JP2019189606A - Ophthalmic composition - Google Patents

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

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

  Epinastine hydrochloride is known as an antihistamine, and attempts to use epinastine hydrochloride for ophthalmology are also being made.

  For example, Patent Document 1 (Japanese Patent No. 6134853) contains only epinastine or a salt thereof at a concentration exceeding 0.075% (w / v) as an active ingredient, and has a preservative and a preservative action substantially. An ophthalmic solution containing no ingredients is disclosed.

Japanese Patent No. 6134853 (Claims and Examples)

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

  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 undeveloped.

  Under such circumstances, the present inventor has conducted extensive studies to solve the above problems, and as a result, a novel ophthalmic composition can be obtained by combining epinastine or a salt thereof and a specific active ingredient, Then, it was found that such ophthalmic compositions may cause precipitation and cloudiness, and that such a precipitation can be efficiently suppressed by a specific surfactant. did.

That is, the present invention relates to the following inventions and the like.
[1]
(A) one or more selected from the group consisting of epinastine and salts thereof,
(B) One or more types selected from the group consisting of pranoprofen and a salt thereof, and (C) an ophthalmic composition containing a surfactant having an HLB value of 16.5 or less.
[2]
(A) one or more selected from the group consisting of epinastine and salts thereof,
(B) One or more types selected from the group consisting of pranoprofen and a salt thereof, and (C) an ophthalmic composition containing a multi-chain surfactant.
[3]
The composition according to [1] or [2], wherein the component (C) has an HLB value of 15.5 or less.
[4]
(C) The composition according to any one of [1] to [3], wherein the component has a plurality of hydrophilic groups.
[5]
The composition according to any one of [1] to [4], wherein the component (C) is a nonionic surfactant having a plurality of hydrophilic groups and an HLB value of 10 to 15.
[6]
(C) The composition in any one of [1]-[5] in which a component contains 1 or more types selected from the group which consists of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.
[7]
(A) The composition in any one of [1]-[6] containing 0.005-0.5 w / v% of a component.
[8]
(B) The composition in any one of [1]-[7] containing 0.005-0.5 w / v% of a component.
[9]
(B) The composition in any one of [1]-[8] whose ratio of a component is 0.01-100 mass parts with respect to 1 mass part of (A) component.
[10]
(C) The composition in any one of [1]-[9] containing 0.001-10 w / v% of a component.
[11]
The ratio of the component (C) is 1 part by mass or more with respect to 1 part by mass of the component (A), and 1 part by mass or more with respect to 1 part by mass of the component (B). The composition as described.
[12]
The composition according to any one of [1] to [11], which has a pH of 4 to 9.
[13]
(C) component contains 1 or more types selected from the group which consists of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil,
(A) The ratio of a component is 0.01-0.1 w / v%,
(B) The ratio of a component is 0.01-0.1 w / v%,
(C) The ratio of a component is 0.01-1 w / v%,
(B) The ratio of a component is 0.1-10 mass parts with respect to 1 mass part of (A) component,
The composition according to any one of [1] to [12], which has a pH of 5 to 8.
[14]
The composition according to any one of [1] to [13], wherein no precipitation occurs.
[15]
The composition according to any one of [1] to [14], which contains water at a ratio of 90% by mass or more with respect to the total amount of the composition and has no precipitation.
[16]
(A) One or more types selected from the group consisting of epinastine and its salts, and (B) One or more types selected from the group consisting of pranoprofen and its salts, and suppressing precipitation in ophthalmic compositions. A method comprising: (C) a surfactant having an HLB value of 16.5 or less in an ophthalmic composition.
[17]
(A) One or more types selected from the group consisting of epinastine and its salts, and (B) One or more types selected from the group consisting of pranoprofen and its salts, and suppressing precipitation in ophthalmic compositions. A method of adding an (C) multi-chain type surfactant to an ophthalmic composition.

  In the present invention, a novel ophthalmic composition can be provided. Such an ophthalmic composition contains pranoprofen and / or a salt thereof in addition to epinastine or a salt thereof, and is an unconventional ophthalmic composition.

  In another aspect of the present invention, an ophthalmic composition capable of suppressing precipitation (white turbidity) can be provided. According to the study of the present inventor, precipitation may occur in a preparation containing a combination of epinastine and / or a salt thereof and pranoprofen and / or a salt thereof. According to the ophthalmic composition of the present invention containing a specific surfactant selected from the components, such precipitation can be efficiently suppressed.

  In another aspect of the present invention, even when other components (such as a pH adjusting agent and a buffering agent) are contained or when water is contained in a high proportion, the precipitation suppressing effect can be effectively exhibited.

  In another embodiment of the present invention, it can be effectively exhibited without impairing the function as a surfactant. The component (C) in the present invention is a surfactant, but even if the component (A) and the component (B) (and other components) are included, the function as a surfactant can be effectively exhibited.

  Thus, the composition of the present invention is extremely practical.

  In the present specification, the unit of content “w / v%” is synonymous with “g / 100 mL”. In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.

[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.

(A) Epinastine and / or salt thereof (component (A))
The salt of epinastine is not particularly limited as long as it is a pharmaceutically or physiologically acceptable salt. For example, an organic acid salt [eg, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitic acid, etc.) Salt, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic Sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate) and the like.

  Preferred epinastine and / or salts thereof include epinastine hydrochloride (monohydrochloride).

  Epinastine and / or a salt thereof may be used alone or in combination of two or more.

  The content of the component (A) in the composition is, for example, 0.0001 w / v% or more (for example, 0.0003 to 5 w / v%), preferably 0.0005 w / v with respect to the total amount of the composition. % Or more (for example, 0.001 to 1 w / v%), more preferably 0.003 w / v% or more (for example, 0.005 to 0.5 w / v%), and still more preferably 0.005 w / v% or more. (For example, 0.007 to 0.2 w / v%), even more preferably 0.008 w / v% or more (for example, 0.01 to 0.1 w / v%), particularly preferably 0.02 w / v%. Or more (for example, 0.03 to 0.1 w / v%), most preferably 0.03 w / v% or more (for example, 0.04 to 0.08 w / v%, 0.045 to 0.06 w / v%) Etc.) degree. Among these, 0.05 w / v%, 0.1 w / v%, and the like are preferable, and 0.05 w / v% is particularly preferable.

(B) Planoprofen and / or a salt thereof (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 this invention, even if it contains a several active ingredient in this way, each function (medicine effect) can be exhibited efficiently.

The salt of pranoprofen may be any salt that is pharmaceutically or physiologically acceptable, such as a salt with an acid (for example, a salt with an inorganic acid, a salt with an organic acid, etc. And salts with 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; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with aluminum, etc.] etc.], etc. , Lactate, hydrochloride, chloride salt, sodium salt, potassium salt and the like.
A preferred pranoprofen and / or salt thereof is pranoprofen and a metal salt thereof, and pranoprofen is particularly preferred.

  Planoprofen and / or a salt thereof may be used alone or in combination of two or more.

  Content of (B) component in a composition is 0.0001 w / v% or more (for example, 0.0003-5 w / v%) with respect to the whole quantity of a composition, Preferably it is 0.0005 w / v. % Or more (for example, 0.001 to 1 w / v%), more preferably 0.003 w / v% or more (for example, 0.005 to 0.5 w / v%), and still more preferably 0.005 w / v% or more. (For example, 0.007 to 0.2 w / v%), even more preferably 0.008 w / v% or more (for example, 0.01 to 0.1 w / v%), particularly preferably 0.02 w / v%. Or more (for example, 0.03 to 0.1 w / v%), most preferably 0.03 w / v% or more (for example, 0.04 to 0.08 w / v%, 0.045 to 0.06 w / v%) Etc.) degree. Among these, 0.05 w / v%, 0.1 w / v%, and the like are preferable, and 0.05 w / v% is particularly preferable.

  The ratio of (B) component is 0.001-1000 mass parts with respect to 1 mass part of (A) component, Preferably it is 0.005-200 mass parts, More preferably, it is 0.01-100 mass parts, 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). It is particularly preferable that the amount is 1 part by mass.

(C) Specific surfactant (component (C))
The composition of the present invention may contain a specific surfactant (C). The surfactant is usually a so-called bipolar component and refers to all substances having a surface-active effect.

  Such a surfactant (C) satisfies the following embodiment (C1) or (C2).

(C1) HLB value of 16.5 or less (C2) Multi-chain type (or having a branched chain)

  The component (C) may be any surfactant that satisfies at least one of the above aspects (C1) and (C2), and a surfactant that satisfies both (HLB value of 16.5 or less, and multi-chain type) Surfactant).

  In the aspect (C1), the HLB value can be selected from the range of 16.5 or less, 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. It may be 8 or less, 14.5 or less, or 14.2 or less.

  In the aspect (C1), the lower limit value of the HLB value is not particularly limited, but 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, It may be 9.2, 9.5, 9.8, 10, 10.2, 10.5, 10.8, 11, 11.2, 11.5, 11.8, 12, etc.

  When a surfactant is used in combination, each surfactant may satisfy the above HLB value, and the HLB value of all the surfactants (mixed HLB value, weighted average of HLB values of each surfactant) Value) may satisfy the HLB value, and the surfactant may include a surfactant that satisfies at least the HLB value.

  The HLB value is not particularly limited, and may be a calculated value or an experimentally obtained value. The calculated value may be a calculated value based on, for example, the Griffin method (20 × sum of formula weight of hydrophilic portion / molecular weight).

  The surfactant satisfying the embodiment (C2) is a multi-chain type (has a branched chain). The multi-chain type means that it is not a linear type, and usually a hydrophilic group (hydrophilic part, hydrophilic group, hydrophilic chain, hydrophilic chain) and / or lipophilic group (lipophilic part) constituting the surfactant. , A lipophilic group, a hydrophobic part, a hydrophobic group, a hydrophobic group) may have a branched structure (branched chain).

  Specific examples of the multi-chain surfactant include surfactants having a lipophilic group having a branched structure [for example, branched chain as lipophilic group (for example, branched alkyl chain such as 2-octyldodecyl group; polyoxypropylene) Surfactant having a polyoxy-branched alkylene chain such as a chain], a surfactant having a plurality of hydrophilic groups (for example, a surfactant having a plurality of hydrophilic groups branched from a lipophilic group), and an interface having a combination thereof An active agent etc. are mentioned.

  Among these, a surfactant having at least a plurality of hydrophilic groups (for example, polyoxyethylene chains) is preferable. In such a surfactant, the number of hydrophilic groups (for example, hydrophilic groups bonded to a lipophilic group) may be 2 or more, and particularly 3 or more.

  The surfactant (C) may be usually nonionic (nonionic).

  As typical component (C) (surfactant satisfying the above-described embodiments (C1) and / or (C2)), 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 Polyoxyethylene hydrogenated castor oil (for example, POE hydrogenated castor oil 10, POE hydrogenated castor oil 25, 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, polysorb Over DOO 60 and polysorbate 65), tyloxapol, polyoxyethylene branched alkyl ethers, polyoxyethylene glycerol fatty acid esters (e.g., monostearate polyoxyethylene glycerin), and the like.

  Among these components (C), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, tyloxapol and the like are preferable, and in particular, polyoxyethylene castor oil (POE castor oil 10, POE castor oil 35, etc.), poly Oxyethylene hydrogenated castor oil (such as POE hydrogenated castor oil 60) is preferred.

  Therefore, the component (C) may contain at least these surfactants.

  You may use a component (C) individually or in combination of 2 or more types.

When combining the component (C), components of the same system (same classification) may be combined, components of different systems (different classification) may be combined, and components having different HLB values [for example, the difference in HLB values is 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) different components] may be combined .
By combining the component (C), precipitation in the composition may be more efficiently suppressed.

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

  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 is, for example, 0.001 to 1000 parts by mass, preferably 0.01. -100 mass parts, More preferably, about 0.02-50 mass parts may be sufficient.

  When the component (C) is contained, the content of the component (C) in the composition is, for example, 0.001 w / v% or more (for example, 0.001 to 10 w / v%) with respect to 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%), particularly preferably It may be 0.05 w / v% or more (for example, 0.1 to 1 w / v%).

  When component (C) is contained, the proportion of component (C) is, for example, 0.02 parts by mass or more (for example, 0.02 to 200 parts by mass), preferably 1 part by mass of component (A), 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), and particularly preferably 1 part by mass or more (for example, 1 ˜20 parts by mass), most preferably about 2 parts by mass or more (for example, 2 to 10 parts by mass).

  When component (C) is contained, the proportion of component (C) is, for example, 0.02 parts by mass or more (for example, 0.02 to 200 parts by mass), preferably 1 part by mass of component (B), 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), and particularly preferably 1 part by mass or more (for example, 1 ˜20 parts by mass), most preferably about 2 parts by mass or more (for example, 2 to 10 parts by mass).

  When the component (C) is contained, the proportion of the component (C) is, 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), and particularly preferably 0. It may be about 5 parts by mass or more (for example, 0.5 to 10 parts by mass), and most preferably about 1 part by mass or more (for example, 1 to 8 parts by mass).

[Other ingredients]
The composition of the present invention may further contain other components. In the present invention, the effects of the present invention can often be secured even if other components are contained. Moreover, the effect of this invention may be implement | achieved more effectively by containing another component.

Amino acids The composition of the present invention may contain amino acids.
Examples of amino acids include amino acids or salts thereof, and amino acid analogs, and include compounds having amino groups and carboxyl groups or sulfone groups in the molecule, or derivatives thereof.

  Specific examples include amino acids or salts thereof, mucopolysaccharides or salts thereof. Among amino acids, examples of amino acids or salts thereof include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid; Examples thereof include diaminomonocarboxylic acids such as arginine and lysine or salts thereof; derivatives such as aminoethylsulfonic acid (taurine) or salts thereof.

  Among amino acids, examples of the mucopolysaccharide or a derivative thereof or a salt thereof include, for example, a derivative such as chondroitin sulfate, hyaluronic acid, or alginic acid or a salt thereof as an acidic mucopolysaccharide.

  Specific amino acids and mucopolysaccharides include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid or the like And the like.

In addition, chondroitin sulfate is a product in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of sugar chains in which D-glucuronic acid and N-acetylglucosamine repeat. The binding position and number of sulfuric acid are various, and there are derivatives of chondroitin sulfate (for example, those in which all or part of N-acetylglucosamine is substituted with iduronic acid).
Such chondroitin sulfate may have any structure. Examples thereof include chondroitin sulfate sulfate (chondroitin sulfate A), chondroitin hexasulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4th and 6th positions of N-acetylglucosamine are sulfated. In addition, chondroitin sulfate may be extracted from animals.

  Amino acid salts or mucopolysaccharide salts include pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include salts with organic acids [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate , Maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate) Etc.), salts with inorganic acids (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, Salts with organic amines such as morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earths Metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] or the like can be illustrated, it is appropriately selected depending on the compound.

  Specific salts include aspartic acid salts (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixtures, etc.), glutamate salts (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, hyaluron Examples include sodium acid.

  Amino acids may be any of D-form, L-form, and DL-form.

  Preferred amino acids include aminoethylsulfonic acid (taurine) or a salt thereof, chondroitin sulfate sodium, aspartate (for example, potassium L-aspartate, magnesium-potassium L-aspartate), epsilon aminocaproic acid or a salt thereof, hyaluron An acid or a salt thereof (such as sodium hyaluronate) is included, and among these, hyaluronic acid or a salt thereof (such as sodium hyaluronate), aminoethylsulfonic acid (taurine) and / or a salt thereof and chondroitin sulfate sodium are preferable.

  Amino acids may be used alone or in combination of two or more.

  When the composition contains amino acids, the content of amino acids in the composition is, for example, 0.001 w / v% or more, preferably 0.01 to 20 w / v%, based on the total amount of the composition. Preferably it is 0.03 to 10 w / v%, more preferably 0.05 to 5 w / v%, still more preferably 0.1 to 3 w / v%, particularly preferably about 0.15 to 2 w / v%. Usually, 0.001 to 10 w / v% [e.g. 0.005 to 10 w / v%, preferably 0.01 to 5 w / v%, more preferably 0.05 to 3 w / v% (for example, 0.1-1 w / v%)].

Coolant The composition of the present invention may contain a refresher.
Combining the (A) component, the (B) component, and the (C) component may reduce or impair the feeling of use, but such a feeling of use can be improved or improved by a cooling agent. For example, while it may be advantageous to increase the pH of the composition in terms of solubility, etc., the higher the pH of the composition, the stronger the discomfort and the feeling of use may be impaired. Use of the agent can relieve such discomfort and improve the feeling of use efficiently.

  Although it does not specifically limit as a refreshing agent, For example, terpenoids, such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and agate, are mentioned. These may be any of d-form, l-form or dl-form. Moreover, essential oils such as mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil and the like can also be mentioned.

  Among these, terpenoids are preferable, and among these, menthol, camphor, geraniol, cineol, borneol, and agate are preferable, menthol, camphor, and borneol are more preferable, menthol and borneol are more preferable, and menthol is most preferable.

  You may use a refreshing agent individually or in combination of 2 or more types. In particular, the refreshing agent preferably includes one or more selected from the group consisting of menthol, borneol and camphor, and when combining two or more, at least combine them (for example, combine menthol, borneol and camphor) Is preferred.

  When the composition contains a refreshing agent, the proportion of the refreshing agent is, for example, 0.00001 w / v% or more, 0.00005 w / v% or more, 0.0001 w / v% or more with respect to the total amount of the composition. 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. May be.

  Moreover, the ratio of a refreshing agent is 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 with respect to the whole quantity of a composition. It may be 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.

  In particular, when the composition of the present invention contains menthol, the ratio of menthol is, for example, 0.00001 w / v% or more (for example, 0.00005 to 2 w / v%), preferably, based on the total amount of the composition. 0.0001 to 0.2 w / v% (for example, 0.0003 to 0.1 w / v%), more preferably 0.0005 to 0.05 w / v% (for example, 0.001 to 0.02 w / v) %) Degree.

  In particular, when the composition of the present invention contains borneol, the proportion of borneol is, for example, 0.00001 w / v% or more (for example, 0.00005 to 3 w / v%), preferably, relative to the total amount of the composition, 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%) There may be.

  In particular, when the composition of the present invention contains camphor, the ratio of camphor is, for example, 0.00001 w / v% or more (for example, 0.00005 to 1 w / v%), preferably with respect to the total amount of the composition, 0.0001 to 0.1 w / v% (for example, 0.0003 to 0.05 w / v%), more preferably 0.0005 to 0.02 w / v% (for example, 0.001 to 0.01 w / v) %) Degree.

Fat-soluble antioxidant The composition of the present invention may contain a fat-soluble antioxidant.

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

  Of these, dibutylhydroxytoluene is preferred.

  You may use a fat-soluble antioxidant individually or in combination of 2 or more types.

  When the composition contains a fat-soluble antioxidant, the content of the fat-soluble antioxidant in the composition is, for example, 0.0001 to 0.1 w / v%, preferably 0, based on the total amount of the composition. .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%, still more preferably 0.003 to 0.007 w / v. It may be about v%, most preferably about 0.0045 to 0.006 w / v%.

Anti-allergic agent The composition of the present invention may contain an anti-allergic agent.

  Examples of the antiallergic agent include tranilast, cromoglycic acid, ibudilast, acitazanolast, tazanolast, suplatast, pemirolast, amlexanox, oxatomide and salts thereof.

  Examples of the salt include the salts exemplified above, for example, alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (for example, hydrochloride salts) , Sulfate, etc.), organic acid salts (eg, tosylate, fumarate, etc.).

  Of these, tranilast, cromoglycic acid and salts thereof are preferred, and tranilast and sodium cromoglycate are more preferred.

  You may use an antiallergic agent individually or in combination of 2 or more types.

  When the composition contains an antiallergic agent, the content of the antiallergic agent in the composition is, for example, 0.1 to 10 w / v%, preferably 0.2 to 8 w / v, based on the total amount of the composition. %, More preferably 0.3-5 w / v%, even more preferably 0.5-3 w / v%, particularly preferably 0.7-2 w / v%, still more preferably 0.8-1.5 w / V%, most preferably about 0.9 to 1.2 w / v%.

Antihistamine The composition of the present invention may contain an antihistamine.
The antihistamine (antihistamine other than epinastine and its salts) is not particularly limited as long as it has a substance having an antihistamine action, and examples thereof include chlorpheniramine, diphenhydramine, ketotifen, olopatadine, levocabastine, iproheptin and salts thereof. .

  The salt may be a pharmaceutically or physiologically acceptable salt. For example, an organic acid salt [eg, maleate, fumarate (eg, ketotifen fumarate, etc.)], inorganic acid [eg, , Hydrochlorides (for example, olopatadine hydrochloride, etc.), sulfates, etc.], examples of the salts such as metal salts, and the like.

  Specific examples of the salt include diphenhydramine hydrochloride, iproheptin hydrochloride, chlorpheniramine maleate, and the like.

  Antihistamines may be used alone or in combination of two or more.

  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, based on the total amount of the composition 0.003 to 5 w / v%, 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, it may be about 0.02 to 0.1 w / v%), most preferably about 0.025 to 0.05 w / v% (for example, 0.03 w / v%), usually 0.01 to 0 It may be about .05 w / v%.

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

  Examples of the salt include the salts exemplified above, such as a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base. For example, sulfate, lactate, hydrochloride, chloride, and the like. Physical salts, sodium salts, potassium salts and the like can be mentioned.

  Specific examples of the salt include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

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

  When the composition contains an anti-inflammatory agent, the content of the anti-inflammatory agent in the composition is, for example, 0.001 w / v% or more (for example, 0.02 w / v%) with respect to the total amount of the composition, Preferably it is 0.005-10 w / v% (for example, 5 w / v%), More preferably, it is 0.01-1 w / v%, Still more preferably, it is 0.1-0.5 w / v% (for example, 0.1%). 3 w / v%), particularly preferably about 0.2 to 0.3 w / v% (for example, 0.25 w / v%).

  The composition of the present invention may contain various components (for example, components that do not belong to the category of the components). Examples of such components (additives) include surfactants, preservatives, buffers, pH adjusters, isotonic agents, thickeners or thickeners, stabilizers, oils, sugars, high Examples include molecular compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), and the like.

  An additive can be used individually or in combination of 2 or more types. Moreover, each additive can be used individually or in combination of 2 or more types.

  Specific examples of the additive are exemplified below.

Other surfactants The composition of the present invention contains other surfactants (surfactants that do not belong to the category of the component (C), that is, HLB values of more than 16.5 and linear type interfaces). An activator).

  The other surfactant is not particularly limited as long as it is a surfactant that does not belong to the category of the component (C) (that is, a linear surfactant having an HLB value exceeding 16.5). For example, polyoxyethylene linear alkyl ether having an HLB value of more than 16.5 [for example, polyoxyethylene lauryl ether (for example, HLB value of about 16.9), etc.], polyoxyethylene having an HLB value of more than 16.5 Examples thereof include ethylene linear fatty acid esters (for example, polyoxyl 40 stearate), polyoxyethylene polyoxypropylene glycols having an HLB value of more than 16.5 (for example, poloxamers such as poloxamer 407), and the like.

  You may use another surfactant individually or in combination of 2 or more types.

  When the composition contains another surfactant, the ratio of the other surfactant to the surfactant (the total amount of the component (C) and the other surfactant) is, for example, 50% by mass or less and 40% by mass or less. 30 mass% or less, 20 mass% or less, 10 mass% or less, etc.

Preservative The composition of the present invention may contain a preservative.
Examples of preservatives include polydronium chloride, alkyl polyaminoethyl glycines (eg, alkyldiaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, etc.), Chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoate (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate , Phenethyl alcohol, benzyl alcohol, biguanide compounds (for example, polyhexanide hydrochloride, etc.), glowkill (manufactured by Rhodia) and the like.

  Among them, alkylpolyaminoethylglycines (for example, alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salt, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoate, biguanide compound Are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are more preferred.

  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, especially 0.00005 w, based on the total amount of the composition. / V% or more, in particular 0.001 w / v% or more, especially 0.005 w / v% or more. The total amount of the preservative is 1 w / v% or less, especially 0.1 w / v% or less, especially 0.05 w / v% or less, especially 0.03 w / v% or less, 0.025 w / v% or less is mentioned.

Buffering Agent The composition of the present invention may contain a buffering agent.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.

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

  Phosphate buffer components include phosphoric acid, phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, And calcium dihydrogen phosphate). The phosphate may be a hydrate.

  Examples of the component of the carbonate buffer include carbonic acid and carbonate (such as potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate). The carbonate may be a hydrate.

  Examples of the citrate buffer component include citric acid and citrate (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate). The citrate may be a hydrate.

  Examples of the component of the acetate buffer include acetic acid and acetate (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). The acetate salt may be a hydrate.

  Among these, a borate buffer is preferable from the viewpoint of storage efficacy and the like, and a phosphate buffer is preferable from the viewpoint of low cytotoxicity, and a borate buffer is more preferable. The boric acid buffer is preferably a combination of boric acid and its salt, more preferably a combination of boric acid and an alkali metal salt of boric acid and / or an alkaline earth metal salt, and an alkali metal of boric acid and boric acid. A combination with a salt is further preferred, and a combination of boric acid and borax is even more preferred.

  When blending a buffering agent in the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the type and amount of other blending components, and cannot be uniformly defined. The total amount of the buffering agent is 0.001 w / v% or more, particularly 0.01 w / v% or more, especially 0.05 w / v% or more, especially 0.1 w / v% or more with respect to the total amount of the composition. It is done. Further, the total amount of the buffering agent with respect to the total amount of the composition is 10 w / v% or less, especially 5 w / v% or less, especially 3 w / v% or less, especially 2.5 w / v% or less, especially 2 w / v%. The following are mentioned.

  In particular, when a borate buffer is used, the ratio of the buffer in the composition is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably based on the whole composition. May be about 0.1 to 4 w / v%, more preferably about 0.2 to 3 w / v%.

pH regulators Examples of pH regulators include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, water Examples include potassium oxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.
You may use a pH adjuster individually or in combination of 2 or more types.

Isotonic agents isotonic agents, such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.
You may use an isotonizing agent individually or in combination of 2 or more types.

Thickener or thickener The ophthalmic composition of the present invention may contain a thickener or thickener.

Examples of thickeners or thickeners include guar gum, hydroxypropyl guar gum, cellulosic polymer compounds (eg, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose), gum arabic, karaya gum, xanthan gum, agar , Alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharide (eg, heparin analog, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.)), starch, chitin and Its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carbo Sivinyl polymer, etc.), polyacrylic acid alkali metal salts (sodium salt, potassium salt, etc.), polyacrylic acid amine salts (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen Pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (such as sodium salt), alginate (such as propylene glycol ester), tragacanth powder, and triisopropanolamine.
You may use a thickener or a thickener individually or in combination of 2 or more types.

Examples of the stabilizer stabilizing agents, e.g., hydroxyalkylamines (or amino alkanols or alkanolamines, e.g., monoethanolamine, diethanolamine, triethanolamine, etc. trometamol), sodium formaldehyde sulfoxylate (Rongalit), Examples thereof include aluminum monostearate and glyceryl monostearate.
You may use a stabilizer individually or in combination of 2 or more types.

Examples of the oil component 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.

Examples of saccharide sugars include monosaccharides, oligosaccharides (such as disaccharides), and specific examples include glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.

Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, Examples thereof include 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 and the like.
Among them, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate are preferable, potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferable, and potassium chloride and sodium chloride are still more preferable.

Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid and ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2- Sodium phosphate, etc.), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or a salt thereof (disodium edetate, tetrasodium edetate, etc.).

  The composition of the present invention can further contain a component having pharmacological activity or physiological activity.

  A pharmacologically active ingredient or a physiologically active ingredient can be used individually or in combination of 2 or more types.

  As such pharmacologically active ingredients and physiologically active ingredients, active ingredients in various pharmaceuticals described in the 2017 edition (supervised by the Japan Society for Regulatory Science) It can be illustrated. Examples include decongestants, eye muscle modifiers, astringents, vitamins, amino acids, antibacterial agents or fungicides, local anesthetic ingredients, soothing agents, sulfa drugs, and the like. Specific examples of these drugs are illustrated below.

Decongestant (vasoconstrictor)
Examples of decongestants include α-adrenergic agonists, specifically imidazoline-based decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochlorides and nitrates, epinephrine, epinephrine hydrochloride, hydrochloric acid, and the like. Examples include ephedrine, phenylephrine hydrochloride, methylephedrine hydrochloride, and epinephrine hydrogen tartrate. These may be d-form, l-form or dl-form.

  The imidazoline vasoconstrictor will be described in detail. The salt of the imidazoline vasoconstrictor may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid salt such as maleate or fumarate; hydrochloric acid Inorganic acid salts such as salts and sulfates; and salts such as metal salts. Among the salts, inorganic acid salts are preferable, hydrochlorides or nitrates are more preferable, and hydrochlorides (tetrahydrozoline hydrochloride and the like) are particularly preferable.

  Among the decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferable, tetrahydrozoline, naphazoline, or a salt thereof is more preferable, and tetrahydrozoline, or a salt thereof is more preferable.

The ocular muscles modifier ocular muscles regulators such as, cholinesterase inhibitors having similar activity center and acetylcholine, specifically neostigmine methylsulfate, tropicamide, Herenien, and the like atropine sulfate.

Vitamins Examples of vitamins include flavin adenine dinucleotide or a salt thereof (for example, flavin adenine dinucleotide sodium), cobalamin or a salt thereof (for example, cyanocobalamin, methylcobalamin), retinol, a salt thereof or a derivative thereof (for example, acetic acid). Retinol, retinol palmitate), pyridoxine or a salt thereof (for example, pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (for example, sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof Or a derivative thereof (eg, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (eg, pyridoxal phosphate), ascorbyl Acid or a salt thereof (e.g., sodium ascorbate, calcium ascorbate) and the like.

Among them, flavin adenine dinucleotide or a salt thereof (especially flavin adenine dinucleotide sodium), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate, retinol palmitate), pyridoxine or a salt thereof Preferred are salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or salts thereof (especially sodium pantothenate, calcium pantothenate), tocopherols, salts or derivatives thereof (especially tocopherol acetate), and pyridoxine hydrochloride and tocopherol acetate. More preferred.
In addition, the composition of this invention does not need to contain pyridoxine and its salt.

Antibacterial agent or bactericidal agent As the antibacterial agent or bactericidal agent, for example, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, Examples include sulfa drugs such as sulfisomezole sodium and sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

Local anesthetic component Examples of the local anesthetic component include procaine hydrochloride and lidocaine hydrochloride.

Base or Carrier The composition of the present invention may comprise a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing the above-mentioned components with a pharmaceutically acceptable base or carrier, for example, as described in the 17th revised Japanese Pharmacopoeia Manual. It can be prepared by the method.

  Examples of the base or carrier include water, polar solvents such as ethanol (particularly water-soluble solvents), oily bases, and the like. A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

  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).

Properties The properties of the composition of the present invention are not particularly limited, and may be any properties such as liquid, fluid, gel, or semi-solid. Moreover, the liquid form, the fluid form, the gel form, or the semi-solid form by preparation at the time of use is also included. The semi-solid state means a property having plasticity that can be deformed by applying force, such as an ointment, and is preferably a liquid.

  Further, as described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), or an oily composition (oil or hydrophobic base or carrier). And mainly an aqueous composition.

  The content of water in the case of an aqueous composition is preferably 50% by mass or more, more preferably 75% by mass or more, and still more preferably 90% by mass or more, with respect to the total amount of the composition (or formulation). Moreover, 95 mass% or more or 98 mass% or more may be sufficient. In addition, the base or carrier may be composed only of water.

  The content of water in the case of an oily composition is preferably less than 50% by mass, more preferably 30% by mass or less, and still more preferably 20% by mass or less, with respect to the total amount of the composition (or formulation).

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 still more preferably 6 or more. Moreover, 10 or less is preferable, 9 or less is more preferable, and 8.5 or less is further more preferable.

The pH of the composition of the present invention may be, for example, 4-9, preferably 4.5-8.5, more preferably 5-8, 5.5-8, 6-8, 6-7. .5, 6.5-7.5, etc.
In the present invention, the effects of the present invention (e.g., precipitation suppression effect) can be efficiently realized even at the above pH.

Osmotic pressure ratio of the composition of the osmotic pressure present invention, for example, preferably 0.4 or more, more preferably 0.5 or more, even more preferably 0.6 or more. Moreover, 5 or less is preferable, 3 or less is more preferable, and 2 or less is still more preferable.

  The osmotic pressure ratio is a 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 revision Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The mixture is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to make exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is used.

Dosage Form The dosage form (dosage form, shape, structure) of the composition of the present invention is not particularly limited. For example, eye drops (also referred to as eye drops or eye drops. Eye drops can be instilled while wearing contact lenses). Eye drops, eye wash, eye ointment (water-soluble ointment, oil-soluble eye ointment), contact lens mounting solution, intraocular injection (eg, intravitreal injection), contact lens solution (cleaning solution, storage) Liquids, disinfectants, multipurpose solutions, package solutions), preservatives for isolated eye tissue such as the cornea for transplantation, and perfusate during surgery. Eye drops, eye washes and eye ointments include those used when wearing contact lenses.

  The “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).

  The dosage form of the composition of the present invention is preferably eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting liquid, contact lens liquid (cleaning liquid, preservative liquid, disinfectant liquid) , Multipurpose solutions, package solutions), and more preferably eye drops, eyewashes, contact lens mounting solutions, contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multipurpose solutions), etc. More preferred are eye drops and eye wash, and particularly preferred are eye drops.

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

Container The composition of the present invention may be contained (filled, injected, sealed) in a container.
The container may be a package having a part (surface) that comes into contact with the composition (formulation), for example, a container body part that contains the composition (for example, a liquid composition), a part that includes the extraction port of the container. (Nozzle, inner plug), suction tube, cap and the like.

  The material constituting the container can be selected from a wide range. For example, at least part or all of the contact portion with the composition is plastic (for example, olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate). Resin, fluororesin, chlorine resin (polyvinyl chloride, etc.), polyamide resin, polyacetal resin, polyphenylene ether resin (modified polyphenylene ether, etc.), polyarylate, polysulfone, polyimide resin, cellulose resin (cellulose acetate) Etc.), hydrocarbon resins which may be substituted with halogen atoms, etc.), metals (aluminum etc.) and the like.

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

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

  Examples of the styrene resin include polystyrene and acrylonitrile-containing styrene resin (for example, acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), and the like).

  Examples of the acrylic resin include resins having a polymerization component such as an acrylate ester such as methyl acrylate, a methacrylate ester such as methyl methacrylate, cyclohexyl methacrylate, and t-butyl cyclohexyl methacrylate.

  Examples of polyester resins include aromatic polyester resins [for example, resins having an alkylene terephthalate unit (alkylene terephthalate resins: for example, polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.), Resin having an alkylene naphthalate unit (for example, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)] and the like.

  Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

  Examples of the polyacetal-based resin include those containing only oxymethylene units and those partially containing oxyethylene units.

  Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.

  Examples of polyarylate include amorphous polyarylate.

  Examples of the polyimide resin include aromatic polyimides such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

  Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

  The material of the container is preferably a plastic such as an olefin resin, a styrene resin, or a polyester resin (that is, a plastic container), more preferably an ethylene resin, a propylene resin, an alkylene terephthalate resin, or polystyrene, polypropylene, Polyethylene terephthalate and polystyrene are more preferred, and polyethylene terephthalate is even more preferred.

  The container may be a polymer blend with a polymer other than the above polymer. When the container material of the container containing the ophthalmic composition of the present invention is a blend polymer with the polymer, the mixing ratio of the polymer and the polymer other than the polymer is not particularly limited as long as the effect of the present invention is exhibited. The total weight of the polymer is preferably 30 w / w% or more, more preferably 50 w / w% or more, and even more preferably 65 w / w% or more with respect to the total amount of the constituent materials. 80 w / w% or more is particularly preferable.

  As for a container, at least one part of the surface which contacts the composition of this invention may be comprised with the said 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 remarkably exhibiting the effects of the present invention, the container itself is preferably molded from the above-mentioned material.

  In addition, the parts constituting the container (the container body part, the part including the extraction port of the container (nozzle, inner plug), the suction tube, the cap, etc.) may be composed of the above materials, and the entire part of the container is composed of the above materials. It may be comprised. In particular, from the viewpoint of remarkably exhibiting the effects of the present invention, it is preferable that the container main body portion is made of the above material, and that all of the container main body portion is made of the above material (a part of the container main body). More preferably, the layer is not made of the above material.

Target disease (use)
The target disease (use) of the composition of the present invention is not particularly limited as long as it is ophthalmic, and includes, for example, allergic symptoms, itchy eyes, eye pain, eye inflammation, blepharitis, eye Haze, redness, foreign body sensation (colossal feeling, etc.), corneal damage, corneal damage, lacrimation (crying), follicles of eyelid conjunctiva, eyelids (eye and eyes), etc. It is useful for enhancement of barrier function, normalization, and corneal protection.

  In addition, lacrimal eyes are a symptom that occurs when the drainage path of tears from the punctum to the lacrimal canal, lacrimal sac, and nasolacrimal duct becomes obstructed by the eyes or the like, or excessive tears are created by stimulation. .

  In this specification, “relief” includes symptom relief, symptom progression inhibition, and “improvement”, “suppression”, and “treatment” mean symptom relief, symptom progression inhibition, healing or completeness. Include.

  In particular, the composition of the present invention is suitable for alleviation, improvement, suppression, or treatment of allergic symptoms (eye allergic symptoms).

  The allergic allergen is not particularly limited, and may be pollen (cedar pollen, cypress pollen, etc.), house dust (indoor dust), or the like.

  In another embodiment, the composition of the present invention may be used for eye itching, eye pain, eye inflammation, blepharitis, blurred vision, redness, tear eyes, foreign body sensation, corneal damage, corneal damage, tear eyes ( It is suitable for the relief, improvement, suppression, or treatment of symptoms such as lacrimation), follicles of the eyelid conjunctiva, and eyelids (eye and eyes). These symptoms may be derived from allergic symptoms or may not be derived.

Method of Use The method of use (use mode) of the composition of the present invention can be appropriately selected according to the properties and the like.

  For example, when the composition of the present invention is a preparation to be applied to the eye such as an eye drop, an eye wash, an eye ointment, etc., the usage varies depending on the target symptom, but for example, once or more twice a day. As mentioned above, it can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Also, it can be 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. It is particularly preferred to administer 4 times a day.

  When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be applied per time, or 1 to 2 drops or 2 to 3 drops may be used. Preferably, 1 to 2 drops may be instilled. One drop can also be used. Moreover, the amount of eyedrops may be preferably 30 to 50 μL.

  When the composition of the present invention is an eye wash, for example, 1 to 30 mL may be used per wash, preferably 1 to 20 mL, and more preferably 4 to 6 mL.

  When the composition of the present invention is an eye ointment, for example, 0.001 to 5 g may be applied to the eye once.

  When the composition of the present invention is a contact lens mounting solution, at the time of wearing or removing the contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops per side and / or one side of the contact lens. It may be worn after being dripped onto both sides and wetted, and it is preferable to wear after wetting both sides of the contact lens.

[2. Suppression of precipitation and cloudiness)
The ophthalmic composition which concerns on this embodiment has an effect that precipitation (white turbidity) in an ophthalmic composition can be suppressed (or dissolution stability can be improved or improved).

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

  An ophthalmic composition comprising (A) one or more selected from the group consisting of epinastine and a salt thereof, and (B) one or more selected from the group consisting of pranoprofen and a salt thereof, (C) an HLB value A method of suppressing precipitation (white turbidity) in an ophthalmic composition, which comprises containing a surfactant of 16.5 or less (method of improving or improving dissolution stability).

  An ophthalmic composition comprising (A) one or more selected from the group consisting of epinastine and a salt thereof, and (B) one or more selected from the group consisting of pranoprofen and a salt thereof; A method for suppressing precipitation (white turbidity) in an ophthalmic composition, which includes containing a type of surfactant (or having a branched chain) (a method for improving or improving dissolution stability).

  Moreover, the following agents are provided as one embodiment of the present invention.

  Suppression of precipitation (white turbidity) in an ophthalmic composition containing (A) one or more selected from the group consisting of epinastine and its salt and (B) one or more selected from the group consisting of pranoprofen and its salt (C) An agent comprising a surfactant having an HLB value of 16.5 or less, (or an agent for improving or improving dissolution stability).

  Suppression of precipitation (white turbidity) in an ophthalmic composition containing (A) one or more selected from the group consisting of epinastine and its salt and (B) one or more selected from the group consisting of pranoprofen and its salt An agent (or an agent for improving or improving dissolution stability), which comprises (C) a multi-chain type surfactant (or a branched chain) surfactant.

  In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(C) component in said each embodiment, [1. As described in [Ophthalmic composition].

  EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples, and many modifications are within the technical scope of the present invention. This is possible by those with ordinary knowledge.

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

200 g (200 cm ³ ) of the prepared composition was filled into a 10 mL glass screw bottle and stored at room temperature for 1 hour, and then the presence and degree of precipitation (white turbidity) were visually confirmed.

And the grade of precipitation with respect to Test Example 1 was evaluated according to the following criteria.
A: Extremely clear O: No precipitation Δ: Equivalent to the degree of precipitation in Test Example 1 ×: More precipitation than in Test Example 1

  The results are shown in the table below. In addition, in the aqueous ophthalmic composition of the following table | surface, the unit of each component is (w / v%). In the surfactant, the numerical value in parentheses is the HLB value.

  As is clear from the results in the above table, surprisingly, precipitation is caused by the combination of epinastine hydrochloride and pranoprofen, even if epinastine hydrochloride or pranoprofen is included, but precipitation does not occur. Was found (Test Examples 1 to 3).

  And such precipitation was able to be efficiently suppressed by using a specific surfactant (Test Examples 4 to 9). In the case of a very general surfactant, not only did the precipitation suppressing effect be observed, but rather the precipitation increased (Test Example 10), and such a result was extremely unexpected.

  Thus, the property etc. were investigated about the composition of Test Examples 4-9 which could confirm the precipitation inhibitory effect.

  First, all of these compositions were able to fill an eye drop container (PET, caliber 6 mm) without hindrance, and were excellent in fillability.

  Moreover, when the composition was dripped from the eye drop container, in all cases, the liquid running out was good. Therefore, it was found that all of the obtained compositions were compositions in which dripping did not easily occur.

  Further, each of the compositions was dropped on a colorless and transparent plastic film to evaporate water. When the state after evaporation was visually confirmed, no white residue (whitening phenomenon or precipitation due to non-volatile content) occurred or hardly occurred. Thus, it was confirmed that all of the obtained compositions were compositions that could be formulated efficiently. In fact, when filling the eye drop container, none of the compositions produced white residue on the production line (nozzle, etc.).

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

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

Claims (17)

(A) one or more selected from the group consisting of epinastine and salts thereof,
(B) One or more types selected from the group consisting of pranoprofen and a salt thereof, and (C) an ophthalmic composition containing a surfactant having an HLB value of 16.5 or less. (A) one or more selected from the group consisting of epinastine and salts thereof,
(B) One or more types selected from the group consisting of pranoprofen and a salt thereof, and (C) an ophthalmic composition containing a multi-chain surfactant.   The composition according to claim 1 or 2, wherein the component (C) has an HLB value of 15.5 or less.   The composition according to any one of claims 1 to 3, wherein the component (C) has a plurality of hydrophilic groups.   The composition according to any one of claims 1 to 4, wherein the component (C) is a nonionic surfactant having a plurality of hydrophilic groups and an HLB value of 10 to 15.   (C) The composition in any one of Claims 1-5 in which a component contains 1 or more types selected from the group which consists of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.   (A) The composition in any one of Claims 1-6 containing 0.005-0.5 w / v% of a component.   (B) The composition in any one of Claims 1-7 containing 0.005-0.5 w / v% of a component.   The ratio of (B) component is 0.01-100 mass parts with respect to 1 mass part of (A) component, The composition in any one of Claims 1-8.   (C) The composition in any one of Claims 1-9 containing 0.001-10 w / v% of components.   The ratio of the component (C) is 1 part by mass or more with respect to 1 part by mass of the component (A), and 1 part by mass or more with respect to 1 part by mass of the component (B). Composition.   pH is 4-9, The composition in any one of Claims 1-11. (C) component contains 1 or more types selected from the group which consists of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil,
(A) The ratio of a component is 0.01-0.1 w / v%,
(B) The ratio of a component is 0.01-0.1 w / v%,
(C) The ratio of a component is 0.01-1 w / v%,
(B) The ratio of a component is 0.1-10 mass parts with respect to 1 mass part of (A) component,
The composition according to any one of claims 1 to 12, wherein the pH is 5 to 8.   The composition according to any one of claims 1 to 13, which has no precipitation.   The composition according to any one of claims 1 to 14, which contains water at a ratio of 90% by mass or more with respect to the total amount of the composition and has no precipitation. (A) One or more types selected from the group consisting of epinastine and its salts, and (B) One or more types selected from the group consisting of pranoprofen and its salts, and suppressing precipitation in ophthalmic compositions. A method comprising: (C) a surfactant having an HLB value of 16.5 or less in an ophthalmic composition. (A) One or more types selected from the group consisting of epinastine and its salts, and (B) One or more types selected from the group consisting of pranoprofen and its salts, and suppressing precipitation in ophthalmic compositions. A method of adding an (C) multi-chain type surfactant to an ophthalmic composition.