JP6962663B2 - Ophthalmic composition and its manufacturing method - 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 indispensable for maintaining the function of the eye in order to prevent the evaporation of water in the tear and remove foreign substances, and it must be stable on the surface of the eye to fully fulfill its role. is necessary. This tear oil layer is composed of lipids (meiboms) 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 proportion of saturated lipids due to aging and hormonal changes, affect the stabilization of the tear oil layer, promote the evaporation of the tear water layer, and cause dry eye symptoms. It is also said to be closely related to eye fatigue. In particular, it is known that in meibomian gland dysfunction, lipid saturation progresses excessively and the above-mentioned symptoms are exacerbated. 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 Patent Application Laid-Open No. 2007-211007). However, these tear oil layer stabilizing effects were insufficient.

Japanese Unexamined Patent Publication No. 2007-211007

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

As a result of diligent studies to achieve the above object, the present inventors have found that liquid paraffin can stabilize a tear oil layer in which saturated lipids are increased due to aging, hormonal changes, meibomian gland dysfunction, and the like. ..

On the other hand, the ophthalmic composition containing liquid paraffin has a problem of appearance stability that the appearance of the composition is difficult to be clear and creaming takes several hours. The ophthalmic composition is preferably clear from the viewpoint of facilitating the foreign matter test, and needs to have a stable appearance. On the other hand, if a surfactant is added to an amount that solubilizes the liquid paraffin, clarification and appearance stabilization can be achieved, but the liquid paraffin solubilized by a large amount of the surfactant can be used. A new problem has arisen in which it becomes difficult to move to the tear oil layer and the effect of stabilizing the tear oil layer is lost. Therefore, in order to facilitate the transfer of liquid paraffin to the tear oil layer, the liquid paraffin and the surfactant are separated by being diluted with tear liquid after instillation, and the liquid paraffin is released to the water surface by promoting the coalescence of the liquid paraffins. We made a diligent study aiming at a composition for ophthalmology. As a result, it was found that this can be achieved by setting the blending amount of the nonionic surfactant as the surfactant to a specific ratio or less with respect to the liquid paraffin, and the tear oil layer stabilizing effect can be maintained. It was also found that the clarity and appearance stability are improved by setting the total blending amount of the nonionic surfactant to a specific ratio or more with respect to the liquid paraffin.

Therefore, the present invention provides the following invention.
[1]. It contains (A) liquid paraffin and (B) nonionic surfactant, and contains (A) component and
(B-1) Polyoxyethylene castor oil (B-2) Polyoxyethylene hydrogenated castor oil The compounding mass ratio of nonionic surfactants other than (B-3) (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 that is.
[2]. The ophthalmic composition according to [1], wherein the (B) nonionic surfactant comprises one or more selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil.
[3]. The ophthalmic composition according to [1] or [2], which further comprises (C) a terpenoid.
[4]. The method for producing an ophthalmic composition according to any one of [1] to [3], which comprises a micronization step by high-pressure emulsification.

According to the present invention, it is possible to provide an ophthalmic composition having a clear appearance by transferring liquid paraffin to the tear oil layer by diluting the tear liquid to stabilize the tear oil layer, and a method for producing the same.

[(A) component]
(A) Liquid paraffin Liquid paraffin is a component having a high effect of stabilizing the tear oil layer with respect to the unstable tear oil layer in which saturated lipids are increased. Liquid paraffin is a vegetable oil composed of triglyceride and an oil having a lower polarity than squalane having a short carbon chain length among hydrocarbons. Liquid paraffin is a mixture of hydrocarbons obtained from crude oil and is liquid at room temperature. For example, it is produced by a method of subjecting crude oil to atmospheric distillation residual oil as a raw material, subjecting it to vacuum distillation and solvent dehistory treatment, and then subjecting it to a solvent refining method or a hydrocracking method. The liquid paraffin used in the present invention is not particularly limited, and one type alone or two or more types may be used in combination as appropriate. Specifically, the carbon chain length of the hydrocarbon is not particularly limited, but those of 15 to 45 are preferably used. The presence or absence of a double bond in the hydrocarbon is not particularly limited, but one containing a large amount of saturated hydrocarbon is preferably used. Further, the hydrocarbon structure may include any of a straight chain, a branched chain and a cyclic structure, and liquid paraffin having any specific density can be used. In particular, liquid paraffin and light liquid paraffin listed in the Japanese Pharmacopoeia are suitable. In addition, a suitable type of tocopherol may be contained as a stabilizer.

In the method of the viscosity of the liquid paraffin it is correlated with its molecular weight, sixteenth revised Japanese Pharmacopoeia first method (37.8 ° C.), preferably has a viscosity of 30 to 100 mm ² / s, viscosity 37~88mm ^{The one of 2} / s is more preferable, and the one of 74 to 88 mm ² / s is further preferable. Two or more kinds within the above viscosity range may be mixed. By setting the viscosity to 30 mm ² / s or more, the tear oil layer stabilizing effect can be further obtained, and by ^{setting the viscosity to 100 mm 2} / s or less, the clarity (transmittance) of the composition is enhanced and at the same time, the clarity (transmittance) of the composition is enhanced. Eye irritation peculiar to liquid paraffin can be further reduced.

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

[(B) component]
(B) Nonionic Surfactant (A) The ophthalmic composition containing liquid paraffin has problems in the clarity and appearance stability of the composition as described above, and there is a problem in blending the surfactant. However, liquid paraffin solubilized with a large amount of surfactant loses the effect of stabilizing the tear oil layer. Among the nonionic surfactants, nonionic surfactants other than (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil (B-3) (B-1) and (B-2) The compounding 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) with /(A)≦10.0, yet clear appearance of the composition, the liquid paraffin and nonionic surfactant by tear dilution separation However, it can promote the coalescence of liquid paraffins, promote the release to the water surface, and exert the effect of stabilizing the tear oil layer. The above components (B-1) and (B-2) can maintain the tear oil layer stabilizing effect even when blended in a relatively high concentration, and thus one or more of them are advantageous in terms of clarity of the composition. It is preferable that it is blended. Further, it is more preferable that two or more kinds of nonionic surfactants are blended from the viewpoint of clarity of the composition and appearance stability. Further, regarding HLB, since it may affect the tear oil layer stabilizing effect, it is preferable to use 10 or more nonionic surfactants, 12.8 or more is more preferable, and 13 or more is further preferable.

(B-1) Polyoxyethylene Glycol Oil Polyoxyethylene Glycol Oil (POE Himashi Oil) is a compound obtained by addition polymerization of ethylene oxide to Himashi Oil, and some of them have different average moles of ethylene oxide. Types are known. The average number of moles of ethylene oxide added to the polyoxyethylene castor oil is not particularly limited, but 3 to 60 moles is exemplified. Specifically, polyoxyethylene castor oil 3 (numerical values are the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil. Examples thereof include oil 40, polyoxyethylene castor oil 50, and polyoxyethylene castor oil 60. These polyoxyethylene castor oils can be used alone or in combination of two or more. From the viewpoint of stabilizing the tear oil layer, it is preferable to use polyoxyethylene castor oil 35.

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

(B-2) Polyoxyethylene hydrogenated castor oil Polyoxyethylene hydrogenated castor oil (POE cured castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and is an average addition of ethylene oxide. Several types with different molar numbers are known. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified by 5 to 100 moles. Specifically, polyoxyethylene cured castor oil 5 (numerical values are the average number of moles of ethylene oxide added, the same applies hereinafter), polyoxyethylene cured castor oil 10, polyoxyethylene cured castor oil 20, polyoxyethylene cured castor oil 30, Examples thereof include polyoxyethylene cured castor oil 40, polyoxyethylene cured castor oil 50, polyoxyethylene cured castor oil 60, polyoxyethylene cured castor oil 80, and polyoxyethylene cured castor oil 100. These polyoxyethylene hydrogenated castor oils can be used alone or in combination of two or more. From the viewpoint of the tear oil layer stabilizing effect, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

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

(B-3) (B- 1) and (B-2) other than the nonionic surfactant polysorbate 80 (monooleate polyoxyethylene (20) sorbitan) (Figures in parentheses average addition mole number of ethylene oxide Polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) represented by (the same applies hereinafter), polyoxyethylene-polyoxypropylene block copolymer (POEPOP glycol) represented by Poroxumer, polyethylene glycol monostearate (4), mono Examples thereof include polyethylene glycol stearate (10), polyethylene glycol monostearate (40), polyethylene glycol monostearate typified by polyethylene glycol monostearate (100), and one type alone or a combination of two or more types as appropriate. Can be used. However, lecithin, hydrogenated lecithin, phospholipids such as phosphatidylcholine and phosphatidylglycerol, which are difficult to desorb from the interface, are not separated from the liquid paraffin by diluting the tear fluid, and the liquid paraffin is less likely to be transferred to the tear oil layer. It is preferable that it is not contained in.

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

The lower limit of the composition of the component (B) can be specified by ((B-1) + (B-2) + (B-3)) / (A), and 0.5 ≦ ((B-1) +). (B-2) + (B-3)) / (A), 1.0 or more is more preferable, and 2.5 or more is further preferable. If it is less than the lower limit of compounding, the clarity of the composition deteriorates. 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 compounding can be specified by ((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. 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 with respect to the component (A). ((B-1) /0.75+ (B-2)/2+ (B-3) /0.2 ) / (A) can obtain the effect of the present invention (B-1), (B-2). ) And (B-3) are specified. These differ depending on the type of component (B). For example, in the case of (A) component 1.0 W / V %, (B-1) alone is 0.5 W / V% or more, 7.5 W / V% or less, and (B-2) alone is 0. .5W / V% or more, 20.0W / V% or less, (B-3) alone long if 0.5 W / V% or more, is required to be less 2.0 W / V%. In the case of a composite composition, if a large amount of (B-3) is blended, only a small amount can be blended as the total nonionic surfactant blending concentration, which is disadvantageous in terms of clarity and stability of the composition. It may be specified as -1) /0.75+ (B-2) /2+ (B-3) /0.05 ) / (A). Although the above ratio is a W / V% ratio, it is the same value as the mass ratio.

It should be noted that 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 the separation of the liquid paraffin and the surfactant by diluting the tear liquid, and the liquid paraffin is less likely to be transferred to the tear oil layer. Therefore, the content is preferably 0.1 W / V% or less in the composition, and is 0. It is more preferably 0.01 W / V% or less, and further preferably not substantially contained.

[(C) component]
The ophthalmic composition of the present invention may further contain a terpenoid. By blending the (C) terpenoid, the liberation of the liquid paraffin by diluting the tear liquid of the composition to the water surface can be adjusted, and the effect of stabilizing the tear oil layer can be enhanced. 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. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the number of carbon atoms. Specific examples thereof include monoterpenes such as menthol, menthone, camphor, borneol, ryunou, geraniol, cineole, linalol, citronellol and limonene, diterpenes such as retinol and retinal, and tetraterpenes such as carotenoids. Above all, it is preferable to use a monoterpene. These terpenoids can be used in any of d-form, l-form or dl-form. Among them, menthol, menthol, camphor, borneol, geraniol, cineole and linalool are preferable, and menthol, camphor, borneol, geraniol, cineole and linalool are more preferable. In the present invention, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, uikyo oil, rose oil, peppermint oil, peppermint oil, sparemint oil, and essential oils of the family Futabagaki family, rosmarin oil, lavender oil and the like. Bergamot oil and eucalyptus oil are preferable from the viewpoint of enhancing the effect of stabilizing the tear oil layer.

The blending amount of the component (C) is 0.0001 to 0.2 W / V% in the composition, and is appropriately selected from the type of the component (C), other blended components such as the component (B), and the blended amount thereof. Will be done. It is preferably 0.001 to 0.1 W / V%. In this compounding concentration range, there is little possibility that (C) terpenoids are precipitated regardless of the type and amount of other compounding components. Further, 0.005 W / V% or more is more preferable from the viewpoint of the tear oil layer stabilizing effect, and 0.075 W / V% or less is further preferable from the viewpoint of reducing the irritation sensation.

[Other ingredients]
The composition of the present invention may contain an appropriate amount of other components as long as the effects of the present invention are not impaired. Examples of 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 individually by 1 type or in combination of 2 or more types as appropriate. The blending amount of the components shown below is a preferable range when blending, and is an amount in the composition.

Oil components other than liquid paraffin include castor oil, soybean oil, olive oil, sesame oil, corn oil, palm oil, almond oil, medium-chain fatty acid triglyceride, acetic acid-d-α-tocopherol, retinol palmitate, white vaseline, and refined lanolin. , Cholesterol, mixed tocopherol and the like. The blending amount of the oil component 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%. ..

As a preservative having a hydrophobic portion such as an alkyl chain or a benzene ring among preservatives, Ji Melo Searle, phenylethyl alcohol, alkyl aminoethyl glycine, chlorhexidine gluconate, Palau carboxymethyl benzoic acid methyl, ethyl parahydroxybenzoate, and the like However, since liquid parabens are less likely to be transferred to the tear oil layer, it is preferably 0.1 W / V% or less, and more preferably substantially not contained in the composition.

Examples of saccharides include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form, or dl-form. The blending amount of the saccharide is preferably 0.001 to 5.0 W / V%, more preferably 0.001 to 1 W / V%, still more preferably 0.001 to 0.1 W / V% in the composition.

Examples of the buffer include citric acid, sodium citrate, boric acid, borosand, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, tromethamole, sodium hydrogen carbonate and the like. The blending amount of the buffer is preferably 0.001 to 5.0 W / V%, more preferably 0.001 to 2 W / V%, still more preferably 0.001 to 1 W / V% in the composition.

Examples of the pH adjuster include an inorganic acid or an inorganic alkaline agent. For example, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. The pH of the composition can be 3.5 to 13.0, preferably 3.5 to 8.0 from the viewpoint of further improving various symptoms caused by instability of the tear oil layer, and 5.5 to 8 .0 is more preferred. The pH is measured at 25 ° C. using a pH meter (HM-25R, DKK-TOA CORPORATION).

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like. Can be mentioned. From the viewpoint of further improving various symptoms caused by the destabilization of the tear oil layer, it is preferable that at least one of sodium chloride and potassium chloride is blended 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 0.83 from the viewpoint of further improving various symptoms caused by instability of the tear oil layer. ~ 1.20 is most preferable. The osmotic pressure is measured at 25 ° C. using an automatic osmotic pressure gauge (A2O, Advanced Instruments).

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. The amount of the stabilizer blended is preferably 0.001 to 5.0 W / V%, more preferably 0.001 to 1 W / V%, still more preferably 0.001 to 0.1 W / V% in the composition. It is more preferable that dibutylhydroxytoluene is substantially not contained because it inhibits the separation of the liquid paraffin and the surfactant by diluting the tear liquid and makes it difficult for the liquid paraffin to be transferred to the tear oil layer.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. When the polyhydric alcohol is blended, 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. 1 W / V% is more preferable.

Examples of the thickener include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. When a viscous agent is blended, the blending amount thereof 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 preferable.

Examples of the drug (pharmaceutical active ingredient) include decongestant components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, nafazoline hydrochloride, nafazoline nitrate, phenilefurin hydrochloride, dl-methylephedrine hydrochloride, etc.). Anti-inflammatory and astringent agents (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantin, velverin chloride hydrate, velverin sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysoteam hydrochloride Salts, etc.), antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamine, pyridoxin hydrochloride, pantenol, calcium pantothenate, sodium pantothenate, etc.) , Amino acids (for example, potassium L-aspartate, magnesium L-aspartate, potassium-magnesium L-aspartate (equal mixture), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa agents and the like. When a drug is blended, the effective appropriate amount of each drug can be selected as the content of the drug, but 0.001 to 5.0 W / V% is preferable in the composition, and 0.001 to 1 W / V is preferable. % 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. emulsified, after pH adjustment, the total volume can be obtained by more adjustments in 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 so as not to foam violently. Is preferable. 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, the mixture is appropriately selected from the range of 40 to 95 ° C. More preferably, a micronization step by high-pressure emulsification is further performed. Under the high-pressure emulsification condition, it is preferable to increase the number of passes at high pressure from the viewpoint of improving the clarity of the composition, and from the viewpoint of improving production efficiency, it is preferable to decrease the number of passes at low pressure, and the injection pressure is high. It is preferably 100 to 245 MPa, more preferably 150 to 245 MPa, and even more preferably 200 to 245 MPa. Further, back pressure is preferably applied, 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 at the time of high-pressure emulsification is appropriately selected from the range of 20 to 90 ° C.

Also, after filling the resulting composition into the resin vessel, sealed by further package may be filled with an inert gas in the space formed between the container and the packaging, for ophthalmic The composition may be filled in a resin container and sealed with a packaging material together with an oxygen scavenger.

[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 to be blended is preferably 90.0 to 99.5 W / V% in the composition from the viewpoint of facilitating mixing with tear fluid, preventing delay in transfer of liquid paraffin, and further obtaining the effect of stabilizing the tear fluid oil layer. , 95.0-98.0 W / V% is more preferable.

The composition of the present invention is preferably a liquid from the viewpoint of facilitating adaptation to the eyes, and the viscosity at 25 ° C. facilitates mixing with tears, prevents delay in transfer of liquid paraffin, and further obtains a tear oil layer stabilizing effect. From the point of view, 20 mPa · s or less is preferable, 10 mPa · s or less is more preferable, 5 mPa · s or less is further preferable, and 2 mPa · s or less is particularly preferable. The viscosity is measured using a cone plate type viscometer (for example, DV2T, Eiko Seiki Co., Ltd.).

The composition of the present invention is preferably clear from the viewpoint of facilitating detection when a foreign substance is mixed. 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 further 90 to 100%. preferable.

The medium diameter of the aggregate of the surfactant and the liquid paraffin contained in the composition of the present invention was measured by a particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.), and the clarity of the composition was measured. From the viewpoint of appearance stability, 1 to 200 nm is preferable, 1 to 100 nm is more preferable, 1 to 60 nm is further preferable, and 1 to 40 nm is most preferable.

The composition of the present invention can be suitably used as an eye drop, an eye drop for contact lenses, an eye wash, etc. It can be suitably used as an eye drop, a contact lens eye drop (a contact lens wearer's eye drop), and the like, because the above is efficiently performed. The contact lens is not particularly limited, such as a hard contact lens and a soft contact lens.

When used as an eye drop or an eye drop for contact lenses, it is preferable to instill 10 to 100 μL of 1 to 3 drops at a time, 1 to 6 times a day, and the effect of stabilizing the tear oil layer is obtained by overflowing from the eyes. Since there is a possibility of decrease, 10 to 50 μL at a time is more preferably 1 to 6 times per day, and 10 to 30 μL at a time is more preferably 1 to 6 times per day. When used as an eye wash, it is preferable to wash the eyes 3 to 6 mL at a time and 3 to 6 times a day.

The composition of the present invention does not merely replenish the tear oil layer with oil or promote the production of oil components from the meibomian glands, but stabilizes the tear oil layer destabilized by meibomian gland dysfunction or the like. It is a thing. Simply promoting the production of the oil component increases the amount of saturated lipids and rather worsens the symptoms, and simply supplementing the tear oil layer with oil cannot stabilize the destabilized tear oil layer. The composition of the present invention is effective for stabilizing the tear oil layer (tear oil layer stabilizer), and further, dry eye symptoms (eye fatigue, blurred / blurred eyes, dry eyes, foreign body sensation, eyes). For improvement of pain, dazzling eyes, heavy eyes, itchy eyes, discomfort in the eyes, eye oil, tearing, congestion, etc. and eye fatigue symptoms (tired eyes, tiredness, stiff shoulders, headache, etc.) It is effective as a dry eye symptom improving agent). In particular, it is effective for improving dry eye symptoms and eye fatigue symptoms caused by instability of the tear oil layer (eye fatigue, blurred / blurred eyes, dry eyes or fatigue improving agent). The more effective symptoms are eye fatigue, blurred / blurred eyes, dry eyes, and tiredness, and the more effective symptoms are tired eyes, blurred / blurred eyes, and the most effective symptoms are eyes. Blurred / blurred. From the above points, for patients with meibomian gland dysfunction, for patients with dry eye, for patients with eye fatigue, especially for patients with tear oil layer instability or dry eye caused by meibomian gland dysfunction, tear oil layer instability or meibomian gland It is useful for patients with eye fatigue caused by glandular dysfunction. Since wearing contact lenses promotes meibomian gland dysfunction, it is preferable to wear them for contact lens wearers, especially for soft contact lens wearers.

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

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. 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 the W / V% ratio. Yes, it is the same value as the mass ratio.

[Examples, comparative examples]
In the table below, each aqueous component was dissolved in 90 mL of water and heated and mixed at 90 ° C. for 15 minutes. Separately, a premix of (A) liquid paraffin and (B) nonionic surfactant was prepared and heated and mixed at 90 ° C. for 15 minutes. Next, a predetermined amount of the premix was added to the above aqueous solution, and the mixture was further heated and mixed at 90 ° C. for 15 minutes. Then, the mixture was cooled to room temperature, the pH was adjusted, and water was added to make 100 mL of water. Further, using a high-pressure emulsifier (Starburst Mini, Sugino Machine Limited), the treatment was performed 5 times at an injection 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 shown in the table. Further, as a result of evaluating the appearance stability after 24 hours after production and storage at 40 ° C. for 6 months, no creaming was observed in Examples, and the appearance was stable, but Comparative Examples 1 and 3 were creaming. .. The viscosity of each example was in the range of 0.5 to 2.0 mPa · s.

[Test of release of liquid paraffin on water surface by dilution]
Human tear fluid is said to have an average of 7 μL, and when 30 to 60 μL of eye drops are instilled, it is diluted about 1.12 to 1.23 times. In this test, in order to evaluate the release of liquid paraffin on the water surface by diluting the composition with tears, physiological saline was used as the model tears, and when diluted at a dilution ratio of about 1.2 times, it was placed on the water surface. 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 further poured to the opening. A volumetric flask having a dilution ratio of 1.2 times when poured to the opening was used, and the area of the opening was 152 mm ² . To observe liquid paraffin on the water surface, light is applied to the liquid surface using a fluorescent lamp as a light source, the interference light of oil floating on the liquid surface is observed, and the ratio of the area of the interference light of oil to the water surface is calculated. It was evaluated according to the following criteria. No oil interference light was observed in any of the examples and comparative examples in the case of undiluted oil.
[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 oil layer stability test]
The stability of the tear oil layer 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 capable of measuring an interference image of light reflected at the interface between the tear oil layer surface and the tear water 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 on the subject, and after 10 minutes, the eyes were blinked several times, and the time from the blink to the collapse of the tear oil layer (oil layer BUT) was measured. The subjects selected 13 eyes from 7 people whose oil layer BUT before instillation was 10 seconds or less. The results are shown by the following evaluation criteria from the average value of 13 eyes of 7 people. The oil reservoir BUT that was 10 seconds or less did not exceed 10 seconds for diurnal and daily fluctuations, and eye drops that did not contain liquid paraffin, and improvement to 10 seconds or more was considered to be sufficiently useful. 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 ● (Yes): Oil layer BUT is 10 seconds or more and less than 30 seconds × (No): Oil layer BUT is less than 10 seconds

[Transmittance (%) (clearness)]
The transmittance of the eye drops immediately after production was measured at a wavelength of 600 nm using a spectrophotometer.
Pass 50% or more.

[Test example]
<In vitro tear oil layer stability test>
In order to investigate the stability of the tear oil layer of each oil component, evaluation was performed by an in vitro evaluation system. As a destabilized tear oil layer model, a chloroform solution was prepared by mixing mybum 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 lipid weight 5 [mu] g / cm ² per unit area (average amount of lipid per unit area of the eye) and a way polytetrafluoroethylene aquarium (45cm ²⁾ in physiology diet salt on the water surface in the Expanded. Further, 675 μL of a chloroform solution of each oil having a predetermined concentration ( ^{30 μL per 2 cm 2 of} an average eye size) was developed and allowed to stand at 37 ° C. for 15 minutes to completely volatilize chloroform and polytetrafluoro. After compressing and stretching 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 according to the following criteria. If the aqueous layer is not exposed in the tear fluid, it is considered that there is a certain level of stability, so it was judged to be possible.
[Tear oil layer stability evaluation]
◎ (Excellent): Uniform oil layer 〇 (Good): Almost uniform oil layer ● (Yes): There is unevenness but the water layer is not exposed × (No): The water layer is exposed

In the destabilized tear oil layer model with increased saturated lipids, liquid paraffin showed a stabilizing effect, but castor oil, sesame oil, medium-chain fatty acid triglyceride, and lecithin did not.

The raw materials used in the above example are shown below. Unless otherwise specified, the amount of each component in the table is a net conversion amount.
Liquid Paraffin 16th Amendment Japanese Pharmacopoeia Law 1 (37.8 ℃) Viscosity 76.6mm ² / s (KAYDOL, manufactured by Shima Trading Co., Ltd.)
Liquid Paraffin 16th Amendment Japanese Pharmacopoeia Law 1 (37.8 ° C) Viscosity 34.8 mm ² / s (HYCOAL M-172, manufactured by Kaneda Co., Ltd.)
Polyoxyethylene glycol oil: Polyoxyethylene glycol oil 35, Uniox C35, Polyoxyethylene hydrogenated castor oil manufactured by Nichiyu Co., Ltd. * 1: Polyoxyethylene hydrogenated castor oil 60, HCO60, Poly made by Nippon Surfant Industry Co., Ltd. Oxyethylene hydrogenated castor oil * 2: Polyoxyethylene hydrogenated castor oil 40, HCO40, Polyethylene glycol monostearate manufactured by Nippon Surfrant Industry Co., Ltd. * 3: Polyethylene glycol monostearate (4), MYS4V, Nippon Surfartant Industry Co., Ltd. Polyethylene Glycol Monostearate * 4: Polyethylene Glycol Monostearate (10), MYS10V, Polyethylene Glycol Monostearate * 5: Polyethylene Glycol Monostearate (40), MYS40MV, Nippon Surfartant Industry Co., Ltd. Polyethylene glycol monostearate * 6: Polyethylene glycol monostearate (100), EMALX8100, POE sorbitan fatty acid ester manufactured by Nippon Emulsion Co., Ltd. * 7: Polysolvate 80 (polyoxyethylene monolaurate (20) sorbitan, Kao ( POEPOP glycol manufactured by Co., Ltd. (polyoxyethylene (196) -polyoxypropylene (67) block copolymer * 8: Lutrol F127, boric acid manufactured by BASF Japan Co., Ltd .: Trometamol manufactured by Kosakai Pharmaceutical Co., Ltd .: Edet manufactured by Kanto Chemical Co., Ltd. Sodium acid hydrate: Quallet N, Nagase Chemtex Co., Ltd. Sodium chloride: Tomita Pharmaceutical Co., Ltd. Sodium hydroxide: Wako Pure Chemical Industries, Ltd. Himasi oil: Kaneda Co., Ltd. Sesame oil: Kaneda Co., Ltd. ) Medium-chain fatty acid triglyceride: NIKKOL Triester F-810, Nikko Chemicals Co., Ltd. Recitin: Egg-derived, MP Biomedicals, Inc. Borneol Co., Ltd .: d-Bolneol, Masami Yanagisawa Shoten Co., Ltd. Geraniol: Takasago Perfume Industry Co., Ltd. Cineol: Takasago Perfume Industry Co., Ltd. Eucalyptus oil manufactured by Ogawa Kaoru Co., Ltd.

Claims (5)

(A) Liquid paraffin 0.001 to 1.0 W / V% having a ^{viscosity of 74 to 88 mm 2} / s according to the measurement method of the 16th revised Japanese Pharmacy Method 1 (37.8 ° C.), and (B) It contains a nonionic surfactant containing at least one selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil , and contains the component (A) and
(B-1) Polyoxyethylene castor oil,
(B-2) Polyoxyethylene hydrogenated castor oil,
(B-3) The compounding mass ratio with one or more selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol monostearate is
2.5 ≦ ((B-1) + (B-2) + (B-3)) / (A), ((B-1) /0.75+ (B-2) / 2+ (B-3)) /0.2)/(A)≤10.0
Der is, the ophthalmic composition transmittance at a wavelength of 600nm is 90% to 100%. The ophthalmic composition according to claim 1, wherein (B) the nonionic surfactant comprises (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil. The amount of the component (A) is 0.05 to 1.0 W / V%, and ((B-1) /0.75+ (B-2)/2+ (B-3) /0.2) / (A). ) ≤ 8.0. The ophthalmic composition according to claim 1 or 2. The ophthalmic composition according to any one of claims 1 to 3, further comprising (C) a terpenoid. The method for producing an ophthalmic composition according to any one of claims 1 to 4, which comprises a micronization step by high-pressure emulsification.