pain, and eye discomfort.
- the effective amount, administration method, formulation and the like are as described above.
- amount of component (A) 0.0001 to 1 mg per adult is divided into 1 to 6 times a day and administered to the eye. To do.
- % of the composition is W / V%.
- the ratio is a W / V% ratio, which is the same value as the mass ratio.
- aqueous component described in the following table was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes.
- a premix of the component (A) and the component (B) was prepared and heated and mixed at 90 ° C. for 15 minutes.
- a predetermined amount of the premix was added to the aqueous solution, and further heated and mixed at 90 ° C. for 15 minutes. Then, it cooled to room temperature, adjusted pH, and added water so that it might be set to 100 mL.
- eye drops obtained in each Example had a viscosity at 25 ° C. in the range of 0.5 to 2.0 mPa ⁇ s.
- the meibomian gland opening near the eyelid (Funakoshi Co., Ltd.) cut out from the rabbit was pressed with a finger, and the extruded meibum was collected with Kimwipe (manufactured by Nippon Paper Crecia Co., Ltd.). Thereafter, the Kimwipe was put in a glass vial, immersed in a 1: 1 mixture (volume ratio) of chloroform and methanol, treated with ultrasonic waves for 10 minutes, and the liquid was transferred to another glass vial. This operation was repeated three times.
- the mixture was filtered using a Terumo syringe washed with the chloroform / methanol mixed solution (Termo Co., Ltd., 50 mL) and a membrane filter (Merck Millipore Co., Ltd., Millex GP, 0.22 ⁇ m), and the dry weight was precisely balanced. (Measured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added to a concentration of 0.5 mg / mL with a micro syringe (manufactured by Hamilton), the rabbit meibum was dissolved, and stored in a ⁇ 20 ° C. freezer. Upon use, the temperature was returned to room temperature, and it was confirmed that there was no precipitate.
- aqueous layer is formed with 1 mL of physiological saline on a 35 mm dish, a rabbit meibum chloroform solution (0.5 mg / mL) is spread on the surface of 100 ⁇ L, 165 ⁇ L of each eye drop is added, and irradiated with UV (254 nm) for 1 hour. The whole amount of this solution was collected in a vial.
Abstract
Description
[1].(A)(A-1)ビタミンA及び(A-2)ビタミンEから選ばれる1種以上と、
(B)(B-1)ポリオキシエチレンヒマシ油、(B-2)ポリオキシエチレン硬化ヒマシ油及び(B-3)その他の非イオン界面活性剤から選ばれる1種以上の非イオン界面活性剤を含有し、これらの配合質量比が、
(A-1)/[(A-1)+(A-2)]≦0.1、
0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)]、
[(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/
[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+
[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/
[(A-1)+(A-2)]×(A-2)/[(A-1)+(A-2)])≦10
を満たし、透過率が70%以上である眼科用組成物。
[2].(A)成分が、(A-2)ビタミンEである[1]記載の眼科用組成物。
[3].(B)非イオン界面活性剤が、(B-1)ポリオキシエチレンヒマシ油及び(B-2)ポリオキシエチレン硬化ヒマシ油から選ばれる1種以上を含む[1]又は[2]記載の眼科用組成物。
[4].さらに、(C)テルペノイドを含む[1]~[3]のいずれかに記載の眼科用組成物。
[5].点眼剤である[1]~[4]のいずれかに記載の眼科用組成物。
[6].涙液油層の過酸化脂質発生抑制用又は過酸化脂質による眼の不快症状の予防用である[1]~[5]のいずれかに記載の眼科用組成物。
[7].高圧乳化による微細化工程を含む、[1]~[6]のいずれかに記載の眼科用組成物を製造する方法。 Accordingly, the present invention provides the following ophthalmic composition and method for producing the same.
[1]. (A) one or more selected from (A-1) vitamin A and (A-2) vitamin E;
One or more nonionic surfactants selected from (B) (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) other nonionic surfactants These blending mass ratios are
(A-1) / [(A-1) + (A-2)] ≦ 0.1,
0.05 <[(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)],
[(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] /
[(A-1) + (A-2)] × (A-1) / [(A-1) + (A-2)] +
[(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] /
[(A-1) + (A-2)] × (A-2) / [(A-1) + (A-2)]) ≦ 10
And an ophthalmic composition having a transmittance of 70% or more.
[2]. The ophthalmic composition according to [1], wherein the component (A) is (A-2) vitamin E.
[3]. The ophthalmologic according to [1] or [2], wherein the (B) nonionic surfactant comprises one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil Composition.
[4]. The ophthalmic composition according to any one of [1] to [3], further comprising (C) a terpenoid.
[5]. The ophthalmic composition according to any one of [1] to [4], which is an eye drop.
[6]. The ophthalmic composition according to any one of [1] to [5], which is used for suppressing the generation of lipid peroxide in a tear oil layer or preventing ocular discomfort caused by lipid peroxide.
[7]. A method for producing an ophthalmic composition according to any one of [1] to [6], comprising a micronization step by high-pressure emulsification.
(A)(A-1)ビタミンA及び(A-2)ビタミンEから選ばれる1種以上
これらは脂溶性ビタミンとして知られている成分である。
(A-1)ビタミンA
ビタミンAとしては、例えば、ビタミンAそれ自体の他に、ビタミンA油等のビタミンA含有混合物、ビタミンA脂肪酸エステル等のビタミンA誘導体等が挙げられ、1種単独で又は2種以上を適宜組み合わせて用いることができる。具体的には、レチノールパルミチン酸エステル、レチノール酢酸エステル、レチノール、レチノイン酸、レチノイド等が挙げられる。中でも、レチノールパルミチン酸エステルが好ましい。 Hereinafter, the present invention will be described in detail.
One or more selected from (A) (A-1) vitamin A and (A-2) vitamin E. These are ingredients known as fat-soluble vitamins.
(A-1) Vitamin A
Examples of vitamin A include, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, etc., alone or in combination of two or more Can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred.
ビタミンEとしては、例えば、トコフェロール、トコトリエノール、これらの塩、誘導体(エステル)を総称する意味で使用される。具体的には、例えば、d-α-トコフェロール、dl-α-トコフェロール、β-トコフェロール、γ-トコフェロール、δ-トコフェロール等があり、これらの誘導体としては、例えば、ビタミンE酢酸エステル(酢酸トコフェロール)、ビタミンEニコチン酸エステル、ビタミンEコハク酸エステル、ビタミンEリノレン酸エステル等が挙げられ、1種単独で又は2種以上を適宜組み合わせて用いることができる。中でも、酢酸トコフェロール(酢酸d-α-トコフェロール、酢酸dl-α-トコフェロール等)が好ましい。(A)成分としては、(A-2)ビタミンEが好ましい。 (A-2) Vitamin E
As vitamin E, for example, tocopherol, tocotrienol, their salts, and derivatives (esters) are used as a generic term. Specifically, for example, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like, and examples of these derivatives include vitamin E acetate (tocopherol acetate). , Vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like can be mentioned, and these can be used singly or in appropriate combination of two or more. Of these, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferable. As the component (A), (A-2) vitamin E is preferable.
本発明の(B)非イオン界面活性剤は、(B-1)ポリオキシエチレンヒマシ油(POEヒマシ油と記載する場合がある)、(B-2)ポリオキシエチレン硬化ヒマシ油(POE硬化ヒマシ油と記載する場合がある)、(B-3)その他の非イオン界面活性剤に分類され、これらから選ばれる1種以上の非イオン界面活性剤である。(B)成分としては、比較的高濃度配合しても組成物からの放出性を維持できるため、組成物の澄明性に有利である点から(B-1)ポリオキシエチレンヒマシ油及び(B-2)ポリオキシエチレン硬化ヒマシ油から選ばれる1種以上を用いることが好ましい。さらに、組成物安定性の点から、非イオン界面活性剤は2種以上配合されていることがより好ましい。 (B) Nonionic surfactant The (B) nonionic surfactant of the present invention includes (B-1) polyoxyethylene castor oil (may be described as POE castor oil), (B-2) polyoxy It is classified into ethylene hardened castor oil (may be described as POE hardened castor oil), (B-3) other nonionic surfactants, and is one or more nonionic surfactants selected from these. As the component (B), since the release from the composition can be maintained even when blended at a relatively high concentration, (B-1) the polyoxyethylene castor oil and (B -2) It is preferable to use at least one selected from polyoxyethylene hydrogenated castor oil. Furthermore, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of composition stability.
ポリオキシエチレンヒマシ油(POEヒマシ油)は、ヒマシ油に酸化エチレンを付加重合することによって得られる化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。ポリオキシエチレンヒマシ油における酸化エチレンの平均付加モル数については、特に限定はないが、3~60モルが例示される。具体的にはポリオキシエチレンヒマシ油3(数値は酸化エチレンの平均付加モル数、以下同様)、ポリオキシエチレンヒマシ油10、ポリオキシエチレンヒマシ油20、ポリオキシエチレンヒマシ油35、ポリオキシエチレンヒマシ油40、ポリオキシエチレンヒマシ油50、ポリオキシエチレンヒマシ油60等が挙げられる。これらのポリオキシエチレンヒマシ油は、1種単独で又は2種以上を適宜組み合わせて用いることができる。中でも、ポリオキシエチレンヒマシ油35を用いることが好ましい。 (B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide to castor oil. The type of is known. The average added mole number of ethylene oxide in the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles are exemplified. Specifically, polyoxyethylene castor oil 3 (the number is the average number of moles of ethylene oxide added, hereinafter the same), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor Examples include oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene castor oil 35.
ポリオキシエチレン硬化ヒマシ油(POE硬化ヒマシ油)は、水添したヒマシ油に酸化エチレンを付加重合することによって得られる化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。ポリオキシエチレン硬化ヒマシ油における酸化エチレンの平均付加モル数については、特に限定はないが、5~100モルが例示される。具体的にはポリオキシエチレン硬化ヒマシ油5(数値は酸化エチレンの平均付加モル数、以下同様)、ポリオキシエチレン硬化ヒマシ油10、ポリオキシエチレン硬化ヒマシ油20、ポリオキシエチレン硬化ヒマシ油30、ポリオキシエチレン硬化ヒマシ油40、ポリオキシエチレン硬化ヒマシ油50、ポリオキシエチレン硬化ヒマシ油60、ポリオキシエチレン硬化ヒマシ油80、ポリオキシエチレン硬化ヒマシ油100等が挙げられる。これらのポリオキシエチレンヒマシ油は、1種単独で又は2種以上を適宜組み合わせて用いることができる。中でも、ポリオキシエチレン硬化ヒマシ油40、ポリオキシエチレン硬化ヒマシ油60を用いることが好ましい。 (B-2) Polyoxyethylene hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil. Several types with different numbers of moles are known. The average added mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified by 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 30, Examples include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, and polyoxyethylene hydrogenated castor oil 100. These polyoxyethylene castor oils can be used singly or in appropriate combination of two or more. Among these, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.
(B-1)及び(B-2)以外の非イオン界面活性剤としては、ポリソルベート80(モノラウリン酸ポリオキシエチレン(20)ソルビタン)(()内数値は酸化エチレンの平均付加モル数、以下同様)に代表されるポリオキシエチレンソルビタン脂肪酸エステル(POEソルビタン脂肪酸エステル)、ポリオキシエチレン-ポリオキシプロピレンブロックコポリマー(POEPOPグリコール)に代表されるポロクサマー、モノステアリン酸ポリエチレングリコール(10)に代表されるモノステアリン酸ポリエチレングリコール等が挙げられ、1種単独で又は2種以上を適宜組み合わせて用いることができる。ただし、界面から脱着しにくいレシチンや水添レシチン、ホスファチジルコリンやホスファチジルグリセロール等のリン脂質類は涙液希釈によってビタミンA又は/及びビタミンEから分離せず、涙液油層へ移行されにくくなるため、実質的に含まれないことが好ましい。 (B-3) Other nonionic surfactants Nonionic surfactants other than (B-1) and (B-2) include polysorbate 80 (polyoxyethylene (20) sorbitan monolaurate) (inside) The values are the average number of moles of ethylene oxide added, the same shall apply hereinafter), polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), poloxamer represented by polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), mono Examples include polyethylene glycol monostearate typified by polyethylene glycol stearate (10), and these can be used alone or in combination of two or more. However, lecithin, hydrogenated lecithin, and phospholipids such as phosphatidylcholine and phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from vitamin A or / and vitamin E by tear dilution, and are hardly transferred to the tear oil layer. It is preferable not to be included.
0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)]、
[(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/
[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+
[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/
[(A-1)+(A-2)]×(A-2)/[(A-1)+(A-2)])≦10、
(B-1)ポリオキシエチレンヒマシ油
(B-2)ポリオキシエチレン硬化ヒマシ油
(B-3)その他の非イオン界面活性剤 (B) The nonionic surfactant of a component is mix | blended in the following ratios. In addition, although the following ratio is W / V% ratio, it becomes the same value as mass ratio.
0.05 <[(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)],
[(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] /
[(A-1) + (A-2)] × (A-1) / [(A-1) + (A-2)] +
[(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] /
[(A-1) + (A-2)] × (A-2) / [(A-1) + (A-2)]) ≦ 10
(B-1) Polyoxyethylene castor oil (B-2) Polyoxyethylene hydrogenated castor oil (B-3) Other nonionic surfactants
[(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/
[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+
[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/
[(A-1)+(A-2)]×(A-2)/[(A-1)+(A-2)])≦10、
であり、これを満たさないと目的とする(A)成分の放出性が得られない。上記比率は≦8が好ましい。なお、
[(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/
[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+
[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/
[(A-1)+(A-2)]×(A-2)/[(A-1)+(A-2)])
の下限は特に限定されないが、透過率の観点から0.25超が好ましい。 On the other hand,
[(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] /
[(A-1) + (A-2)] × (A-1) / [(A-1) + (A-2)] +
[(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] /
[(A-1) + (A-2)] × (A-2) / [(A-1) + (A-2)]) ≦ 10
If this is not satisfied, the desired component (A) release property cannot be obtained. The ratio is preferably ≦ 8. In addition,
[(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] /
[(A-1) + (A-2)] × (A-1) / [(A-1) + (A-2)] +
[(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] /
[(A-1) + (A-2)] × (A-2) / [(A-1) + (A-2)])
The lower limit is not particularly limited, but is preferably more than 0.25 from the viewpoint of transmittance.
本発明の組成物には、本発明の効果を損なわない範囲で、その他の成分を適量配合することができる。その他の成分としては、油成分、防腐剤、糖類、緩衝剤、pH調整剤、張化剤、安定化剤、多価アルコール、粘稠剤、薬物等が挙げられる。これらの成分は、1種単独で又は2種以上を適宜組み合わせて配合することができる。下記に示す成分の配合量は、配合する場合の好ましい範囲である。 [Other ingredients]
An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired. Examples of other components include oil components, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can be blended singly or in appropriate combination of two or more. The compounding amount of the components shown below is a preferable range when blending.
本発明の組成物の製造方法は特に限定されないが、例えば、(A)成分等の油性成分と(B)成分等の界面活性剤成分との混合溶液を、水性成分を含む水溶液と混合して乳化し、pH調整後、総体積を水により調製することにより得ることができる。各液体の混合方法は、一般的な方法でよく、パルセーター、プロペラ羽根、パドル羽根、タービン羽根等を用いて適宜行われるが、回転数は特に限定されず、激しく泡立たない程度に設定することが好ましい。各液体の混合温度は特に限定しないが、油性成分と界面活性剤成分が共に融解温度以上であることが好ましく、具体的には40~95℃の範囲から適宜選定される。より好ましくは高圧乳化による微細化工程を行う。高圧乳化条件は、組成物の澄明性を向上させる観点からは高圧でパス回数を多くすることが好ましく、生産効率を向上させる観点からは低圧でパス回数を少なくすることが好ましく、噴射圧は100~245MPaが好ましく、150~245MPaがより好ましく、200~245MPaがさらに好ましい。さらに背圧を印加することが好ましく、1~10MPaが好ましく、2~5MPaがより好ましい。さらにパス回数は1~10回が好ましく、1~5回がより好ましい。高圧乳化時の温度は20~90℃の範囲から適宜選定される。 [Production method]
The production method of the composition of the present invention is not particularly limited. For example, a mixed solution of an oil component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component. After emulsification and pH adjustment, the total volume can be obtained 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 rotation speed is not particularly limited and should be set to a level that does not cause intense foaming. Is preferred. The mixing temperature of each liquid is not particularly limited, but it is preferable that both the oily component and the surfactant component are equal to or higher than the melting temperature, and specifically, appropriately selected from the range of 40 to 95 ° C. More preferably, a miniaturization step by high-pressure emulsification is performed. From the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes at a high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes at a low pressure, and the injection pressure is 100. To 245 MPa is preferable, 150 to 245 MPa is more preferable, and 200 to 245 MPa is more preferable. Further, it is preferable to apply a back pressure, preferably 1 to 10 MPa, more preferably 2 to 5 MPa. Further, the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times. The temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.
本発明の組成物は、「水性眼科用組成物」であることが好ましい。本発明において、「水性眼科用組成物」とは、媒質が水である眼科用組成物をいう。なお、水の配合量は、涙液との混合を容易にし(A)成分の涙液への移行を容易にする点から、組成物中90.0~99.5W/V%が好ましく、95.0~98.0W/V%がより好ましい。 [Ophthalmic composition]
The composition of the present invention is preferably an “aqueous ophthalmic composition”. In the present invention, the “aqueous ophthalmic composition” refers to an ophthalmic composition in which the medium is water. The amount of water is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tears and facilitating transfer of the component (A) to tears. It is more preferably 0.0 to 98.0 W / V%.
下記表に記載の各水性成分を90mLの水に溶解し、90℃・15分間加温混合した。同時に、(A)成分と(B)成分のプレミックスを作製し、90℃・15分間加熱混合した。次に、プレミックスを水溶液に所定量加え、さらに90℃・15分間加熱混合した。その後、室温まで冷却し、pH調整を行い、100mLになるように水を加えた。さらに、高圧乳化機(スターバーストミニ、(株)スギノマシン)を用い、噴射圧200MPa・背圧3MPaにて5回処理を行い、点眼剤(眼科用組成物)を調製した。得られた点眼剤について、下記評価を行った。結果を表中に併記する。なお、各実施例で得られた点眼剤の25℃における粘度は0.5~2.0mPa・sの範囲であった。 [Examples and Comparative Examples]
Each aqueous component described in the following table was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes. At the same time, a premix of the component (A) and the component (B) was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the aqueous solution, and further heated and mixed at 90 ° C. for 15 minutes. Then, it cooled to room temperature, adjusted pH, and added water so that it might be set to 100 mL. Further, using a high-pressure emulsifier (Starburst Mini, Sugino Machine Co., Ltd.), treatment was performed 5 times at an injection pressure of 200 MPa and a back pressure of 3 MPa to prepare eye drops (ophthalmic composition). The following evaluation was performed about the obtained eye drop. The results are also shown in the table. The eye drops obtained in each Example had a viscosity at 25 ° C. in the range of 0.5 to 2.0 mPa · s.
ヒトの涙液は平均7μLと言われており点眼剤30~60μLを点眼した場合、約1.12~1.23倍希釈されることになる。本試験では組成物の涙液希釈によって可溶化していた(A)成分が、気液界面に浮遊してくること(放出性)を評価するため、モデル涙液として生理食塩水を使用し、希釈倍率約1.2倍で組成物を希釈した時の水面上への(A)成分遊離を観察した。観察を容易にするため開口部の狭いメスフラスコを使用した。具体的には、50mLメスフラスコに生理食塩水10mLを加え、さらに点眼剤を開口部まで注いだ。なお、開口部まで注いだときの希釈率が1.2倍となるメスフラスコを使用し、開口部の面積は152mm2であった。水面上の(A)成分の観察は、蛍光灯を光源として光を液面にあて、液面に浮かんでいる油の干渉光を観察し、水面に占める油の干渉光の面積の割合を算出し、以下の基準で評価した。なお、いずれの実施例と比較例において非希釈の場合は油の干渉光は観察されなかった。○及び◎を合格とする。
[評価基準]
◎:水面の10%以上に油の干渉光が観察される
○:水面の10%未満に油の干渉光が観察される
×:油の干渉光は観察されない [Release of component (A) by dilution]
The average amount of human tears is said to be 7 μL, and when an eye drop of 30 to 60 μL is instilled, it will be diluted about 1.12 to 1.23 times. In this test, in order to evaluate that the component (A), which was solubilized by dilution of the tears of the composition, floats at the gas-liquid interface (release), physiological saline was used as a model tear. Release of component (A) on the water surface was observed when the composition was diluted at a dilution ratio of about 1.2. A volumetric flask with a narrow opening was used to facilitate observation. Specifically, 10 mL of physiological saline was added to a 50 mL volumetric flask, and eye drops were poured into the opening. A volumetric flask having a dilution ratio of 1.2 times when poured into the opening was used, and the area of the opening was 152 mm 2 . The component (A) on the surface of the water is observed by using a fluorescent lamp as the light source and applying light to the surface of the liquid. And evaluated according to the following criteria. In any of the examples and comparative examples, no oil interference light was observed in the undiluted case. ○ and ◎ are acceptable.
[Evaluation criteria]
◎: Oil interference light is observed at 10% or more of the water surface ○: Oil interference light is observed at less than 10% of the water surface ×: Oil interference light is not observed
モデル涙液油層としては、ウサギマイバムクロロホルム溶液を生理食塩水で模した水槽上に展開することで作製した油膜を使用した。マイバムの種によって脂質組成の違いはあるものの、膜の安定性はヒトマイバムとウサギマイバムで相違がないことが確認できたため入手の容易なウサギマイバムを用いることとした。ウサギから切り出した眼瞼(フナコシ(株))のマイボーム腺開口部付近を指で圧迫し、圧出されたマイバムをキムワイプ(日本製紙クレシア(株)製)にて採取した。その後、そのキムワイプをガラスバイアルに入れ、クロロホルムとメタノールの1:1混液(容積比)に浸し、超音波10分処理し、液を別のガラスバイアルに移した。この操作を3回繰り返した。その後、上記クロロホルム・メタノール混液にて洗浄したテルモシリンジ(テルモ(株)製、50mL)とメンブランフィルター(メルクミリポア(株)製、Millex GP、0.22μm)を用いろ過し、乾燥重量を精密天秤((株)島津製作所製、XS-104)にて測定した。その後、クロロホルムをマイクロシリンジ(ハミルトン社製)にて0.5mg/mLになるように加え、ウサギマイバムを溶解し、-20℃冷凍庫にて保存した。使用の際は室温まで戻し、析出物がないことを確認した。35mmディッシュに生理食塩水1mLで水層を形成させ、ウサギマイバムクロロホルム溶液(0.5mg/mL)を100μL水面に展開し、各点眼剤を165μL添加し、UV(254nm)で1時間照射後、この溶液をバイアルに全量回収し、これに35%TCA(trichloro acetic acid)溶液を0.5mL、0.5%TBA(Thiobarbituric acid)溶液を1.0mL、0.2%BHT(butylated hydroxytoluene)溶液0.05mL、0.5%SDS(sodium dodecyl sulfate)溶液を0.05mL加えた後、100℃で30分加熱した。冷却後、酢酸0.5mL、クロロホルム1.0mLを加えて攪拌後、遠心分離(3,000rpm×10分)を行い、上層の吸光度を532nmで測定した。ブランクは上記方法においてウサギマイバムクロロホルム溶液を展開しない以外は同等の操作を行ったときの吸光度とした。得られた吸光度から、下記式に基づき、涙液油層からの過酸化脂質の発生抑制率(%)を算出した。結果を下記評価基準で示す。●、○及び◎を合格とする。
涙液油層からの過酸化脂質の発生抑制率(%)=
(1-(点眼剤添加時の吸光度-ブランク)/(点眼剤非添加時の吸光度-ブランク))×100
[評価基準]
◎:50%以上
○:30%以上50%未満
●:10%以上30%未満
×:10%未満 [Inhibition rate of lipid peroxide from tear oil layer by UV irradiation (%)]
As a model tear oil layer, an oil film prepared by spreading a rabbit meibom chloroform solution on a water tank imitated with physiological saline was used. Although there was a difference in lipid composition depending on the species of meibum, it was confirmed that there was no difference in membrane stability between human meibum and rabbit meibum, so we decided to use an easily available rabbit meibum. The meibomian gland opening near the eyelid (Funakoshi Co., Ltd.) cut out from the rabbit was pressed with a finger, and the extruded meibum was collected with Kimwipe (manufactured by Nippon Paper Crecia Co., Ltd.). Thereafter, the Kimwipe was put in a glass vial, immersed in a 1: 1 mixture (volume ratio) of chloroform and methanol, treated with ultrasonic waves for 10 minutes, and the liquid was transferred to another glass vial. This operation was repeated three times. Thereafter, the mixture was filtered using a Terumo syringe washed with the chloroform / methanol mixed solution (Termo Co., Ltd., 50 mL) and a membrane filter (Merck Millipore Co., Ltd., Millex GP, 0.22 μm), and the dry weight was precisely balanced. (Measured by Shimadzu Corporation, XS-104). Thereafter, chloroform was added to a concentration of 0.5 mg / mL with a micro syringe (manufactured by Hamilton), the rabbit meibum was dissolved, and stored in a −20 ° C. freezer. Upon use, the temperature was returned to room temperature, and it was confirmed that there was no precipitate. An aqueous layer is formed with 1 mL of physiological saline on a 35 mm dish, a rabbit meibum chloroform solution (0.5 mg / mL) is spread on the surface of 100 μL, 165 μL of each eye drop is added, and irradiated with UV (254 nm) for 1 hour. The whole amount of this solution was collected in a vial. To this, 0.5 mL of 35% TCA (trichloroacetic acid) solution, 1.0 mL of 0.5% TBA (Thiobarbituric acid) solution, 0.2% BHT (butyrated hydroxytoluene) After adding 0.05 mL of a solution and 0.05 mL of a 0.5% SDS (sodium dodecyl sulfate) solution, the mixture was heated at 100 ° C. for 30 minutes. After cooling, 0.5 mL of acetic acid and 1.0 mL of chloroform were added and stirred, followed by centrifugation (3,000 rpm × 10 minutes), and the absorbance of the upper layer was measured at 532 nm. The blank was the absorbance when the same operation was performed except that the rabbit meibom chloroform solution was not developed in the above method. From the obtained absorbance, the lipid peroxide generation inhibition rate (%) from the tear fluid layer was calculated based on the following formula. A result is shown by the following evaluation criteria. ●, ○ and ◎ are acceptable.
Inhibition rate of lipid peroxide from tear oil layer (%) =
(1- (Absorbance when eye drops are added-blank) / (Absorbance when no eye drops are added-blank)) × 100
[Evaluation criteria]
◎: 50% or more ○: 30% or more and less than 50% ●: 10% or more and less than 30% ×: less than 10%
健常人3名に各点眼剤を30μLずつ両眼に点眼し、VDT作業(コンピューター作業)を課し、点眼前、点眼10分後、点眼60分後における眼の疲れ、異物感、眼の痛み、眼の不快感の自覚症状を0(全く感じない)~10(非常に感じる)でスコア化した。結果を、3人の平均から下記評価基準で示す。●、○及び◎を合格とする。
[評価基準]
◎:60分後5点未満(10分後5点未満の中で60分後も5点未満のもの)
○:10分後5点未満
●:10分後5点以上7点未満
×:10分後7点以上 [Symptom prevention effect by VDT work]
Three healthy individuals were instilled with 30 μL of each eye drop in both eyes and imposed VDT work (computer work). Eye fatigue, foreign body sensation, eye pain before instillation, 10 minutes after instillation, and 60 minutes after instillation. The subjective symptoms of eye discomfort were scored from 0 (not felt at all) to 10 (very felt). A result is shown with the following evaluation criteria from the average of three persons. ●, ○ and ◎ are acceptable.
[Evaluation criteria]
: Less than 5 points after 60 minutes (less than 5 points after 10 minutes and less than 5 points after 60 minutes)
○: Less than 5 points after 10 minutes ●: 5 points or more after 10 minutes and less than 7 points ×: 7 points or more after 10 minutes
製造直後の点眼剤を、日立分光光度計U-3310を用いて、波長600nmの透過率を測定した。70%以上を合格とする。 [Transmissivity]
The transmittance of the eye drop immediately after production was measured using a Hitachi spectrophotometer U-3310 at a wavelength of 600 nm. 70% or more is acceptable.
レチノールパルミチン酸エステル(DSMニュートリションジャパン(株)製)
酢酸d-α-トコフェロール(理研Eアセテートα、理研ビタミン(株)製)
流動パラフィン(KAYDOL、島貿易(株)製)
ヒマシ油(マルトクA、伊藤製油(株)製)
ゴマ油((株)カネダ製)
ポリオキシエチレンヒマシ油35:酸化エチレンの平均付加モル数35(ユニオックスC35、日油(株)製)
ポリオキシエチレン硬化ヒマシ油40(HCO40、日本サーファクタント工業(株)製)
ポリオキシエチレン硬化ヒマシ油60(HCO60、日本サーファクタント工業(株)製)
モノステアリン酸ポリエチレングリコール*1:酸化エチレンの平均付加モル数10(MYS10V、日本サーファクタント工業(株)製)
モノステアリン酸ポリエチレングリコール*2:酸化エチレンの平均付加モル数40(MYS40MV、日本サーファクタント工業(株)製)
モノステアリン酸ポリエチレングリコール*3:酸化エチレンの平均付加モル数100(EMALEX8100、日本エマルション(株)製)
POEソルビタン脂肪酸エステル(ポリソルベート80、花王(株)製)
POEPOPグリコール(ポリオキシエチレン(196)-ポリオキシプロピレン(67)ブロックコポリマー(LutrolF127、BASFジャパン(株)製)
ホウ酸(小堺製薬(株)製)
トロメタモール(関東化学(株)製)
エデト酸ナトリウム水和物(クワレットN、ナガセケムテックス(株)製)
塩化ナトリウム(富田製薬(株)製)
水酸化ナトリウム(和光純薬工業(株)製)
メントール(l-メントール、鈴木薄荷(株)製)
dl-カンフル(日本精化(株)製)
ボルネオール(d-ボルネオール、柳沢正巳商店(株)製)
ゲラニオール(高砂香料工業(株)製)
シネオール(高砂香料工業(株)製)
リナロール(高砂香料工業(株)製)
ベルガモット油(山本香料(株)製)
ユーカリ油(小川香料(株)製) The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Retinol palmitate (DSM Nutrition Japan Co., Ltd.)
D-α-Tocopherol acetate (RIKEN E Acetate α, manufactured by Riken Vitamin Co., Ltd.)
Liquid paraffin (KAYDOL, manufactured by Shima Trading Co., Ltd.)
Castor oil (Maltok A, manufactured by Ito Oil Co., Ltd.)
Sesame oil (manufactured by Kaneda Corporation)
Polyoxyethylene castor oil 35: average added mole number of ethylene oxide 35 (Uniox C35, manufactured by NOF Corporation)
Polyoxyethylene hydrogenated castor oil 40 (HCO40, manufactured by Nippon Surfactant Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 60 (HCO 60, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 1: Average addition mole number of ethylene oxide (MYS10V, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 2: Average added mole number of ethylene oxide 40 (MYS40MV, manufactured by Nippon Surfactant Co., Ltd.)
Polyethylene glycol monostearate * 3: average added moles of ethylene oxide 100 (EMALEX 8100, manufactured by Nippon Emulsion Co., Ltd.)
POE sorbitan fatty acid ester (Polysorbate 80, manufactured by Kao Corporation)
POEPOP glycol (polyoxyethylene (196) -polyoxypropylene (67) block copolymer (Lutrol F127, manufactured by BASF Japan Ltd.))
Boric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.)
Trometa Mall (Kanto Chemical Co., Ltd.)
Edetate sodium hydrate (Quaret N, manufactured by Nagase ChemteX Corporation)
Sodium chloride (Tonda Pharmaceutical Co., Ltd.)
Sodium hydroxide (Wako Pure Chemical Industries, Ltd.)
Menthol (l-menthol, manufactured by Suzuki Hikaru Co., Ltd.)
dl-Camphor (manufactured by Nippon Seika Co., Ltd.)
Borneol (d-Bornole, manufactured by Yanagisawa Masami Shoten Co., Ltd.)
Geraniol (manufactured by Takasago International Corporation)
Cineol (manufactured by Takasago International Corporation)
Linalool (manufactured by Takasago International Corporation)
Bergamot oil (manufactured by Yamamoto Fragrance Co., Ltd.)
Eucalyptus oil (Ogawa Fragrance Co., Ltd.)
Claims (7)
- (A)(A-1)ビタミンA及び(A-2)ビタミンEから選ばれる1種以上と、
(B)(B-1)ポリオキシエチレンヒマシ油、(B-2)ポリオキシエチレン硬化ヒマシ油及び(B-3)その他の非イオン界面活性剤から選ばれる1種以上の非イオン界面活性剤を含有し、これらの配合質量比が、
(A-1)/[(A-1)+(A-2)]≦0.1、
0.05<[(B-1)+(B-2)+(B-3)]/[(A-1)+(A-2)]、
[(B-1)/0.25+(B-2)/0.01+(B-3)/0.1]/
[(A-1)+(A-2)]×(A-1)/[(A-1)+(A-2)]+
[(B-1)/0.1+(B-2)/0.2+(B-3)/0.05]/
[(A-1)+(A-2)]×(A-2)/[(A-1)+(A-2)])≦10
を満たし、透過率が70%以上である眼科用組成物。 (A) one or more selected from (A-1) vitamin A and (A-2) vitamin E;
One or more nonionic surfactants selected from (B) (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) other nonionic surfactants These blending mass ratios are
(A-1) / [(A-1) + (A-2)] ≦ 0.1,
0.05 <[(B-1) + (B-2) + (B-3)] / [(A-1) + (A-2)],
[(B-1) /0.25+ (B-2) /0.01+ (B-3) /0.1] /
[(A-1) + (A-2)] × (A-1) / [(A-1) + (A-2)] +
[(B-1) /0.1+ (B-2) /0.2+ (B-3) /0.05] /
[(A-1) + (A-2)] × (A-2) / [(A-1) + (A-2)]) ≦ 10
And an ophthalmic composition having a transmittance of 70% or more. - (A)成分が、(A-2)ビタミンEである請求項1記載の眼科用組成物。 The ophthalmic composition according to claim 1, wherein the component (A) is (A-2) vitamin E.
- (B)非イオン界面活性剤が、(B-1)ポリオキシエチレンヒマシ油及び(B-2)ポリオキシエチレン硬化ヒマシ油から選ばれる1種以上を含む請求項1又は2記載の眼科用組成物。 The ophthalmic composition according to claim 1 or 2, wherein the (B) nonionic surfactant comprises one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. object.
- さらに、(C)テルペノイドを含む請求項1~3のいずれか1項記載の眼科用組成物。 The ophthalmic composition according to any one of claims 1 to 3, further comprising (C) a terpenoid.
- 点眼剤である請求項1~4のいずれか1項記載の眼科用組成物。 The ophthalmic composition according to any one of claims 1 to 4, which is an eye drop.
- 涙液油層の過酸化脂質発生抑制用又は過酸化脂質による眼の不快症状の予防用である請求項1~5のいずれか1項記載の眼科用組成物。 The ophthalmic composition according to any one of claims 1 to 5, which is used for suppressing the generation of lipid peroxide in the tear fluid layer or for preventing eye discomfort caused by lipid peroxide.
- 高圧乳化による微細化工程を含む、請求項1~6のいずれか1項記載の眼科用組成物を製造する方法。 The method for producing an ophthalmic composition according to any one of claims 1 to 6, comprising a micronization step by high pressure emulsification.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018557757A JPWO2018117014A1 (en) | 2016-12-19 | 2017-12-18 | Ophthalmic composition and method for producing the same |
KR1020197006629A KR102453524B1 (en) | 2016-12-19 | 2017-12-18 | Ophthalmic composition and manufacturing method thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016-245713 | 2016-12-19 | ||
JP2016245713 | 2016-12-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018117014A1 true WO2018117014A1 (en) | 2018-06-28 |
Family
ID=62627716
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2017/045278 WO2018117014A1 (en) | 2016-12-19 | 2017-12-18 | Ophthalmic composition and method for manufacturing same |
Country Status (4)
Country | Link |
---|---|
JP (1) | JPWO2018117014A1 (en) |
KR (1) | KR102453524B1 (en) |
TW (1) | TWI787221B (en) |
WO (1) | WO2018117014A1 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6470413A (en) * | 1987-05-15 | 1989-03-15 | Santen Pharmaceutical Co Ltd | Aqueous preparation of vitamin e |
JPH06293639A (en) * | 1993-04-08 | 1994-10-21 | Lion Corp | Eye drop having solubilized stable vitamin as and vitamin es |
JP2002104959A (en) * | 2000-09-29 | 2002-04-10 | Lion Corp | Ophthalmic composition |
JP2002356420A (en) * | 2001-03-27 | 2002-12-13 | Santen Pharmaceut Co Ltd | Table aqueous liquid medicine |
JP2013253063A (en) * | 2012-06-08 | 2013-12-19 | Lion Corp | Ophthalmic composition including high sorbability vitamin a-including nanoemulsion particle and method for producing the same |
JP2014028790A (en) * | 2012-06-27 | 2014-02-13 | Rohto Pharmaceut Co Ltd | Aqueous ophthalmic composition |
JP2014129330A (en) * | 2012-06-08 | 2014-07-10 | Lion Corp | Composition for mucosa |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU684950B2 (en) * | 1994-05-06 | 1998-01-08 | Alcon Laboratories, Inc. | Use of vitamin E tocopheryl derivatives in ophthalmic compositions |
US6194457B1 (en) * | 1997-01-29 | 2001-02-27 | A. Glenn Braswell | Liquid eye drop composition |
JP5549669B2 (en) * | 2009-06-25 | 2014-07-16 | ライオン株式会社 | Ophthalmic composition, dry eye treatment and method for stabilizing vitamin A |
WO2013183778A1 (en) * | 2012-06-08 | 2013-12-12 | ライオン株式会社 | Composition for mucous membranes |
CN104797241B (en) * | 2012-12-04 | 2018-03-27 | 乐敦制药株式会社 | aqueous ophthalmic composition |
JP6260230B2 (en) * | 2013-11-28 | 2018-01-17 | ライオン株式会社 | Ophthalmic composition |
JP6225832B2 (en) * | 2014-05-26 | 2017-11-08 | ライオン株式会社 | Liquid composition and method for producing the same |
-
2017
- 2017-12-18 KR KR1020197006629A patent/KR102453524B1/en active IP Right Grant
- 2017-12-18 WO PCT/JP2017/045278 patent/WO2018117014A1/en active Application Filing
- 2017-12-18 JP JP2018557757A patent/JPWO2018117014A1/en active Pending
- 2017-12-18 TW TW106144455A patent/TWI787221B/en active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6470413A (en) * | 1987-05-15 | 1989-03-15 | Santen Pharmaceutical Co Ltd | Aqueous preparation of vitamin e |
JPH06293639A (en) * | 1993-04-08 | 1994-10-21 | Lion Corp | Eye drop having solubilized stable vitamin as and vitamin es |
JP2002104959A (en) * | 2000-09-29 | 2002-04-10 | Lion Corp | Ophthalmic composition |
JP2002356420A (en) * | 2001-03-27 | 2002-12-13 | Santen Pharmaceut Co Ltd | Table aqueous liquid medicine |
JP2013253063A (en) * | 2012-06-08 | 2013-12-19 | Lion Corp | Ophthalmic composition including high sorbability vitamin a-including nanoemulsion particle and method for producing the same |
JP2014129330A (en) * | 2012-06-08 | 2014-07-10 | Lion Corp | Composition for mucosa |
JP2014028790A (en) * | 2012-06-27 | 2014-02-13 | Rohto Pharmaceut Co Ltd | Aqueous ophthalmic composition |
Also Published As
Publication number | Publication date |
---|---|
KR20190098949A (en) | 2019-08-23 |
TWI787221B (en) | 2022-12-21 |
JPWO2018117014A1 (en) | 2019-12-12 |
KR102453524B1 (en) | 2022-10-12 |
TW201822761A (en) | 2018-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7388418B2 (en) | Ophthalmic composition and method for producing the same | |
KR101690817B1 (en) | Ophthalmic composition | |
JP7047768B2 (en) | Ophthalmic composition | |
WO2013183778A1 (en) | Composition for mucous membranes | |
JP2009196983A (en) | Ophthalmic composition | |
JP7230825B2 (en) | Aqueous ophthalmic composition and method for atomizing emulsion particles | |
JP2009161454A (en) | Ophthalmic composition | |
JP2007169232A (en) | Ophthalmic composition | |
JP5041761B2 (en) | Ocular mucosa application | |
WO2018117014A1 (en) | Ophthalmic composition and method for manufacturing same | |
JP7192766B2 (en) | Ophthalmic composition and manufacturing method thereof | |
JP7467911B2 (en) | Ophthalmic composition and method for stabilizing appearance | |
JP7139703B2 (en) | Aqueous ophthalmic composition | |
JP7056480B2 (en) | Ophthalmic composition and tear oil layer stabilizer | |
JP7102964B2 (en) | Ophthalmic composition and defoaming promotion method | |
WO2021246172A1 (en) | Ophthalmic composition, photostabilization method and method for suppressing discoloration | |
JP2021100918A (en) | Liquid composition, production method of liquid composition, and stabilization method | |
JP2020066590A (en) | Aqueous ophthalmic composition and method for improving preservation efficacy | |
JP2022099522A (en) | Ophthalmic composition, and external appearance stabilization method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17884126 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2018557757 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20197006629 Country of ref document: KR Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 17884126 Country of ref document: EP Kind code of ref document: A1 |