Ophthalmic components

Abstract

To provide a novel ophthalmic composition. [Solution] The ophthalmic composition is composed of (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

Description

Technical Field

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

Background Art

[0002] Pranoprofen is known as an anti-inflammatory agent, and an eye drop containing pranoprofen as an active ingredient is also known (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a novel ophthalmic composition.

Means for Solving the Problems

[0005] As described above, pranoprofen is used in eye drops, but an eye drop combining such pranoprofen and other active ingredients is still under development.

[0006] On the other hand, in eye drops containing pranoprofen, there seem to be problems such as being prone to foaming, difficult for bubbles to disappear, and insufficient photo stability due to pranoprofen.

[0007] Under these circumstances, the inventors diligently conducted research to solve the above problems and found that a novel ophthalmic composition can be obtained by combining pranoprofen or a salt thereof with a specific active ingredient, and that such an ophthalmic composition can solve problems thought to originate from pranoprofen or a salt thereof, such as foaming (for example, it is possible to perform dissolution confirmation or foreign matter confirmation during manufacturing in a short time and to suppress variations in the amount of drops dispensed). Further research led to the completion of the present invention.

[0008] In other words, the present invention relates to the following inventions, etc. [1] (A) One or more selected from the group consisting of pranoprofen and its salts, (B) An ophthalmic composition containing one or more selected from the group consisting of epinastine and salts thereof. [2] (A) The composition according to [1], containing 0.005 to 0.5 w / v% of component (A). [3] (B) The composition according to [1] or [2], containing 0.005 to 0.5 w / v% of component (B). [4] The composition according to any one of [1] to [3], wherein the proportion of component (B) is 0.01 to 100 parts by mass per 1 part by mass of component (A). [5] A composition according to any one of [1] to [4], wherein the pH is 4 to 9. [6] A composition contained in a container, wherein at least a portion of the material of the part of the container that comes into contact with the composition is glass and / or plastic, as described in any one of [1] to [5]. [7] (A) The proportion of component is 0.01 to 0.15 w / v%, (B) The proportion of component is 0.01 to 0.15 w / v%, The proportion of component (B) is 0.2 to 5 parts by mass per 1 part by mass of component (A). The pH is 5-8. It is contained in a container, and at least a portion of the material of the part of the container that comes into contact with the composition is made of plastic. A composition according to any one of [1] to [6]. [8] A composition contained in a container, wherein at least a portion of the material of the part of the container that comes into contact with the composition is polyethylene terephthalate, according to any one of [1] to [7]. [9] A method for suppressing foaming in an ophthalmic composition by combining (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[10] A method for improving the defoaming rate in an ophthalmic composition by combining (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[11] A method for improving the photostability of an ophthalmic composition by combining (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[12] (A) A method for suppressing foaming, improving defoaming rate, and improving photostability in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, wherein (B) one or more selected from the group consisting of epinastine and salts thereof are included in the ophthalmic composition.

[13] The method according to any one of [9] to

[12] , wherein the ophthalmic composition is contained in a container, and at least a portion of the material of the part of the container that comes into contact with the composition is glass and / or plastic.

[14] The method according to any one of [9] to

[13] , wherein the ophthalmic composition is contained in a container, and at least a portion of the material of the part of the container that comes into contact with the composition is polyethylene terephthalate. [Effects of the Invention]

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

[0010] In another aspect of the present invention, an ophthalmic composition with less (or capable of suppressing) foaming can be provided. In a preparation containing pranoprofen and / or its salt (furthermore, a preparation containing epinastine and / or its salt), foaming may occur or the degree of foaming may be large. However, according to the study by the present inventor, by combining pranoprofen and / or its salt with epinastine and / or its salt, such foaming can be reduced (or foaming can be suppressed).

[0011] In another aspect of the present invention, an ophthalmic composition with a fast defoaming rate can be provided. As described above, in a preparation containing pranoprofen and / or its salt (furthermore, a preparation containing epinastine and / or its salt), foaming may occur, but such generated foam may not disappear easily and may remain for a long time. According to the study by the present inventor, by combining pranoprofen and / or its salt with epinastine and / or its salt, even if foaming occurs, it can disappear (defoam) in a relatively short time.

[0012] In another aspect of the present invention, an ophthalmic composition capable of suppressing a state with less (or no) foaming over a long period can be provided. As described above, by combining pranoprofen and / or its salt with epinastine and / or its salt, the foaming itself can be made less (or non-existent), and such a state with less (or no) foaming can be maintained over a long period.

[0013] In another aspect of the present invention, an ophthalmic composition excellent in light stability can be provided. In a preparation containing pranoprofen and / or its salt, it may be colored (yellowed) by light due to pranoprofen and / or its salt. According to the study by the present inventors, by combining pranoprofen and / or its salt with epinastine and / or its salt, an ophthalmic composition excellent in light stability (or with less coloring or yellowing) can be provided.

[0014] In another aspect of the present invention, even if it contains further other components (such as a pH adjuster, a buffer, etc.), the above-described effects can be effectively exhibited.

[0015] Thus, the composition of the present invention is extremely highly practical.

Mode for Carrying Out the Invention

[0016] In this specification, the unit of content "w / v%" is synonymous with "g / 100 mL". Also, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene and "POP" means polyoxypropylene.

[0017] 〔1. Ophthalmic Composition〕 The ophthalmic composition of the present invention contains at least (A) pranoprofen and / or its salt, and (B) epinastine and / or its salt.

[0018] (A) Pranoprofen and / or its salt (Component (A)) As salts of pranoprofen, any pharmaceutically or physiologically acceptable salt is acceptable, including salts with acids (e.g., salts with inorganic acids, salts with organic acids, etc., as exemplified in section (B) below), as well as salts with bases {e.g., salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.) and salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum, etc.]}, and examples include sulfates, lactates, hydrochlorides, chlorides, sodium salts, and potassium salts. Preferred pranoprofen and / or its salts are pranoprofen and its metal salts, with pranoprofen being particularly preferred.

[0019] Pranoprofen and / or its salts may be used alone or in combination of two or more types.

[0020] The content of component (A) in the composition is, for example, 0.0001 w / v% or more (e.g., 0.0003 to 5 w / v%), preferably 0.0005 w / v% or more (e.g., 0.001 to 1 w / v%), more preferably 0.003 w / v% or more (e.g., 0.005 to 0.5 w / v%), and even more preferably 0.005 w / v% or more (e.g., 0.007 w / v%), relative to the total amount of the composition. The w / v% may be approximately ~0.2 w / v%, more preferably 0.008 w / v% or more (e.g., 0.01~0.15 w / v%, 0.01~0.1 w / v%, etc.), particularly preferably 0.02 w / v% or more (e.g., 0.03~0.1 w / v%), and most preferably 0.03 w / v% or more (e.g., 0.04~0.08 w / v%, 0.045~0.06 w / v%). Among these, 0.05 w / v%, 0.1 w / v%, etc. are preferred, and 0.05 w / v% is particularly preferred.

[0021] (B) Epinastine and / or its salt (Component (B)) The composition of the present invention contains pranoprofen and / or a salt thereof, in addition to epinastine and / or a salt thereof. According to the composition of the present invention, even with the presence of multiple active ingredients, each of the functions (pharmacological effects) can be efficiently exerted.

[0022] The salts of epinastine are not particularly limited as long as they are pharmaceutically or physiologically acceptable, and examples include organic salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), etc.

[0023] Preferred epinastine and / or its salts include epinastine hydrochloride (monohydrochloride).

[0024] Epinastine and / or its salts may be used alone or in combination of two or more types.

[0025] The content of component (B) in the composition is, for example, 0.0001 w / v% or more (e.g., 0.0003 to 5 w / v%), preferably 0.0005 w / v% or more (e.g., 0.001 to 1 w / v%), more preferably 0.003 w / v% or more (e.g., 0.005 to 0.5 w / v%), and even more preferably 0.005 w / v% or more (e.g., 0.007 w / v%), relative to the total amount of the composition. The w / v% may be approximately ~0.2 w / v%, more preferably 0.008 w / v% or more (e.g., 0.01~0.15 w / v%, 0.01~0.1 w / v%, etc.), particularly preferably 0.02 w / v% or more (e.g., 0.03~0.1 w / v%), and most preferably 0.03 w / v% or more (e.g., 0.04~0.08 w / v%, 0.045~0.06 w / v%). Among these, 0.05 w / v%, 0.1 w / v%, etc. are preferred, and 0.05 w / v% is particularly preferred.

[0026] The proportion of component (B) may be, 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, and 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.) per 1 part by mass of component (A).

[0027] In particular, the proportions of component (B) and component (A) may be relatively close, for example, the proportion of component (B) may be 0.2 to 5 parts by mass (for example, 0.3 to 3 parts by mass, 0.4 to 2.5 parts by mass, 0.5 to 2 parts by mass, 0.6 to 1.7 parts by mass, 0.7 to 1.4 parts by mass, 0.8 to 1.2 parts by mass, 0.9 to 1.1 parts by mass, or approximately 1 part by mass) per 1 part by mass of component (A).

[0028] [Other ingredients] The composition of the present invention may or may not contain other components. In many cases, the effects of the present invention can be guaranteed even if other components are included. Furthermore, in some cases, the effects of the present invention can be more effectively realized by including other components.

[0029] 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, as well as compounds or derivatives thereof that have an amino group and a carboxyl group or a sulfone group in their molecule.

[0030] Specifically, examples include amino acids or their salts, and mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid (epsilonaminocaproic acid, etc.); monoaminodicarboxylic acids such as aspartic acid and glutamic acid or their salts; diaminomonocarboxylic acids such as arginine and lysine or their salts; and derivatives such as aminoethylsulfonic acid (taurine) or their salts.

[0031] Furthermore, among amino acids, examples of mucopolysaccharides or their derivatives or salts include acidic mucopolysaccharides such as chondroitin sulfate, hyaluronic acid, alginic acid, and their derivatives or salts.

[0032] Specific examples of amino acids and mucopolysaccharides include, preferably, glycine, alanine, gamma-aminobutyric acid, gamma-aminovaleric acid, epsilon-aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, or salts thereof.

[0033] Chondroitin sulfate is formed by esterifying sulfuric acid to all or part of the hydroxyl groups of the repeating sugar chains of D-glucuronic acid and N-acetylglucosamine. The position and number of sulfuric acid bonds vary, and derivatives of chondroitin sulfate also exist (for example, in which all or part of N-acetylglucosamine is replaced with iduronic acid). Such chondroitin sulfates may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E, in which the 4th and 6th positions of N-acetylglucosamine are sulfated. Furthermore, chondroitin sulfates may be extracted from animals.

[0034] The salts of amino acids or mucopolysaccharides include salts that are pharmaceutically, pharmacologically, or physiologically acceptable. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acids (fumarate, maleate, etc.), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, 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.), and salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum, etc.], etc.], and are appropriately selected depending on the compound.

[0035] Specific examples of 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, and sodium hyaluronate.

[0036] The amino acids may be in D, L, or DL ​​form.

[0037] Preferred amino acids include aminoethylsulfonic acid (taurine) or its salts, chondroitin sulfate sodium, aspartates (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilonaminocaproic acid or its salts, hyaluronic acid or its salts (such as sodium hyaluronate), and among these, hyaluronic acid or its salts (such as sodium hyaluronate), aminoethylsulfonic acid (taurine) and / or its salts and chondroitin sulfate sodium are preferred.

[0038] Amino acids may be used individually or in combination of two or more types.

[0039] If the composition contains amino acids, the amount of 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%, even more preferably 0.05 to 5 w / v%, even more preferably 0.1 to 3 w / v%, and particularly preferably around 0.15 to 2 w / v%, relative to the total amount of the composition, and may usually be 0.001 to 10 w / v% [for example, 0.005 to 10 w / v%, preferably 0.01 to 5 w / v%, and even more preferably 0.05 to 3 w / v% (for example, 0.1 to 1 w / v%)].

[0040] Cooling agent The composition of the present invention may contain a cooling agent. Combining components (A) and (B) (and other components) may reduce or impair the user experience, but cooling agents can improve or enhance this user experience. For example, while increasing the pH of a composition may be advantageous in terms of solubility, a higher pH can lead to increased discomfort and impair the user experience. However, the use of cooling agents can alleviate this discomfort and efficiently improve the user experience.

[0041] The cooling agent is not particularly limited, but examples include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and bonito flakes. These may be in d, l, or dl form. Essential oils such as peppermint oil, cool mint oil, spearmint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil can also be used.

[0042] Among these, terpenoids are preferred, and among these, menthol, camphor, geraniol, cineole, borneol, and liquor are preferred, menthol, camphor, and borneol are more preferred, menthol and borneol are even more preferred, and menthol is the most preferred.

[0043] Cooling agents may be used alone or in combination of two or more. In particular, it is preferable that the cooling agent contains one or more selected from the group consisting of menthol, borneol, and camphor, and when two or more are used in combination, it is preferable to use at least these (for example, a combination of menthol, borneol, and camphor).

[0044] If 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, or 0.001 w / v% or more, relative to the total amount of the composition.

[0045] Furthermore, 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, or 0.6 w / v% or less, relative to the total amount of the composition.

[0046] In particular, if the composition of the present invention contains menthol, the proportion of menthol may be, for example, 0.00001 w / v% or more (e.g., 0.00005 to 2 w / v%), preferably 0.0001 to 0.2 w / v% (e.g., 0.0003 to 0.1 w / v%), and more preferably about 0.0005 to 0.05 w / v% (e.g., 0.001 to 0.02 w / v%) relative to the total amount of the composition.

[0047] 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 (e.g., 0.00005 to 3 w / v%), preferably 0.0001 to 2 w / v% (e.g., 0.0003 to 1 w / v%), and more preferably about 0.0005 to 0.8 w / v% (e.g., 0.001 to 0.5 w / v%) relative to the total amount of the composition.

[0048] In particular, if the composition of the present invention contains camphor, the proportion of camphor may be, for example, 0.00001 w / v% or more (e.g., 0.00005 to 1 w / v%), preferably 0.0001 to 0.1 w / v% (e.g., 0.0003 to 0.05 w / v%), and more preferably about 0.0005 to 0.02 w / v% (e.g., 0.001 to 0.01 w / v%) relative to the total amount of the composition.

[0049] Lipid-soluble antioxidants The composition of the present invention may contain a lipid-soluble antioxidant.

[0050] Examples of lipid-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbic acid palmitate, ascorbic acid stearate, aminopropyl ascorbic acid phosphate, tocopherol ascorbic acid phosphate, ascorbic acid triphosphate, and ascorbic acid phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinoline-2one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; and CoQ10.

[0051] Of these, dibutylhydroxytoluene is preferred.

[0052] Lipid-soluble antioxidants may be used alone or in combination of two or more types.

[0053] If the composition contains a lipid-soluble antioxidant, the amount of the lipid-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%, even 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%, relative to the total amount of the composition.

[0054] Antihistamines The composition of the present invention may contain an anti-allergic agent.

[0055] Examples of antiallergic agents include tranilast, cromoglycic acid, ibudilast, acitazanollast, tazanollast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, anlexanox, oxatomide, and their salts.

[0056] Examples of salts include the salts exemplified above, such as alkali metal or alkaline earth metal salts (e.g., sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate), inorganic salts (e.g., hydrochloride salts, sulfate salts), and organic salts (e.g., tosylate salts, fumarate salts).

[0057] Of these, tranilast, cromoglycic acid, and their salts are preferred, and tranilast and sodium cromoglycate are more preferred.

[0058] Antiallergic agents may be used alone or in combination of two or more types.

[0059] If the composition contains an anti-allergic agent, the amount 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 more preferably 0.8 to 1.5 w / v%, and most preferably 0.9 to 1.2 w / v%, relative to the total amount of the composition.

[0060] Antihistamines The composition of the present invention may contain an antihistamine. Antihistamines (antihistamines other than epinastine and its salts) are not particularly limited as long as they have antihistamine activity, and examples include chlorpheniramine, diphenhydramine, ketotifen, olopatadine, levocabastine, iproheptine and their salts.

[0061] The salt can be any pharmaceutically or physiologically acceptable salt, such as organic salts [e.g., maleates, fumarates (e.g., ketotifen fumarate)], inorganic salts (e.g., olopatadine hydrochloride), metal salts, and other examples of salts mentioned above.

[0062] Specific examples of salts include diphenhydramine hydrochloride, iproheptine hydrochloride, and chlorpheniramine maleate.

[0063] Antihistamines may be used alone or in combination of two or more types.

[0064] If the composition contains an antihistamine, the amount of the antihistamine in the composition may be, for example, 0.0001 w / v% or more, preferably 0.001 to 10 w / v%, more preferably 0.003 to 5 w / v%, even 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% (e.g., 0.02 to 0.1 w / v%), most preferably 0.025 to 0.05 w / v% (e.g., 0.03 w / v%), and usually around 0.01 to 0.05 w / v%.

[0065] Anti-inflammatory drugs The composition of the present invention may contain anti-inflammatory agents other than pranoprofen and its salts. Anti-inflammatory agents (hereinafter, referring to anti-inflammatory agents other than pranoprofen and its salts) are not particularly limited as long as they have anti-inflammatory effects, and examples include indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme and their salts.

[0066] Examples of salts include those exemplified above, such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Examples include sulfates, lactates, hydrochlorides, chlorides, sodium salts, and potassium salts.

[0067] Specific examples of salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

[0068] Anti-inflammatory agents may be used alone or in combination of two or more.

[0069] If the composition contains an anti-inflammatory agent, the amount of the anti-inflammatory agent in the composition may be, for example, 0.001 w / v% or more, preferably 0.005 to 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%) relative to the total amount of the composition.

[0070] The composition of the present invention may contain various components (for example, components not belonging to the category of the above components). Examples of such components (additives) include surfactants, preservatives, buffering agents, pH adjusters, isotonic agents, thickeners or viscosity modifiers, stabilizers, oils, sugars, polymer compounds, polyhydric alcohols, inorganic salts, non-lipid soluble antioxidants (or water-soluble antioxidants).

[0071] Additives can be used individually or in combination of two or more. Furthermore, each additive can be used individually or in combination of two or more.

[0072] Specific examples of additives are given below.

[0073] surfactants The composition of the present invention may contain a surfactant. Examples of surfactants include nonionic surfactants.

[0074] Nonionic surfactants include polysorbates (POE sorbitan fatty acid esters) such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer POE·POP glycols such as -403, poloxamer 237, poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80; POE castor oils such as 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; polymonostearate Ethylene glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., polyoxyl 40 stearate), poly Examples include polyethylene glycol monostearate such as ethylene glycol (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; and POE alkylphenyl ethers such as POE(10) nonylphenyl ether.In the compounds exemplified above, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

[0075] Among these, POE sorbitan fatty acid esters; POE-POP glycols; POE hydrogenated castor oil; POE castor oil; and polyethylene glycol monostearate are preferred, with polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl stearate 40 being more preferred, polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

[0076] Surfactants may be used alone or in combination of two or more types.

[0077] When the composition of the present invention contains a surfactant (particularly a nonionic surfactant), the proportion of the surfactant may be, for example, 0.001 w / v% or more, preferably 0.005 w / v% or more, more preferably 0.01 w / v% or more, and most preferably 0.05 w / v% or more, relative to the total amount of the composition.

[0078] Furthermore, the proportion of surfactant may be, for example, 5 w / v% or less, preferably 1 w / v% or less, relative to the total amount of the composition.

[0079] Preservatives The composition of the present invention may contain a preservative. Examples of preservatives include polydronium chloride, alkyl polyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride), chlorhexidine gluconate, alexidine, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, parahydroxybenzoic acid esters (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride), and Glokill (manufactured by Rhodia).

[0080] Among these, alkyl polyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, parahydroxybenzoic acid esters, and biguanide compounds are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are even more preferred.

[0081] If the composition contains a preservative, the proportion of the preservative in the composition may be, for example, 0.000001 w / v% or more, more specifically 0.00001 w / v% or more, more specifically 0.00005 w / v% or more, more specifically 0.001 w / v% or more, or more specifically 0.005 w / v% or more, relative to the total amount of the composition. Furthermore, the total amount of preservative relative to the total amount of the composition may be 1 w / v% or less, more specifically 0.1 w / v% or less, more specifically 0.05 w / v% or less, more specifically 0.03 w / v% or less, or more specifically 0.025 w / v% or less.

[0082] cushioning agent The composition of the present invention may contain a buffering agent. Examples of buffering agents include boric acid buffers, phosphate buffers, carbonate buffers, citrate buffers, and acetate buffers.

[0083] The components of boric acid buffers include boric acid and borates (such as sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax). The borates may also be in hydrate form.

[0084] Components of phosphate buffers include phosphoric acid and phosphates (such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, and calcium dihydrogen phosphate). The phosphates may also be in hydrate form.

[0085] The components of a carbonate buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.). The carbonate may also be in hydrate form.

[0086] The components of citrate buffers include citric acid and citrate salts (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate). The citrate salts may also be in hydrate form.

[0087] Components of acetic acid buffers include acetic acid and acetates (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). The acetates may also be in hydrate form.

[0088] Among these, borate buffers are preferred from the viewpoint of preservative efficacy, phosphate buffers are preferred from the viewpoint of low cytotoxicity, and borate buffers are more preferred. As for borate buffers, a combination of boric acid and its salts is preferred, a combination of boric acid and an alkali metal salt and / or alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is even more preferred, and a combination of boric acid and borax is even more preferred.

[0089] Furthermore, when the buffering agent is composed of multiple components, their proportions may be appropriately selected depending on the range in which the buffering function can be exerted. For example, when combining boric acid and borate (such as borax), the proportions may be approximately 0.1 to 100 parts by mass of borate, preferably 0.5 to 80 parts by mass, more preferably 1 to 50 parts by mass, and especially 2 to 40 parts by mass (for example, 3 to 30 parts by mass, 5 to 25 parts by mass, 7 to 22 parts by mass, or 10 to 20 parts by mass) per 100 parts by mass of boric acid.

[0090] The composition of the present invention can efficiently exhibit functions such as foam suppression and excellent photostability, even when containing such a buffer (boric acid buffer).

[0091] When a buffering agent is incorporated into the composition of the present invention, the amount of buffering agent to be incorporated will vary depending on the type of buffering agent, the type and amount of other components, etc., and cannot be uniformly specified. However, for example, the total amount of buffering agent relative to the total amount of the composition may be 0.001 w / v% or more, more specifically 0.01 w / v% or more, more specifically 0.05 w / v% or more, or more specifically 0.1 w / v% or more. Alternatively, the total amount of buffering agent relative to the total amount of the composition may be 10 w / v% or less, more specifically 5 w / v% or less, more specifically 3 w / v% or less, more specifically 2.5 w / v% or less, or more specifically 2 w / v% or less.

[0092] In particular, when using a boric acid buffer (total amount of boric acid and borate), the proportion of the buffer in the composition may be approximately 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 4 w / v%, and even more preferably 0.2 to 3 w / v% (for example, 0.2 to 2.5 w / v%, 0.3 to 2 w / v%, 0.3 to 1.5 w / v%, 0.4 to 1 w / v%, etc.) relative to the entire composition.

[0093] pH adjuster Examples of pH adjusting agents include hydrochloric acid, sulfuric acid, polyphosphate, organic acids (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, and diisopropanolamine. pH adjusters may be used alone or in combination of two or more types.

[0094] Isotonic agent Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol. Isotonic agents may be used alone or in combination of two or more types.

[0095] Thickening agent or viscosity-enhancing agent The ophthalmic composition of the present invention may contain a thickening agent or a viscosity-enhancing agent.

[0096] Examples of thickeners or viscosity-enhancing agents include guar gum, hydroxypropyl guar gum, cellulosic polymers (e.g., methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), acacia gum, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, hyaluronic acid salts (sodium salts, etc.), etc.), starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbitan Examples include tol, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt and 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 esters (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine. Thickening agents or viscosity-reducing agents may be used alone or in combination of two or more types.

[0097] Stabilizer Examples of stabilizers include hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), sodium formaldehyde sulfoxylate (longalit), aluminum monostearate, and glyceryl monostearate. Stabilizers may be used alone or in combination of two or more types.

[0098] oil Examples of oils include animal oils such as squalane and refined lanolin, mineral oils such as liquid paraffin and white petrolatum, and vegetable oils such as castor oil and sesame oil.

[0099] Sugars Examples of sugars include monosaccharides and oligosaccharides (such as disaccharides), specifically including glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol.

[0100] polyhydric alcohols Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

[0101] Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including anhydrous sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium bisulfite, sodium sulfite, potassium acetate, sodium acetate, and sodium thiosulfate. Among these, potassium chloride, sodium chloride, calcium chloride, sodium bicarbonate, 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.

[0102] Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid-2-sulfate, sodium ascorbate, magnesium ascorbic acid-2-phosphate, and sodium ascorbic acid-2-phosphate), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, EDTA or its salts (such as disodium EDTA and tetrasodium EDTA).

[0103] The composition of the present invention may further contain components having pharmacological or physiological activity.

[0104] Pharmacologically active ingredients or physiologically active ingredients can be used alone or in combination of two or more.

[0105] Examples of such pharmacologically and physiologically active ingredients include the active ingredients in various pharmaceuticals listed in the "Guidelines for Manufacturing and Marketing Approval Standards and Application Practices for Prescription-Only and Over-the-Counter Drugs 2017 Edition" (supervised by the Regulatory Science Society). For example, these include decongestants, ocular muscle regulators, astringents, vitamins, amino acids, antibacterial or antiseptic agents, local anesthetic components, analgesics, and sulfonamides. Specific examples of these drugs are given below.

[0106] Decongestive agents (vasoconstrictors) Examples of decongestants include α-adrenergic agonists, specifically imidazoline-based decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or their hydrochloride salts, nitrates, etc., as well as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methyl ephedrine hydrochloride, and epinephrine bitartrate. These may be in d-isomer, l-isomer, or dl-isomer.

[0107] Regarding imidazoline vasoconstrictors, the salts of imidazoline vasoconstrictors can be any pharmaceutically or physiologically acceptable salts, such as organic salts like maleates and fumarates; inorganic salts like hydrochlorides and sulfates; and metal salts. Among the salts, inorganic salts are preferred, hydrochlorides or nitrates are more preferred, and hydrochlorides (such as tetrahydrozoline hydrochloride) are particularly preferred.

[0108] Among decongestants (vasoconstrictors), imidazoline-based vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or their salts are more preferred, and tetrahydrozoline or its salts are even more preferred.

[0109] Eye muscle regulator Examples of ocular muscle modulators include cholinesterase inhibitors that have an active site similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

[0110] Vitamins Examples of vitamins include flavin adenine dinucleotide or its salts (e.g., flavin adenine dinucleotide sodium), cobalamin or its salts (e.g., cyanocobalamin, methylcobalamin), retinol, its salts or derivatives (e.g., retinol acetate, retinyl palmitate), pyridoxine or its salts (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, its salts or derivatives (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or its salts (e.g., pyridoxal phosphate), ascorbic acid or its salts (e.g., sodium ascorbate, calcium ascorbate), and others.

[0111] Among these, flavin adenine dinucleotide or its salts (especially flavin adenine dinucleotide sodium), cobalamin or its salts (especially cyanocobalamin), retinol, its salts or derivatives (especially retinol acetate, retinyl palmitate), pyridoxine or its salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (especially sodium pantothenate, calcium pantothenate), tocopherol, its salts or derivatives (especially tocopherol acetate) are preferred, with pyridoxine hydrochloride and tocopherol acetate being more preferred. The composition of the present invention may not contain pyridoxine or its salts.

[0112] Antibacterial agent or disinfectant Examples of antibacterial or disinfectant agents include sulfonamides such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, as well as alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

[0113] Local anesthetic components Examples of local anesthetic components include procaine hydrochloride and lidocaine hydrochloride.

[0114] Base or carrier The composition of the present invention may contain a base or a carrier. Compositions containing such bases or carriers can be prepared, for example, by mixing each of the above components with a pharmaceutically acceptable base or carrier, using the conventional methods described in the 17th edition of the Japanese Pharmacopoeia Commentary. The composition may be heated as appropriate during preparation.

[0115] Examples of bases or carriers include water, polar solvents such as ethanol (especially water-soluble solvents), and oily bases. The base or carrier can be used individually or in combination of two or more.

[0116] 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). In such compositions (especially aqueous compositions), each component may normally be dissolved.

[0117] Properties The properties of the composition of the present invention are not particularly limited and may be any of the following: liquid, fluid, gel, or semi-solid. It may also be a liquid, fluid, gel, or semi-solid when prepared at the time of use. A semi-solid state refers to a state that has plasticity and can be deformed by applying force, such as an ointment. The preferred state of the composition is liquid (liquid).

[0118] Furthermore, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), an oily composition (mainly containing an oily or hydrophobic base or carrier), or in particular an aqueous composition.

[0119] 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. Furthermore, the base or carrier may consist only of water.

[0120] 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).

[0121] pH The pH of the composition of the present invention is preferably 3 or higher (for example, 4 or higher), more preferably 5 or higher (for example, 5.5 or higher), and even more preferably 6 or higher. It is also preferably 10 or lower, more preferably 9 or lower, and even more preferably 8.5 or lower.

[0122] 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 this invention, foam suppression and other effects can be efficiently achieved even at the pH levels described above.

[0123] Osmotic pressure The osmotic pressure ratio of the composition of the present invention is preferably 0.4 or higher, more preferably 0.5 or higher, and even more preferably 0.6 or higher. It is also preferably 5 or lower, more preferably 3 or lower, and even more preferably 2 or lower.

[0124] 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 edition of the Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th edition of the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0125] Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited and includes, for example, eye drops (also called eye solutions or eye drops; eye drops include eye drops that can be instilled while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens insertion solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multi-purpose solutions, packaged solutions), preservatives for excised eye tissue such as corneas for transplantation, and surgical irrigation solutions. Eye drops, eye washes, and eye ointments also include those used while wearing contact lenses.

[0126] Furthermore, "contact lenses" include hard contact lenses and soft contact lenses (which encompass both ionic and nonionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0127] Preferably, the composition of the present invention can be in the form of eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens insertion solution, contact lens solution (cleaning solution, storage solution, disinfecting solution, multi-purpose solution, packaging solution), more preferably eye drops, eye wash, contact lens insertion solution, contact lens solution (cleaning solution, storage solution, disinfecting solution, multi-purpose solution), even more preferably eye drops and eye wash, and particularly preferably eye drops.

[0128] The composition of the present invention may be in single-use unit doses or reusable multi-dose forms, and may be contained and used in multi-dose form.

[0129] container The composition of the present invention may be contained in a container (filled, injected, sealed). The container can be any packaging body having a portion (surface) that comes into contact with the composition (formulation), and may consist of, for example, a container body portion that contains the composition (e.g., a liquid composition), a portion of the container including an outlet (nozzle, inner stopper), a suction tube, a cap, etc.

[0130] The materials that make up the container can be selected from a wide range, for example, at least part or all of the part that comes into contact with the composition may be plastic (e.g., olefin resins, styrene resins, acrylic resins, polyester resins, polycarbonate resins, fluororesins, chlorine resins (such as polyvinyl chloride), polyamide resins, polyacetal resins, polyphenylene ether resins (such as modified polyphenylene ether), polyarylate, polysulfone, polyimide resins, cellulose resins (such as cellulose acetate), hydrocarbon resins which may be substituted with halogen atoms, etc.), glass, metal (such as aluminum), etc.

[0131] The container may be made of a single material or two or more materials.

[0132] Examples of olefin resins include ethylene resins [for example, 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 [for example, polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], and methylpentene resins (for example, polymethylpentene, etc.).

[0133] Examples of styrene-based resins include polystyrene and acrylonitrile-containing styrene-based resins (e.g., acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

[0134] Examples of acrylic resins include resins that use acrylic acid esters such as methyl acrylate, methacrylate esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate as polymerization components.

[0135] Examples of polyester resins include aromatic polyester resins [for example, resins having alkylene terephthalate units (alkylene terephthalate resins: for example, polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.), and resins having alkylene naphthalate units (for example, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)].

[0136] Examples of fluororesins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesins, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-chlorotrifluoroethylene copolymer.

[0137] Polyacetal resins include those consisting solely of oxymethylene units, as well as those containing some oxyethylene units.

[0138] Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ether.

[0139] Examples of polyarylates include amorphous polyarylates.

[0140] Examples of polyimide resins include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0141] Examples of cellulose acetates include cellulose diacetate and cellulose triacetate.

[0142] Glass, plastic, and the like are preferred materials for the container. Therefore, at least a part of the container (or the material of the container) may be made of glass, plastic, or the like.

[0143] In particular, plastics such as olefin resins, styrene resins, and polyester resins (i.e., plastic containers) are preferred, ethylene resins, propylene resins, alkylene terephthalate resins, and polystyrene are more preferred, polypropylene, polyethylene terephthalate, and polystyrene are even more preferred, and polyethylene terephthalate is even more preferred.

[0144] While compositions containing components (A) and (B) may exhibit different foaming tendencies depending on the container (or its material), the compositions of the present invention, which combine these components, can exhibit foaming suppression effects in a relatively wide variety of containers (or their materials, such as glass, plastic, and especially plastics such as PET). In particular, the compositions of the present invention can exhibit foaming suppression effects more efficiently in containers made of plastics such as PET.

[0145] The container material may also be a polymer blend with polymers other than the aforementioned polymer. When the container material of the container for containing the ophthalmic composition of the present invention is a polymer blend with the aforementioned polymer, the mixing ratio of the aforementioned polymer to polymers other than the aforementioned polymer is not particularly limited as long as the effects of the present invention are achieved. However, it is preferable that the total weight of the aforementioned polymer is 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, relative to the total amount of the constituent material.

[0146] The container may have at least a portion of the part (contacting surface) that comes into contact with the composition of the present invention 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.

[0147] Furthermore, the parts constituting the container (the container body, the part including the dispenser opening (nozzle, inner stopper), the suction tube, the cap, etc.) may be made of the above material, and the entire 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 is made of the above material, and it is more preferable that the entire container body is made of the above material (where only a part of the layers constituting the container body is made of the above material).

[0148] Target diseases (uses) The target diseases (uses) of the composition of the present invention are not particularly limited as long as they are for ophthalmic use, but are useful for alleviating, improving, suppressing, or treating allergic symptoms, itchy eyes, painful eyes, inflammation of the eyes, blepharitis, blurred vision, redness, foreign body sensation (gritty feeling, etc.), corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, eye discharge, etc., as well as for enhancing, normalizing, and protecting the corneal barrier function.

[0149] Watery eyes are a symptom that occurs when the tear drainage pathway, from the puncta to the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct, becomes blocked by eye discharge or other substances, or when excessive tears are produced due to irritation.

[0150] In this specification, "alleviation" encompasses the reduction of symptoms and the suppression of symptom progression, while "improvement," "suppression," and "treatment" encompass the reduction of symptoms, the suppression of symptom progression, and cure or complete recovery.

[0151] In particular, the compositions of the present invention are suitable for alleviating, improving, suppressing, or treating allergic symptoms (allergic symptoms of the eyes).

[0152] The allergens causing allergic symptoms are not limited to any one other, but may include pollen (such as cedar pollen and cypress pollen) and house dust (indoor dust).

[0153] In another embodiment, the compositions of the present invention are suitable for alleviating, improving, suppressing, or treating symptoms such as itchy eyes, eye pain, eye inflammation, blepharitis, blurred vision, redness, watery eyes, foreign body sensation, corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, and eye discharge. These symptoms may or may not be caused by allergies.

[0154] How to use The method (mode of use) of the composition of the present invention can be appropriately selected according to its properties and other factors.

[0155] For example, if the composition of the present invention is a formulation applied to the eye, such as eye drops, eye wash, or eye ointment, the method of use will vary depending on the target symptoms, but for example, it may be administered once or more, twice or more, three or more, four or more, five or more, or six or more times a day. It may also be administered nine or fewer times a day, eight or fewer times a day, seven or fewer times a day, six or fewer times a day, five or fewer times a day, or four or fewer times a day. Administering it four times a day is particularly preferable.

[0156] When the composition of the present invention is an eye drop, for example, it is sufficient to instill 1 to 3 drops per dose, or 1 to 2 drops, or 2 to 3 drops. Preferably, 1 to 2 drops are sufficient. It can also be 1 drop. Furthermore, the amount of one drop may preferably be 30 to 50 μL.

[0157] If the composition of the present invention is an eye wash, for example, 1 to 30 mL should be used per wash, preferably 1 to 20 mL, and more preferably 4 to 6 mL.

[0158] If the composition of the present invention is an eye ointment, for example, 0.001 to 5 g should be applied to the eye at one time.

[0159] When the composition of the present invention is a contact lens insertion solution, when inserting or removing contact lenses, for example, 1 to 3 drops, preferably 1 to 2 drops, are dropped onto one and / or both sides of the contact lens to wet it before insertion, and it is preferable to wet both sides of the contact lens before insertion.

[0160] [2. Suppression of foaming] The ophthalmic composition according to this embodiment can suppress (or prevent) foaming (or improve or enhance antifoaming properties) in the ophthalmic composition.

[0161] Accordingly, the following method is provided as an embodiment of the present invention.

[0162] A method for suppressing (or preventing) foaming (foaming) in an ophthalmic composition (a method for improving or enhancing antifoaming properties) by combining (or including in combination) (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[0163] (A) A method for suppressing (or preventing) foaming (foaming) in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof (a method for improving or enhancing antifoaming properties), wherein (B) a method for incorporating one or more selected from the group consisting of epinastine and salts thereof into the ophthalmic composition.

[0164] (B) A method for suppressing (or preventing) foaming (foaming) in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof (a method for improving or enhancing antifoaming properties), wherein the ophthalmic composition contains one or more selected from the group consisting of pranoprofen and salts thereof.

[0165] Furthermore, the following agent is provided as an embodiment of the present invention.

[0166] (A) An agent for suppressing (or preventing) foaming (improving or enhancing antifoaming properties) in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) an agent comprising one or more selected from the group consisting of epinastine and salts thereof.

[0167] (B) An agent for suppressing (or preventing) foaming (improving or enhancing antifoaming properties) in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising one or more selected from the group consisting of (A) pranoprofen and salts thereof.

[0168] [3. Improvement of defoaming speed] The ophthalmic composition according to this embodiment can improve (or enhance) the defoaming rate in the ophthalmic composition.

[0169] Accordingly, the following method is provided as an embodiment of the present invention.

[0170] A method for improving (or enhancing) the defoaming rate in an ophthalmic composition by combining (or including in combination) (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[0171] (A) A method for improving (or enhancing) the defoaming rate of an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, wherein (B) the ophthalmic composition contains one or more selected from the group consisting of epinastine and salts thereof.

[0172] (B) A method for improving (or enhancing) the defoaming rate in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising (A) one or more selected from the group consisting of pranoprofen and salts thereof, wherein the ophthalmic composition contains one or more.

[0173] Furthermore, the following agent is provided as an embodiment of the present invention.

[0174] (A) An agent for improving (or enhancing) the defoaming rate in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) an agent comprising one or more selected from the group consisting of epinastine and salts thereof.

[0175] (B) An agent for improving (or enhancing) the defoaming rate in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising one or more selected from the group consisting of (A) pranoprofen and salts thereof.

[0176] [4. Maintaining minimal foaming] The ophthalmic composition according to this embodiment can maintain a defoamed state (or reduced foaming) in the ophthalmic composition.

[0177] Accordingly, the following method is provided as an embodiment of the present invention.

[0178] A method for maintaining the antifoaming state in an ophthalmic composition by combining (or including in combination) (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[0179] (A) A method for maintaining the antifoaming state of an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) a method for incorporating one or more selected from the group consisting of epinastine and salts thereof into the ophthalmic composition.

[0180] (B) A method for maintaining the antifoaming state of an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising (A) one or more selected from the group consisting of pranoprofen and salts thereof in the ophthalmic composition.

[0181] Furthermore, the following agent is provided as an embodiment of the present invention.

[0182] (A) an agent for maintaining the antifoaming state in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) an agent comprising one or more selected from the group consisting of epinastine and salts thereof.

[0183] (B) An agent for maintaining the antifoaming state in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising one or more selected from the group consisting of pranoprofen and salts thereof.

[0184] [5. Improved photostability] The ophthalmic composition according to this embodiment can improve (or enhance) the photostability of the ophthalmic composition.

[0185] Accordingly, the following method is provided as an embodiment of the present invention.

[0186] A method for improving (or enhancing) the photostability of an ophthalmic composition by combining (or including in combination) (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[0187] (A) A method for improving (or enhancing) the photostability of an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) a method for incorporating one or more selected from the group consisting of epinastine and salts thereof into the ophthalmic composition.

[0188] (B) A method for improving (or enhancing) the photostability of an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising (A) one or more selected from the group consisting of pranoprofen and salts thereof, wherein the ophthalmic composition contains one or more.

[0189] Furthermore, the following agent is provided as an embodiment of the present invention.

[0190] (A) An agent for improving (or enhancing) the photostability of an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) an agent comprising one or more selected from the group consisting of epinastine and salts thereof.

[0191] (B) An agent for improving (or enhancing) the photostability of an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising one or more selected from the group consisting of (A) pranoprofen and salts thereof.

[0192] [6. Suppression of discoloration] The ophthalmic composition according to this embodiment can suppress (or prevent) discoloration (such as yellowing) in the ophthalmic composition. Note that the discoloration may be caused by (or associated with) light (light exposure).

[0193] Accordingly, the following method is provided as an embodiment of the present invention.

[0194] A method for suppressing (or preventing) discoloration in an ophthalmic composition by combining (or including in combination) (A) one or more selected from the group consisting of pranoprofen and its salts, and (B) one or more selected from the group consisting of epinastine and its salts.

[0195] (A) A method for suppressing (or preventing) discoloration in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) a method for incorporating one or more selected from the group consisting of epinastine and salts thereof into the ophthalmic composition.

[0196] (B) A method for suppressing (or preventing) discoloration in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising (A) one or more selected from the group consisting of pranoprofen and salts thereof in the ophthalmic composition.

[0197] Furthermore, the following agent is provided as an embodiment of the present invention.

[0198] (A) An agent for inhibiting (or preventing) discoloration in an ophthalmic composition comprising one or more selected from the group consisting of pranoprofen and salts thereof, and (B) an agent comprising one or more selected from the group consisting of epinastine and salts thereof.

[0199] (B) An agent for inhibiting (or preventing) discoloration in an ophthalmic composition comprising one or more selected from the group consisting of epinastine and salts thereof, comprising one or more selected from the group consisting of (A) pranoprofen and salts thereof.

[0200] The types and amounts of components (A) to (B) in each of the above embodiments, the types and amounts of other components, the formulation form and use of the ophthalmic composition, etc., are as described in [1. Ophthalmic Composition].

[0201] Furthermore, each of the above embodiments may be combined in two or more forms. For example, when combining embodiments [2] and [3], the embodiment may include a method for suppressing (or preventing) foaming (foaming) in an ophthalmic composition and improving (or enhancing) the defoaming rate by combining (or including in combination) one or more selected from the group consisting of (A) pranoprofen and its salts and (B) one or more selected from the group consisting of epinastine and its salts. [Examples]

[0202] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples, and many modifications are possible within the technical concept of the present invention by those with ordinary skill in the art.

[0203] Test Example 1 (Antifoaming test, combined use of component (A) and component (B)) Aqueous ophthalmic compositions (eye drops) with the compositions shown in the table below were prepared, and foaming was evaluated as follows.

[0204] Specifically, 30 mL of each aqueous ophthalmic composition was filled into glass containers (centrifuge tubes) (capacity 50 mL), and these were shaken 1500 times at 300 rpm using a RECIPAD SHAKER SR-2DW (TAITEC). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually inspected, and the height of the foam portion (the difference in height between the aqueous solution portion and the foam portion) was measured.

[0205] The results are shown in the table below. Note that in the aqueous ophthalmic compositions listed in the table below, the unit for each component is (w / v%) (the same applies hereafter).

[0206] [Table 1]

[0207] As is clear from the results in the table above, combining pranoprofen and epinastine hydrochloride was able to suppress foaming.

[0208] In particular, the improvement in foaming was significantly greater when pranoprofen was used in combination with epinastine hydrochloride.

[0209] Surprisingly, foaming was also observed when epinastine hydrochloride was used. However, quite unexpectedly, by combining it with pranoprofen, which also exhibited foaming, an improvement in the foaming observed when using epinastine hydrochloride was observed.

[0210] Test Example 2 (Defoaming Test, Change in Proportion) As shown in the table below, aqueous ophthalmic compositions (eye drops) were prepared in the same manner as in Test Example 1, except that the proportions of pranoprofen and / or epinastine hydrochloride were changed, and foaming was evaluated.

[0211] The results are shown in the table below. For ease of comparison, some of the results obtained in Test Example 1 are also shown in the table below.

[0212] [Table 2]

[0213] As is clear from the results in the table above, foaming could be prevented or suppressed even when the ratio of epinastine hydrochloride or pranoprofen was changed.

[0214] Test Example 3 (Defoaming Test, Container Change) In Test Example 1, the container was changed from a glass container to a polyethylene terephthalate (PET) container (50 mL capacity, centrifuge tube, Corning No. 430304), and the aqueous ophthalmic compositions (eye drops) shown in the table below were prepared in the same manner as in Test Example 1, and the foaming was evaluated.

[0215] The results are shown in the table below.

[0216] [Table 3]

[0217] As is clear from the results in the table above, foaming due to pranoprofen was also observed when the container was a PET container. Although the degree of foaming due to pranoprofen differed slightly from that in the case of glass containers, foaming could be prevented or suppressed even in the case of PET containers by combining pranoprofen with epinastine hydrochloride.

[0218] Test Example 3' (Antifoaming test, change in ingredients) In Test Example 3, foaming was evaluated in the same manner as in Test Example 1, except that the aqueous ophthalmic composition (eye drops) shown in the table below was prepared and used.

[0219] The results are shown in the table below.

[0220] [Table 4]

[0221] As is clear from the results in the table above, similar trends were observed when ingredients other than pranoprofen and epinastine hydrochloride were changed, and foaming could be prevented or suppressed.

[0222] Test Example 4 (Defoaming Test: Change in Foaming over Time) In the above test examples 1-3, foaming was observed immediately after shaking when pranoprofen was used without combining it with epinastine hydrochloride. However, tests were conducted to confirm how this foaming changes after shaking.

[0223] Specifically, as shown in the table below, aqueous ophthalmic compositions (eye drops) in which pranoprofen is not combined with epinastine hydrochloride were prepared in the same manner as in Test Example 1 and shaken.

[0224] Furthermore, in order to confirm the effect of the container, in addition to the glass container used in Test Example 1, a PET container, the same as in Test Example 3, was used.

[0225] Next, after shaking, the mixture was allowed to stand, and the foam height after a predetermined time, as shown in the table below, was measured in the same manner as in Test Example 1.

[0226] The results are shown in the table below.

[0227] [Table 5]

[0228] As is clear from the results in the table above, the foaming that occurred when pranoprofen was not combined with epinastine hydrochloride persisted even after a predetermined time had elapsed and was difficult to eliminate.

[0229] On the other hand, when pranoprofen and epinastine hydrochloride were combined, no foaming occurred after a predetermined time, indicating that the antifoaming effect of this combination is long-lasting.

[0230] Test Example 4' (Defoaming Test, Change in Foaming over Time) In Test Example 4, the test was conducted in the same manner as Test Example 4, except that the aqueous ophthalmic composition (eye drops) shown in the following table was prepared and used. A PET container was used as the container.

[0231] The results are shown in the following table.

[0232] [Table 6]

[0233] As is clear from the results in the above table, the same tendency was observed even when the components other than pranoprofen and epinastine hydrochloride were changed.

[0234] Test Example 5 (Photostability Test) [[ID=......]]<......>An ophthalmic composition (eye drops) having the composition shown in the following table was prepared, and its photostability (coloration) was evaluated. That is, 5 mL each of the respective ophthalmic compositions shown in the following table was filled into a 13 mL polyethylene terephthalate (PET) container and irradiated with a light tester (LT120A WCD, manufactured by NAGANO, 11114, white lamp). The irradiation conditions were 4000 Lx and 442 kLx·h.

[0235] Then, 200 μL each of the ophthalmic composition was added from the samples after light irradiation to a 96-well plate, the absorbance (wavelength: 420 nm) was measured, and the improvement rate of coloration (yellow) defined by the following formula was determined.

[0236] Improvement rate of yellow coloration (%) = {[(Absorbance in Test Example 5B - Absorbance in Test Example 5A) - (Absorbance in Test Example 5C - Absorbance in Test Example 5A)] / (Absorbance in Test Example 5B - Absorbance in Test Example 5A)} × 100

[0237] The results are shown in the following table. The yellowing results are the average values of three times (N = 3).

[0238] [Table 7]

[0239] As is clear from the results in the above table, by combining pranoprofen with epinastine hydrochloride, coloring (yellowing) due to light could be prevented or suppressed. This means that the formulation combining these has excellent light stability (or can improve or enhance the light stability of pranoprofen).

[0240] And such light stability was found to be particularly excellent when the mass ratio of pranoprofen to epinastine hydrochloride was close (Test Example 5C). <000​​​​​​​​​​​​​​​​​​​​​​​​​​​[Table 8] [Industrial applicability]

[0247] The present invention provides ophthalmic compositions that are useful as eye drops and the like.

Claims

[Claim 1] The invention described herein.

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