JP7516756B2 - Liquid composition, method for producing liquid composition and method for stabilizing liquid composition - Google Patents

Description

The present invention relates to a liquid composition containing liquid paraffin, a method for producing the liquid composition, and a method for stabilizing the liquid composition.

The tear oil layer is composed of lipids secreted from the meibomian glands. It is known that the quality of lipids in the tear oil layer deteriorates due to aging and changes in hormone balance. It is also known that this deterioration is accelerated by wearing contact lenses. The deterioration of lipid quality deteriorates the tear oil layer, which leads to the onset of dry eye and is one of the causes of eye strain. The present inventors have found that an aqueous composition containing liquid paraffin is effective in stabilizing this tear oil layer (Patent Document 1).

Liquid paraffin is a hydrocarbon that is liquid at room temperature and is characterized by its low polarity. Conventionally, it has been widely used as a base for eye ointments in ophthalmic compositions. On the other hand, when formulated as a liquid composition, liquid paraffin needs to be uniformly dispersed in water, but because of its low polarity, liquid paraffin becomes cloudy even when a surfactant is used, making it difficult to increase the transmittance. Therefore, conventionally, in order to improve the transmittance of liquid compositions containing liquid paraffin, a high-pressure emulsification process (Patent Document 2) or the incorporation of a high concentration of a surfactant was necessary. However, high-pressure emulsification processing and increasing the amount of surfactant have the problem of impairing the stability of the active ingredient and worsening the feeling of use.

JP 2017-186266 A International Publication No. 2018/105681

The present invention has been made in consideration of the above problems, and aims to provide a liquid composition containing liquid paraffin and a nonionic surfactant and having high transmittance.

As a result of extensive research into achieving the above object, the inventors discovered that the above problems could be solved by a manufacturing method in which liquid paraffin is emulsified together with a nonionic surfactant in a small amount of water and then further diluted, and thus came up with the present invention.

Therefore, the present invention provides the following inventions.
1. (A) Liquid paraffin,
mixing (B) a nonionic surfactant and (C1) water to prepare a mixture having a (C1) content of 8 to 30 w/v %;
(C2) mixing the resulting mixture with water and/or a dilute aqueous solution;
A method for producing a liquid composition.
2. (A) Liquid paraffin,
A step of mixing (B) a nonionic surfactant, (C1) water, and (D) one or more selected from vitamin A and vitamin E to prepare a mixture having a (C1) content of 8 to 30 w/v %;
(C2) mixing the resulting mixture with water and/or a dilute aqueous solution;
A method for producing a liquid composition.
3. (A) Liquid paraffin,
(B) a nonionic surfactant,
A liquid composition comprising (C) water, and (D) one or more selected from vitamin A and vitamin E, the emulsion particles having a particle size of 100 nm or less, and a span (D ₉₀ -D ₁₀ )/D ₅₀ of 1-4.
4. The liquid composition according to 3, wherein the blending mass ratio represented by (B)/(A) is 5 to 20.
5. A method for stabilizing a liquid composition containing (A) liquid paraffin, (B) a nonionic surfactant, and (C) water, comprising blending one or more types selected from (D) vitamin A and vitamin E into the liquid composition.

According to the present invention, a liquid composition with high transmittance can be obtained without high-pressure emulsification or the addition of a high concentration of surfactant.

The present invention will be described in detail below.
[Component (A)]
Liquid paraffin is a component that has a high tear oil layer stabilizing effect against an unstable tear oil layer. Liquid paraffin is an oil component that has a low polarity compared to vegetable oils composed 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. It is produced by a method in which the crude oil atmospheric distillation residual oil is used as a raw material, subjected to reduced pressure distillation and solvent deasphalting treatment, and then subjected to a solvent refining method or hydrocracking treatment. There is no particular restriction on the liquid paraffin used in the present invention, and one type alone or two or more types in appropriate combination can be used. There is no particular restriction on the carbon chain length of the hydrocarbon, but those with a carbon chain length of 15 to 45 are preferably used. There is also no particular restriction on the presence or absence of double bonds in the hydrocarbon, but those containing a large amount of saturated hydrocarbons are preferably used. Furthermore, the structure of the hydrocarbon may include any of straight chain, branched chain, and cyclic structures, and liquid paraffins of any specific gravity can be used. In particular, liquid paraffins and light liquid paraffins listed in the Japanese Pharmacopoeia are suitable. Additionally, a suitable type of tocopherol may be included as a stabilizer.

The viscosity of liquid paraffin is correlated with its molecular weight, and in the measurement method of the Japanese Pharmacopoeia, 16th Edition, Method 1 (37.8°C), the kinetic viscosity is preferably 30 to 100 mm ² /s, more preferably 37 to 88 mm ² /s, and even more preferably 74 to 88 mm ² /s. Two or more types within the above viscosity ranges may be mixed. By making the viscosity 30 mm ² /s or more, the tear lipid layer stabilizing effect can be further obtained. From the viewpoint of further enhancing the tear lipid layer stabilizing effect, 74 to 88 mm ² /s is preferable. Furthermore, by making the viscosity 100 mm ² /s or less, the external transmittance can be increased and at the same time, eye irritation specific to liquid paraffin can be further reduced. From the viewpoints of external transmittance and reduction of eye irritation, 37 to 88 mm ² /s is preferable.

From the viewpoint of stabilizing the tear oil layer, the amount of component (A) in the liquid composition (hereinafter sometimes referred to as the composition) is preferably 0.001 to 2 w/v% (mass/volume%, g/100 mL), more preferably 0.005 to 1 w/v%, even more preferably 0.01 to 0.25 w/v%, and most preferably 0.05 to 0.2 W/V%. By setting the amount in this range, a tear oil layer stabilization effect can be expected, there is no eye irritation, and the composition can be made clearer.

[Component (B)]
The nonionic surfactant (B) is not particularly limited, and the nonionic surfactants used in ophthalmic compositions can be used alone or in appropriate combination of two or more. Specific examples include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and nonionic surfactants other than the above. The component (B) preferably contains one or more selected from polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average added moles of ethylene oxide are known. The average added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but examples include 3 to 60 moles. Specific examples include polyoxyethylene castor oil 3 (average added moles of EO: 3), polyoxyethylene castor oil 10 (average added moles of EO: 10), polyoxyethylene castor oil 20 (average added moles of EO: 20), polyoxyethylene castor oil 35 (average added moles of EO: 35), polyoxyethylene castor oil 40 (average added moles of EO: 40), polyoxyethylene castor oil 50 (average added moles of EO: 50), and polyoxyethylene castor oil 60 (average added moles of EO: 60). These polyoxyethylene castor oils can be used alone or in appropriate combination of two or more. It is preferable to use polyoxyethylene castor oil 35 in order to reduce the irritation felt when instilled into the eyes.

Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average added moles of ethylene oxide are known. There are no particular limitations on the average added moles of ethylene oxide in polyoxyethylene hydrogenated castor oil, but examples include 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (average number of moles of EO added: 5), polyoxyethylene hydrogenated castor oil 10 (average number of moles of EO added: 10), polyoxyethylene hydrogenated castor oil 20 (average number of moles of EO added: 20), polyoxyethylene hydrogenated castor oil 30 (average number of moles of EO added: 30), polyoxyethylene hydrogenated castor oil 40 (average number of moles of EO added: 40), polyoxyethylene hydrogenated castor oil 50 (average number of moles of EO added: 50), polyoxyethylene hydrogenated castor oil 60 (average number of moles of EO added: 60), polyoxyethylene hydrogenated castor oil 80 (average number of moles of EO added: 80), polyoxyethylene hydrogenated castor oil 100 (average number of moles of EO added: 100), etc. can be mentioned. These polyoxyethylene hydrogenated castor oils can be used alone or in appropriate combination of two or more kinds. From the viewpoint of reducing the irritation when applied to the eyes, it is preferable to use polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60.

Nonionic surfactants other than those mentioned above include polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) represented by polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyoxyethylene polyoxypropylene glycols (POEPOP glycols) represented by poloxamer, polyethylene glycol monostearate represented by polyethylene glycol (10) monostearate and polyethylene glycol (40) monostearate, and the like.

The amount of component (B) to be blended is not particularly limited, but is preferably 0.01 to 10 w/v % of the composition, and more preferably 0.1 to 5 w/v %.
When polyoxyethylene castor oil is included, it is preferably contained in an amount of 0.05 to 10 w/v % in the composition, more preferably 0.1 to 5 w/v %, and even more preferably 0.2 to 3 w/v %.
When polyoxyethylene hydrogenated castor oil is included, it is preferably contained in an amount of 0.05 to 10 w/v % in the composition, more preferably 0.1 to 5 w/v %, and even more preferably 0.2 to 3 w/v %.
When a nonionic surfactant other than those mentioned above is added, the amount of the surfactant in the composition is preferably 0.0003 to 1 w/v %, more preferably 0.0003 to 0.5 w/v %, and even more preferably 0.003 to 0.1 w/v %.

The blending mass ratio of component (A) to component (B), represented by (B)/(A), is preferably 5 to 20, more preferably 7.5 to 20, and even more preferably 10 to 20. By setting it within this range, the transmittance of the composition is further improved. Note that this ratio is a w/v % ratio, which is the same as the mass ratio (hereinafter, the ratio of components is the same).

[Component (C)]
The water is not particularly limited and may be purified water, but the amount of water in the composition is preferably 90.0 to 99.5 w/v %, and more preferably 95.0 to 97.5 w/v %, from the viewpoints of facilitating mixing with tears and achieving a greater effect of stabilizing the tear lipid layer.
The amount of component (C) used in the production method will be described later.

[Component (D)]
The transmittance of the composition is further improved by blending one or more kinds selected from (D) vitamin A and vitamin E. The (D) component can be used alone or in combination of two or more kinds. In addition, blending of the (D) component assists in dissolving the (A) component, improves the clarity of the composition, and enhances the emulsion stability.

Examples of vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. One type may be used alone, or two or more types may be used in appropriate combination. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoids. Of these, retinol palmitate is preferred.

Vitamin E is used as a general term for, for example, tocopherol, tocotrienol, their salts, and derivatives (esters). Specific examples include d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and the like. Derivatives of these include, for example, vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linoleate, and the like. One type may be used alone, or two or more types may be used in appropriate combination. Among these, tocopherol acetate (d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.) is preferred.

The amount of (D) in the composition is preferably 0.0001 to 1 w/v %, more preferably 0.001 to 0.5 w/v %, and even more preferably 0.01 to 0.2 w/v %.
The amount of vitamin A in the composition is preferably 0.0001 to 0.1 w/v %, more preferably 0.005 to 0.05 w/v %, and even more preferably 0.006 to 0.04 w/v %.
The amount of vitamin E in the composition is preferably 0.001 to 0.15 w/v %, more preferably 0.01 to 0.15 w/v %, and even more preferably 0.02 to 0.15 w/v %.

The blending mass ratio represented by (D)/(A) is preferably 0.6 to 1.4, more preferably 0.7 to 1.2, and even more preferably 0.7 to 1.0. By keeping it in this range, the particle size distribution of the emulsion particles will be sharp.

[Other ingredients]
The composition of the present invention may contain other components to be added to ophthalmic compositions in appropriate amounts, provided that the effects of the present invention are not impaired. Examples of other components include preservatives, sugars, buffers, pH adjusters, isotonicity agents, stabilizers, polyhydric alcohols, cooling agents, thickening agents, drugs, etc. These components may be added alone or in appropriate combination of two or more. The amounts of the components shown below are the preferred ranges when added, and are the amounts in the composition.

Among preservatives, examples of preservatives having a hydrophobic portion such as an alkyl chain or a benzene ring include thimerosal, phenylethyl alcohol, alkylaminoethylglycine, chlorhexidine gluconate, methyl parahydroxybenzoate, and ethyl parahydroxybenzoate. However, since liquid paraffin is less likely to migrate into the tear lipid layer, the content of these preservatives in the composition is preferably 0.1 w/v% or less, more preferably 0.01 w/v% or less, even more preferably 0.001 w/v% or less, and even more preferably substantially none.

Examples of sugars include glucose, cyclodextrin, xylitol, sorbitol, mannitol, etc. These may be in the D-, L-, or DL-form. When sugars are added, the amount of sugar added is preferably 0.001 to 5.0 w/v% of the composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of buffering agents include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium bicarbonate, etc. When a buffering agent is added, the amount of the buffering agent added is preferably 0.001 to 5.0 w/v % of the composition, more preferably 0.001 to 2 w/v %, and even more preferably 0.001 to 1 w/v %.

Examples of pH adjusters include inorganic acids and inorganic alkali agents. For example, an example of an inorganic acid is (dilute) hydrochloric acid. Examples of inorganic alkali agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the composition can be set to 3.5 to 13.0, and is preferably 3.5 to 8.0, and more preferably 5.5 to 8.0, from the viewpoint of further improving various symptoms caused by destabilization of the tear lipid layer. The pH is measured at 25°C using a pH meter (HM-25R, DKK Toa Corporation).

Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. From the viewpoint of further improving the symptoms caused by destabilization of the tear lipid layer, it is preferable to combine at least one of sodium chloride and potassium chloride to make the composition isotonic. From the viewpoint of further improving the symptoms caused by destabilization of the tear lipid layer, the osmotic pressure ratio of the composition to physiological saline is preferably 0.60 to 2.00, more preferably 0.60 to 1.55, and most preferably 0.83 to 1.20. The osmotic pressure is measured at 25°C using an automatic osmometer (A2O, Advance Instruments).

Examples of stabilizers include sodium edetate, cyclodextrin, sulfite, and dibutylhydroxytoluene. When a stabilizer is added, the amount of the stabilizer in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of polyhydric alcohols include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. When polyhydric alcohols are included, the amount of polyhydric alcohol in the composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

Examples of cooling agents include menthol, camphor, borneol, geraniol, cineol, linalool, etc. Any of the d-, l- or dl-isomers may be used. The amount of cooling agent in the composition is preferably 0.0001 to 0.2 w/v%.

Examples of thickening agents include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, etc. When a thickening agent is added, the amount of the thickening agent added is preferably 0.001 to 5.0 w/v% of the composition, more preferably 0.001 to 1 w/v%, and even more preferably 0.001 to 0.1 w/v%.

(A) Oil components other than liquid paraffin and (D) include soybean oil, olive 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. When oil components other than liquid paraffin are blended, the blending amount 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%.

Drugs (pharmaceutical active ingredients) include, for example, congestion relief ingredients (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.), anti-inflammatory/astringent agents (e.g., neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lithium zozyme hydrochloride, 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 (e.g., potassium L-aspartate, magnesium L-aspartate, potassium and magnesium L-aspartate (mixture of equal amounts), aminoethylsulfonic acid, etc.), sulfa drugs, etc. When drugs are added, the amount of each drug to be added can be selected based on the effective amount of each drug, but 0.001 to 5.0 w/v% of the composition is preferable, 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 liquid composition of the present invention comprises the steps of:
(A) liquid paraffin,
mixing (B) a nonionic surfactant and (C1) water to prepare a mixture having a (C1) content of 8 to 30 w/v %;
The method further comprises a step of mixing the obtained mixture with (C2) water and/or a dilute aqueous solution, and in the case where the component (D) is contained,
(A) liquid paraffin,
A step of mixing (B) a nonionic surfactant, (C1) water, and (D) one or more selected from vitamin A and vitamin E to prepare a mixture having a (C1) content of 8 to 30 w/v %;
The method includes a step (C2) of mixing the obtained mixture with water and/or a dilute aqueous solution.

(C1) refers to water that is mixed into the mixture of components (A), (B) and, if necessary, (D) (hereinafter, sometimes referred to as the first mixture). A composition with high transmittance can be obtained by a manufacturing method in which (A) liquid paraffin is emulsified with a small amount of water together with (B) a nonionic surfactant, and then further diluted.

Preferred ranges in the first mixture will be described below.
The content of (C) in the first mixture is 8 to 30 w/v %, more preferably 9 to 25 w/v %, and even more preferably 10 to 20 w/v %.
The blending mass ratio of (C1)/((A)+(B)+(C1))×100 is preferably from 8 to 30, more preferably from 9 to 25, and even more preferably from 10 to 20. By setting it within this range, the transmittance of the composition is further improved.
The blending mass ratio represented by (C1)/((A)+(B)+(C1)+(D))×100 is preferably 8 to 30, more preferably 9 to 25, and even more preferably 10 to 20. By setting it within this range, the transmittance of the composition is further improved.

The blending mass ratio represented by (A)/((A)+(B)+(C1))×100 is preferably 3.4 to 9.5. By setting it in this range, the transmittance of the composition is further improved.
The blending mass ratio represented by ((A)+(D))/((A)+(B)+(C1)+(D))×100 is preferably 10 to 20. By setting it in this range, the transmittance of the composition is further improved.

<Step of preparing the first mixture>
First, (A) liquid paraffin, (B) nonionic surfactant, (C-1) water, and (D) one or more selected from vitamin A and vitamin E as required are mixed. The order of mixing is not particularly limited, but (C-1) water may be added after mixing component (A), component (B), and (D) as required. When mixing component (A), component (B), and (D) as required, the mixing temperature is, for example, 30 to 90°C, and the mixing time is about 1 to 30 minutes. The temperature of the mixture including (C-1) water is preferably 50 to 90°C, more preferably 70 to 90°C, and it is sufficient to mix until the temperature reaches such a temperature, but it is more preferable to mix for about 3 to 10 minutes.

<Step (C2) of mixing the obtained first mixture with water and/or a dilute aqueous solution>
The obtained first mixture is mixed with (C2) water and/or a diluted aqueous solution to obtain a mixture (hereinafter, sometimes referred to as a second mixture). The "diluted aqueous solution" refers to an aqueous solution in which a drug or the like has been dissolved in advance. The mixing method in the step of mixing the obtained first mixture with (C-2) water and/or a diluted aqueous solution is not particularly limited, and the first mixture may be added to (C-2) water and/or a diluted aqueous solution, or the first mixture may be added to (C-2) water and/or a diluted aqueous solution. (C-2) water and/or a diluted aqueous solution may be used alone or together, and the order does not matter. After the first mixture is mixed with (C-2) water, the drug or the like may be further mixed.

The blending mass ratio of the first mixture (mixture of (A), (B), and (C1)) to (C2) water and/or diluted aqueous solution is preferably 0.01 to 0.03.
The blending mass ratio of the first mixture (mixture of (A), (B), (C1), and (D)) to (C2) water and/or diluted aqueous solution is preferably 0.005 to 0.03.

(C2) The temperature of the water or diluted aqueous solution is preferably 30 to 90°C, more preferably 50 to 90°C, and more preferably 70 to 90°C. The second mixture obtained by mixing is mixed at 30 to 90°C, preferably 50 to 90°C, and more preferably 70 to 90°C. The mixing time is not particularly limited as long as the composition becomes homogeneous, and is selected from, for example, 1 to 120 minutes.

(C2) The amount of water or diluted aqueous solution is preferably 30 to 99 w/v% of the aqueous composition (final amount), more preferably 90 to 99 w/v%, and even more preferably 96 to 99 w/v%.

Then, (C2) the mixture with water and/or a diluted aqueous solution is cooled to room temperature, for example, 20 to 30°C, and if necessary, a process of adding more water to the final volume (weight-up process) is carried out, and the pH and osmotic pressure can also be adjusted. The above mixing is appropriately carried out using general mixing methods such as a pulsator, propeller blade, paddle blade, turbine blade, etc.

The manufacturing method of the present invention makes it possible to obtain a liquid composition with a high transmittance equivalent to those of the above-mentioned compositions without the need for high-pressure emulsification or the addition of a high concentration of surfactant. Therefore, when component (D) is added in particular, it is possible to achieve both high transmittance of the composition and storage stability of component (D).

[Composition]
The composition obtained by the above-mentioned production method is a liquid composition containing the components (A), (B) and (C), and further, if necessary, the component (D).
The particle size of the emulsified particles (association of component (A) and component (B)) contained in the composition of the present invention can be 1,000 nm or less, preferably 100 nm or less, more preferably 50 nm or less. The lower limit is not particularly limited, but can be 1 nm. In the present invention, the particle size refers to the average diameter (D ₅₀ , median diameter) of the volume-based particle size distribution calculated from the scattered light intensity. The particle size is measured using various measuring devices that apply the principle of light scattering, etc., in a thermostatic bath under a constant temperature condition of 25°C. As such a device, for example, the particle size measuring device (ELSZ-200ZS, manufactured by Otsuka Electronics Co., Ltd.) can be used to measure by the dynamic scattering method. In addition, the value span (D ₉₀ -D ₁₀ )/D _{50 calculated from the particle sizes D 90} , D 10 , and D ₅₀ corresponding to 90%, ₁₀ %, and 50 _% of the integrated value of the volume-based particle size distribution using the following formula is preferably 1 to 4, more preferably 1 to 2. By making the particle size distribution sharp, coalescence of particles is suppressed, resulting in a stable composition that is free of oily residues even after long-term storage.

Specifically, the transmittance of the composition of the present invention is preferably 80 to 100%, more preferably 90 to 100%, and even more preferably 95 to 100%, at a wavelength of 600 nm measured using a spectrophotometer (e.g., UV-1800, Shimadzu Corporation).

The composition of the present invention is preferably a liquid in order to facilitate application to the eye, and the viscosity at 25°C is preferably 20 mPa·s or less, more preferably 10 mPa·s or less, and even more preferably 5 mPa·s or less, in order to facilitate mixing with tears and to obtain a greater effect of stabilizing the tear lipid layer. The viscosity is measured using a cone-plate viscometer (DV2T, Eiko Seiki Co., Ltd.).

The composition of the present invention is suitable as an ophthalmic composition, and can be particularly suitably used as eye drops, eye drops for contact lenses, eyewash, etc., but can be suitably used as eye drops and eye drops for contact lenses (eye drops for contact lens wearers) because it has a high tear dilution ratio, promotes the release of surfactant from liquid paraffin, and efficiently delivers liquid paraffin. Examples of contact lenses include, but are not limited to, hard contact lenses, _O2 hard contact lenses, soft contact lenses, silicone hydrogel soft contact lenses, etc.

When used as eye drops or contact lens eye drops, it is preferable to instill 10-100 μL, 1-3 drops, 1-6 times per day. Because overflow from the eye may reduce the tear lipid layer stabilizing effect, it is more preferable to instill 10-50 μL, 1-3 drops, 1-6 times per day. It is even more preferable to instill 10-30 μL, 1-3 drops, 1-6 times per day. When used as an eyewash, it is preferable to instill 3-6 mL, 3-6 times per day.

[Stabilization method]
The stabilization method of the present invention is a method for stabilizing a liquid composition containing (A) liquid paraffin, (B) a nonionic surfactant, and (C) water, characterized in that the liquid composition is blended with (D) one or more selected from vitamin A and vitamin E, and the preferred components and blending amounts are the same as those described above. "Stabilization of a liquid composition" refers to "high temperature stability of the composition."

The present invention will be specifically explained below with examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates "w/v % (g/100 mL)" and the ratio indicates w/v % (same as mass ratio).

[Examples and Comparative Examples]
Component (A), component (B), and, if necessary, component (D) were mixed at 60°C or higher for 15 minutes. Component (C-1) was added to the mixed solution, and mixed until homogeneous at the first mixture temperature shown in the table to obtain a mixture. Meanwhile, other components were dissolved in water to prepare a diluted aqueous solution, and the temperature was adjusted to the temperature shown in the table (diluted aqueous solution temperature). The first mixture was added to the diluted aqueous solution to obtain a second mixture, which was further mixed until homogeneous at the second mixture temperature shown in the table. Thereafter, the mixture was cooled to room temperature, pH was adjusted, and water was added so that the total volume was 100 mL to obtain a composition. The compositions obtained in the above examples were evaluated as follows. The results are also shown in the table.

Test 1 <Average transmittance (%) of 3 lots>
Immediately after production, the transmittance (%) of three lots of the composition at a wavelength of 600 nm was measured using an ultraviolet-visible-near infrared spectrophotometer UV-1800 (Shimadzu Corporation), and the average was calculated.

Test 2 <Average _D50 of 3 lots>
Immediately after production, the D ₅₀ of the emulsified particles in the three lots of the composition was measured by a dynamic scattering method using an ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.), and the average was calculated.

Test 3 <Average span (D ₉₀ -D ₁₀ )/D ₅₀ of three lots>
The _D50 , _D90 and _D10 of the emulsified particles in three lots of the composition immediately after production were measured by a dynamic scattering method using an ELSZ-200ZS (manufactured by Otsuka Electronics Co., Ltd.), and the span: average of _D90 - _D10 / _D50 was calculated. The span is a value calculated from the particle sizes _D90 , _D10 and D50 corresponding to 90%, 10% and ₅₀ % of the integrated value of the particle size distribution according to the following formula.
Span = ( _D90 - _D10 ) / _D50

Test 4 <Stability of 2M composition at 50°C>
20 g of the composition immediately after production was stored in a sealed glass ampoule at 50° C. for 2 months, and the appearance of the composition was then visually evaluated.

Test 5 <50℃・2M, Vitamin A (VA) Residual Rate (%)>
20 g of the composition immediately after production was stored in a sealed glass ampoule at 50° C. for 2 months, and then the vitamin A content was measured. The measurement was performed using high performance liquid chromatography. From the obtained vitamin A content, the vitamin A residual rate (%) was calculated based on the following formula: Vitamin A residual rate (%) = Vitamin A content after storage / Vitamin A content immediately after production × 100

The raw materials used in the above examples are shown below. Unless otherwise specified, the amounts of each component in the table are calculated as pure amounts.
Liquid paraffin: 1st method of the 16th edition of the Japanese Pharmacopoeia (37.8°C) kinematic viscosity 76.6 ^mm2 /s (KAYDOL, Shima Trading Co., Ltd.)
POE hydrogenated castor oil 60: Polyoxyethylene hydrogenated castor oil 60 (HCO60, manufactured by Nippon Surfactant Kogyo Co., Ltd.); HLB 14
POE castor oil 35: Polyoxyethylene castor oil 35 (Uniox C35, NOF Corp.); HLB 13
POE sorbitan fatty acid ester: Polysorbate 80, POE (20) sorbitan monooleate (Rheodol TW-O120V, manufactured by Kao Corporation): HLB 15
POEPOP glycol: polyoxyethylene (196) polyoxypropylene (67) block copolymer (Lutrol F127, manufactured by BASF Japan Ltd.); HLB 22
Boric acid (Kosakai Pharmaceutical Co., Ltd.)
VA: Retinol palmitate (retinol palmitate [1.74 million IU/g], manufactured by DSM)
VE: d-α-tocopherol acetate (Riken E Acetate α, manufactured by Riken Vitamin Co., Ltd.)

Claims (6)

(A) liquid paraffin,
A step of mixing (B) a nonionic surfactant and (C1) water to prepare a first mixture having a content of (C1) of 8 to 30 w/v % in the first mixture ;
(C2) mixing the obtained first mixture with water and/or a dilute aqueous solution to obtain a second mixture ;
A method for producing a liquid composition (however, this does not include a method for producing an ophthalmic composition containing (a) an oily component and (b) a nonionic surfactant having an HLB of 12.8 or more, in which a mixture containing the above-mentioned components (a) and (b) is high-pressure emulsified at an injection pressure of 100 MPa or more and a back pressure of 1 MPa or more). (A) liquid paraffin,
A step of mixing (B) a nonionic surfactant, (C1) water, and (D) one or more selected from vitamin A and vitamin E to prepare a first mixture having a content of (C1) of 8 to 30 w/v % in the first mixture ;
(C2) mixing the obtained first mixture with water and/or a dilute aqueous solution to obtain a second mixture ;
A method for producing a liquid composition (however, this does not include a method for producing an ophthalmic composition containing (a) an oily component and (b) a nonionic surfactant having an HLB of 12.8 or more, in which a mixture containing the above-mentioned components (a) and (b) is high-pressure emulsified at an injection pressure of 100 MPa or more and a back pressure of 1 MPa or more). (A) liquid paraffin having a kinetic viscosity of 74 to 88 mm ² /s as measured by the Japanese Pharmacopoeia, 16th Edition, Method 1 (37.8°C);
(B) a nonionic surfactant,
(C) water, and (D) vitamin A and vitamin E.
A liquid composition comprising: a) an emulsion having an emulsion particle diameter of 100 nm or less; and a span (D ₉₀ -D ₁₀ )/D ₅₀ of 1 to 4; The liquid composition according to claim 3, wherein the blending mass ratio represented by (B)/(A) is 5 to 20. 5. The liquid composition according to claim 3, which has a transmittance of 80% or more at a wavelength of 600 nm. The liquid composition according to any one of claims 3 to 5, wherein the component (B) comprises at least one selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.