Ophthalmic composition

Abstract

To provide an ophthalmic composition.SOLUTION: An ophthalmic composition has (A) at least one selected from the group consisting of epinastine and a salt thereof, (B) at least one selected from the group consisting of pranoprofen and a salt thereof, and (C) a surfactant and / or a multichain surfactant with an HLB value of 16.5 or less.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition (or ophthalmic agent).

Background Art

[0002] Epinastine hydrochloride is known as an antihistamine agent, and attempts are being made to use epinastine hydrochloride for ophthalmic use.

[0003] For example, Patent Document 1 (Japanese Patent No. 6134853) discloses an eye drop containing only epinastine or a salt thereof at a concentration exceeding 0.075% (w / v) as an active ingredient and substantially containing no preservative and no ingredient having a preservative effect.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a novel ophthalmic composition.

Means for Solving the Problems

[0006] As described above, epinastine or a salt thereof is used as a single active ingredient, and ophthalmic preparations combined with other active ingredients are still in an undeveloped state.

[0007] Under such circumstances, as a result of intensive studies to solve the above problems, the present inventors have found that a novel ophthalmic composition can be obtained by combining epinastine or a salt thereof with a specific active ingredient, that precipitation or turbidity may occur in such an ophthalmic composition, and that a specific surfactant can efficiently suppress such precipitation. Through further studies, the present invention has been completed.

[0008] That is, the present invention relates to the following inventions. [1] (A) At least one selected from the group consisting of epinastine and salts thereof, (B) At least one selected from the group consisting of pranoprofen and salts thereof, and (C) An ophthalmic composition containing a surfactant having an HLB value of 16.5 or less. [2] (A) At least one selected from the group consisting of epinastine and salts thereof, (B) At least one selected from the group consisting of pranoprofen and salts thereof, and (C) An ophthalmic composition containing a multi-chain surfactant. [3] The composition according to [1] or [2], wherein the HLB value of component (C) is 15.5 or less. [4] The composition according to any one of [1] to [3], wherein component (C) has a plurality of hydrophilic groups. [5] The composition according to any one of [1] to [4], wherein component (C) is a nonionic surfactant having a plurality of hydrophilic groups and an HLB value of 10 to 15. [6] The composition according to any one of [1] to [5], wherein component (C) includes at least one selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. [7] The composition according to any one of [1] to [6], containing component (A) in an amount of 0.005 to 0.5 w / v%. [8] The composition according to any one of [1] to [7], containing component (B) in an amount of 0.005 to 0.5 w / v%. [9] The composition according to any one of [1] to [8], wherein the ratio of the (B) component is 0.01 to 100 parts by mass with respect to 1 part by mass of the (A) component.

[10] The composition according to any one of [1] to [9], containing 0.001 to 10 w / v% of the (C) component.

[11] The composition according to any one of [1] to

[10] , wherein the ratio of the (C) component is 1 part by mass or more with respect to 1 part by mass of the (A) component and 1 part by mass or more with respect to 1 part by mass of the (B) component.

[12] The composition according to any one of [1] to

[11] , having a pH of 4 to 9.

[13] The (C) component includes one or more selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil, the ratio of the (A) component is 0.01 to 0.1 w / v%, the ratio of the (B) component is 0.01 to 0.1 w / v%, the ratio of the (C) component is 0.01 to 1 w / v%, the ratio of the (B) component is 0.1 to 10 parts by mass with respect to 1 part by mass of the (A) component, The composition according to any one of [1] to

[12] , having a pH of 5 to 8.

[14] The composition according to any one of [1] to

[13] , having no precipitation.

[15] The composition according to any one of [1] to

[14] , containing water in a ratio of 90% by mass or more based on the total amount of the composition and having no precipitation.

[16] One or more selected from the group consisting of (A) epinastine and its salts, and A method for suppressing precipitation in an ophthalmic composition containing one or more selected from the group consisting of (B) pranoprofen and its salts, the method comprising adding a surfactant having an HLB value of 16.5 or less as the (C) component to the ophthalmic composition.

[17] One or more selected from the group consisting of (A) epinastine and its salts, and A method for suppressing precipitation in an ophthalmic composition containing one or more selected from the group consisting of pranoprofen and its salts, the method comprising adding (C) a multi-chain surfactant to the ophthalmic composition.

Advantages of the Invention

[0009] The present invention can provide a novel ophthalmic composition. Such an ophthalmic composition contains epinastine or its salt in addition to pranoprofen and / or its salt, and is an ophthalmic composition with an unprecedented formulation.

[0010] In another aspect of the present invention, an ophthalmic composition capable of suppressing precipitation (clouding) can be provided. According to the study by the present inventor, precipitation may occur in a preparation containing a combination of epinastine and / or its salt and pranoprofen and / or its salt. However, according to the ophthalmic composition of the present invention containing a specific surfactant selected from a wide variety of components in addition to these, such precipitation can be efficiently suppressed.

[0011] In another aspect of the present invention, even when further containing other components (such as a pH adjuster, a buffer, etc.) or when containing a high proportion of water, the precipitation suppressing effect can be effectively exerted.

[0012] In another aspect of the present invention, it can be effectively exerted without impairing the function as a surfactant. The component (C) in the present invention is a surfactant, and even when containing the component (A) and the component (B) (and further other components), it can effectively exert the function as a surfactant.

[0013] Thus, the composition of the present invention is extremely practical.

Modes for Carrying Out the Invention

[0014] In this specification, the unit of content "w / v%" is synonymous with "g / 100 mL". Further, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene.

[0015] 〔1. Ophthalmic Composition〕 The ophthalmic composition of the present invention contains at least (A) epinastine and / or a salt thereof, and (B) pranoprofen or a salt thereof.

[0016] (A) Epinastine and / or its salt ((A) component) The salt of epinastine is not particularly limited as long as it is a pharmaceutically or physiologically acceptable salt. Examples include organic acid salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (lactate, tartrate, citrate, etc.), organic sulfonic acid salts (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), etc.

[0017] Preferred epinastine and / or its salts include epinastine hydrochloride (monohydrochloride).

[0018] Epinastine and / or its salts may be used alone or in combination of two or more.

[0019] The content of component (A) in the composition is, for example, 0.0001 w / v% or more (e.g., 0.0003 - 5 w / v%), preferably 0.0005 w / v% or more (e.g., 0.001 - 1 w / v%), more preferably 0.003 w / v% or more (e.g., 0.005 - 0.5 w / v%), still more preferably 0.005 w / v% or more (e.g., 0.007 - 0.2 w / v%), even more preferably 0.008 w / v% or more (e.g., 0.01 - 0.1 w / v%), particularly preferably 0.02 w / v% or more (e.g., 0.03 - 0.1 w / v%), most preferably 0.03 w / v% or more (e.g., 0.04 - 0.08 w / v%, 0.045 - 0.06 w / v%, etc.) with respect to the total amount of the composition. Among them, 0.05 w / v%, 0.1 w / v%, etc. are preferred, and 0.05 w / v% is particularly preferred.

[0020] (B) Pranoprofen and / or its salt ((B) component) In addition to epinastine and / or a salt thereof, the composition of the present invention contains pranoprofen and / or a salt thereof. According to the composition of the present invention, even when containing a plurality of active ingredients in this way, each function (pharmaceutical effect) can be efficiently exhibited.

[0021] The salt of pranoprofen may be any pharmaceutically or physiologically acceptable salt. In addition to salts with acids (for example, the salts exemplified in the section of component (A) such as salts with inorganic acids and salts with organic acids), salts with bases {for example, salts with organic bases (for example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [for example, ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.], etc.} can be mentioned. For example, sulfate, lactate, hydrochloride, chloride salt, sodium salt, potassium salt, etc. can be mentioned. Preferred pranoprofen and / or a salt thereof are pranoprofen and its metal salts, and pranoprofen is particularly preferred.

[0022] Pranoprofen and / or a salt thereof may be used alone or in combination of two or more.

[0023] The content of component (B) in the composition may be, for example, 0.0001 w / v% or more (for example, 0.0003 - 5 w / v%), preferably 0.0005 w / v% or more (for example, 0.001 - 1 w / v%), more preferably 0.003 w / v% or more (for example, 0.005 - 0.5 w / v%), still more preferably 0.005 w / v% or more (for example, 0.007 - 0.2 w / v%), still more preferably 0.008 w / v% or more (for example, 0.01 - 0.1 w / v%), particularly preferably 0.02 w / v% or more (for example, 0.03 - 0.1 w / v%), most preferably about 0.03 w / v% or more (for example, 0.04 - 0.08 w / v%, 0.045 - 0.06 w / v%, etc.). Among them, 0.05 w / v%, 0.1 w / v%, etc. are preferred, and 0.05 w / v% is particularly preferred.

[0024] (B) The ratio of the component is, for example, 0.001 to 1000 parts by mass, preferably 0.005 to 200 parts by mass, more preferably 0.01 to 100 parts by mass, particularly preferably 0.05 to 20 parts by mass, most preferably 0.1 to 10 parts by mass (for example, 0.2 to 5 parts by mass, 0.3 to 3 parts by mass, 0.5 to 2 parts by mass, etc.) with respect to 1 part by mass of the (A) component, and particularly preferably 1 part by mass.

[0025] (C) Specific surfactant ((C) component) The composition of the present invention may contain a specific surfactant (C). A surfactant is usually a so-called amphiphilic component and refers to all substances having a surfactant action.

[0026] Such a surfactant (C) satisfies the following aspect (C1) or (C2).

[0027] (C1) HLB value of 16.5 or less (C2) Multichain type (or having a branched chain)

[0028] Component (C) may be any surfactant that satisfies at least one of the above aspects (C1) or (C2), and may also be a surfactant that satisfies both (a surfactant having an HLB value of 16.5 or less and being a multichain type).

[0029] In aspect (C1), the HLB value can be selected from the range of 16.5 or less, and may be, for example, 16.2 or less, 16 or less, 15.8 or less, 15.5 or less, 15.2 or less, 15 or less, 14.8 or less, 14.5 or less, 14.2 or less, etc.

[0030] In embodiment (C1), the lower limit value of the HLB value is not particularly limited, and may be, for example, 2, 2.5, 3, 3.5, 4, 4.5, 4.8, 5, 5.2, 5.5, 5.8, 6, 6.2, 6.5, 6.8, 7, 7.2, 7.5, 7.8, 8, 8.2, 8.5, 8.8, 9, 9.2, 9.5, 9.8, 10, 10.2, 10.5, 10.8, 11, 11.2, 11.5, 11.8, 12, etc.

[0031] When using surfactants in combination, each surfactant may satisfy the above HLB value, or the HLB value of the entire plurality of surfactants (mixed HLB value, weighted average value of the HLB values of each surfactant) may satisfy the above HLB value, and the surfactant may contain at least a surfactant that satisfies the above HLB value.

[0032] Note that the HLB value is not particularly limited and may be a calculated value or a value obtained experimentally. The calculated value may be, for example, a calculated value based on the Griffin method (20 × sum of the formula weights of the hydrophilic parts / molecular weight).

[0033] The surfactant satisfying embodiment (C2) is multi-chain (having a branched chain). Multi-chain means not linear, and usually, the hydrophilic group (hydrophilic part, hydrophilic group, hydrophilic chain, hydrophilic chain) and / or lipophilic group (lipophilic part, lipophilic group, hydrophobic part, hydrophobic group, hydrophobic group) constituting the surfactant may have a branched structure (branched chain).

[0034] Specific multi-chain surfactants include surfactants having a branched structure in the lipophilic group [for example, surfactants having a branched chain (for example, a branched alkyl chain such as 2-octyldodecyl group; a polyoxybranched alkylene chain such as a polyoxypropylene chain) as the lipophilic group], surfactants having a plurality of hydrophilic groups (for example, surfactants having a plurality of hydrophilic groups branched from the lipophilic group), and surfactants having a combination thereof.

[0035] Among these, surfactants having at least a plurality of hydrophilic groups (for example, polyoxyethylene chains) are preferred. In such surfactants, the number of hydrophilic groups (for example, hydrophilic groups bonded to lipophilic groups) may be 2 or more, and particularly may be 3 or more.

[0036] Surfactant (C) may usually be nonionic.

[0037] Typical component (C) (surfactant satisfying the above-described aspect (C1) and / or (C2)) includes, for example, polyoxyethylene castor oil (for example, POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil 50, etc.), polyoxyethylene hydrogenated castor oil (for example, POE hydrogenated castor oil 10, POE hydrogenated castor oil 20, POE hydrogenated castor oil 25, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80, etc.), polysorbate (POE sorbitan fatty acid ester, for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, etc.), tyloxapol, polyoxyethylene branched alkyl ether, polyoxyethylene glycerin fatty acid ester (for example, polyoxyethylene glycerin monostearate), etc.

[0038] Among these components (C), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, tyloxapol, etc. are preferred, and particularly, polyoxyethylene castor oil (POE castor oil 10, POE castor oil 35, etc.), polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil 60, etc.) are preferred.

[0039] Therefore, component (C) may contain at least these surfactants.

[0040] Component (C) may be used alone or in combination of two or more.

[0041] When combining component (C), components of the same system (same classification) may be combined, components of different systems (different classifications) may be combined, and components with different HLB values [for example, components with an HLB value difference of 0.5 or more (for example, 1 or more, 1.5 or more, 2 or more, 2.5 or more, 3 or more, 3.5 or more, 4 or more, 4.5 or more, 5 or more, etc.) different components] may be combined. By combining component (C), precipitation in the composition may be suppressed more efficiently in some cases.

[0042] Typical combinations include combinations of two or more selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. In particular, a combination of polyoxyethylene castor oil (one or more selected from the group consisting of polyoxyethylene castor oil) and polyoxyethylene hydrogenated castor oil (one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil) is preferred.

[0043] When combining polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil, the ratio of polyoxyethylene hydrogenated castor oil to 1 part by mass of polyoxyethylene castor oil may be, for example, 0.001 to 1000 parts by mass, preferably 0.01 to 100 parts by mass, and more preferably about 0.02 to 50 parts by mass.

[0044] When containing component (C), the content of component (C) in the composition may be, for example, 0.001 w / v% or more (for example, 0.001 to 10 w / v%) based on the total amount of the composition, preferably 0.005 w / v% or more (for example, 0.007 to 5 w / v%), more preferably 0.01 w / v% or more (for example, 0.03 to 2 w / v%), and particularly preferably 0.05 w / v% or more (for example, 0.1 to 1 w / v%).

[0045] When containing component (C), the proportion of component (C) may be, for example, 0.02 parts by mass or more (for example, 0.02 to 200 parts by mass), preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass), more preferably 0.2 parts by mass or more (for example, 0.2 to 40 parts by mass), particularly preferably 1 part by mass or more (for example, 1 to 20 parts by mass), and most preferably 2 parts by mass or more (for example, 2 to 10 parts by mass) with respect to 1 part by mass of component (A).

[0046] When containing component (C), the proportion of component (C) may be, for example, 0.02 parts by mass or more (for example, 0.02 to 200 parts by mass), preferably 0.1 parts by mass or more (for example, 0.1 to 100 parts by mass), more preferably 0.2 parts by mass or more (for example, 0.2 to 40 parts by mass), particularly preferably 1 part by mass or more (for example, 1 to 20 parts by mass), and most preferably 2 parts by mass or more (for example, 2 to 10 parts by mass) with respect to 1 part by mass of component (B).

[0047] When containing component (C), the proportion of component (C) may be, for example, 0.01 parts by mass or more (for example, 0.01 to 100 parts by mass), preferably 0.05 parts by mass or more (for example, 0.05 to 50 parts by mass), more preferably 0.1 parts by mass or more (for example, 0.1 to 20 parts by mass), particularly preferably 0.5 parts by mass or more (for example, 0.5 to 10 parts by mass), and most preferably 1 part by mass or more (for example, 1 to 8 parts by mass) with respect to 1 part by mass of the total amount of components (A) and (B).

[0048] [Other components] The composition of the present invention may further contain other components. In the present invention, in many cases, the effects of the present invention can be ensured even when other components are contained. Also, in some cases, the effects of the present invention can be more effectively realized by containing other components.

[0049] Amino acids The composition of the present invention may contain amino acids. Examples of amino acids include amino acids or their salts, and amino acid analogs, and compounds having an amino group and a carboxyl group or a sulfone group in the molecule or their derivatives, etc.

[0050] Specific examples include amino acids or their salts, mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and amino caproic acid; monoamino dicarboxylic acids such as aspartic acid and glutamic acid or their salts; diamino monocarboxylic acids such as arginine and lysine or their salts; derivatives such as aminoethylsulfonic acid (taurine) or their salts.

[0051] Among amino acids, examples of mucopolysaccharides or their derivatives or their salts include, for example, as acidic mucopolysaccharides, derivatives such as chondroitin sulfate, hyaluronic acid, and alginic acid or their salts.

[0052] Specific amino acids and mucopolysaccharides include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, ε-amino caproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, or their salts, etc.

[0053] Chondroitin sulfate is a substance in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of a sugar chain in which D-glucuronic acid and N-acetylglucosamine repeat. The bonding position and number of sulfuric acid are diverse, and chondroitin sulfate also has derivatives (for example, those in which all or part of N-acetylglucosamine is substituted with iduronic acid). Such chondroitin sulfate may have any structure. For example, chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4th and 6th positions of N-acetylglucosamine are sulfated, etc. may be mentioned. Also, chondroitin sulfate may be extracted from animals.

[0054] The salts of amino acids or mucopolysaccharides include pharmaceutically, pharmacologically or physiologically acceptable salts. Such salts include salts with organic acids [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylic acid salts (fumarate, maleate, etc.), oxycarboxylic acid salts (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate salts (methanesulfonate, toluenesulfonate, tosylate, etc.), etc.], salts with inorganic acids (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.], etc., and are appropriately selected according to the compound.

[0055] Specific salts include salts of aspartic acid (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium potassium aspartate mixture, etc.), salts of glutamic acid (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, sodium hyaluronate, etc.

[0056] The amino acids may be in any of the D-form, L-form, or DL-form.

[0057] Preferred amino acids include aminoethylsulfonic acid (taurine) or its salt, sodium chondroitin sulfate, aspartate salts (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilon-aminocaproic acid or its salt, hyaluronic acid or its salt (such as sodium hyaluronate), etc. Among these, hyaluronic acid or its salt (such as sodium hyaluronate), aminoethylsulfonic acid (taurine) and / or its salt and sodium chondroitin sulfate are preferred.

[0058] The amino acids may be used alone or in combination of two or more.

[0059] When the composition contains amino acids, the content of the amino acids in the composition may be, for example, 0.001 w / v% or more, preferably 0.01 to 20 w / v%, more preferably 0.03 to 10 w / v%, still more preferably 0.05 to 5 w / v%, even more preferably 0.1 to 3 w / v%, particularly preferably about 0.15 to 2 w / v% with respect to the total amount of the composition, and is usually 0.001 to 10 w / v% [for example, 0.005 to 10 w / v%, preferably 0.01 to 5 w / v%, still more preferably 0.05 to 3 w / v% (for example, 0.1 to 1 w / v%)].

[0060] Cooling agent The composition of the present invention may contain a cooling agent. (A) component, (B) component and (C) component may be combined, and the feeling of use may be reduced or impaired, but such a feeling of use can be improved or ameliorated by the cooling agent. For example, while it may be advantageous to increase the pH of the composition from the viewpoint of solubility and the like, the higher the pH of the composition, the stronger the discomfort and the feeling of use may be impaired, but by using the cooling agent, such discomfort can be alleviated and the feeling of use can be efficiently improved.

[0061] The cooling agent is not particularly limited, and examples thereof include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and borneol. These may be any of the d-form, l-form or dl-form. Also included are essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, perilla oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

[0062] Among them, terpenoids are preferred, and among these, menthol, camphor, geraniol, cineole, borneol, and borneolum are preferred, menthol, camphor, and borneol are more preferred, menthol and borneol are even more preferred, and menthol is most preferred.

[0063] The cooling agent may be used alone or in combination of two or more. In particular, the cooling agent preferably contains one or more selected from the group consisting of menthol, borneol, and camphor, and when combining two or more, it is also preferred to combine at least these (for example, combining menthol, borneol, and camphor).

[0064] When the composition contains a cooling agent, the proportion of the cooling agent may be, for example, 0.00001 w / v% or more, 0.00005 w / v% or more, 0.0001 w / v% or more, 0.0003 w / v% or more, 0.0005 w / v% or more, 0.0007 w / v% or more, 0.0008 w / v% or more, 0.0009 w / v% or more, 0.001 w / v% or more based on the total amount of the composition.

[0065] Also, the proportion of the cooling agent may be 5 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1.2 w / v% or less, 1 w / v% or less, 0.9 w / v% or less, 0.8 w / v% or less, 0.7 w / v% or less, 0.6 w / v% or less based on the total amount of the composition.

[0066] In particular, when the composition of the present invention contains menthol, the proportion of menthol may be, for example, 0.00001 w / v% or more (for example, 0.00005 - 2 w / v%), preferably 0.0001 - 0.2 w / v% (for example, 0.0003 - 0.1 w / v%), and more preferably about 0.0005 - 0.05 w / v% (for example, 0.001 - 0.02 w / v%) based on the total amount of the composition.

[0067] In particular, when the composition of the present invention contains borneol, the proportion of borneol may be, for example, 0.00001 w / v% or more (for example, 0.00005 to 3 w / v%), preferably 0.0001 to 2 w / v% (for example, 0.0003 to 1 w / v%), more preferably about 0.0005 to 0.8 w / v% (for example, 0.001 to 0.5 w / v%) based on the total amount of the composition.

[0068] In particular, when the composition of the present invention contains camphor, the proportion of camphor may be, for example, 0.00001 w / v% or more (for example, 0.00005 to 1 w / v%), preferably 0.0001 to 0.1 w / v% (for example, 0.0003 to 0.05 w / v%), more preferably about 0.0005 to 0.02 w / v% (for example, 0.001 to 0.01 w / v%) based on the total amount of the composition.

[0069] Liposoluble antioxidant The composition of the present invention may contain a fat-soluble antioxidant.

[0070] Examples of the fat-soluble antioxidant include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbyl palmitate, ascorbyl stearate, ascorbyl phosphate aminopropyl, ascorbyl phosphate tocopherol, ascorbyl trilinoleate, ascorbyl phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; CoQ10 and the like.

[0071] Among these, dibutylhydroxytoluene is preferred.

[0072] The fat-soluble antioxidant may be used alone or in combination of two or more.

[0073] When the composition contains a fat-soluble antioxidant, the content of the fat-soluble antioxidant in the composition may be, for example, 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.0007 to 0.009 w / v%, still more preferably 0.001 to 0.008 w / v%, even more preferably 0.003 to 0.007 w / v%, and most preferably about 0.0045 to 0.006 w / v% based on the total amount of the composition.

[0074] Anti-allergic agent The composition of the present invention may contain an antiallergic agent.

[0075] Examples of the antiallergic agent include tranilast, cromoglycic acid, ibudilast, acitazanolast, tazanolast, sprastanolast, pemirolast, anlelexanox, oxatomide, and salts thereof.

[0076] Examples of the salts include the salts exemplified above, such as alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, etc.), and organic acid salts (e.g., tosylate, fumarate, etc.).

[0077] Among these, tranilast, cromoglycic acid, and salts thereof are preferred, and tranilast and sodium cromoglycate are more preferred.

[0078] The antiallergic agent may be used alone or in combination of two or more.

[0079] When the composition contains an anti-allergic agent, the content of the anti-allergic agent in the composition may be, for example, 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to 5 w / v%, even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2 w / v%, even particularly preferably 0.8 to 1.5 w / v%, and most preferably about 0.9 to 1.2 w / v% based on the total amount of the composition.

[0080] Anti-histamine agent The composition of the present invention may contain an antihistamine. The antihistamine (antihistamines other than epinastine and its salts) is not particularly limited as long as it is a substance having an antihistamine action, and examples thereof include chlorpheniramine, diphenhydramine, ketotifen, olopatadine, levocabastine, iproheptin, and their salts.

[0081] The salt may be a pharmaceutically or physiologically acceptable salt, and examples thereof include organic acid salts [e.g., maleate, fumarate (e.g., ketotifen fumarate, etc.)], inorganic acid salts [e.g., hydrochloride (e.g., olopatadine hydrochloride, etc.), sulfate, etc.], and the salts exemplified above such as metal salts.

[0082] Specific salts include, for example, diphenhydramine hydrochloride, iproheptin hydrochloride, chlorpheniramine maleate, and the like.

[0083] The antihistamine may be used alone or in combination of two or more.

[0084] When the composition contains an antihistamine, the content of the antihistamine in the composition is, for example, 0.0001 w / v% or more, preferably 0.001 to 10 w / v%, more preferably 0.003 to 5 w / v%, still more preferably 0.005 to 1 w / v%, even more preferably 0.01 to 0.5 w / v%, particularly preferably 0.015 to 0.3 w / v% (for example, 0.02 to 0.1 w / v%), most preferably about 0.025 to 0.05 w / v% (for example, 0.03 w / v%) with respect to the total amount of the composition, and may usually be about 0.01 to 0.05 w / v%.

[0085] Anti-inflammatory agent The composition of the present invention may contain an anti-inflammatory agent. The anti-inflammatory agent (an anti-inflammatory agent other than pranoprofen and its salts) is not particularly limited as long as it is a substance having an anti-inflammatory action, and examples thereof include indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme, and salts thereof.

[0086] Examples of the salts include the salts exemplified above such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases, and examples thereof include sulfates, lactates, hydrochlorides, chloride salts, sodium salts, potassium salts, and the like.

[0087] Specific examples of the salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, lysozyme chloride, and the like.

[0088] The anti-inflammatory agent may be used alone or in combination of two or more.

[0089] When the composition contains an anti-inflammatory agent, the content of the anti-inflammatory agent in the composition may be, for example, 0.001 w / v% or more (e.g., 0.02 w / v%), preferably 0.005 to 10 w / v% (e.g., 5 w / v%), more preferably 0.01 to 1 w / v%, even more preferably 0.1 to 0.5 w / v% (e.g., 0.3 w / v%), and particularly preferably about 0.2 to 0.3 w / v% (e.g., 0.25 w / v%) based on the total amount of the composition.

[0090] The composition of the present invention may contain various components (e.g., components not belonging to the category of the above components). Such components (additives) include, for example, surfactants, preservatives, buffers, pH adjusters, isotonic agents, thickeners or gelling agents, stabilizers, oils, saccharides, polymer compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), and the like.

[0091] The additives can be used alone or in combination of two or more. Also, each additive can be used alone or in combination of two or more.

[0092] Specific examples of the additives are illustrated below.

[0093] Other surfactant The composition of the present invention may contain other surfactants (surfactants not belonging to the category of the component (C), that is, surfactants having an HLB value exceeding 16.5 and being linear surfactants).

[0094] The other surfactants are not particularly limited as long as they are surfactants not belonging to the category of the component (C) (that is, surfactants having an HLB value exceeding 16.5 and being linear surfactants). Examples include polyoxyethylene linear alkyl ethers having an HLB value exceeding 16.5 [e.g., polyoxyethylene lauryl ether (e.g., HLB value of about 16.9), etc.], polyoxyethylene linear fatty acid esters having an HLB value exceeding 16.5 (e.g., polyoxyl 40 stearate, etc.), polyoxyethylene polyoxypropylene glycols having an HLB value exceeding 16.5 (e.g., poloxamers such as poloxamer 407), and the like.

[0095] Other surfactants may be used alone or in combination of two or more.

[0096] When the composition contains other surfactants, the proportion of the other surfactants to the total amount of the surfactants ((component (C) and other surfactants)) may be, for example, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, etc.

[0097] Preservative The composition of the present invention may contain a preservative. Examples of the preservative include poly dodecyl pyridinium chloride, alkyl polyaminoethyl glycines (such as alkyl diaminethyl glycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (such as benzalkonium chloride, benzetonium chloride, etc.), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters (such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (such as polyhexanide hydrochloride, etc.), and glochil (manufactured by Rhodia), etc.

[0098] Among them, alkyl polyaminoethyl glycines (such as alkyl diaminethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, biguanide compounds are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, biguanide compounds are more preferred, and benzalkonium chloride, polyhexanide hydrochloride are even more preferred.

[0099] When the composition contains a preservative, the proportion of the preservative in the composition is, for example, 0.000001 w / v% or more, particularly 0.00001 w / v% or more, particularly 0.00005 w / v% or more, particularly 0.001 w / v% or more, particularly 0.005 w / v% or more, based on the total amount of the composition. Also, the total amount of the preservative is 1 w / v% or less, particularly 0.1 w / v% or less, particularly 0.05 w / v% or less, particularly 0.03 w / v% or less, particularly 0.025 w / v% or less, based on the total amount of the composition.

[0100] Buffer The composition of the present invention may contain a buffering agent. Examples of the buffering agent include boric acid buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, and the like.

[0101] Examples of the components of the boric acid buffer include boric acid, borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate may be a hydrate.

[0102] Examples of the components of the phosphate buffer include phosphoric acid, phosphates (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.). The phosphate may be a hydrate.

[0103] Examples of the components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate, etc.). The carbonate may be a hydrate.

[0104] Examples of the components of the citrate buffer include citric acid, citrates (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.). The citrate may be a hydrate.

[0105] Examples of the components of the acetate buffer include acetic acid, acetate salts (such as ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). The acetate salt may be a hydrate.

[0106] Among them, from the viewpoint of storage efficacy and the like, a borate buffer is preferred, and from the viewpoint of low cytotoxicity and the like, a phosphate buffer is preferred, and a borate buffer is more preferred. As the borate buffer, a combination of boric acid and its salt is preferred, a combination of boric acid and an alkali metal salt and / or an alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is further preferred, and a combination of boric acid and borax is even more preferred.

[0107] When a buffer is incorporated into the composition of the present invention, the amount of the buffer incorporated varies depending on the type of the buffer, the types and amounts of other incorporated components, etc., and cannot be uniformly defined. For example, based on the total amount of the composition, the total amount of the buffer is 0.001 w / v% or more, among which 0.01 w / v% or more, among which 0.05 w / v% or more, among which 0.1 w / v% or more can be mentioned. Also, based on the total amount of the composition, the total amount of the buffer is 10 w / v% or less, among which 5 w / v% or less, among which 3 w / v% or less, among which 2.5 w / v% or less, among which 2 w / v% or less can be mentioned.

[0108] In particular, when a borate buffer is used, the proportion of the buffer in the composition may be 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 4 w / v%, and still more preferably about 0.2 to 3 w / v% based on the whole composition.

[0109] pH adjuster Examples of the pH adjuster include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (such as propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, etc. The pH adjuster may be used alone or in combination of two or more.

[0110] Isotonic agent Examples of the isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol. The isotonic agent may be used alone or in combination of two or more.

[0111] Thickening agent or viscosifying agent The ophthalmic composition of the present invention can contain a thickening agent or a viscosifying agent.

[0112] Examples of the thickening agent or the viscosifying agent include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (for example, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, etc.), gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (for example, heparin-like substances, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.)), starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinyl-based polymer compounds (polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, potassium salt, etc.), amine salts of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.), alginate ester (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine. The thickening agent or the viscosifying agent may be used alone or in combination of two or more.

[0113] Stabilizer Examples of stabilizers include hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, tromethamine, etc.), sodium formaldehyde sulfoxylate (rongalit), aluminum monostearate, and glycerin monostearate. The stabilizer(s) may be used alone or in combination of two or more.

[0114] Oil component Examples of oils include squalane, animal oils such as purified lanolin, mineral oils such as liquid paraffin and white petrolatum, and vegetable oils such as castor oil and sesame oil.

[0115] Sugars Examples of saccharides include monosaccharides, oligosaccharides (such as disaccharides), etc., and specifically include glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, etc.

[0116] Polyhydric alcohol Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, polyvinyl alcohol, etc.

[0117] Inorganic salts Examples of inorganic salts include, for example, potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, sodium carbonate (including anhydrous sodium carbonate), potassium hydrogen carbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, sodium thiosulfate, etc. Among them, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including anhydrous sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred.

[0118] Water-soluble antioxidant Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as sodium ascorbate-2-sulfate, sodium ascorbate, magnesium ascorbate-2-phosphate, sodium ascorbate-2-phosphate, etc.), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or its salts (such as disodium edetate, tetrasodium edetate, etc.).

[0119] Components having pharmacological activity or physiological activity can be further incorporated into the composition of the present invention.

[0120] The pharmacological active ingredient or physiological active ingredient can be used alone or in combination of two or more.

[0121] Examples of such pharmacological active ingredients and physiological active ingredients include the active ingredients in various pharmaceuticals described in the Guidelines for the Manufacture, Sale, and Approval of Pharmaceuticals Requiring Guidance and for General Use, 2017 Edition (supervised by the Regulatory Science Society of Japan). For example, decongestants, eye muscle regulators, astringents, vitamins, amino acids, antibacterial agents or bactericides, local anesthetic components, soothing agents, sulfonamides, etc. are included. Specific examples of these drugs are exemplified below.

[0122] Hyperemia remover (vasoconstrictor) Examples of the decongestant include, for example, α - adrenergic agonists, specifically imidazoline - based decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as their hydrochlorides, nitrates, etc., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methyl ephedrine hydrochloride, epinephrine hydrogen tartrate, etc. These may be in the form of d - form, l - form, or dl - form.

[0123] Regarding the imidazoline - based vasoconstrictors in detail, the salts of imidazoline - based vasoconstrictors may be pharmaceutically or physiologically acceptable salts, for example, organic acid salts such as maleate, fumarate, etc.; inorganic acid salts such as hydrochloride, sulfate, etc.; salts such as metal salts. Among the salts, inorganic acid salts are preferred, hydrochloride or nitrate is more preferred, and hydrochloride (such as tetrahydrozoline hydrochloride) is particularly preferred.

[0124] Among the decongestants (vasoconstrictors), imidazoline - based vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or their salts are more preferred, and tetrahydrozoline or its salts are more preferred.

[0125] Ocular muscle regulator Examples of the oculomotor regulator include, for example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate, etc.

[0126] Vitamins Examples of vitamins include riboflavin adenine dinucleotide or a salt thereof (e.g., riboflavin adenine dinucleotide sodium), cobalamin or a salt thereof (e.g., cyanocobalamin, methylcobalamin), retinol, a salt thereof or a derivative thereof (e.g., retinol acetate, retinol palmitate), pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof or a derivative thereof (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (e.g., pyridoxal phosphate), ascorbic acid or a salt thereof (e.g., sodium ascorbate, calcium ascorbate), and the like.

[0127] Among them, riboflavin adenine dinucleotide or a salt thereof (especially riboflavin adenine dinucleotide sodium), cobalamin or a salt thereof (especially cyanocobalamin), retinol, a salt thereof or a derivative thereof (especially retinol acetate, retinol palmitate), pyridoxine or a salt thereof (especially pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (especially sodium pantothenate, calcium pantothenate), tocopherol, a salt thereof or a derivative thereof (especially tocopherol acetate) are preferred, and pyridoxine hydrochloride and tocopherol acetate are more preferred. Note that the composition of the present invention may not contain pyridoxine and its salts.

[0128] Antibacterial agent or bactericide Examples of antibacterial or bactericidal agents include sulfonamides such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomezole sodium, sulfisomidine sodium, alkyl polyaminoethyl glycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

[0129] Local anesthetic component Examples of local anesthetic components include, for example, procaine hydrochloride, lidocaine hydrochloride, and the like.

[0130] Base or carrier The composition of the present invention may contain a base or a carrier. A composition containing such a base or carrier can be prepared, for example, by mixing the above components with a pharmaceutically acceptable base or carrier by a conventional method described in the Explanation Book of the 17th Revised Japanese Pharmacopoeia.

[0131] Examples of the base or carrier include polar solvents such as water and ethanol (especially water-soluble solvents), oily bases, and the like. The base or carrier can be used alone or in combination of two or more.

[0132] In particular, the composition of the present invention may be an aqueous composition (for example, a composition containing water or a mixed solvent of water and a water-soluble solvent).

[0133] Properties The properties of the composition of the present invention are not particularly limited, and may be any properties such as liquid, flowing, gel, or semi-solid. Also included are those that become liquid, flowing, gel, or semi-solid by preparation at the time of use. The semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment, and is preferably a liquid preparation.

[0134] Also, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic substance as a base or carrier) or an oily composition (mainly containing an oily or hydrophobic substance as a base or carrier) as described above, and particularly may be an aqueous composition.

[0135] In the case of an aqueous composition, the water content is preferably 50% by mass or more, more preferably 75% by mass or more, and even more preferably 90% by mass or more, based on the total amount of the composition (or formulation). It may also be 95% by mass or more, or 98% by mass or more. Further, the base or carrier may consist only of water.

[0136] In the case of an oily composition, the water content is preferably less than 50% by mass, more preferably 30% by mass or less, and even more preferably 20% by mass or less, based on the total amount of the composition (or formulation).

[0137] pH The pH of the composition of the present invention is preferably 3 or more (for example, 4 or more), more preferably 5 or more (for example, 5.5 or more), and even more preferably 6 or more. Also, it is preferably 10 or less, more preferably 9 or less, and even more preferably 8.5 or less.

[0138] The pH of the composition of the present invention may be, for example, 4 to 9, preferably 4.5 to 8.5, more preferably 5 to 8, and may also be 5.5 to 8, 6 to 8, 6 to 7.5, 6.5 to 7.5, etc. In the present invention, even at the pH as described above, the effects of the present invention (such as precipitation inhibition effect) can be efficiently realized.

[0139] Osmotic pressure The osmotic pressure ratio of the composition of the present invention is preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. Also, it is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less.

[0140] The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th revised Japanese Pharmacopoeia. For the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) is dried at 500 - 650 °C for 40 - 50 minutes, then cooled in a desiccator (silica gel), 0.900 g of it is accurately weighed, dissolved in purified water and accurately adjusted to 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is used.

[0141] Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited. For example, eye drops (also referred to as eye drop solution or eye medicine. Eye drops include those that can be instilled during contact lens wear), eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens soaking solution, intraocular injection agent (e.g., intravitreal injection agent), solution for contact lenses (cleaning solution, storage solution, disinfecting solution, multipurpose solution, package solution), preservative for excised eye tissues such as cornea for transplantation, irrigation fluid during surgery, etc. are included. Eye drops, eye wash, and eye ointment also include those used during contact lens wear.

[0142] Note that "contact lens" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0143] As the dosage form of the composition of the present invention, preferably, eye drops, eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multi-purpose solutions, package solutions), etc. may be mentioned. More preferably, eye drops, eye washes, contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multi-purpose solutions, package solutions), etc. may be mentioned. Even more preferably, eye drops and eye washes may be mentioned. Particularly preferably, eye drops may be mentioned.

[0144] The composition of the present invention may be in a single-dose unit dose or a multi-dose that can be used repeatedly, and may be accommodated and used in the form of a multi-dose.

[0145] Container The composition of the present invention may be accommodated (filled, injected, enclosed) in a container. The container may be any packaging body having a portion (surface) in contact with the composition (preparation). For example, it may be composed of a container body portion for accommodating the composition (for example, a liquid composition), a portion including the extraction port of the container (nozzle, stopper), a suction tube, a cap, etc.

[0146] The material constituting the container can be selected from a wide range. For example, at least a part or all of the portion in contact with the composition is made of plastic (for example, olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate resin, fluororesin, chlorine resin (such as polyvinyl chloride), polyamide resin, polyacetal resin, polyphenylene ether resin (such as modified polyphenylene ether), polyarylate, polysulfone, polyimide resin, cellulose resin (such as cellulose acetate), hydrocarbon resin that may be substituted with a halogen atom, etc.), metal (such as aluminum), etc.

[0147] The container may be composed of a single material or two or more materials.

[0148] Examples of olefin resins include ethylene resins [e.g., polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymers, etc.], propylene resins [e.g., polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], methylpentene resins (e.g., polymethylpentene, etc.).

[0149] Examples of styrene resins include, for example, polystyrene, acrylonitrile-containing styrene resins (e.g., acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

[0150] Examples of acrylic resins include resins having, as polymerization components, acrylic esters such as methyl acrylate, methacrylic esters such as methyl methacrylate, cyclohexyl methacrylate, t-butylcyclohexyl methacrylate, etc.

[0151] Examples of polyester resins include, for example, aromatic polyester resins [e.g., resins having alkylene terephthalate units (alkylene terephthalate resins: e.g., polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.), resins having alkylene naphthalate units (e.g., polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)].

[0152] Examples of fluororesins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, ethylene tetrafluoride / hexafluoropropylene copolymer, ethylene / tetrafluoroethylene copolymer, ethylene / chlorotrifluoroethylene copolymer, etc.

[0153] Examples of polyacetal resins include those composed only of oxymethylene units and those containing some oxyethylene units in part.

[0154] Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ethers.

[0155] Examples of polyarylate include amorphous polyarylate.

[0156] Examples of polyimide resins include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0157] Examples of cellulose acetate include cellulose diacetate, cellulose triacetate, and the like.

[0158] As the material of the container, plastics such as olefin resins, styrene resins, and polyester resins (that is, plastic containers) are preferable, ethylene resins, propylene resins, alkylene terephthalate resins, and polystyrene are more preferable, polypropylene, polyethylene terephthalate, and polystyrene are even more preferable, and polyethylene terephthalate is even more preferably used.

[0159] Note that the container may be a polymer blend of the container material with a polymer other than the above polymer. When the container material of the container for accommodating the ophthalmic composition of the present invention is a blend polymer with the above polymer, the mixing ratio of the above polymer and the polymer other than the above polymer is not particularly limited as long as the effects of the present invention are exhibited, but the total weight of the above polymer is preferably 30 w / w% or more, more preferably 50 w / w% or more, even more preferably 65 w / w% or more, and particularly preferably 80 w / w% or more with respect to the total amount of the entire constituent material.

[0160] The container may be such that at least a part of the surface in contact with the composition of the present invention is made of the above material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container itself is molded from the above material.

[0161] In addition, the parts constituting the container (the container body part, the parts including the extraction port of the container (nozzle, inner stopper), the suction tube, the cap, etc.) may be made of the above material, and all parts of the container may be made of the above material. In particular, from the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container body part is made of the above material, and it is more preferable that all of the container body part is made of the above material (a state where not a part of the layers constituting the container body is made of the above material).

[0162] Target disease (use) The target disease (use) of the composition of the present invention is not particularly limited as long as it is for ophthalmic use. For example, it is useful for alleviating, improving, suppressing, or treating allergic symptoms, eye itching, eye pain, eye inflammation, blepharitis, eye haziness, congestion, foreign body sensation (such as a feeling of something rolling around), corneal damage, corneal injury, epiphora (lacrimation), follicles of the palpebral conjunctiva, eye discharge (eye gunk), etc., and for enhancing, normalizing the corneal barrier function, and corneal protection.

[0163] Note that epiphora is a symptom that occurs when the tear drainage path from the lacrimal punctum to the lacrimal canaliculus, lacrimal sac, and nasolacrimal duct is blocked by eye discharge or the like, or when tears are excessively produced by irritation.

[0164] In this specification, "alleviation" includes alleviating symptoms and suppressing the progression of symptoms, and "improvement", "suppression", and "treatment" include alleviating symptoms, suppressing the progression of symptoms, healing or complete recovery.

[0165] In particular, the composition of the present invention is suitable for alleviating, improving, suppressing, or treating allergic symptoms (ocular allergic symptoms).

[0166] The allergens causing allergic symptoms are not particularly limited, and may be, for example, pollen (such as cedar pollen and cypress pollen), house dust (indoor dust), etc.

[0167] In another aspect, the composition of the present invention is suitable for alleviating, improving, suppressing, or treating symptoms such as eye itching, eye pain, eye inflammation, blepharitis, eye haziness, congestion, watering eyes, foreign body sensation, corneal damage, corneal injury, watering eyes (epiphora), follicles on the palpebral conjunctiva, eye gunk (eye mucus), etc. These symptoms may or may not be derived from allergic symptoms.

[0168] Method of use The method of using (usage mode) the composition of the present invention can be appropriately selected according to its properties, etc.

[0169] For example, when the composition of the present invention is a preparation applied to the eyes such as eye drops, eye washes, or eye ointments, its usage varies depending on the target symptoms. For example, it can be administered 1 time or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, or 6 times or more per day. Also, it can be administered 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less per day. Administration 4 times a day is particularly preferred.

[0170] When the composition of the present invention is eye drops, for example, 1 to 3 drops can be instilled per application, and it can also be 1 to 2 drops or 2 to 3 drops. Preferably, 1 to 2 drops can be instilled per application. It can also be 1 drop. Also, the volume of one drop for instillation is preferably 30 to 50 μL.

[0171] When the composition of the present invention is an eye wash, for example, 1 to 30 mL can be used for eye washing per application, preferably 1 to 20 mL, and more preferably 4 to 6 mL for eye washing per application.

[0172] When the composition of the present invention is an eye ointment, for example, 0.001 to 5 g can be applied to the eyes per application.

[0173] When the composition of the present invention is a contact lens wearing solution, when wearing or removing the contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops, per application, can be dropped onto one side and / or both sides of the contact lens and wetted, and then worn. Preferably, it is worn after wetting both sides of the contact lens.

[0174] [2. Suppression of precipitation and turbidity] The ophthalmic composition according to the present embodiment has the effect of suppressing precipitation (turbidity) (or improving or enhancing dissolution stability) in the ophthalmic composition.

[0175] Therefore, as one embodiment of the present invention, the following method is provided.

[0176] (A) One or more selected from the group consisting of epinastine and its salts, and (B) One or more selected from the group consisting of pranoprofen and its salts are included in the ophthalmic composition, and (C) A surfactant having an HLB value of 16.5 or less is contained. A method for suppressing precipitation (turbidity) in an ophthalmic composition (a method for improving or enhancing dissolution stability).

[0177] (A) One or more selected from the group consisting of epinastine and its salts, and (B) One or more selected from the group consisting of pranoprofen and its salts are included in the ophthalmic composition, and (C) A multi-chain type (or having a branched chain) surfactant is contained. A method for suppressing precipitation (turbidity) in an ophthalmic composition (a method for improving or enhancing dissolution stability).

[0178] Also, as one embodiment of the present invention, the following agent is provided.

[0179] (A) One or more selected from the group consisting of epinastine and its salts, and (B) One or more selected from the group consisting of pranoprofen and its salts are included in the ophthalmic composition. An agent for suppressing precipitation (turbidity) (or an agent for improving or enhancing dissolution stability), which contains (C) A surfactant having an HLB value of 16.5 or less.

[0180] (A) One or more selected from the group consisting of epinastine and its salts, and (B) One or more selected from the group consisting of pranoprofen and its salts, an agent for suppressing precipitation (cloudiness) in an ophthalmic composition (or an agent for improving or enhancing dissolution stability), which comprises (C) A multi-chain (or branched-chain) surfactant.

[0181] In addition, regarding the types and contents of components (A) to (C), the types and contents of other components, the pharmaceutical forms and uses of the ophthalmic composition, etc. in each of the above embodiments, they are as described in [1. Ophthalmic Composition].

Examples

[0182] The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples, and many modifications are possible by those with ordinary knowledge in the art within the technical idea of the present invention.

[0183] An aqueous ophthalmic composition (eye drop) having the composition shown in the following table was prepared, and precipitation was evaluated as follows.

[0184] 200 g (200 cm 3 ) of the prepared composition was filled into 10 mL glass screw bottles and stored at room temperature for 1 hour each, and then the presence and degree of precipitation (cloudiness) were visually confirmed.

[0185] Then, the degree of precipitation relative to Test Example 1 was evaluated according to the following criteria. ◎: Extremely clear 〇: No precipitation △: Equivalent to Test Example 1 in terms of the degree of precipitation ×: More precipitation than Test Example 1

[0186] The results are shown in the following table. In the aqueous ophthalmic composition in the following table, the unit of each component is (w / v%). Also, in the surfactant, the numerical value in parentheses is the HLB value.

[0187]

Table 1

[0188] As is clear from the results in the above table, unexpectedly, although precipitation does not occur when only epinastine hydrochloride or pranoprofen is included, it was found that precipitation occurs when epinastine hydrochloride and pranoprofen are combined (Test Examples 1 to 3).

[0189] And such precipitation could be efficiently suppressed by using a specific surfactant (Test Examples 4 to 9). With very common surfactants, not only was there no precipitation suppression effect, but rather the precipitation increased (Test Example 10), and such results were extremely unexpected.

[0190] Regarding the compositions in Test Examples 4 to 9 in which the precipitation suppression effect could be confirmed in this way, the properties and the like were further examined.

[0191] First, all of these compositions could be filled into eye drop containers (made of PET, diameter 6 mm) without any problems and had excellent fillability.

[0192] Also, when the compositions were dropped from the eye drop containers, the liquid breakage was good in all cases. Therefore, it was found that all of the obtained compositions were compositions in which dripping was less likely to occur.

[0193] Furthermore, the compositions were each dropped onto a colorless and transparent plastic film and the water was evaporated. When the state after evaporation was visually confirmed, in all cases, no white residue (whitening phenomenon or precipitation due to non-volatile components) occurred or hardly occurred. Thus, it was confirmed that all of the obtained compositions were compositions that could be efficiently formulated. Actually, when filling the above-mentioned eye drop containers, none of the compositions caused white residue on the production line (nozzles, etc.).

[0194] [Formulation Example] An ophthalmic composition was prepared according to the formulation described in the following table. In the following table, the unit of each component is (w / v%).

[0195]

Table 2

Industrial Applicability

[0196] In the present invention, an ophthalmic composition useful as an eye drop or the like can be provided.

Claims

【Claim 1】 The invention described in this specification.

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