JP7388418B2 - Ophthalmic composition and method for producing the same - Google Patents

Description

The present invention relates to an ophthalmic composition containing liquid paraffin and a method for producing the same.

The tear oil layer is essential for maintaining eye function as it prevents the evaporation of tear water and removes foreign substances, and in order to fully fulfill its role, it must be stable on the ocular surface. 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, the proportion of saturated lipids in these components increases with age and hormonal changes, which affects the stabilization of the tear oil layer, leading to increased evaporation of the tear aqueous layer and triggering dry eye symptoms. Furthermore, it is said that there is a deep relationship with eye fatigue. In particular, it is known that in meibomian gland dysfunction, lipid saturation progresses excessively and the above symptoms worsen. On the other hand, it has been reported that the tear oil layer is made uniform by supplying an ophthalmic composition containing lecithin to the tear oil layer (Patent Document 1: Japanese Unexamined Patent Publication No. 2007-211007). However, the effect of stabilizing the tear oil layer was insufficient.

Japanese Patent Application Publication No. 2007-211007

The present invention was made in view of the above circumstances, and an object of the present invention is to provide an ophthalmic composition that stabilizes the tear oil layer and has a clear appearance, and a method for producing the same.

As a result of intensive studies to achieve the above object, the present inventors found that liquid paraffin can stabilize the tear oil layer, which has increased saturated lipids due to aging, hormonal changes, meibomian gland dysfunction, etc. .

On the other hand, ophthalmological compositions containing liquid paraffin have problems with appearance stability, such as difficulty in making the composition clear in appearance and creaming within a few hours. The ophthalmological composition is preferably clear in order to facilitate foreign body testing, and needs to have a stable appearance. On the other hand, if a surfactant is added to the amount that liquid paraffin is solubilized, it is possible to clarify and stabilize the appearance, but liquid paraffin solubilized by a large amount of surfactant is A new problem has arisen in that it becomes difficult to transfer to the tear oil layer and loses its stabilizing effect on the tear oil layer. Therefore, in order to make it easier for liquid paraffin to transfer to the tear oil layer, the liquid paraffin and surfactant are separated by being diluted with tear fluid after instillation, and the liquid paraffin is released to the water surface by promoting the coalescence of liquid paraffin. We conducted extensive research with the aim of creating an ophthalmological composition. As a result, they found that this can be achieved by setting the amount of nonionic surfactant as a surfactant to liquid paraffin at a specific ratio or less, and that the tear oil layer stabilizing effect can be maintained. Furthermore, it has been found that clarity and appearance stability can be improved by setting the total amount of nonionic surfactant to liquid paraffin at a specific ratio or higher.

Therefore, the present invention provides the following inventions.
[1]. Contains (A) liquid paraffin and (B) a nonionic surfactant, and (A) component;
(B-1) Polyoxyethylene castor oil (B-2) Polyoxyethylene hydrogenated castor oil (B-3) The blending mass ratio of nonionic surfactants other than (B-1) and (B-2) is
0.5≦((B-1)+(B-2)+(B-3))/(A), ((B-1)/0.75+(B-2)/2+(B-3) /0.2)/(A)≦10.0
An ophthalmic composition.
[2]. (B) The ophthalmological composition according to [1], wherein the nonionic surfactant contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
[3]. The ophthalmological composition according to [1] or [2], further comprising (C) a terpenoid.
[4]. A method for producing an ophthalmic composition according to any one of [1] to [3], which includes a micronization step by high-pressure emulsification.

According to the present invention, it is possible to provide an ophthalmic composition that has a clear appearance by transferring liquid paraffin to the tear oil layer through tear dilution, thereby stabilizing the tear oil layer, and a method for producing the same.

[(A) Component]
(A) Liquid Paraffin Liquid paraffin is a component that has a high stabilizing effect on the tear oil layer, which is unstable due to an increase in saturated lipids. Liquid paraffin is an oil component that has lower polarity than vegetable oil consisting of triglycerides and squalane, which has a short carbon chain length among hydrocarbons. Liquid paraffin is a mixture of hydrocarbons obtained from crude oil and is liquid at room temperature. For example, it is produced by using residual oil from atmospheric distillation of crude oil as a raw material, subjecting it to vacuum distillation and solvent deasphalting treatment, and then subjecting it to solvent refining or hydrocracking. The liquid paraffin used in the present invention is not particularly limited, and can be used singly or in an appropriate combination of two or more. Specifically, the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used. Furthermore, there is no particular restriction on the presence or absence of double bonds in the hydrocarbons, but those containing a large amount of saturated hydrocarbons are preferably used. Further, the structure of the hydrocarbon may include any of a straight chain, a branched chain, and a cyclic structure, and liquid paraffin having any specific gravity can be used. Particularly suitable are liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia. Note that an appropriate type of tocopherol may be included as a stabilizer.

The viscosity of liquid paraffin is correlated with its molecular weight, and according to the measurement method of the 16th edition Japanese Pharmacopoeia Method 1 (37.8°C), those with a viscosity of 30 to 100 mm ² /s are preferable, and those with a viscosity of 37 to 88 mm ² /s is more preferred, and 74 to 88 mm ² /s is even more preferred. Two or more types within the above viscosity range may be mixed. By setting the viscosity to 30 mm ² /s or more, the effect of stabilizing the tear oil layer can be further obtained, and by setting the viscosity to 100 mm ² /s or less, the clarity (transmittance) of the composition can be improved, and at the same time, Eye irritation specific to liquid paraffin can be further reduced.

The blending amount of component (A) is preferably 0.001 to 25.0 W/V% (mass/volume %, g/100 mL or less), more preferably 0.001 to 2.5 W/V% in the composition. , 0.001 to 1.0 W/V% is more preferred, 0.01 to 0.5 W/V% is particularly preferred, and 0.05 to 0.25 W/V% is most preferred. When the content is 0.001 W/V% or more, the effect of stabilizing the tear oil layer can be further obtained, and when the content is 25.0 W/V% or less, the clarity of the composition is further enhanced, and at the same time, the eye characteristic of liquid paraffin can be improved. Irritation can be further reduced.

[(B) Component]
(B) Nonionic surfactant (A) Ophthalmic compositions containing liquid paraffin have problems with the clarity and appearance stability of the composition, as described above, and there are problems with the combination of surfactants. However, liquid paraffin solubilized with a large amount of surfactant loses its tear oil layer stabilizing effect. Among nonionic surfactants, (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil (B-3) Nonionic interfaces other than (B-1) and (B-2) The blending mass ratio of the activator is 0.5≦((B-1)+(B-2)+(B-3))/(A), ((B-1)/0.75+(B-2) )/2+(B-3)/0.2)/(A)≦10.0, while the appearance of the composition is clear, liquid paraffin and nonionic surfactant can be separated by tear dilution. It also promotes the coalescence of liquid paraffins and their release onto the water surface, thereby exerting the effect of stabilizing the tear oil layer. One or more of the above (B-1) and (B-2) components are advantageous for the clarity of the composition because they can maintain the tear oil layer stabilizing effect even when blended at a relatively high concentration. It is preferable that it is blended. Furthermore, from the viewpoint of clarity and appearance stability of the composition, it is more preferable that two or more types of nonionic surfactants are blended. Regarding HLB, it is preferable to use a nonionic surfactant of 10 or more, more preferably 12.8 or more, and even more preferably 13 or more, since it may affect the tear oil layer stabilization effect.

(B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerizing ethylene oxide to castor oil, and has several different average numbers of added moles of ethylene oxide. types are known. The average number of moles of ethylene oxide added to polyoxyethylene castor oil is not particularly limited, but is exemplified by 3 to 60 moles. Specifically, polyoxyethylene castor oil 3 (the numerical value is the average number of added moles of ethylene oxide, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil Oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used alone or in an appropriate combination of two or more. From the viewpoint of the tear oil layer stabilizing effect, it is preferable to use polyoxyethylene castor oil 35.

The amount of component (B-1) is not particularly limited as long as it satisfies the above ratio, but it is preferably 0.0005 to 25.0 W/V%, and 0.0005 to 20.0 W/V% in the composition. It is more preferably 0.001 to 10.0 W/V%, even more preferably 0.0025 to 6.0 W/V%. From the viewpoint of the tear oil layer stabilizing effect, it is preferably 5.0 W/V% or less, more preferably 2.5 W/V% or less, and even more preferably 1.0 W/V% or less.

(B-2) Polyoxyethylene hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerizing ethylene oxide to hydrogenated castor oil. Several types with different numbers of moles are known. The average number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified as 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average number of added moles of ethylene oxide, 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 hydrogenated castor oils can be used alone or in an appropriate combination of two or more. From the viewpoint of the tear oil layer stabilizing effect, polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60 are preferably used.

The blending amount of component (B-2) is not particularly limited as long as it satisfies the above ratio, but it is preferably 0.0005 to 20.0 W/V%, and 0.0010 to 10.0 W/V% in the composition. More preferably, 0.0025 to 6.0 W/V% is even more preferable. From the viewpoint of the tear oil layer stabilizing effect, it is preferably 5.0 W/V% or less, more preferably 2.5 W/V% or less, and even more preferably 1.0 W/V% or less.

(B-3) Nonionic surfactant other than (B-1) and (B-2) Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) (The value in parentheses is the average number of added moles of ethylene oxide , polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester), polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol), typified by poloxamer, polyethylene glycol monostearate (4), Examples include polyethylene glycol monostearate represented by polyethylene glycol stearate (10), polyethylene glycol monostearate (40), and polyethylene glycol monostearate (100), which may be used alone or in an appropriate combination of two or more. It can be used as However, lecithin, hydrogenated lecithin, phosphatidylcholine, phosphatidylglycerol, and other phospholipids, which are difficult to desorb from the interface, are not separated from liquid paraffin by tear dilution, making it difficult for liquid paraffin to transfer to the tear oil layer, so It is preferable that it not be included in

When blending component (B-3), the blending amount of component (B-3) is not particularly limited as long as it satisfies the following ratio, but from the viewpoint of tear oil layer stabilization effect, 1.0W in the composition /V% or less is preferable, 0.5W/V% or less is more preferable, and even more preferably 0.4W/V% or less.

The lower limit of the combination of component (B) can be defined as ((B-1)+(B-2)+(B-3))/(A), and 0.5≦((B-1)+ (B-2)+(B-3))/(A), more preferably 1.0 or more, and even more preferably 2.5 or more. If the amount is less than the lower limit, the clarity of the composition will deteriorate. Note that the upper limit of ((B-1)+(B-2)+(B-3))/(A) is not particularly limited, but is usually 20 or less. On the other hand, the upper limit of the mixture can be defined as ((B-1)/0.75+(B-2)/2+(B-3)/0.2)/(A), and ((B-1) /0.75+(B-2)/2+(B-3)/0.2)/(A)≦10.0, more preferably 8.0 or less, and even more preferably 3.3 or less. Note that the lower limit of ((B-1)/0.75+(B-2)/2+(B-3)/0.2)/(A) is not particularly limited, but is usually 0.25 or more.

"((B-1)+(B-2)+(B-3))/(A)" defines the amount of (B) nonionic surfactant relative to component (A). ((B-1)/0.75+(B-2)/2+(B-3)/0.2)/(A) means that (B-1) and (B-2) can obtain the effects of the present invention. ) and (B-3). These differ depending on the type of component (B). For example, when (A) component is 1.0 W/V%, (B-1) alone is 0.5 W/V% or more and 7.5 W/V% or less, (B-2) is 0 when alone. .5W/V% or more and 20.0W/V% or less; if (B-3) is used alone, it needs to be 0.5W/V% or more and 2.0W/V% or less. In the case of a composite composition, if a large amount of (B-3) is blended, the total nonionic surfactant concentration can only be blended in a small amount, which is disadvantageous in terms of clarity and stability of the composition. -1)/0.75+(B-2)/2+(B-3)/0.05)/(A). Note that although the above ratio is a W/V% ratio, it has the same value as the mass ratio.

Cationic surfactants such as benzalkonium chloride and benzethonium chloride, anionic surfactants such as sodium lauryl sulfate and sorbic acid or their salts, and amphoteric surfactants such as lauramine oxide. The agent inhibits the separation of liquid paraffin and surfactant due to tear dilution and makes it difficult for liquid paraffin to be transferred to the tear oil layer. It is more preferable that the content is .01 W/V% or less, and even more preferable that it is substantially free.

[(C) Component]
The ophthalmic composition of the present invention may further contain a terpenoid. (C) By incorporating the terpenoid, it is possible to adjust the release of liquid paraffin, such as increasing the release of liquid paraffin to the water surface due to tear dilution of the composition, and to enhance the tear oil layer stabilizing effect. The terpenoid in the present invention has a structure having an isoprene unit as a constituent unit, and examples thereof include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. Depending on the number of carbon atoms, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. Specific examples include monoterpenes such as menthol, menthone, camphor, borneol, rhyno, geraniol, cineole, linalool, citronellol, and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Among them, it is preferable to use monoterpenes. These terpenoids can be used in any of the d-, l-, or dl-forms. Among them, menthol, menthone, camphor, borneol, geraniol, cineole, and linalool are preferred, and menthol, camphor, borneol, geraniol, cineole, and linalool are more preferred. In addition, in the present invention, essential oils containing the above-mentioned compounds may be used as the terpenoids. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, essential oils of dipterocarp family plants, rosmarine oil, lavender oil, and the like. Bergamot oil and eucalyptus oil are preferred from the viewpoint of enhancing the tear oil layer stabilizing effect.

The amount of component (C) is 0.0001 to 0.2 W/V% in the composition, and is appropriately selected from the type of component (C), other components such as component (B), and their amounts. be done. 0.001 to 0.1 W/V% is preferable. In this blended concentration range, there is little risk that (C) terpenoids will precipitate, regardless of the types and amounts of other blended components. In addition, from the viewpoint of stabilizing the tear oil layer, it is more preferably 0.005 W/V% or more, and from the viewpoint of reducing irritation, it is even more preferably 0.075 W/V% or less.

[Other ingredients]
The composition of the present invention may contain appropriate amounts of other components as long as the effects of the present invention are not impaired. Other components include oil components other than liquid paraffin, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyhydric alcohols, thickeners, drugs, and the like. These components can be blended singly or in an appropriate combination of two or more. The blending amounts of the components shown below are the preferred ranges when blending, and are the amounts in the composition.

Oil components other than liquid paraffin include castor oil, soybean oil, olive oil, sesame oil, corn oil, coconut oil, almond oil, medium chain fatty acid triglyceride, d-α-tocopherol acetate, retinol palmitate, white petrolatum, refined lanolin. , cholesterol, mixed tocopherols, etc. The blending amount of oil components other than liquid paraffin is preferably 0.001 to 1.0 W/V%, more preferably 0.001 to 0.5 W/V%, and most preferably 0.001 to 0.25 W/V%. .

Among preservatives, thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, etc. are listed as preservatives having hydrophobic moieties such as alkyl chains and benzene rings. Since paraffin is less likely to be transferred to the tear oil layer, it is preferably contained in the composition at 0.1 W/V% or less, and more preferably substantially free.

Examples of 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 amount of saccharides in the composition is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 1 W/V%, even more preferably 0.001 to 0.1 W/V%.

Examples of the buffer 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 amount of buffering agent in the composition is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 2 W/V%, even more preferably 0.001 to 1 W/V%.

Examples of the pH adjuster include inorganic acids and inorganic alkaline agents. For example, the inorganic acid includes (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate. The pH of the composition may be 3.5 to 13.0, preferably 3.5 to 8.0, and preferably 5.5 to 8.0, from the viewpoint of further improving symptoms caused by tear oil layer instability. .0 is more preferable. Note that pH measurement is performed at 25° C. using a pH meter (HM-25R, Toa DKK Co., Ltd.).

Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. Can be mentioned. In order to further improve various symptoms caused by destabilization of the tear oil layer, it is preferable that at least one of sodium chloride and potassium chloride is blended to make the tonicity isotonic. The osmotic pressure ratio of the composition to physiological saline is preferably from 0.60 to 2.00, more preferably from 0.60 to 1.55, and more preferably from 0.83 to improve symptoms caused by destabilization of the tear oil layer. ˜1.20 is most preferred. The osmotic pressure is measured at 25° C. using an automatic osmometer (A2O, Advanced Instruments).

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene, and the like. The blending amount of the stabilizer in the composition is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 1 W/V%, even more preferably 0.001 to 0.1 W/V%. Dibutylhydroxytoluene inhibits the separation of liquid paraffin and surfactant due to tear dilution and makes it difficult for liquid paraffin to be transferred to the tear oil layer, so it is more preferable that it is substantially not included.

Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, polyethylene glycol, and the like. When blending a polyhydric alcohol, the blending amount of the polyhydric alcohol is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 1 W/V%, and 0.001 to 0.0% in the composition. 1 W/V% is more preferable.

Examples of the thickening agent include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. When blending a thickening agent, the blending amount is preferably 0.001 to 5.0 W/V%, more preferably 0.001 to 1 W/V%, and 0.001 to 0.1 W/V% in the composition. % is more preferred.

Examples of drugs (pharmaceutical active ingredients) include decongestants (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.); Anti-inflammatory and astringent agents (e.g. 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 (e.g. diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc.) , amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium/magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, and the like. When compounding drugs, the content of the drug can be selected to be an effective and appropriate amount of each drug, but it is preferably 0.001 to 5.0 W/V% in the composition, and 0.001 to 1 W/V%. % is more preferable, and 0.001 to 0.1 W/V% is even more preferable.

[Production method]
The method for producing the composition of the present invention is not particularly limited, but for example, a mixed solution of an oily component such as component (A) and a surfactant component such as component (B) is mixed with an aqueous solution containing an aqueous component. It can be obtained by emulsifying, adjusting the pH, and then adjusting the total volume with water. The mixing method of each liquid may be a general method, and may be carried out using a pulsator, propeller blade, paddle blade, turbine blade, etc. as appropriate, but the rotation speed is not particularly limited and should be set to an extent that does not cause violent 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 at least the melting temperature, and specifically, it is appropriately selected from the range of 40 to 95°C. More preferably, a micronization step by high-pressure emulsification is further performed. Regarding the high-pressure emulsification conditions, from the viewpoint of improving the clarity of the composition, it is preferable to use high pressure and a large number of passes, and from the viewpoint of improving production efficiency, it is preferable to use low pressure and reduce the number of passes. The pressure is preferably 100 to 245 MPa, more preferably 150 to 245 MPa, even more preferably 200 to 245 MPa. It is preferable to further 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, more preferably 1 to 5 times. The temperature during high-pressure emulsification is appropriately selected from the range of 20 to 90°C.

Further, after filling the obtained composition into a resin container, the resin container may be further sealed with a packaging body, and an inert gas may be filled in the space formed between the container and the packaging body, and the ophthalmological composition The product may be filled into a resin container and sealed together with an oxygen absorber in a package.

[Ophthalmic composition]
The composition of the present invention is preferably an "aqueous ophthalmic composition." In the present invention, the term "aqueous ophthalmic composition" refers to an ophthalmic composition whose medium is water. The amount of water blended in the composition is preferably 90.0 to 99.5 W/V% in the composition from the viewpoint of facilitating mixing with tear fluid, preventing delay in liquid paraffin migration, and obtaining a greater effect of stabilizing the tear oil layer. , 95.0 to 98.0 W/V% is more preferable.

The composition of the present invention is preferably liquid from the viewpoint of ease of adaptation to the eye, and the viscosity at 25°C facilitates mixing with lachrymal fluid, prevents delay in liquid paraffin migration, and improves the effect of stabilizing the tear oil layer. From this point of view, the pressure is preferably 20 mPa·s or less, more preferably 10 mPa·s or less, even more preferably 5 mPa·s or less, and particularly preferably 2 mPa·s or less. The viscosity is measured using a cone plate viscometer (for example, DV2T, manufactured by Hideko Seiki Co., Ltd.).

The composition of the present invention is preferably clear in order to facilitate detection of foreign matter contamination. Specifically, the transmittance at a wavelength of 600 nm measured using a spectrophotometer (UV-1800, Shimadzu Corporation) is preferably 50 to 100%, more preferably 75 to 100%, and even more preferably 90 to 100%. preferable.

The median diameter of the aggregate of the surfactant and liquid paraffin contained in the composition of the present invention was measured using a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.), and the clarity of the composition was measured. In terms of appearance stability, the thickness is preferably 1 to 200 nm, more preferably 1 to 100 nm, even more preferably 1 to 60 nm, and most preferably 1 to 40 nm.

The composition of the present invention can be suitably used as eye drops, eye drops for contact lenses, eyewash, etc., but it has a high lacrimal dilution ratio, further promotes the release of surfactant from liquid paraffin, and delivers liquid paraffin. It can be particularly suitably used as eye drops and contact lens eye drops (eye drops for contact lens wearers) because of the fact that this can be carried out efficiently. Contact lenses include hard contact lenses, soft contact lenses, and the like, but are not particularly limited.

When used as eye drops or contact lens eye drops, it is preferable to instill 1 to 3 drops of 10 to 100 μL at a time, 1 to 6 times a day, and the effect of stabilizing the tear oil layer is achieved by overflowing from the eyes. Since there is a risk of reduction, it is more preferable to use 1 to 3 drops of 10 to 50 μL per time, 1 to 6 times per day, and even more preferably 1 to 3 drops of 10 to 30 μL per time, 1 to 6 times per day. When used as an eyewash, it is preferable to wash the eyes 3 to 6 mL at a time, 3 to 6 times a day.

The composition of the present invention does not simply replenish oil to the tear oil layer or promote the production of oil components from the meibomian glands, but rather stabilizes the tear oil layer that has become unstable due to meibomian gland dysfunction, etc. It is something. If the production of oil components is simply promoted, saturated lipids will increase, which will actually worsen the symptoms, and simply replenishing the tear oil layer with oil will not stabilize the destabilized tear oil layer. The composition of the present invention is effective as a tear oil layer stabilizer (a tear oil layer stabilizer), and is also effective for dry eye symptoms (eye fatigue, eye blur/blur, eye dryness, foreign body sensation, For the improvement of eye fatigue symptoms (eye fatigue, fatigue, stiff shoulders, headaches, etc.) It is effective as a dry eye symptom improving agent). It is particularly effective as an agent for improving dry eye symptoms and eye fatigue symptoms caused by destabilization of the tear oil layer (eye fatigue, blurred/hazy eyes, dryness of the eyes, or feeling of fatigue). The more effective symptoms are eye fatigue, blurred/blurred eyes, dry eyes, and fatigue; It is blurry and hazy. From the above points, for patients with meibomian gland dysfunction, for patients with dry eye, for patients with eye fatigue, especially for patients with dry eye caused by tear oil layer destabilization or meibomian gland dysfunction, tear oil layer destabilization or meibomian gland function. It is useful for patients with eye fatigue caused by glandular dysfunction. In addition, since contact lens wearing promotes meibomian gland dysfunction, it is preferably for contact lens wearers, especially soft contact lens wearers.

The effective amount, administration method, preparation method, etc. are as described above, and for example, liquid paraffin is administered to the eye in an amount of 0.01 to 1 mg per adult, divided into 1 to 6 times a day.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples and Comparative Examples, but the present invention is not limited to the Examples below. In addition, ((B-1)+(B-2)+(B-3))/(A), ((B-1)/0.75+(B-2)/2+(B-3)/0 .2)/(A), ((B-1)/0.75+(B-2)/2+(B-3)/0.05)/(A), the above ratio is W/V% ratio. Yes, the value is the same as the mass ratio.

[Examples, comparative examples]
Each aqueous component shown in the table below was dissolved in 90 mL of water and mixed while heating at 90° C. for 15 minutes. Separately, a premix of (A) liquid paraffin and (B) nonionic surfactant was prepared and mixed under heating at 90° C. for 15 minutes. Next, a predetermined amount of the premix was added to the above aqueous solution, and the mixture was heated and mixed at 90° C. for 15 minutes. Thereafter, the mixture was cooled to room temperature, the pH was adjusted, and water was added to make the volume 100 mL. Further, using a high-pressure emulsifier (Starburst Mini, Sugino Machine Co., Ltd.), treatment was performed five times at a jetting pressure of 200 MPa and a back pressure of 3 MPa to prepare eye drops. The obtained composition was evaluated as follows. The results are also listed in the table. In addition, as a result of evaluating the appearance stability after 24 hours of production and after storage at 40°C for 6 months, the appearance was stable with no creaming observed in Examples, but creaming was observed in Comparative Examples 1 and 3. . Note that the viscosity of each example was in the range of 0.5 to 2.0 mPa·s.

[Release test of liquid paraffin on water surface by dilution]
It is said that the average amount of human tear fluid is 7 μL, and when 30 to 60 μL of eye drops are instilled into the eye, it will be diluted approximately 1.12 to 1.23 times. In this test, in order to evaluate the release of liquid paraffin onto the water surface due to tear dilution of the composition, physiological saline was used as a model tear fluid, and the release of liquid paraffin onto the water surface when diluted at a dilution rate of approximately 1.2 times was performed. Liquid paraffin release was observed. 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 the composition was poured up to the opening. A volumetric flask was used in which the dilution rate was 1.2 times when poured up to the opening, and the area of the opening was 152 mm ² . To observe liquid paraffin on the water surface, use a fluorescent lamp as a light source and shine light onto the liquid surface, observe the interference light of the oil floating on the liquid surface, and calculate the area ratio of the interference light of the oil to the water surface. Evaluation was made based on the following criteria. In addition, in any of the Examples and Comparative Examples, no oil interference light was observed in the case of non-dilution.
[Evaluation criteria]
◎: Oil interference light is observed on 10% or more of the water surface ○: Oil interference light is observed on less than 10% of the water surface ×: Oil interference light is not observed

[Tear fluid stability test]
The tear oil layer stability was evaluated by measuring the BUT (break up time) of the tear oil layer using a dry eye observation device DR-1 (manufactured by Kowa Co., Ltd.). DR-1 is a device that can measure the interference image of light reflected at the interface between the tear oil layer surface and the tear aqueous layer. In a healthy eye, a uniform gray or white interference image is observed, and the interference image disappears when the tear oil layer collapses. 30 μL of each eye drop was instilled into the subject's eyes, and after 10 minutes had elapsed, the subjects blinked several times, and the time from blink to collapse of the tear oil layer (oil layer BUT) was measured. Subjects were selected from 13 eyes of 7 people whose oil layer BUT before instillation was 10 seconds or less. The results are shown using the following evaluation criteria based on the average values of 13 eyes of 7 people. The oil layer BUT, which was less than 10 seconds, fluctuates within and between days, and does not exceed 10 seconds for eye drops that do not contain liquid paraffin, so improvement to 10 seconds or more is considered acceptable as it has sufficient usefulness. It was judged.
[Evaluation criteria]
◎ (Excellent): Oil layer BUT is 60 seconds or more 〇 (Good): Oil layer BUT is 30 seconds or more and less than 60 seconds ● (Acceptable): Oil layer BUT is 10 seconds or more and less than 30 seconds × (Not acceptable): Oil layer BUT is less than 10 seconds

[Transmittance (%) (clarity)]
The transmittance of the eye drops immediately after manufacture at a wavelength of 600 nm was measured using a spectrophotometer.
A score of 50% or higher is considered a pass.

[Test example]
<In vitro tear oil layer stability test>
In order to examine the tear oil layer stability of each oil component, evaluation was performed using an in vitro evaluation system. As a destabilized tear oil layer model, a chloroform solution was prepared by mixing meibum extracted from rabbit eyelids with stearyl stearate and cholesteryl stearate as saturated lipids at a mass ratio of 100:3.3:6.7. The solution was spread on the physiological saline surface in a polytetrafluoroethylene water tank (45 cm ² ) so that the amount of lipid per unit area was 5 μg/cm ² (the amount of lipid per unit area of an average eye). . Furthermore, 675 μL of a chloroform solution of each oil at a predetermined concentration (30 μL per 2 cm ² of average eye size) was developed and allowed to stand at 37°C for 15 minutes to completely volatilize the chloroform and After compression and stretching was performed 10 times with an ethylene rod, the interference light of the oil layer was visually observed, and the stability of the tear oil layer was evaluated based on the following criteria. If the aqueous layer is not exposed in the tear fluid, it is considered to be stable above a certain level, so it was judged to be acceptable.
[Tear fluid oil layer stability evaluation]
◎ (Excellent): Uniform oil layer 〇 (Good): Almost uniform oil layer ● (Acceptable): There is unevenness, but the water layer is not exposed × (Unacceptable): The water layer is exposed

In a destabilized tear oil film model with increased saturated lipid content, liquid paraffin had a stabilizing effect, but castor oil, sesame oil, medium-chain fatty acid triglycerides, and lecithin had no stabilizing effect.

The raw materials used in the above examples are shown below. In addition, unless otherwise specified, the amount of each component in the table is a pure equivalent amount.
Liquid paraffin 16th revised Japanese Pharmacopoeia Law 1 (37.8℃) Viscosity 76.6mm ² /s (KAYDOL, manufactured by Shima Boeki Co., Ltd.)
Liquid paraffin, 16th revised Japanese Pharmacopoeia Act 1 (37.8°C), viscosity 34.8 mm ² /s (Hicol M-172, manufactured by Kaneda Corporation)
Polyoxyethylene castor oil: Polyoxyethylene castor oil 35, Uniox C35, NOF Corporation Polyoxyethylene hydrogenated castor oil *1: Polyoxyethylene hydrogenated castor oil 60, HCO60, Nippon Surfactant Industries Co., Ltd. Poly Oxyethylene hydrogenated castor oil *2: Polyoxyethylene hydrogenated castor oil 40, HCO40, manufactured by Nippon Surfactant Kogyo Co., Ltd. Polyethylene glycol monostearate *3: Polyethylene glycol monostearate (4), MYS4V, Nippon Surfactant Kogyo Co., Ltd. Polyethylene glycol monostearate *4: Polyethylene glycol monostearate (10), MYS10V, manufactured by Nippon Surfactant Kogyo Co., Ltd. Polyethylene glycol monostearate *5: Polyethylene glycol monostearate (40), MYS40MV, Nippon Surfactant Kogyo ( Co., Ltd. polyethylene glycol monostearate *6: Polyethylene glycol monostearate (100), EMALEX 8100, Nippon Emulsion Co., Ltd. POE sorbitan fatty acid ester *7: Polysorbate 80 (polyoxyethylene monolaurate (20) sorbitan, Kao ( POEPOP glycol (polyoxyethylene (196)-polyoxypropylene (67) block copolymer *8: Lutrol F127 manufactured by BASF Japan Co., Ltd., boric acid manufactured by BASF Japan Co., Ltd.: Trometamol manufactured by Kosakai Pharmaceutical Co., Ltd.: Edet manufactured by Kanto Kagaku Co., Ltd. Sodium acid hydrate: Qualet N, Nagase ChemteX Co., Ltd. Sodium chloride: Tomita Pharmaceutical Co., Ltd. Sodium hydroxide: Wako Pure Chemical Industries, Ltd. Castor oil: Kaneda Co., Ltd. Sesame oil: Kaneda Co., Ltd. ) Medium-chain fatty acid triglyceride manufactured by NIKKOL Triester F-810, Nikko Chemicals Co., Ltd. Lecithin: Egg-derived, MP Biomedicals, Inc. Menthol: L-menthol, Suzuki Thing Co., Ltd. dl-Camphor: Nippon Fine Chemicals Borneol manufactured by Co., Ltd.: d-borneol, Geraniol manufactured by Masami Yanagisawa Shoten Co., Ltd.: Cineol manufactured by Takasago Fragrance Industries Co., Ltd.: Linalool manufactured by Takasago Fragrance Industries Co., Ltd.: Bergamot oil manufactured by Takasago Fragrance Industries Co., Ltd.: Yamamoto Perfume Co., Ltd. Eucalyptus oil manufactured by Ogawa Kogyo Co., Ltd.

Claims (5)

(A) Liquid paraffin with a viscosity of 74 to 88 mm ² /s according to the method of measurement according to the 16th revised Japanese Pharmacopoeia No. 1 (37.8°C) , and (B) the following (B-1), (B- Contains a nonionic surfactant containing one or more selected from 2) and (B-3) ,
(B-1) Polyoxyethylene castor oil (B-2) Polyoxyethylene hydrogenated castor oil (B-3) Polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol monostearate
The blending mass ratio of the component (A) and the nonionic surfactant (B) is:
1.0≦((B-1)+(B-2)+(B-3))/(A), ((B-1)/0.75+(B-2)/2+(B-3) /0.2)/(A)≦10.0
An ophthalmic composition (provided that
At least one member selected from the group consisting of rebamipide, rebamipide derivatives, and salts thereof, and
Excludes topical mucosal aqueous compositions containing oily components. ). The ophthalmic composition according to claim 1, which has a transmittance of 50 to 100% at a wavelength of 600 nm. The ophthalmological composition according to claim 1 or 2, wherein the nonionic surfactant (B) contains one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. thing. The ophthalmic composition according to any one of claims 1 to 3, further comprising (C) a terpenoid. A method for producing an ophthalmic composition according to any one of claims 1 to 4, comprising a micronization step by high-pressure emulsification.