TW201825077A - Ophthalmological composition and method for producing same - Google Patents

Abstract

Provided is an ophthalmological composition which stabilizes the lacrimal lipid layer and has a clear external appearance. The ophthalmological composition contains (A) liquid paraffin and (B) a non-ionic surfactant, wherein the compounding mass ratio of (A) component, and (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor oil, and (B-3) a non-ionic surfactant other than (B-1) and (B-2) satisfy the expressions 0.5 ≤ ((B-1)+(B-2)+(B-3))/(A) and ((B-1)/0.75+(B-2)/2+(B-3)/0.05))/(A) ≤ 10.0.

Description

Ophthalmic composition and manufacturing method thereof

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

The tear oil layer prevents the evaporation of tear water and removes foreign substances. Therefore, it is essential to maintain the function of the eye. In order to fully exert its function, it is necessary to stabilize the surface of the eye. The tear oil layer contains lipids (meibo lipids) secreted from the eyelid 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 according to age or hormonal changes, which affects the stabilization of the tear oil layer, and accelerates the evaporation of the tear water layer, which also causes dry eye symptoms. It is said that it has a lot to do with eye fatigue. In particular, it is known that with regard to palpebral gland insufficiency, the saturation of lipids progresses excessively, causing the symptoms to 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 Patent Laid-Open No. 2007-211007). However, the stabilization effect of these tear oil layers is not sufficient. [Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2007-211007

[Problems to be Solved by the Invention] The present invention has been made in view of the above circumstances, and an object thereof is to provide an ophthalmic composition that stabilizes a tear oil layer and has a clear appearance, and a method for producing the same. [Means for solving problems]

The present inventors conducted diligent research in order to achieve the above-mentioned object, and as a result, they found that liquid paraffin stabilizes the tear oil layer due to an increase in saturated lipids caused by aging, hormonal changes, and palpebral dysfunction.

On the other hand, regarding the ophthalmic composition containing liquid paraffin, there is a problem in that the appearance of the composition is difficult to be clarified, and the appearance stability of creaming over a period of several hours is a problem. The ophthalmic composition is preferably clarified from the viewpoint that the foreign body test can be easily performed, and it needs to have stable appearance. On the other hand, if the surfactant is prepared to the amount that makes the liquid paraffin soluble, clarification or appearance stabilization can be performed, but the liquid paraffin that is soluble by a large amount of the surfactant produces a difficult to migrate to the tear oil layer. The new problem of losing the stabilization effect of the tear oil layer. Therefore, efforts have been made with the goal of an ophthalmic composition that separates the liquid paraffin from the surfactant by diluting the liquid paraffin in the tear fluid after the eye drops in order to make the liquid paraffin easily migrate to the tear oil layer. Promote the unity of liquid paraffin, thereby releasing it to the water surface. As a result, it was found that by setting the blending amount of the nonionic surfactant as a surfactant to a liquid paraffin to a specific ratio or less, the above situation can be achieved, and the tear oil layer stabilizing effect can be maintained. In addition, it has been found that by setting the total amount of the nonionic surfactant to a specific ratio or more with respect to the liquid paraffin, the clarity and appearance stability are improved.

Accordingly, the present invention provides the following inventions. [1]. An ophthalmic composition comprising (A) liquid paraffin and (B) a nonionic surfactant, and (A) a component and (B-1) polyoxyethylene castor oil and (B-2) poly The blending mass ratio of oxyethylene hydrogenated castor oil and (B-3) non-ionic 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. [2]. The ophthalmic composition according to [1], wherein (B) the nonionic surfactant comprises a member selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil More than one of them. [3]. The ophthalmic composition according to [1] or [2], further comprising (C) a terpenoid. [4] A method for producing the ophthalmic composition according to any one of [1] to [3], the method including a miniaturization step by high-pressure emulsification. [Effect of the invention]

According to the present invention, there can be provided an ophthalmic composition that stabilizes a tear oil layer by diluting the tear liquid to the tear oil layer to stabilize the tear oil layer, and a method for producing the same.

[(A) Component] (A) Liquid paraffin Liquid paraffin is a component that has an unstable tear oil layer that increases in saturated lipids and has a high stabilizing effect on the tear oil layer. Liquid paraffin is a low-polarity oil component compared with vegetable oil containing triglycerides or squalene with short carbon chain length in hydrocarbons. In addition, liquid paraffin is a mixture of hydrocarbons obtained from crude oil, and is liquid at normal temperature. For example, liquid paraffin can be produced by a method of using a distillation residue of crude oil at atmospheric pressure as a raw material, vacuum distillation, solvent deasphalting treatment, and subsequent solvent purification or hydrodecomposition treatment. The liquid paraffin used in the present invention is not particularly limited, and it may be used singly or in a suitable combination of two or more. Specifically, the carbon chain length of the hydrocarbon is not particularly limited, and 15 to 45 can be preferably used. The presence or absence of double bonds in the hydrocarbon is not particularly limited, and those containing a large amount of saturated hydrocarbons can be preferably used. Further, as the structure of the hydrocarbon, any of linear, branched, and cyclic structures may be included, and liquid paraffin of any specific gravity may be used. In particular, liquid paraffin and light liquid paraffin included in the Japanese Pharmacopoeia are preferred. Furthermore, a suitable type of tocopherol may be included as a stabilizer.

The viscosity of liquid paraffin is related to its molecular weight. In the measurement method of the first method (37.8 ° C) of the Sixteenth Edition of the Japanese Pharmacopoeia Law, the viscosity is preferably 30 mm ² / s to 100 mm ² / s, and the viscosity is 37. mm ² / s to 88 mm ² / s, and further preferably 74 mm ² / s to 88 mm ² / s. It is also possible to mix two or more kinds in the viscosity range. By setting the viscosity to 30 mm ² / s or more, the effect of stabilizing the tear oil layer can be further obtained. 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, the composition can be further improved. Reduces eye irritation peculiar to liquid paraffin.

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

[(B) Component] (B) Nonionic surfactant As described above, the ophthalmic composition containing (A) liquid paraffin has a problem in terms of clarification of the composition or stability of the appearance. The formulation of the agent solves the problem, but the liquid paraffin which is soluble by a large amount of a surfactant loses the effect of stabilizing the tear oil layer. The non-ionic surfactant (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil, (B-3) except (B-1) and (B-2) The blending mass ratio of the non-ionic surfactants is set to 0.5 ≦ ((B-1) + (B-2) + (B-3)) / (A), ((B-1) /0.75+ (B- 2) / 2 + (B-3) /0.2) / (A) ≦ 10.0, the appearance of the composition is clarified, and the liquid paraffin and non-ionic surfactant are separated by the dilution of tear fluid, promoting the unity of the liquid paraffin with each other, And promote the release to the water surface, so that the tear oil layer stabilization effect can be exerted. The component (B-1) and the component (B-2) can maintain the stabilizing effect of the tear oil layer even if they are blended at a relatively high concentration. Therefore, it is preferred that the composition has a favorable clarity. Blend more than one. Furthermore, it is more preferable to mix | blend two or more types of nonionic surfactant with respect to the clarity of a composition, or an external appearance stability. In addition, regarding the hydrophilic-lipophile balance (HLB), there is a concern that the effect of stabilizing the tear oil layer may be affected. Therefore, it is preferable to use a non-ionic surfactant of 10 or more, more preferably 12.8 or more, and further Preferably it is 13 or more.

(B-1) Polyoxyethylene castor oil Polyoxyethylene castor oil (POE castor oil) is a compound obtained by adding polymerized ethylene oxide to castor oil, and it is known that the average addition moles of ethylene oxide are different Of several species. The average addition mole number of ethylene oxide in polyoxyethylene castor oil is not particularly limited, and examples include 3 to 60 moles. Specific examples include: polyoxyethylene castor oil 3 (the value is the average addition mole number of ethylene oxide, the same applies hereinafter), polyoxyethylene castor oil 10, polyoxyethylene castor oil 20, polyoxyethylene castor oil 35 , Polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, and the like. These polyoxyethylene castor oils can be used singly or in a suitable combination of two or more. In terms of stabilizing effect of the tear oil layer, polyoxyethylene castor oil 35 is preferably used.

(B-1) The blending amount of the component is not particularly limited as long as it satisfies the ratio, and it is preferably 0.0005 W / V% to 25.0 W / V%, and more preferably 0.0005 W / V% to 20.0 in the composition. W / V%, more preferably 0.001 W / V% to 10.0 W / V%, and even more preferably 0.0025 W / V% to 6.0 W / V%. In terms of stabilizing effect of the tear oil layer, it is preferably 5.0 W / V% or less, more preferably 2.5 W / V% or less, and still 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 adding polymerized ethylene oxide to hydrogenated castor oil, and the average addition of ethylene oxide is known There are several species with different Morse numbers. The average addition mole number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is not particularly limited, and examples include 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (the numerical value is the average addition mole number of ethylene oxide, the same applies hereinafter), polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, and polyoxyethylene Hydrogenated castor oil 30, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polyoxyethylene hydrogenated castor oil 100, and the like. These polyoxyethylene castor oils can be used singly or in a suitable combination of two or more. From the viewpoint of stabilizing the tear oil layer, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

(B-2) The blending amount of the components is not particularly limited as long as the ratio is satisfied, and it is preferably 0.0005 W / V% to 20.0 W / V%, and more preferably 0.0010 W / V% to 10.0 in the composition. W / V%, more preferably 0.0025 W / V% to 6.0 W / V%. In terms of stabilizing effect of the tear oil layer, it is preferably 5.0 W / V% or less, more preferably 2.5 W / V% or less, and still more preferably 1.0 W / V% or less.

(B-3) Non-ionic surfactants other than (B-1) and (B-2) polysorbate 80 (polylauric acid monolaurate (20) sorbitan anhydride) (inside) It is the average addition mole number of ethylene oxide, and the same applies hereinafter. Polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters), and polyoxygen poloxamer Ethylene-polyoxypropylene block copolymer (POEPOP diol), polyethylene glycol monostearate (4), polyethylene glycol monostearate (10), polyethylene glycol monostearate (40) The polyethylene glycol monostearate represented by polyethylene glycol monostearate (100) can be used alone or in a suitable combination of two or more. Among them, phospholipids such as lecithin or hydrogenated lecithin, phosphatidylcholine, and phospholipids and glycerol, which are difficult to desorb from the interface, are not separated from liquid paraffin by dilution with tear fluid, and it is difficult for liquid paraffin to migrate to the tear oil layer. Therefore, it is preferably not substantially contained.

In the case of blending the (B-3) component, the blending amount of the (B-3) component is not particularly limited as long as it satisfies the following ratios, and it is preferable in the composition in terms of the effect of stabilizing the tear oil layer. It is 1.0 W / V% or less, more preferably 0.5 W / V% or less, and even more preferably 0.4 or less.

The lower limit of the (B) component can be specified by ((B-1) + (B-2) + (B-3)) / (A), which is 0.5 ≦ ((B-1) + (B-2) + (B-3)) / (A), more preferably 1.0 or more, and even more preferably 2.5 or more. If it is less than the blending lower limit, the clarity of the composition is deteriorated. The upper limit of ((B-1) + (B-2) + (B-3)) / (A) is not particularly limited, and is usually 20 or less. On the other hand, the upper limit of allocation can be specified by ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2) / (A) as ((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 value of ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2) / (A) is not particularly limited, and is usually 0.25 or more.

"((B-1) + (B-2) + (B-3)) / (A)" is the one that specifies the amount of (B) non-ionic surfactant relative to (A) component. ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2) / (A) are (B-1), (B-2), ( B-3) the measurer. These differ according to the kind of (B) component. For example, when the component (A) is 1.0 W / V%, if (B-1) is alone, it must be set to 0.5 W / W% or more and 7.5 W / V% or less. If (B-2) is alone, It must be set to 0.5 W / W% or more and 20.0 W / V% or less, and (B-3) alone, it must be set to 0.5 W / W% or more and 2.0 W / V% or less. In the case of multiple compositions, if a large amount of (B-3) is blended, then only a small amount is blended as the concentration of all non-ionic surfactants, which is disadvantageous in terms of clarity or stability of the composition. In terms of aspects, it can also be specified as ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.05) / (A). The ratio is a W / V% ratio and has the same value as the mass ratio.

Furthermore, a cationic surfactant represented by benzalconium chloride or benzethonium chloride, a sodium lauryl sulfate or an anionic surfactant represented by sorbic acid or a salt thereof The amphoteric surfactant represented by the lauryl amine oxide hinders the separation of the liquid paraffin from the surfactant caused by the dilution of the tear fluid, and the liquid paraffin is difficult to migrate to the tear oil layer, so the composition is preferably set to 0.1 W / V % Or less, more preferably 0.01 W / V% or less, and more preferably substantially no inclusion.

[(C) Component] The ophthalmic composition of the present invention may further contain terpenes. By blending the (C) terpenes, the freeness of the liquid paraffin on the water surface caused by the tearing of the composition by dilution of the composition can be improved, and the freeness can be adjusted, thereby improving the stabilizing effect of the tear oil layer. The terpenes of the present invention have a structure having an isoprene unit as a constituent unit, and examples thereof include terpene, terpene alcohol, terpene aldehyde, and terpene ketone. In addition, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes depending on the carbon number. Specific examples include monoterpenes such as menthol, menthol, camphor, borneol, borneol, geraniol, eucalyptol, linalool, citronellol, and limonene, and retinol and retinaldehyde. Terpenes, such as terpenes, carotenoids, etc. Among these, monoterpene is preferably used. These terpenes may be used in any of d-form, l-form, or d-form. Among them, menthol, menthol, camphor, borneol, geraniol, eucalyptol, and linalool, more preferably menthol, camphor, borneol, geraniol, eucalyptol, and linalool. Furthermore, in the present invention, as the terpenoid, an essential oil containing the compound may be used. Examples of such essential oils include eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, Peppermint oil, green peppermint oil, and essential oils of borneol, rosemary oil, Lavender oil and more. In terms of enhancing the effect of stabilizing the tear oil layer, bergamot oil and eucalyptus oil are preferred.

The amount of the component (C) to be mixed is 0.0001 W / V% to 0.2 W / V% in the composition, and can be appropriately selected according to the type of the component (C), other components such as the component (B), and the amount of the component. It is preferably 0.001 W / V% to 0.1 W / V%. In this blending concentration range, regardless of the kind or blending amount of other blending ingredients, there is less concern about (C) the precipitation of terpenes. 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 more preferably 0.075 W / V% or less.

[Other components] To the extent that the effects of the present invention are not impaired, an appropriate amount of other components may be blended in the composition of the present invention. Examples of the other components include oil components other than liquid paraffin, preservatives, sugars, buffers, pH adjusters, tonicity agents, stabilizers, polyols, thickeners, and drugs. These components can be used individually by 1 type or in combination of 2 or more types suitably, and can be mix | blended. The blending amount of the components shown below is a preferred range at the time of blending, and is the amount in the composition.

Examples of 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 triglycerides, acetic acid-d-α-tocopherol, and retinol. Alcohol palmitate, white petrolatum, purified lanolin, cholesterol, mixed tocopherols, etc. The blending amount of oil components other than liquid paraffin is preferably 0.001 W / V% to 1.0 W / V%, more preferably 0.001 W / V% to 0.5 W / V%, and most preferably 0.001 W / V% to 0.25 W / V%.

Examples of the preservative having a hydrophobic part such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, and gluconic acid chloride. It is difficult for liquid paraffin to migrate to the tear oil layer, such as hexamidine, methyl paraoxonate, ethyl paraoxonate, etc., so it is preferably 0.1 W / V% or less in the composition, more preferably it is substantially not included.

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

Examples of the buffering agent include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, tromethamine, and sodium bicarbonate. The blending amount of the buffering agent in the composition is preferably 0.001 W / V% to 5.0 W / V%, more preferably 0.001 W / V% to 2 W / V%, and even more preferably 0.001 W / V% to 1 W. / V%.

Examples of the pH adjusting agent include inorganic acids and inorganic alkali agents. Examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the composition may also be set to 3.5 to 13.0. In terms of further improving various symptoms caused by the instability of the tear oil layer, it is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0. The pH was measured at 25 ° C using a pH meter (HM-25R, East Asia DKK (stock)).

Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. In order to further improve various symptoms caused by the destabilization of the tear oil layer, it is preferable to prepare at least one type of sodium chloride and potassium chloride for tonication. In terms of further improving various symptoms caused by destabilization of the tear oil layer, the relative physiological saline osmotic pressure of the composition 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 was 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 W / V% to 5.0 W / V%, more preferably 0.001 W / V% to 1 W / V%, and further preferably 0.001 W / V% to 0.1 W. / V%. Dibutyl hydroxytoluene prevents the separation of the liquid paraffin from the surfactant due to tear dilution, and it is difficult for liquid paraffin to migrate to the tear oil layer, so it is more preferable that it is not substantially contained.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. In the case of blending a polyol, the blending amount of the polyol in the composition is preferably 0.001 W / V% to 5.0 W / V%, more preferably 0.001 W / V% to 1 W / V%, and even more preferably 0.001 W / V% to 0.1 W / V%.

Examples of the viscosity agent include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, Carboxy vinyl polymers and the like. In the case of blending a thickening agent, the blending amount in the composition is preferably 0.001 W / V% to 5.0 W / V%, more preferably 0.001 W / V% to 1 W / V%, and further preferably 0.001. W / V% ～ 0.1 W / V%.

Examples of the drug (pharmaceutical active ingredient) include decongestant components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, and naphazoline salts). Acid salt, naphthozoline nitrate, phenylephrine, dl-methylephedrine hydrochloride, etc.), anti-inflammatory and astringent agents (eg, neostigmine methyl sulfate, ε-amino group) Caproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, etc.), Antihistamines (for example, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine sodium dinucleotide sodium), cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, etc., amino acids (for example, L-aspartic acid) Potassium, L-asparagine Magnesium acid, L-aspartic acid potassium · magnesium (equivalent mixture), aminoethylsulfonic acid, chondroitin sodium sulfate, etc.), sulfa drug, etc. In the case of formulating drugs, the effective content of each drug can be selected for the content of the drug, but it is preferably 0.001 W / V% to 5.0 W / V%, and more preferably 0.001 W / V% to the composition. 1 W / V%, more preferably 0.001 W / V% to 0.1 W / V%.

[Manufacturing method] The manufacturing method of the composition of the present invention is not particularly limited, and can be obtained, for example, by mixing a mixed solution of an oily component such as (A) component and a surfactant component such as (B) component with an aqueous solution After the components of the aqueous solution were mixed and emulsified, and the pH was adjusted, the total volume was prepared using water. The mixing method of each liquid can be a general method, and it is suitable to use a pulsator, a propeller blade, a blade, a turbine blade, etc. There is no restriction | limiting in rotation speed, It is preferable to set it to the level which does not blister intensely. . The mixing temperature of each liquid is not particularly limited, and it is preferred that both the oily component and the surfactant component are above the melting temperature, and specifically, it is suitably selected from the range of 40 ° C to 95 ° C. More preferably, the miniaturization step by high-pressure emulsification is performed. Regarding high-pressure emulsification conditions, from the viewpoint of improving the clarity of the composition, it is preferable to increase the number of passes under high pressure, and from the viewpoint of improving production efficiency, it is preferable to reduce the number of passes under low pressure, and the injection pressure is better. It is 100 MPa to 245 MPa, more preferably 150 MPa to 245 MPa, and even more preferably 200 MPa to 245 MPa. It is preferable to further apply back pressure, and it is preferably 1 MPa to 10 MPa, and more preferably 2 MPa to 5 MPa. Furthermore, the number of passes is preferably 1 to 10 times, and more preferably 1 to 5 times. The temperature during high-pressure emulsification is suitably selected from the range of 20 ° C to 90 ° C.

In addition, after the obtained composition is filled in a resin container, it may be sealed with a packaging body, and the inert gas concentration in the space formed between the container and the packaging body may be sealed. The ophthalmic composition was filled in a resin container, and sealed with a package together with a deoxidizer.

[Composition for Ophthalmology] The composition of the present invention is preferably an "aqueous composition for ophthalmology". In the present invention, the "aqueous ophthalmic composition" refers to an ophthalmic composition whose vehicle is water. In addition, in terms of being easily mixed with tears to prevent liquid paraffin migration delay and to further stabilize the tear oil layer, the amount of water blended in the composition is preferably 90.0 W / V% to 99.5 W / V%. More preferably, it is 95.0 W / V% to 98.0 W / V%.

In terms of easy adaptation to the eye, the composition of the present invention is preferably liquid, and in terms of being easily mixed with tears to prevent liquid paraffin migration delay, and further obtaining a stabilizing effect of the tear oil layer, the viscosity at 25 ° C. is relatively high. It is preferably 20 mPa · s or less, more preferably 10 mPa · s or less, even more preferably 5 mPa · s or less, and even more preferably 2 mPa · s or less. In addition, a viscosity measurement method is performed using a cone-plate viscometer (for example, DV2T, Hidehiro Seiki Co., Ltd.).

The composition of the present invention is preferably clarified from the viewpoint of easy discovery when foreign matter 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 even more preferably 90. % To 100%.

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

The composition of the present invention can be preferably used as an eye drop, an eye drop for contact lenses, an eye wash, etc., in terms of high tear dilution rate, further promoting the release of the surfactant from the liquid paraffin, and effectively carrying the liquid paraffin. From the aspect, it can be particularly preferably used as an eye drop and an eye drop for contact lenses (eye drops for contact lens installers). Contact lenses are not particularly limited to hard contact lenses, soft contact lenses, and the like.

When it is used as an eye drop or an eye drop for contact lenses, it is preferably 1 to 3 drops of 10 μL to 100 μL each time and 1 to 6 times per day, and tears may be caused by overflow from the eyes. There is a concern that the oil layer stabilization effect will be reduced, so it is more preferable to use 1 to 3 drops of 10 μL to 50 μL each time and 1 to 6 drops per day, and even more preferable to use 1 to 3 drops of 10 μL to 30 μL each time. Drops 1 to 6 times a day. In the case of using as an eye wash, it is preferably 3 mL to 6 mL each time and eye wash 3 to 6 times per day.

The composition of the present invention is not only a person who replenishes the tear oil layer or promotes the production of oil components from the eyelid glands, but a person who stabilizes the tear oil layer which is not stabilized due to insufficiency of the eyelid glands and the like. If the production of oil components is simply promoted and even saturated lipids increase, it will become the main cause of worsening symptoms. If the tear oil layer is only replenished with oil, the unstable tear oil layer cannot be stabilized. The composition of the present invention is effectively used for stabilizing the tear oil layer (tear oil layer stabilizer), and further effectively used for dry eye symptoms (eye fatigue, blurry and hazy eyes, dry eyes, foreign body sensation, eye pain, glare, eyelid weight, Itching eyes, eye discomfort, eye fat, tears, congestion, etc.) and the improvement of eye fatigue symptoms (eye fatigue, fatigue, shoulder pain, headache, etc.) (dry eye symptom improver). It is particularly effective for improving dry eye symptoms and eye fatigue symptoms caused by destabilization of the tear oil layer (eye fatigue, eyes blur, haze, dry eyes, or fatigue improving agents). More effective symptoms are eye fatigue, blurred and hazy eyes, dry eyes, and fatigue. Further effective symptoms are tired eyes, blurred and hazy eyes, and the most effective symptoms are blurred and hazy eyes. In terms of the above, it is suitable for patients with blepharoplasty, dry eye, and eye fatigue, especially for patients with dry eye due to instability of the tear oil layer or dysfunction of the eyelid gland. Useful for patients with eye fatigue caused by stabilization or dysfunction of the eyelid glands. Furthermore, contact lens installation promotes insufficiency of the eyelid glands, so it is preferably used by contact lens wearers, especially by soft contact lens wearers.

The effective amount, method of preparation, preparation method, etc. are as described, for example, as a liquid paraffin, an ophthalmic drug is 0.01 mg to 1 mg per adult once to 6 times a day. [Example]

The present invention will be specifically described below with examples and comparative examples, but the present invention is not limited to the following examples. Furthermore, ((B-1) + (B-2) + (B-3)) / (A), ((B-1) /0.75+ (B-2) / 2 + (B-3) / The ratios described in 0.2) / (A), ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.05) / (A) are W / V% ratios, and become the quality Than the same value.

[Examples and Comparative Examples] In the following table, each aqueous component was dissolved in 90 mL of water, and the mixture was heated and mixed at 90 ° C for 15 minutes. In addition, a premix of (A) liquid paraffin and (B) non-ionic surfactant was prepared, and heated and mixed at 90 ° C for 15 minutes. Next, a predetermined amount of the premix is 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 become 100 mL in water. Furthermore, a high-pressure emulsifier (Star Burst Mini, sugino machine (stock)) was used to perform five treatments at a spray 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 described in a table together. In addition, the appearance stability after storage at 40 ° C. for 6 months was evaluated 24 hours after manufacture. As a result, no thickening was observed in the examples, and the appearance was stable. However, in Comparative Example 1 and Comparative Example 3, condensation occurred. thick. The viscosity of each example is in a range of 0.5 mPa · s to 2.0 mPa · s.

[Test on the Freeness of Liquid Paraffin on the Water Surface by Dilution] It is said that the average human tear is 7 μL, and in the case of eye drops of 30 μL to 60 μL, the dilution is about 1.12 times to 1.23 times. In this test, in order to evaluate the freeness of the liquid paraffin on the water surface caused by the dilution of the tear fluid with the composition, the release of the liquid paraffin on the water surface when physiological saline was used as the model tear fluid and diluted at a dilution factor of about 1.2 was observed. Use a narrow measuring bottle for easy observation. Specifically, 10 mL of physiological saline was added to a 50 mL measuring bottle, and the composition was poured into the opening. In addition, a measuring bottle having a dilution rate of 1.2 times when injected into the opening was used, and the area of the opening was 152 mm ² . For the observation of liquid paraffin on the water surface, a fluorescent lamp is used as a light source and the liquid surface is irradiated with light. The interference light of the oil floating on the liquid surface is observed. Evaluation was performed based on the following criteria. In addition, in any of the examples and comparative examples, the interference light of the oil was not observed without being diluted. [Evaluation Criteria] ◎: Interference light of oil was observed at 10% or more of the water surface ○: Interference light of oil was observed at less than 10% of the water surface ×: Interference light of oil was not observed

[Tear oil layer stability test] The tear oil layer stability was evaluated by measuring the break up time (BUT) of the tear oil layer using a dry eye observation device DR-1 (manufactured by Xingwa Co., Ltd.). DR-1 is a device capable of measuring an interference image of light reflected from a boundary surface of a tear oil layer surface and a tear water layer. In healthy eyes, a uniform gray or white interference image is observed. If the tear oil layer decays, the interference image disappears. After 30 minutes of each eye drop of the test subject was dropped for 10 minutes, the eyes were blinked several times, and the time from the blink to the decay of the tear oil layer (BUT) was measured. The subjects selected 13 eyes of 7 persons who had a BUT of the oil layer in front of the eyes for 10 seconds or less. The results are shown based on the average of 7 13 eyes and the following evaluation criteria. The oil layer BUT of less than 10 seconds in eye drops that do not contain liquid paraffin does not exceed 10 seconds when it is changed during the day or during the day, and it is judged as a person with sufficient usefulness if it is improved to 10 seconds or more. . [Evaluation criteria] ◎ (Excellent): BUT of the oil layer is 60 seconds or more ○ (Good): BUT of the oil layer is 30 seconds or more and less than 60 seconds ● (Enable): BUT of the oil layer is 10 seconds or more and less than 30 seconds × (Not possible): Reservoir BUT is less than 10 seconds

[Transmittance (%) (clarity)] A spectrophotometer was used to measure the transmittance at a wavelength of 600 nm for eye drops immediately after manufacture. Pass 50% or more.

[Table 1]

[Table 2]

[table 3]

[Table 4]

[table 5]

[TABLE 6]

[TABLE 7]

[TABLE 8]

[TABLE 9]

[TABLE 10]

[Test example] <in vitro tear oil layer stability test> In order to investigate the tear oil layer stability of each oil component, evaluation was performed using an in vitro evaluation system. As a destabilized tear fluid layer model, chloroform was prepared by mixing stearyl stearate and cholesterol stearate as a saturated lipid to meibole extracted from rabbit eyelids at a mass ratio of 100: 3.3: 6.7. A solution in which a saline solution in a polytetrafluoroethylene water tank (45 cm ² ) is spread so that the fat mass per unit area becomes 5 μg / cm ² (the average fat mass per unit area of the eye). Surface. Furthermore, 675 μL of a chloroform solution of each oil was spread to a predetermined concentration (the average eye size became 30 μL per 2 cm ² ), and it was left to stand at 37 ° C. for 15 minutes, and the chloroform was completely evaporated. Polytetrafluoroethylene was used. After the rod was compressed and stretched 10 times, 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 water layer is not exposed in the tear fluid, it is considered to have a certain stability or more, and therefore it is judged as acceptable. [Evaluation of tear oil layer stability] ◎ (Excellent): Uniform oil layer ○ (Good): Approximately uniform oil layer ● (Possible): The water layer was not exposed despite unevenness × (Impossible): The water layer was exposed

[TABLE 11]

In the model of destabilized tear oil layer with increased saturated lipids, the stabilization effect was seen in liquid paraffin, but the stabilization effect was not seen in castor oil, sesame oil, medium-chain fatty acid triglycerides, and lecithin.

The raw materials used in the examples are shown below. In addition, as long as there is no special indication, the amount of each component in the table is a purity conversion amount. Liquid paraffin Japanese Pharmacopoeia 16th edition first method (37.8 ° C) viscosity 76.6 mm ² / s (KAYDOL, manufactured by Island Trading Co., Ltd.) Liquid paraffin Japanese Pharmacopoeia 16th edition first method (37.8 ° C) viscosity 34.8 mm ² / s (Hicall M-172, manufactured by Kaneda Co., Ltd.) Polyoxyethylene castor oil: Polyoxyethylene castor oil 35, Unioxs C35, Nippon Oil Co., Ltd. polyoxyethylene hydrogenated castor oil * 1: Polyoxygen Ethylene hydrogenated castor oil 60, HCO60, made by Japan Surfactant Industry Co., Ltd. * 2: Polyoxyethylene hydrogenated castor oil 40, HCO40, Japan Surfactant Industry (stock) Manufacturing of monostearic acid polyethylene glycol * 3: Monostearic acid polyethylene glycol (4), MYS4V, Japan Surfactant Industry (stock) Manufacturing of monostearic acid polyethylene glycol * 4: single Stearic acid polyethylene glycol (10), MYS10V, manufactured by Japan Surfactant Industry Co., Ltd. * 5: Monostearic acid polyethylene glycol (40), MYS40MV, Monostearic acid polymer made by Japan Surfactant Industry Diol * 6: Polyethylene glycol monostearate (100), EMALEX8100, POE sorbitan fatty acid ester manufactured by Nihon emulsion (stock) * 7: Polysorbate 80 (monolauric acid) Polyoxyethylene (20) sorbitan), POEPOP diol (polyoxyethylene (196) -polyoxypropylene (67) block copolymer * 8) made by Kao (stock): Lutrol F127, BASF Japan (stock) Production of boric acid: Komori Pharmaceutical Co., Ltd. Production of tromethamine: Kanto Chemical Co., Ltd. Production of sodium edetate hydrate: Clewat N, Nagase Chemical Co., Ltd. Production of sodium chloride: Tomita Pharmaceutical Co., Ltd. production of sodium hydroxide : Castor oil manufactured by Wako Pure Chemical Industries, Ltd .: Sesame oil manufactured by Kaneda Co., Ltd .: Sesame oil manufactured by Kaneda Co., Ltd .: Medium-chain fatty acid triglyceride: NIKKOL triester F-810, manufactured by Nikko Chemical Co., Ltd. Lecithin: Derived from eggs, manufactured by Abe Medical Co., Ltd. (MP Biomedicals, Inc.) Menthol: l-menthol, manufactured by Suzuki Mint (stock) dl-camphor: Japanese refined chemical (stock) made borneol: d-borneol , Manufactured by Yanagisawa Masaaki Store (shares) Leaf alcohol: Takasago International (shares) Manufacturing eucalyptol: Takasago International (shares) Manufacturing linalool: Takasago International (shares) manufacturing bergamot oil: Yamamoto spices (shares) Manufacturing eucalyptus oil: Ogawa spices (shares) Manufacturing

no

no

Claims (4)

An ophthalmic composition containing (A) liquid paraffin and (B) non-ionic surfactant, and (A) component and (B-1) polyoxyethylene castor oil, (B-2) polyoxyethylene hydrogenated castor The mass ratio of sesame oil and (B-3) non-ionic surfactants other than (B-1) and (B-2) is 0.5 ≦ ((B-1) + (B-2) + (B-3) )) / (A) and ((B-1) /0.75+ (B-2) / 2 + (B-3) /0.2) / (A) ≦ 10.0. The ophthalmic composition according to item 1 of the scope of patent application, wherein (B) the nonionic surfactant is selected from (B-1) polyoxyethylene castor oil and (B-2) polyoxyethylene hydrogenated castor oil More than one. The ophthalmic composition according to claim 1 or claim 2, further comprising (C) a terpenoid. A method for manufacturing an ophthalmic composition, the method for manufacturing the ophthalmic composition according to any one of claims 1 to 3 of the patent application scope, the method comprising a miniaturization step by high-pressure emulsification.