JP7159501B1 - ophthalmic composition - Google Patents

Abstract

An object of the present invention is to provide an ophthalmic composition that contains a terpenoid, a tocopherol and/or a benzylammonium compound and is inhibited from wetting a container. (A) An ophthalmic composition containing one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof, wherein a part of the part in contact with the ophthalmic composition or An ophthalmic composition housed in a container entirely made of a resin containing cyclic olefins. [Selection figure] None

Description

The present invention relates to ophthalmic compositions.

Benzyl ammonium compounds such as terpenoids, tocopherols and/or benzalkonium are sometimes incorporated into ophthalmic compositions (eg US Pat.

On the other hand, containers made of polypropylene, polyethylene, polyethylene terephthalate, etc. are widely used as containers for storing ophthalmic pharmaceutical preparations (eg, Patent Document 3).

Japanese Patent Application Laid-Open No. 2011-21002 JP 2012-006962 A JP 2009-196988 A

The present inventor discovered a novel problem that when an ophthalmic composition contains a terpenoid, a tocopherol and/or a benzylammonium compound, the dynamic contact angle with respect to commonly used resins is small and the composition is easy to wet. If a container made of these resins is easily wetted, the liquid may remain or the liquid may not be easily drained, which may lead to deterioration in the quality of the ophthalmic composition and deterioration in usability. be.

An object of the present invention is to provide an ophthalmic composition that contains a terpenoid, a tocopherol and/or a benzylammonium compound and is inhibited from wetting a container.

The present inventors found that (A) an ophthalmic composition containing one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof, a container formed of a resin containing cyclic olefins However, it has been found that the dynamic contact angle is larger (that is, wetting is suppressed) compared to containers made of commonly used resins.

In addition, the present inventors have found that when an ophthalmic composition containing component (A) is stored in a container made of a resin containing cyclic olefins, the fragrance is reduced or the odor is exacerbated during storage. In response to this, (B) an ophthalmic composition further containing a buffering agent unexpectedly retains the fragrance, or suppresses the change in odor, such as improving the odor. I found

The present invention is based on this finding, and provides the following inventions.

[1]
(A) an ophthalmic composition containing one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof, wherein part or all of the portion in contact with the ophthalmic composition is a cyclic olefin An ophthalmic composition contained in a container made of a resin containing
[2]
The ophthalmic composition according to [1], wherein the resin forming the container further contains polyethylene.
[3]
(B) The ophthalmic composition according to [1] or [2], further comprising a buffering agent.
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the total content of component (A) is 0.00001 to 1.0 w/v% based on the total amount of the ophthalmic composition.
[5]
The ophthalmic composition according to any one of [1] to [4], wherein the total content of component (B) is 1 to 7000 parts by mass per 1 part by mass of component (A).
[6]
The ophthalmic composition according to any one of [1] to [5], wherein the ophthalmic composition has a pH of 4.0 to 9.5.
[7]
The ophthalmic composition according to any one of [1] to [6], wherein the water content is 80 w/v% or more and less than 100 w/v% based on the total amount of the ophthalmic composition.
[8]
The ophthalmology according to any one of [1] to [7], wherein the container made of a resin containing a cyclic olefin has a maximum light transmittance of 50% or more in the visible light region with a wavelength of 400 to 700 nm. Composition.
[9]
The ophthalmic composition according to any one of [1] to [8], wherein the amount per drop is 1 to 99 μL.
[10]
The ophthalmic composition according to any one of [1] to [9], which is used a few times or only once.
[11]
(A) a terpenoid, a tocopherol, and a benzylammonium compound and salts thereof, comprising blending the ophthalmic composition with one or more selected from the group consisting of cyclic olefin-containing resins. A method for imparting a wetting suppression action.
[12]
(A) one or more selected from the group consisting of terpenoids, tocopherols, benzylammonium compounds and salts thereof, and ( B) A method of imparting an odor change-suppressing effect to the ophthalmic composition, comprising blending a buffering agent.

Since the ophthalmic composition of the present invention is housed in a container made of a resin containing cyclic olefins, it is less likely to cause damage to the container than an ophthalmic composition housed in a container made of a commonly used resin. It has the effect of increasing the dynamic contact angle (suppressing wetting). As a result, the ophthalmic composition is prevented from remaining in liquid, and the effect of improving liquid depletion is exhibited. In addition, it is possible to suppress the deterioration of the quality of the ophthalmic composition and the deterioration of usability.

Further, when the ophthalmic composition of the present invention further contains (B) a buffering agent, the ophthalmic composition containing component (A) is housed in a container made of a resin containing cyclic olefins. However, it has the effect of suppressing changes in odors, such as maintaining aromatic properties or improving odors.

DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

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

[1. Ophthalmic composition]
The ophthalmic composition according to the present embodiment contains (A) one or more selected from the group consisting of terpenoids, tocopherols, benzylammonium compounds and salts thereof (also referred to simply as "(A) component"). do.

<(A) Component>
Terpenoids include cyclic terpenes and acyclic terpenes, and are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

Cyclic terpenes are terpenoids with at least one ring structure in the molecule. Cyclic terpenes include, for example, menthol, carvone, anethole, eugenol, limonene, pinene, derivatives thereof, and the like.

Acyclic terpenes are terpenoids without ring structures in the molecule. Acyclic terpenes include, for example, geraniol, citronellol, linalool, linalyl acetate, derivatives thereof, and the like.

Further, in the present invention, essential oils containing the above compounds may be used as terpenoids. Examples of such essential oils include bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil.

Terpenoids may be d-, l-, or dl-forms, and examples include l-menthol, d-menthol, and dl-menthol. However, some terpenoids, such as geraniol, do not have optical isomers.

Terpenoids are preferably free of camphor, borneol, menthone, cineole and eucalyptus oil. As the terpenoid, menthol is preferred, and l-menthol is more preferred.

Commercially available terpenoids can also be used. A terpenoid may be used individually by 1 type, or may be used in combination of 2 or more type.

When terpenoids are contained as component (A), the content of terpenoids in the ophthalmic composition according to the present embodiment is, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. The total content of terpenoids is preferably 0.00005 to 1 w/v%, more preferably 0.0001 to 0.5 w/v%, and 0.001 to 0.1 w/v%. is more preferably 0.001 to 0.08 w/v%, even more preferably 0.002 to 0.07 w/v%, particularly preferably 0.002 to 0.06 w/v% is more particularly preferred, 0.003 to 0.05 w/v% is even more preferred, and 0.003 to 0.03 w/v% is most preferred.

Tocopherols include tocopherol and its derivatives. Tocopherol may be any of α, β, γ and δ forms, and may be any of d, l and dl forms. -tocopherol, δ-tocopherol. Derivatives of tocopherol include, for example, tocopherol acetate, tocopherol nicotinate, and tocopherol succinate.

As tocopherols, tocopherol acetate is preferred, and d-α-tocopherol acetate is more preferred.

Commercially available tocopherols can also be used. Tocopherols may be used singly or in combination of two or more.

When tocopherols are contained as component (A), the content of tocopherols in the ophthalmic composition according to the present embodiment is, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. As, the total content of tocopherols is preferably 0.00001 to 1.0 w/v%, more preferably 0.0005 to 0.5 w/v%, 0.0005 to 0.1 w /v%, even more preferably 0.0005 to 0.05w/v%, particularly preferably 0.001 to 0.04w/v%, and 0.003 to 0 0.03 w/v % is more particularly preferred, and 0.006 to 0.03 w/v % is even more particularly preferred.

A benzylammonium compound is a quaternary ammonium compound having a benzyl group. Examples of benzylammonium compounds include benzalkonium and benzethonium. Salts of benzylammonium compounds include, for example, benzalkonium chloride and benzethonium chloride.

As the benzylammonium compound or its salt, benzalkonium or its salt is preferable, and benzalkonium chloride is more preferable.

A commercially available benzylammonium compound or a salt thereof can also be used.

When a benzylammonium compound or a salt thereof is contained as the component (A), the content of the benzylammonium compound or a salt thereof in the ophthalmic composition according to the present embodiment may be, for example, , Based on the total amount of the ophthalmic composition, the total content of the benzylammonium compound or its salt is preferably 0.00001 to 0.5 w/v%, preferably 0.00005 to 0.1 w/v% is more preferable, and 0.0001 to 0.02 w/v% is even more preferable.

(A) component may be used individually by 1 type, or may be used in combination of 2 or more types.

The content of component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of component (A), the type and content of other ingredients, the application and formulation form of the ophthalmic composition, and the like. is set as appropriate. As for the content of the component (A), from the viewpoint of exhibiting the effect of the present invention more remarkably, for example, the total content of the component (A) is 0.00001 to 1.0 w based on the total amount of the ophthalmic composition. /v%, more preferably 0.00005 to 0.8w/v%, even more preferably 0.0001 to 0.5w/v%, 0.001 to 0.3w /v% is even more preferred, 0.001 to 0.25w/v% is particularly preferred, 0.001 to 0.20w/v% is even more preferred, and 0.001 to More particularly preferably 0.15 w/v%, even more particularly preferably 0.001 to 0.12 w/v%, particularly preferably 0.001 to 0.08 w/v%, 0.001 to 0.06 w/v% is most preferred.

<(B) Component>
The ophthalmic composition according to the present embodiment preferably further contains (B) a buffering agent (also simply referred to as "component (B)"). When the ophthalmic composition further contains component (B), the effects of the present invention are exhibited more remarkably. Further, when the ophthalmic composition further contains the component (B), even when the ophthalmic composition containing the component (A) is housed in a container made of a resin containing a cyclic olefin, It has the effect of suppressing changes in odors, such as maintaining fragrant properties or improving odors. The buffer includes inorganic buffers and organic buffers, and is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

Inorganic buffers are buffers derived from inorganic acids. Examples of inorganic buffers include borate buffers, phosphate buffers, carbonate buffers and the like.

Boric acid buffers include boric acid or salts thereof (alkali metal borates, alkaline earth metal borates, etc.). Phosphate buffers include phosphoric acid and salts thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Carbonic acid buffers include carbonic acid or salts thereof (alkali metal carbonates, alkaline earth metal carbonates, etc.). Borate or phosphate hydrates may also be used as the borate buffer or phosphate buffer. More specific examples include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Alternatively, salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.) can be exemplified.

Organic buffers are buffers derived from organic acids or organic bases. Examples of organic buffers include citrate buffers, acetate buffers, Tris buffers, epsilon aminocaproate buffers, AMPD buffers and the like.

Citric acid buffers include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). The acetate buffer includes acetic acid or salts thereof (alkali metal acetate, alkaline earth metal acetate, etc.). In addition, a citrate or acetate hydrate may be used as the citrate buffer or acetate buffer. More specific examples include citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as a citric acid buffer; acetic acid as an acetic acid buffer Alternatively, salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) can be exemplified. Tris buffers include, for example, trometamol or salts thereof (trometamol hydrochloride, etc.). Epsilon aminocaproic acid buffers include, for example, epsilon aminocaproic acid or salts thereof. AMPD buffers include, for example, 2-amino-2-methyl-1,3-propanediol or salts thereof.

Among these buffers are borate buffers (such as a combination of boric acid and borax), phosphate buffers (such as a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and epsilon aminocaprone. Acid buffers (eg, epsilon aminocaproic acid) are preferred.

Commercially available buffers can also be used. A buffering agent may be used individually by 1 type, or may be used in combination of 2 or more types.

The content of component (B) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of component (B), the type and content of other ingredients, the application and formulation form of the ophthalmic composition, and the like. It is set accordingly. As for the content of the component (B), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of the component (B) is 0.0001 to 9 w/v based on the total amount of the ophthalmic composition. %, more preferably 0.001 to 9 w/v%, even more preferably 0.005 to 8 w/v%, further preferably 0.01 to 8 w/v%. More preferably, 0.01 to 6 w/v% is particularly preferable.

The content ratio of component (B) to component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the use, formulation form, etc. of the ophthalmic composition. As for the content ratio of component (B) to component (A), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of component (A) contained in the ophthalmic composition according to the present embodiment is 1 mass. The total content of component (B) is preferably 1 to 7,000 parts by mass, more preferably 5 to 4,000 parts by mass, even more preferably 10 to 2,000 parts by mass, It is even more preferably 10 to 1000 parts by mass, particularly preferably 10 to 600 parts by mass, even more preferably 10 to 400 parts by mass, and even more preferably 20 to 300 parts by mass. , 20 to 200 parts by weight, particularly preferably 20 to 180 parts by weight, most preferably 20 to 150 parts by weight.

The ophthalmic composition according to this embodiment may further contain a nonionic surfactant. When the ophthalmic composition further contains a nonionic surfactant, the effects of the present invention are exhibited more remarkably.

Specific examples of nonionic surfactants include, for example, POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60) , POE sorbitan fatty acid esters such as POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80); POE (5) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 5) , POE (10) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 10), POE (20) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 20), POE (30) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 30 ), POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), POE (80) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 80), POE hydrogenated castor oil such as POE (100) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 100); POE (3) castor oil (polyoxyethylene castor oil 3), POE (10) castor oil (polyoxyethylene POE castor oils such as ethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35), POE (70) castor oil (polyoxyethylene castor oil 70); POE such as POE (9) lauryl ether Alkyl ether; POE-POP alkyl ether such as POE(20) POP(4) cetyl ether; POE(20) POP(20) glycol (Pluronic L44), POE(42) POP(67) glycol (poloxamer 403, Pluronic P123 ), POE(54) POP(39) glycol (Poloxamer 235, Pluronic P85), POE(120) POP(40) glycol (Pluronic F87), POE(160) POP(30) glycol (Poloxamer 188, Pluronic F68), POE/POP glycols such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127) and POE (200) POP (70) glycol; polyethylene glycol monostearate such as polyoxyl 10 stearate and polyoxyl 40 stearate; is mentioned. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

As nonionic surfactants, POE sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, POE/POP glycol and polyethylene glycol monostearate are preferable, and polysorbate 80 and polyoxyethylene hydrogenated castor oil 60 are preferred. is more preferred.

Commercially available nonionic surfactants can also be used. A nonionic surfactant may be used individually by 1 type, or may be used in combination of 2 or more type.

The content of the nonionic surfactant in the ophthalmic composition according to the present embodiment is not particularly limited. etc., and is set as appropriate. As for the content of the nonionic surfactant, from the viewpoint of exhibiting the effect of the present invention more remarkably, for example, the total content of the nonionic surfactant is 0.00001 to 10w based on the total amount of the ophthalmic composition. /v%, more preferably 0.0001 to 8 w/v%, even more preferably 0.001 to 5 w/v%, and 0.01 to 4 w/v% is even more preferable, particularly preferably 0.01 to 3 w/v%, more particularly preferably 0.01 to 2 w/v%, and 0.01 to 1.5 w/v% More particularly preferably 0.01 to 0.8 w/v%, even more particularly preferably 0.01 to 0.6 w/v%, particularly preferably 0.01 to 0.5 w/v% is most preferred.

The ophthalmic composition according to the present embodiment further contains vitamins (excluding tocopherols), antioxidants, oils, preservatives (excluding benzylammonium compounds or salts thereof), polysaccharides, vinyl compounds, amino acids. and polyhydric alcohols. These components are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

Vitamins can be appropriately selected from known vitamins and used. Specific examples of vitamins include, for example, vitamin A (retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.), derivatives thereof, fat-soluble vitamins such as salts thereof, vitamin B1, vitamin B2 ( flavin adenine dinucleotide), niacin (nicotinic acid and nicotinamide), pantothenic acid, panthenol, vitamin B6 (pyridoxine, pyridoxal and pyridoxamine), biotin, folic acid and vitamin B12 (cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin ) and salts thereof. Specific examples of vitamin salts include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, calcium pantothenate and sodium pantothenate. Specific examples of vitamin derivatives include, for example, retinol acetate and retinyl palmitate.

Preferred vitamins are cyanocobalamin, flavin adenine dinucleotide, panthenol, pyridoxine, retinol, derivatives thereof, and salts thereof, and more preferred are cyanocobalamin, flavin adenine dinucleotide sodium, panthenol, pyridoxine hydrochloride and retinol palmitate.

Commercially available vitamins can also be used. A vitamin may be used individually by 1 type, or may be used in combination of 2 or more type.

Antioxidants are compounds, and salts thereof, that inhibit detrimental reactions involving oxygen. As the antioxidant, a known antioxidant can be appropriately selected and used.

Specific examples of antioxidants include butylhydroxyanisole, dibutylhydroxytoluene, ascorbic acid and salts thereof.

As the antioxidant, butylhydroxyanisole, dibutylhydroxytoluene, and salts thereof are preferable, and butylhydroxyanisole and dibutylhydroxytoluene are more preferable.

A commercially available antioxidant can also be used. The antioxidants may be used singly or in combination of two or more.

Oils include vegetable oils of plant origin, animal oils of animal origin, and mineral oils, natural or synthetic. As the oil, a known oil can be appropriately selected and used.

Specific examples of oils include soybean oil, rice oil, rapeseed oil, cottonseed oil, sesame oil, safflower oil, almond oil, castor oil, olive oil, cacao oil, camellia oil, sunflower oil, palm oil, linseed oil, perilla oil, Vegetable oils such as shea oil, coconut oil, jojoba oil, grapeseed oil, and avocado oil; animal oils such as beeswax, lanolin (refined lanolin, etc.), orange roughy oil, squalane, and horse oil; and petroleum jelly (white petrolatum, yellow petrolatum, etc.) ) and mineral oils such as liquid paraffin.

Sesame oil, castor oil, beeswax, lanolin, petrolatum and liquid paraffin are preferred as the oil.

Commercially available oils can also be used. One type of oil may be used alone, or two or more types may be used in combination.

Preservatives are compounds with bactericidal or bacteriostatic action, and salts thereof. The antiseptic can be appropriately selected from known antiseptics and antibacterial agents and used.

Specific examples of preservatives include quaternary ammonium compounds (chlorhexidine, alexidine, polyhexanide), alkylpolyaminoethylglycine, benzoic acid, chlorobutanol, sorbic acid, dehydroacetic acid, parabens (e.g., methyl paraoxybenzoate, paraoxy Ethyl benzoate, parahydroxybenzoic acid esters such as propyl parahydroxybenzoate and butyl parahydroxybenzoate), oxyquinoline, phenylethyl alcohol, benzyl alcohol, polyquaterniums, Glokyl (manufactured by Rhodia, trade name), zinc, sulphate and isoxazole, sulfisomidine and sulfamethoxazole, and salts thereof.

Specific examples of preservative salts include alkyldiaminoethylglycine hydrochloride, sodium benzoate, chlorhexidine gluconate, potassium sorbate, sodium dehydroacetate, oxyquinoline sulfate, polyhexanide hydrochloride, polydronium chloride, zinc chloride, sulfiso Midine sodium and sulfamethoxazole sodium.

Preferred preservatives include quaternary ammonium compounds, alkylpolyaminoethylglycine, chlorobutanol, sorbic acid, parabens, phenylethyl alcohol and zinc, polyhexamethylene biguanide, chlorhexidine gluconate, potassium sorbate, alexidine, polyhexanide hydrochloride, Chlorobutanol, potassium sorbate, paraben, phenylethyl alcohol and zinc chloride are more preferred.

A commercially available antiseptic can also be used. Preservatives may be used singly or in combination of two or more.

Polysaccharides include dextrans, acidic polysaccharides, cellulosic polymers and salts thereof. Polysaccharides can be appropriately selected from known polysaccharides and used.

Specific examples of dextran include, for example, dextran 40 and dextran 70.

Acidic polysaccharides are polysaccharides having acidic groups. Specific examples of acidic polysaccharides include acidic mucopolysaccharides such as hyaluronic acid, chondroitin sulfate, chitosan, heparin, heparan, alginic acid, and derivatives thereof (eg, acetylated forms), xanthan gum, and gellan gum.

As the cellulosic polymer compound, cellulose and polymer compounds in which the hydroxyl groups of cellulose are substituted with other functional groups can be used. Functional groups that substitute hydroxyl groups of cellulose include, for example, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, carboxymethoxy and carboxyethoxy groups. Specific examples of cellulosic polymer compounds include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, and carboxyethylcellulose.

As polysaccharides, dextran, acidic polysaccharides, cellulosic polymer compounds and salts thereof are preferable, and dextran, acidic polysaccharides, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are more preferable. Polysaccharides, xanthan gum, gellan gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are more preferred, and dextran, chondroitin sulfate, hyaluronic acid, xanthan gum, gellan gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are preferred. Especially preferred.

Commercially available polysaccharides can also be used. One type of polysaccharide may be used alone, or two or more types may be used in combination.

Vinyl compounds include vinyl polymer compounds and salts thereof. The vinyl compound can be appropriately selected from known vinyl compounds and used.

Specific examples of vinyl compounds include vinyl alcohol polymers such as polyvinyl alcohol (completely or partially saponified), vinylpyrrolidone polymers such as polyvinylpyrrolidone, carboxyvinyl polymers, and salts thereof.

The vinyl compound is preferably polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer and salts thereof, more preferably polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone. K30, polyvinylpyrrolidone K90, carboxyvinyl polymer and salts thereof are more preferred, and polyvinyl alcohol, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, carboxyvinyl polymer and salts thereof are particularly preferred.

A commercially available vinyl compound can also be used. A vinyl compound may be used individually by 1 type, or may be used in combination of 2 or more type.

Amino acids are compounds having an amino group and a carboxyl group in the molecule, derivatives thereof, and salts thereof. Amino acids can be appropriately selected from known amino acids and used.

Amino acids include, for example, amino acids and salts thereof, and amino acid derivatives and salts thereof. Specific examples of amino acids and salts thereof include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid and aminovaleric acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid; and diamino acids such as arginine and lysine. monocarboxylic acids, and salts thereof. Specific examples of amino acid derivatives and salts thereof include amino acid derivatives such as aminoethylsulfonic acid (taurine) and salts thereof. Amino acids may be in D-, L- or DL-form.

Preferred amino acids are monoaminodicarboxylic acids, amino acid derivatives and salts thereof, more preferred are glycine, aspartic acid, glutamic acid, arginine, taurine and salts thereof, glycine, potassium aspartate, magnesium aspartate and sodium glutamate. , arginine and taurine are more preferred.

Commercially available amino acids can also be used. Amino acids may be used singly or in combination of two or more.

A polyhydric alcohol is an alcohol having two or more hydroxyl groups in the molecule and a salt thereof. The polyhydric alcohol can be appropriately selected from known polyhydric alcohols and used.

Examples of polyhydric alcohols include aliphatic polyhydric alcohols such as glycerin, propylene glycol, ethylene glycol, diethylene glycol, and polyethylene glycol (300, 400, 4000, 6000) (aliphatic alcohols having two or more hydroxyl groups in ), sugar alcohols such as glucose, lactose, maltose, fructose, sorbitol, maltitol, mannitol, xylitol, and trehalose, and salts thereof.

As polyhydric alcohols, aliphatic polyhydric alcohols and sugar alcohols are preferred, and glycerin, propylene glycol, polyethylene glycol, sorbitol and mannitol are more preferred.

A commercially available polyhydric alcohol can also be used. A polyhydric alcohol may be used individually by 1 type, or may be used in combination of 2 or more type.

The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, and more preferably 4.5 to 9.0. is more preferred, 4.5 to 8.5 is even more preferred, and 5.0 to 8.5 is even more preferred.

The ophthalmic composition according to the present embodiment can be adjusted to have an osmotic pressure ratio within a range acceptable to living organisms, if necessary. An appropriate osmotic pressure ratio can be appropriately set according to the application, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, and 0.6 to 3.0. , more preferably 0.8 to 2.2, even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 16th revision of the Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (freezing point depression method). The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then placing it in a desiccator (silica gel). After allowing to cool, 0.900 g thereof is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution) can be used.

The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The viscosity of the ophthalmic composition according to the present embodiment is, for example, a viscosity at 20° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Tosangyo Co., Ltd., rotor; 1°34′×R24) of 0.01 to It is preferably 10000 mPa·s, more preferably 0.05 to 8000 mPa·s, even more preferably 0.1 to 1000 mPa·s.

The ophthalmic composition according to the present embodiment contains, in addition to the above components, an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components within a range that does not impair the effects of the present invention. good too. The ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs described in the 2012 version of the Approval Standards for Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Specific examples of components used in ophthalmic drugs include the following components.

Antihistamines: for example, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, olopatadine hydrochloride, levocabastine hydrochloride and the like.
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, acitazanolast and the like.
Steroid agents: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide and the like.
Antiphlogistic agents: for example, glycyrrhetinic acid, dipotassium glycyrrhizinate, pranoprofen, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, berberine, sodium azulene sulfonate, lysozyme chloride, zinc sulfate, zinc lactate, licorice and the like.
Decongestants: tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Ocular muscle modulating agents: For example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate, and the like.
Astringents: For example, zinc white, zinc lactate, zinc sulfate and the like.
Local anesthetics: eg lidocaine, procaine and the like.
Others: rebamipide and the like.

In the ophthalmic composition according to the present embodiment, various additives are appropriately selected in accordance with conventional methods according to the application and formulation form, as long as the effects of the present invention are not impaired, and one or more additives are added. may be used in combination and contained in an appropriate amount. Examples of such additives include various additives described in the Encyclopedia of Pharmaceutical Excipients 2007 (edited by the Japan Pharmaceutical Excipients Association).
Typical ingredients include the following additives.
Carrier: For example, an aqueous solvent such as water or hydrous ethanol.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and the like.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, Plastibase and the like.
pH adjuster: hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine and the like.
Stabilizers: sodium formaldehyde sulfoxylate (Rongalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine and the like.
Anionic surfactants: polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, N-acyl taurate and the like.
Amphoteric surfactants: betaine lauryldimethylaminoacetate and the like.

When the ophthalmic composition according to the present embodiment contains water, the water content is, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. , preferably 80 w/v% or more and less than 100 w/v%, more preferably 85 w/v% or more and 99.5 w/v% or less, and 90 w/v% or more and 99.2 w/v% or less is more preferred.

The water used in the ophthalmic composition according to this embodiment may be pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such water include distilled water, ordinary water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 16th revision of the Japanese Pharmacopoeia.

The ophthalmic composition according to the present embodiment can be prepared by adding and mixing a desired amount of component (A) and, if necessary, other components to a desired concentration. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration or the like.

The ophthalmic composition according to this embodiment can take various formulation forms depending on the purpose. Formulations include, for example, liquids, gels, semi-solids (ointments, etc.) and the like.

The ophthalmic composition according to the present embodiment includes, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be dropped while wearing contact lenses), artificial tears, and eye washes. (Also referred to as eye wash or eye wash. Eye wash includes eye wash that can be washed while wearing contact lenses.), contact lens composition [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaning preservative, etc.]. The term "contact lens" includes hard contact lenses and soft contact lenses (both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

When the ophthalmic composition according to the present embodiment is an eye drop, the usage and dosage are not particularly limited as long as they are effective and have few side effects. In the case of children as described above, a method of using 1 to 2 drops per time, 4 times a day, and a method of using 2 to 3 drops per time, 5 to 6 times a day can be exemplified.

<Container>
The ophthalmic composition according to the present embodiment is placed in a container formed of a resin containing cyclic olefins (also referred to simply as “resin containing cyclic olefins”) in part or all of the portion that contacts the ophthalmic composition. accommodated and provided.

Examples of the cyclic olefin-containing resin include a resin containing a cyclic olefin polymer (also simply referred to as "COP-containing resin") and a resin containing a cyclic olefin copolymer (also simply referred to as "COC-containing resin"). mentioned. As the cyclic olefin-containing resin, a COC-containing resin is preferable from the viewpoint of exhibiting the effects of the present invention more significantly.

The COP-containing resin is not particularly limited as long as it contains a polymer obtained by copolymerizing a single cyclic olefin, a polymer obtained by copolymerizing two or more cyclic olefins, or a hydrogenated product thereof. The COP-containing resin preferably contains a ring-opening polymer of a cyclic olefin or a hydrogenated product thereof. Moreover, the COP-containing resin preferably contains an amorphous polymer.

The COC-containing resin is not particularly limited as long as it contains a polymer obtained by copolymerizing a cyclic olefin and a non-cyclic olefin, or a hydrogenated product thereof.

Cyclic olefins include, for example, vinyl-containing monocyclic or polycyclic cycloalkanes, monocyclic or polycyclic cycloalkenes, and derivatives thereof. Preferred cyclic olefins are norbornene, tetracyclododecene, and derivatives thereof. Acyclic olefins include, for example, α-olefins such as ethylene, propylene, 1-butene, 1-pentene, and 1-hexene.

As the COP-containing resin, a resin containing a polymer of a cyclic olefin having a norbornene skeleton or a hydrogenated product thereof is preferable from the viewpoint of exhibiting the effects of the present invention more remarkably. As the COC-containing resin, a resin containing a polymer obtained by copolymerizing norbornene and ethylene is preferable from the viewpoint of exhibiting the effects of the present invention more remarkably. A polymer obtained by copolymerizing a cyclic olefin and a non-cyclic olefin may contain other monomers as constituents of the polymer.

In addition, cyclic olefin-containing resins include, for example, polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE)), polypropylene (PP), polycarbonate, (meth ) Other polymers such as acrylic polymers, polystyrene (PS), polyethylene naphthalate (PEN), polyethylene terephthalate (PET), and polyarylates may also be included. From the viewpoint of exhibiting the effects of the present invention more remarkably, the cyclic olefin-containing resin preferably further contains polyethylene (PE) and/or polypropylene (PP). When the cyclic olefin-containing resin contains polyethylene (PE) and / or polypropylene (PP), the content of polyethylene (PE) and / or polypropylene (PP) is 0 based on the total amount of the cyclic olefin-containing resin. It is preferably 0.001 to 50% by mass, more preferably 0.01 to 45% by mass, even more preferably 0.05 to 40% by mass, and 0.1 to 35% by mass. is even more preferable, particularly preferably 0.5 to 30% by mass, more particularly preferably 1 to 25% by mass, even more preferably 2 to 20% by mass, even more preferably 5 to 15% by mass is most preferred. In addition, when the cyclic olefin-containing resin contains polyethylene (PE) and/or polypropylene (PP), the content of polyethylene (PE) and/or polypropylene (PP) is 10 mass based on the mass of the entire container. % or more, more preferably 15% by mass or more, still more preferably 20% by mass or more, even more preferably 25% by mass or more, and 30% by mass or more. It is particularly preferred, more preferably 35% by mass or more, even more preferably 38% by mass or more, and most preferably 40% by mass or more. In addition, when the cyclic olefin-containing resin contains polyethylene (PE) and/or polypropylene (PP), the content of polyethylene (PE) and/or polypropylene (PP) is 95 mass based on the mass of the entire container. % or less, more preferably 90% by mass or less, even more preferably 85% by mass or less, even more preferably 80% by mass or less, and 75% by mass or less. Particularly preferably, it is 70% by mass or less, more preferably 65% by mass or less, and most preferably 60% by mass or less.

In the cyclic olefin-containing resin according to the present embodiment, the content of the polymer obtained by copolymerizing the cyclic olefin and the non-cyclic olefin is 55 to 98% by mass based on the total amount of the cyclic olefin-containing resin. Preferably, it is 60 to 98% by mass, more preferably 65 to 98% by mass, even more preferably 70 to 98% by mass, and particularly preferably 75 to 98% by mass. , more preferably 80 to 98% by mass, even more preferably 85 to 98% by mass, most preferably 90 to 95% by mass. In addition, in the cyclic olefin-containing resin according to the present embodiment, the content of the polymer obtained by copolymerizing the cyclic olefin and the non-cyclic olefin is preferably 10% by mass or more based on the mass of the entire container. It is more preferably 15% by mass or more, still more preferably 20% by mass or more, even more preferably 25% by mass or more, particularly preferably 30% by mass or more, and 35% by mass or more. It is more particularly preferred that the content is 40% by mass or more, and most preferably 45% by mass or more. In addition, in the cyclic olefin-containing resin according to the present embodiment, the content of the polymer obtained by copolymerizing the cyclic olefin and the non-cyclic olefin is preferably 95% by mass or less based on the mass of the entire container. It is more preferably 90% by mass or less, still more preferably 85% by mass or less, even more preferably 80% by mass or less, particularly preferably 75% by mass or less, and 70% by mass or less. It is more particularly preferable that the content is 65% by mass or less, and most preferably 60% by mass or less.

The cyclic olefin-containing resin may contain additives such as stabilizers and modifiers. Moreover, the cyclic olefin copolymer-containing resin may be reinforced by including a reinforcing agent such as glass fiber.

As the cyclic olefin-containing resin, commercially available products can be used without particular limitation. Commercially available COP-containing resins include, for example, Zeonex (registered trademark) (manufactured by Nippon Zeon Co., Ltd.) and Zeonor (registered trademark) (manufactured by Nippon Zeon Co., Ltd.). Commercially available COC-containing resins include, for example, TOPAS (registered trademark) (manufactured by Polyplastics) and APEL (registered trademark) (manufactured by Mitsui Chemicals, Inc.).

The type of the cyclic olefin-containing resin container may be a container commonly used in the field of ophthalmology. It may be a care liquid storage container (including a contact lens cleaning solution storage container, a contact lens storage solution storage container, a contact lens disinfectant storage container, a contact lens multi-purpose solution storage container, etc.). The types of the cyclic olefin-containing resin container are preferably an eye drop container, a contact lens wetting liquid container, and a contact lens care liquid container. The term "contact lens" includes hard contact lenses and soft contact lenses (both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses). Portions of these containers that come into contact with the ophthalmic composition include, for example, the inner plug, the perforated inner plug, and the inner surface of the container (the innermost layer when the container has a structure consisting of multiple layers).

In the cyclic olefin-containing resin container according to the present embodiment, part or all of the portion that comes into contact with the ophthalmic composition is formed of a cyclic olefin-containing resin. For example, when the cyclic olefin-containing resin container is a container having a perforated inner plug (nozzle), only the perforated inner plug portion may be formed of the cyclic olefin-containing resin, and the storage portion other than the perforated inner plug may be formed. etc. may be formed of a resin containing cyclic olefins, or the entire container may be formed of a resin containing cyclic olefins.

The cyclic olefin-containing resin container may be formed of a cyclic olefin-containing resin at a part of the portion that comes into contact with the ophthalmic composition. It is preferable that the entire contacting portion is made of a resin containing cyclic olefins. When part of the container is formed of a resin containing cyclic olefins, the type of resin forming the other part is not particularly limited, but examples include polyethylene terephthalate (PET), polystyrene (PS), acrylonitrile butadiene styrene ( ABS), polycarbonate, polyethylene (PE), polypropylene (PP), polymethyl methacrylate, ethylene-vinyl acetate copolymer and ethylene-vinyl alcohol copolymer. It may be

The shape and volume of the cyclic olefin-containing resin container are not particularly limited, and may be appropriately set according to the application. In addition, the cyclic olefin-containing resin container may be a container that accommodates a composition that is used a large number of times (e.g., 25 times or more), or a container that is used a few times (e.g., 2 times or more and less than 25 times). It can be a container that holds a single dose of the composition, or it can be a container that holds a single dose of the composition.

When the cyclic olefin-containing resin container is a container for containing an eye drop or a contact lens wetting solution, for example, the volume may be 0.01 mL or more and 50 mL or less, preferably 0.05 mL or more and 40 mL or less. .1 mL or more and 25 mL or less is more preferable. When the cyclic olefin-containing resin container is a container for containing an eye drop or a contact lens wetting solution and is used a small number of times (e.g., 2 times or more and less than 25 times) or a single time, for example, The volume may be 0.01 mL or more and 7 mL or less, preferably 0.05 mL or more and 6 mL or less, more preferably 0.1 mL or more and 5 mL or less, and still more preferably 0.1 mL or more and 3 mL or less. , more preferably 0.2 mL or more and 2 mL or less, and particularly preferably 0.2 mL or more and 1 mL or less. In addition, when the cyclic olefin-containing resin container is a container for containing an eyewash or contact lens care liquid, the volume may be, for example, 40 mL or more and 600 mL or less, preferably 45 mL or more and 550 mL or less. When the cyclic olefin-containing resin container is a container for containing an eye wash or a contact lens care solution and is used a small number of times (for example, 2 times or more and less than 25 times) or a single time, for example, , the volume may be 10 mL or more and 150 mL or less, preferably 10 mL or more and 130 mL or less.

The cyclic olefin-containing resin container may be a container in which a composition containing portion and a spout are integrally formed, or may be a container having a perforated inner plug. The cyclic olefin-containing resin container is a container for containing an eye drop or a contact lens wetting solution, is used a few times (for example, 2 times or more and less than 25 times) or is a single use container, and has a volume of 0.5 times. When it is 1 mL or more and 3 mL or less, it is preferably a container in which a composition containing portion and an outlet are integrally molded.

The cyclic olefin-containing resin container is preferably a container having transparency from the viewpoint that confirmation of foreign matter, confirmation of the remaining amount, etc. can be observed with the naked eye. The cyclic olefin-containing resin container may be colorless or colored as long as it has transparency. The cyclic olefin-containing resin container may be a container having transparency that ensures internal visibility to the extent that the inside can be observed with the naked eye. The entire surface of the container does not necessarily have to have uniform transparency. As for the transparency, for example, the maximum value of light transmittance in the visible light region with a wavelength of 400 to 700 nm (hereinafter also referred to as "maximum light transmittance") of the resin container containing cyclic olefins may be 50% or more. , is preferably 60% or more, more preferably 70% or more, and even more preferably 80% or more. The maximum light transmittance can be obtained from each light transmittance obtained by measuring the light transmittance every 10 nm between wavelengths of 400 to 700 nm using, for example, a microplate reader or the like. In addition, when the inner plug portion is formed of a resin containing cyclic olefins and the maximum light transmittance cannot be measured due to its shape, size, etc., the transparency when observed with the naked eye is similar. The transparency of the inner plug can also be obtained by obtaining the maximum light transmittance of a commercially available resin containing cyclic olefins. In addition, the transparency of the inner plug can be confirmed by performing the insoluble foreign matter inspection method specified in the Japanese Pharmacopoeia.

The thickness of the cyclic olefin-containing resin container may be 0.01 to 3.0 mm, preferably 0.05 to 2.0 mm, from the viewpoint of more remarkably exhibiting the effect of improving liquid drainage. It is more preferably 0.1 to 1.5 mm, even more preferably 0.1 to 1.2 mm, even more preferably 0.1 to 1.0 mm, and 0.1 to 0.8 mm. is particularly preferred, 0.1 to 0.6 mm is more preferred, 0.1 to 0.5 mm is even more preferred, and 0.1 to 0.4 mm is most preferred. .

The amount per drop of the ophthalmic composition according to the present embodiment is preferably designed to be 1 to 99 μL, more preferably 1 to 79 μL, from the viewpoint of exhibiting the effects of the present invention more significantly. more preferably 7 to 79 μL, even more preferably 13 to 79 μL, and particularly preferably 33 to 79 μL.

The volume of the ophthalmic composition, the amount per drop, the size of the container, the shape of the inner plug, and the shape of the spout are adjusted so that the ophthalmic composition according to the present embodiment can be used a few times or only once. etc. can be designed as appropriate.

The ophthalmic composition according to this embodiment can also be provided as an ophthalmic composition in a resin container containing cyclic olefins. The present invention can also be regarded as an ophthalmic product (eye drops, eye washes, contact lens-related products, etc.) containing the ophthalmic composition of the present invention in a cyclic olefin-containing resin container.

[2. Suppression of Wetting of Resins Containing Cyclic Olefins]
The ophthalmic composition according to this embodiment is inhibited from wetting a resin containing cyclic olefins. Therefore, as one embodiment of the present invention, the ophthalmic composition comprises blending (A) one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof. Provided is a method for imparting an effect of suppressing wetting to a resin containing cyclic olefins to an object. Further, as another embodiment of the present invention, the ophthalmic composition comprises blending (A) one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof. A method for suppressing wetting of a resin containing cyclic olefins in a composition is provided.

The type and content of component (A), the type and content of other components, and the formulation form and use of the ophthalmic composition in this embodiment are described in [1. ophthalmic composition].

[3. Suppression of changes in odor]
The ophthalmic composition according to the present embodiment, which is housed in a container made of a resin containing a cyclic olefin, retains its fragrance or suppresses its odor when it further contains the component (B). The change in odor is suppressed. Therefore, as one embodiment of the present invention, an ophthalmic composition contained in a container made of a resin containing cyclic olefins contains (A) a group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof. Provided is a method for imparting an odor change suppressing action to the ophthalmic composition, which comprises blending one or more selected from the above and (B) a buffering agent. In another embodiment of the present invention, an ophthalmic composition containing (A) a terpenoid, a tocopherol, and a benzylammonium compound and a salt thereof is contained in a container made of a resin containing a cyclic olefin. Provided is a method for suppressing change in odor of the ophthalmic composition, which comprises blending one or more selected from the group and (B) a buffer.

The type and content of components (A) and (B), the type and content of other components, and the formulation form and application of the ophthalmic composition in the present embodiment are described in [1. ophthalmic composition].

Further, as one embodiment of the present invention, there is provided a method for using an ophthalmic composition, wherein the ophthalmic composition is (A) one or more selected from the group consisting of terpenoids, tocopherols, and benzylammonium compounds and salts thereof. and contained in a container formed of a resin containing cyclic olefins, and is used a few times or once. In addition, especially in a small number of times or a single use, suppression of liquid residue and improvement of liquid drainage are required in order to exhibit the desired pharmacological effect. , and benzylammonium compounds and salts thereof. , and the effect of improving liquid depletion is exhibited.

The present invention will be specifically described below based on test examples, but the present invention is not limited to these.

[Test method: Dynamic contact angle (advancing angle) measurement method]
Using a contact angle meter DM-501 (manufactured by Kyowa Interface Science Co., Ltd.), the dynamic contact angle (advancing angle) of each test liquid was measured according to the measurement procedure of the expansion/contraction method of the same contact angle meter. The dynamic contact angle (advancing angle) is the contact angle as the solid-liquid interface moves.

Specifically, each sheet-shaped container material with a thickness of 0.2 mm (low density polyethylene (LDPE), linear low density polyethylene (LLDPE), polypropylene (PP), cyclic olefin copolymer (COC; TOPAS8007 (polyplastic Sus Co.))) or a resin containing two or more of these) was placed on the stage of the contact angle meter, and the test liquid was set in the dispenser. At room temperature, a droplet of 1 μL of the test liquid was dropped on each container material to form a hemispherical droplet. Next, the tip of the liquid discharge part of the dispenser was quickly brought into contact with the upper hemisphere. In this state, the test liquid was continuously discharged at a discharge rate of 6 μL/sec, and the shape of the droplet was photographed 15 times from the side every 0.1 sec. In order to match the measurement conditions, the test liquids paired when calculating the rate of change of the dynamic contact angle were continuously measured under the same temperature conditions (room temperature) using the same material of each container.

Next, using the analysis software FAMAS of the same contact angle meter, the left and right contact angles were obtained for each image. Here, the contact angle is the tangent line drawn to the test liquid from the contact point P between the surface of each sheet-shaped container material with a thickness of 0.2 mm, the test liquid and air, and the tangent line drawn to the surface of each sheet-shaped container material. means the angle on the side containing the test solution among the angles formed by There are two contact points P, left and right, for each droplet. As the droplet spreads according to the discharge of the test liquid, the contact angle changed and then became almost constant. Therefore, the average value of the left and right contact angles is calculated for each image, and when the average values are arranged in the order in which the images were taken and five continuous values are selected, the standard deviation of the five average values is first 2. The first average value (average value of the left and right contact angles in the first captured image among the 5 average values) when it became 0° or less was taken as the measured value of the dynamic contact angle in the same measurement. For all test liquids, no standard deviation greater than 2.0° was observed after the standard deviation first became 2.0° or less. Dynamic contact angle measurements were also obtained according to the above criteria when the contact angle did not change during the process of droplet expansion.

For each test liquid, the above operation was repeated three times, and the average value of the obtained three measured values was taken as the dynamic contact angle of the test liquid. The standard deviation of the three measurements was 2.0° or less for all test liquids.

[Test Example 1: Evaluation of dynamic contact angle (advancing angle) (1)]
A test solution for each test example shown in Tables 1 to 3 was prepared by a conventional method. The unit of each component in Tables 1-3 is w/v %.

The dynamic contact angle for each test liquid was determined (average of three measurements) according to the procedure set forth in Test Methods above. Then, the rate of change of the dynamic contact angle of the test liquid of the test example with respect to the corresponding formulation liquid was calculated according to the following [Formula 1]. The calculated results are shown in Tables 1-3.
[Formula 1] Rate of change in dynamic contact angle (%) = {(dynamic contact angle of test liquid/dynamic contact angle of corresponding prescription liquid) -1} × 100
The corresponding formulation solution is the formulation of each test solution excluding component (A), and Test Example 1-1 for Test Example 1-2 and Test Example 1- 3, Test Example 1-5 for Test Example 1-6, Test Example 1-7 for Test Example 1-8, Test Example 1-9 for Test Example 1-10, and Test Example for Test Example 1-12 1-11, Test Example 1-13 for Test Examples 1-14 and 1-15, Test Example 1-16 for Test Example 1-17, Test Example 1-18 for Test Examples 1-19 to 1-22 , Test Example 1-23 for Test Examples 1-24 and 1-25, Test Example 1-26 for Test Example 1-27, Test Example 1-28 for Test Example 1-29, and Test Example 1-31 is Test Example 1-30.

As shown in Table 1, when low-density polyethylene (LDPE) or polypropylene (PP) is used as the container material, the dynamic contact angle of the test liquid containing component (A) is It can be seen that it is smaller than the dynamic contact angle. That is, it has been clarified that the composition containing the component (A) has a small dynamic contact angle with respect to a resin containing low-density polyethylene (LDPE) or polypropylene (PP) and is easily wetted.

On the other hand, as shown in Tables 2 and 3, when a cyclic olefin copolymer (COC) is used as the container material, the dynamic contact angle of the test liquid containing component (A) is lower than that of the test liquid not containing component (A). It is larger than the contact angle and can suppress wetting of the container. In addition, when a resin containing low-density polyethylene (LDPE) in addition to the cyclic olefin copolymer (COC) is used as the container material, the dynamic contact angle is further increased compared to the resin containing only the cyclic olefin copolymer (COC). It is large and can further suppress wetting of the container. As the container material, a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) and having a polyethylene (PE) content of more than 10 w/w% and not more than 50 w/w% is used. A similar effect was shown even when

[Test Example 2: Evaluation of dynamic contact angle (advancing angle) (2)]
A test solution for each test example shown in Table 4 and a formulation solution corresponding to each test example were prepared by a conventional method. The unit of each component in Table 4 is w/v %. The corresponding formulation solution is a formulation obtained by removing components other than component (A) from the formulation of each test solution and adjusting the pH with appropriate amounts of hydrochloric acid and sodium hydroxide (remainder is purified water). Moreover, the container material is all cyclic olefin copolymers (COC).

The dynamic contact angle of the test liquid of each example was determined (average of three measurements) according to the procedure shown in the test method above. Then, the rate of change of the dynamic contact angle of the test liquid of each test example with respect to the corresponding formulation liquid was calculated according to the following [Equation 2].
[Formula 2] Rate of change in dynamic contact angle (%) = {(dynamic contact angle of test liquid in each test example/dynamic contact angle of corresponding prescription liquid) -1} x 100

In addition, the osmotic pressure ratio of the test solution was obtained as the ratio of the osmotic pressure of the test solution to 286 mOsm (the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution) based on the 16th revision of the Japanese Pharmacopoeia. Specifically, it was measured based on the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. As the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution), a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was used.

As shown in Table 4, the ophthalmic composition containing the component (A) in combination with the component (B) has a larger dynamic contact angle than the test solution containing only the component (A). can suppress wetting. The same effect can be obtained even when a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) with a polyethylene (PE) content of 50 w/w% or less is used as the container material. showed that.

[Test Example 3: Evaluation of dynamic contact angle (advancing angle) (3)]
A test solution for each test example shown in Tables 5 to 7 was prepared by a conventional method. The unit of each component in Tables 5-7 is w/v%. The corresponding formulation solution is the formulation of each test solution excluding the component (A) and ethanol. For Test Examples 3-6 to 3-8, the corresponding prescription liquid was used as Test Example 3-5. Moreover, the container material is all cyclic olefin copolymers (COC).

The dynamic contact angle of the test liquid of each test example was determined according to the procedure shown in the test method above (average value of three measurements). Then, the rate of change of the dynamic contact angle of the test liquid of each test example with respect to the corresponding prescription liquid was calculated according to the following [Equation 3].
[Formula 3] Rate of change in dynamic contact angle (%) = {(dynamic contact angle of test liquid in each test example/dynamic contact angle of corresponding prescription liquid) -1} x 100

As shown in Tables 5 to 7, test liquids with a water content of 84.892% (w/v) or more have a large dynamic contact angle and can suppress wetting of the container. The same effect can be obtained even when a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) with a polyethylene (PE) content of 50 w/w% or less is used as the container material. showed that.

[Test Example 4: Evaluation of dynamic contact angle (advancing angle) (4)]
A test solution for each test example shown in Tables 8 to 10 was prepared by a conventional method. The unit of each component in Tables 8-10 is w/v %. The corresponding formulation solution is a formulation obtained by removing the component (A) from the formulation of each test solution. Moreover, the container material is all cyclic olefin copolymers (COC).

The dynamic contact angle of the test liquid of each test example was determined according to the procedure shown in the test method above (average value of three measurements). However, the contact angle (average value of the left and right contact angles) was measured three times during the time when 10% of the liquid droplet amount dropped onto each container material was discharged, and the average value was calculated as the dynamic contact of the test example. angled. Tables 8 to 10 show the droplet amount, which is the droplet amount when the dynamic contact angle is measured, and the sum of the droplet deposition amount and the ejection amount. Next, the rate of change of the dynamic contact angle of the test liquid of each test example with respect to the corresponding prescription liquid was calculated according to the following [Equation 4].
[Formula 4] Rate of change in dynamic contact angle (%) = {(dynamic contact angle of test liquid in each test example/dynamic contact angle of corresponding prescription liquid) -1} x 100

As shown in Tables 8 and 10, in the test liquid containing l-menthol and the test liquid containing benzalkonium chloride as the component (A), in the test liquid having a droplet volume of 79 μl or less, the component (A) The dynamic contact angle with respect to the test liquid that does not contain is increased, and wetting of the container can be suppressed.

Further, as shown in Table 9, in the test solution containing d-α-tocopherol acetate as the component (A), the test solution with a droplet volume of 99 μl or less does not contain the component (A) Dynamic contact with the test solution The angle becomes large, and wetting of the container can be suppressed.

The same effect can be obtained even when a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) with a polyethylene (PE) content of 50 w/w% or less is used as the container material. showed that.

[Test Example 5: Sensory evaluation (1)]
A test solution for each test example shown in Table 11 was prepared by a conventional method, and 1 mL each was filled in a 5 mL capacity glass ampoule tube. The unit of each component in Table 11 is w/v %. Further, a piece of container material having a width of 2 mm, a length of 20 mm and a thickness of 0.2 mm was immersed one by one and quickly sealed. The container material is a cyclic olefin copolymer (COC; TOPAS8007 (manufactured by Polyplastics)). Next, a heat treatment was performed in a constant temperature bath at 60° C. for 5 hours. After that, 20 μL of each test solution before and after the heat treatment was dropped on the arms of four subjects who are sensitive to odors, spread with a finger in a circular shape with a diameter of about 2 cm, smelled, and evaluated by the VAS (Visual Analog Scale) method. That is, regarding "fragrance", at both ends of a straight line of 100 mm, "not at all felt" was set to 0 mm, and "strongly felt" was set to 100 mm. The distance (mm) from the point of 0 mm was measured, and the average value of 4 people was calculated and used as the VAS value of the test solution. Then, the VAS change value before and after the heat treatment was calculated by the following [Formula 5-1]. After that, according to the following [Equation 5-2], the aromatic retention rate of the test liquid of the test example relative to Test Example 5-1 in which the material of the container was not immersed was calculated. The calculated results are shown in Table 11.
[Formula 5-1] VAS change value = VAS value of test liquid before heat treatment - VAS value of test liquid after heat treatment [Formula 5-2] Fragrance retention (%) = {1-(of each test example VAS change value / VAS change value of Test Example 5-1)} × 100

As shown in Table 11, Test Example 5-2, in which the COC-containing resin container material was immersed in the test solution containing component (A), was a test in which the COC-containing resin container material was not immersed in the test solution containing component (A). Compared to Example 5-1, the fragrance retention rate deteriorated. On the other hand, in Test Examples 5-3 to 5-8 containing components (A) and (B), Test Example 5-1 does not immerse the COC-containing resin container material in the test solution containing component (A). Compared to , the retention rate of fragrance was improved. The same effect can be obtained even when a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) with a polyethylene (PE) content of 50 w/w% or less is used as the container material. showed that.

[Test Example 6: Sensory evaluation (2)]
A test solution for each test example shown in Table 12 was prepared by a conventional method, and 1 mL each was filled in a 5 mL capacity glass ampoule tube. The unit of each component in Table 12 is w/v %. Further, a piece of container material having a width of 2 mm, a length of 20 mm and a thickness of 0.2 mm was immersed one by one and quickly sealed. The container material is a cyclic olefin copolymer (COC; TOPAS8007 (manufactured by Polyplastics)) or a container material containing 90 w/w% COC and 10 w/w% low density polyethylene (LDPE). Next, a heat treatment was performed in which the film was allowed to stand at 70° C. for two days in a constant temperature bath. After that, 20 μL of each test solution before and after the heat treatment was dropped on the arms of four subjects who are sensitive to odors, spread with a finger in a circular shape with a diameter of about 2 cm, smelled, and evaluated by the VAS (Visual Analog Scale) method. That is, regarding "odor", at both ends of a straight line of 100 mm, 0 mm indicates "no smell" and 100 mm indicates "very bad smell". The distance (mm) from the point of 0 mm was measured, and the average value of 4 people was calculated and used as the VAS value of the test solution. Next, the odor improvement rate before and after the heat treatment was calculated according to the following [Equation 6]. The calculated results are shown in Table 12.
[Formula 6] Odor improvement rate (%) = {1-(VAS value of test liquid after heat treatment/VAS value of test liquid before heat treatment)} x 100

As shown in Table 12, Test Examples 5-10 containing component (A) deteriorated in odor after heat treatment. On the other hand, in Test Examples 5-11 to 5-17 containing the components (A) and (B), the odor was improved after the heat treatment. As the container material, a resin containing a cyclic olefin copolymer (COC) and polyethylene (PE) and having a polyethylene (PE) content of more than 10 w/w% and not more than 50 w/w% is used. A similar effect was shown even when

[Test Example 7: Evaluation of dynamic contact angle (advancing angle) (5)]
A test solution for each test example shown in Tables 13 to 16 was prepared by a conventional method. The unit of each component in Tables 13-16 is w/v %. The container material is a resin containing a cyclic olefin copolymer (COC; TOPAS8007 (manufactured by Polyplastics Co., Ltd.)), or a resin containing COC and low density polyethylene (LDPE) or linear low density polyethylene (LLDPE). , the unit of each component contained in the container material in Tables 13 to 16 is w/w%.

The dynamic contact angle for each test liquid was determined (average of three measurements) according to the procedure set forth in Test Methods above. Then, the rate of change of the dynamic contact angle of the test liquid of the test example with respect to the corresponding formulation liquid was calculated according to the following [Equation 7]. The calculated results are shown in Tables 13-16.
[Formula 7] Rate of change in dynamic contact angle (%) = {(dynamic contact angle of test liquid/dynamic contact angle of corresponding prescription liquid) -1} x 100
The corresponding formulation liquids are Test Examples 1-13 for Test Examples 7-1 to 7-6, Test Examples 7-7 and Test Examples 7-10 to 7-7 for Test Examples 7-8 and 7-9. -12 for Test Example 1-13, Test Examples 7-14 to 7-17 for Test Example 7-13, Test Examples 7-19 to 7-24 for Test Example 7-18, Test Example 7-26 to 7-28 is Test Example 7-25, and Test Examples 7-30 to 7-32 are Test Example 7-29.

When COC is used as the container material, the dynamic contact angle of the test liquid containing the component (A) is larger than the dynamic contact angle of the test liquid not containing the component (A), and wetting of the container can be suppressed. . In addition, when a resin containing LDPE or LLDPE in addition to COC is used as a container material, the dynamic contact angle is further increased compared to a resin containing only COC, and wetting of the container can be further suppressed. In particular, the resins containing COC and LLDPE showed even greater dynamic contact angles.

[Test Example 8: Sensory Evaluation (3)]
A test solution for each test example shown in Table 17 was prepared by a conventional method, and 1 mL each was filled in a 5 mL capacity glass ampoule tube. The unit of each component in Table 17 is w/v %. Further, a piece of container material having a width of 2 mm, a length of 20 mm and a thickness of 0.2 mm was immersed one by one and quickly sealed. The container material is a resin containing a cyclic olefin copolymer (COC; TOPAS8007 (manufactured by Polyplastics)), or a resin containing COC and low density polyethylene (LDPE) or linear low density polyethylene (LLDPE). The unit of each component contained in the container material in 17 is w/w%. Next, a heat treatment was performed in a constant temperature bath at 60° C. for 5 hours. After that, 20 μL of each test solution before and after the heat treatment was dropped on the arms of four subjects who are sensitive to odors, spread with a finger in a circular shape with a diameter of about 2 cm, smelled, and evaluated by the VAS (Visual Analog Scale) method. That is, regarding "fragrance", at both ends of a straight line of 100 mm, "not at all felt" was set to 0 mm, and "strongly felt" was set to 100 mm. The distance (mm) from the point of 0 mm was measured, and the average value of 4 people was calculated and used as the VAS value of the test solution. Then, the VAS change value before and after the heat treatment was calculated by the following [Formula 8-1]. Then, according to the following [Equation 8-2], the aromatic retention rate of the test liquid of the test example relative to Test Example 8-1 in which the container material was not immersed was calculated. The calculated results are shown in Table 17.
[Formula 8-1] VAS change value = VAS value of test liquid before heat treatment - VAS value of test liquid after heat treatment [Formula 8-2] Fragrance retention (%) = {1-(of each test example VAS change value / VAS change value of Test Example 8-1)} × 100

Test Example 8-2, in which the COC-containing resin container material was immersed in the test solution containing component (A), compared with Test Example 8-1 in which the COC-containing resin container material was not immersed in the test solution containing component (A). As a result, the fragrance retention deteriorated. On the other hand, in Test Examples 8-3 to 8-7 containing components (A) and (B), Test Example 8-1 does not immerse the COC-containing resin container material in the test solution containing component (A). Compared to , the retention rate of fragrance was improved. In addition, in Test Examples 8-4 to 8-7 using resins containing COC and LDPE or COC and LLDPE as container materials, the fragrance retention rate was further improved compared to Test Example 8-1. In particular, when a resin containing COC and LLDPE was used as the material of the container, the fragrance retention rate was further improved (Test Examples 8-6 and 8-7).

[Test Example 9: Sensory Evaluation (4)]
A test solution for each test example shown in Table 18 was prepared by a conventional method, and 1 mL each was filled in a 5 mL capacity glass ampoule tube. The unit of each component in Table 18 is w/v%. Further, a piece of container material having a width of 2 mm, a length of 20 mm and a thickness of 0.2 mm was immersed one by one and quickly sealed. The container material is a resin containing a cyclic olefin copolymer (COC; TOPAS8007 (manufactured by Polyplastics)), or a resin containing COC and low density polyethylene (LDPE) or linear low density polyethylene (LLDPE). The unit of each component contained in the container material in 18 is w/w%. Next, a heat treatment was performed in which the film was allowed to stand at 70° C. for two days in a constant temperature bath. After that, 20 μL of each test solution before and after the heat treatment was dropped on the arms of four subjects who are sensitive to odors, spread with a finger in a circular shape with a diameter of about 2 cm, smelled, and evaluated by the VAS (Visual Analog Scale) method. That is, regarding "odor", at both ends of a straight line of 100 mm, 0 mm indicates "no smell" and 100 mm indicates "very bad smell". The distance (mm) from the point of 0 mm was measured, and the average value of 4 people was calculated and used as the VAS value of the test solution. Next, the odor improvement rate before and after the heat treatment was calculated according to the following [Equation 9]. The calculated results are shown in Table 18.
[Formula 9] Odor improvement rate (%) = {1-(VAS value of test liquid after heat treatment/VAS value of test liquid before heat treatment)} x 100

Test Example 9-1 containing component (A) deteriorated in odor after the heat treatment. On the other hand, in Test Examples 9-2 to 9-5 containing components (A) and (B), the odor was improved after the heat treatment. In Test Examples 9-3 to 9-5 using resins containing COC and LDPE or COC and LLDPE as the container material, the odor was further improved compared to Test Example 9-1, and particularly the container material Using a resin containing COC and LLDPE as the odor further improved the odor (Test Examples 9-4 and 9-5).

From the above results, the ophthalmic composition according to the present embodiment has the effect of suppressing wetting, and therefore liquid residue is suppressed. As a result, contamination due to contamination by bacteria and foreign substances can be suppressed, and high sanitary quality required for delicate ocular mucosa tissue can be realized. In addition, since the ophthalmic composition according to the present embodiment has the effect of suppressing wetting, the liquid drainage is improved. This makes it possible to reduce variations in the amount of drops required for use on the eye or contact lens, which are relatively small sites. Furthermore, since the ophthalmic composition according to the present embodiment has the effect of suppressing changes in odor, it is possible to suppress generation of offensive odors due to contact with containers.

Claims (4)

(A) An ophthalmic composition containing one or more selected from the group consisting of menthol, tocopherols, and benzylammonium compounds and salts thereof, wherein part or all of the portion in contact with the ophthalmic composition is a cyclic olefin An ophthalmic composition (provided by the following general formula ( 1)

[In the formula, X represents a halogen atom. ] or a salt thereof, or an aqueous composition containing a solvate thereof). The ophthalmic composition according to claim 1, further comprising (B) a buffering agent. The ophthalmic composition according to claim 1 or 2, wherein the water content is 80 w/v% or more and less than 100 w/v% based on the total amount of the ophthalmic composition. 4. The container according to any one of claims 1 to 3, wherein the container formed of a resin containing a cyclic olefin copolymer and polyethylene has a maximum light transmittance of 50% or more in the visible light region with a wavelength of 400 to 700 nm. ophthalmic composition.