Ophthalmic components

Abstract

To provide a containerized ophthalmic composition with excellent stability of azulene or azulene derivative as a component. [Solution] An ophthalmic composition contained in a container, wherein the ophthalmic composition contains azulene or an azulene derivative, and the filling rate of the ophthalmic composition in the container is 80% by volume or more.

Description

Technical Field

[0001] The present disclosure relates to an ophthalmic composition.

Background Art

[0002] Azulene and its derivatives are known as components having an anti-inflammatory effect and may be incorporated into ophthalmic compositions. For example, Patent Document 1 discloses an aqueous ophthalmic composition containing (A) a zinc salt and at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid and their salts, and (B) at least one selected from the group consisting of chondroitin sulfate and its salts, wherein the content of component (B) is 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] An ophthalmic composition contained in a container (ophthalmic composition in a container) may be stored for a long period of time after its production until it is used. Therefore, the components in the ophthalmic composition preferably exist stably over a long period of time. One aspect of the present disclosure aims to provide an ophthalmic composition in a container having excellent stability of azulene or an azulene derivative as a contained component.

Means for Solving the Problems

[0005] The present inventors have found that in a containerized ophthalmic composition containing azulene or an azulene derivative, the stability of azulene or an azulene derivative can be improved by keeping the filling rate of the ophthalmic composition in the container within a specific range. This disclosure provides, in several aspects, the following [1] to [5]. [1] An ophthalmic composition contained in a container, wherein the ophthalmic composition contains azulene or an azulene derivative, and the filling rate of the ophthalmic composition in the container is 80% by volume or more. [2] The ophthalmic composition according to [1], further comprising at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, allantoin, vitamin E, berberine and its salts, terpenoids, and vegetable oils. [3] The ophthalmic composition according to [1], further comprising at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, and allantoin. [4] The ophthalmic composition according to [1], further comprising at least one selected from the group consisting of vitamin E, berberine and its salts, terpenoids, and vegetable oils. [5] A method for improving the stability of azulene or an azulene derivative in an ophthalmic composition comprising azulene or an azulene derivative, comprising filling the ophthalmic composition into a container, wherein the filling rate of the ophthalmic composition in the container is 80% by volume or more. [Effects of the Invention]

[0006] According to one aspect of this disclosure, a containerized ophthalmic composition is provided that exhibits excellent stability of azulene or azulene derivative as a constituent component. [Modes for carrying out the invention]

[0007] The embodiments of this disclosure are described in detail below. This disclosure is not limited to the embodiments described below.

[0008] An ophthalmic composition according to one embodiment contains azulene or an azulene derivative. The azulene derivative is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The azulene derivative may be substituted azulene or a salt thereof. A substituted azulene is a compound in which one or more of the hydrogen atoms of azulene are substituted with substituents such as alkyl groups or sulfo groups. A substituted azulene may be a compound in which one or more of the hydrogen atoms of azulene are substituted with substituents of at least one of alkyl groups and sulfo groups.

[0009] Examples of substituted azulenes include 1,4-dimethyl-7-isopropylazulene (guaiazulene), 1,4-dimethyl-7-isopropylazulene-3-sulfonic acid (guaiazulene sulfonic acid or azulene sulfonic acid), 1,4-dimethyl-7-ethylazulene (chamazulene), 1,4-dimethyl-7-ethylazulene-3-sulfonic acid (chamazulene sulfonic acid), and 4,8-dimethyl-2-isopropylazulene (vetiveazulene).

[0010] The salt of substituted azulene may be, for example, an alkali metal salt of substituted azulene. Examples of alkali metal salts of substituted azulene include sodium salts and potassium salts. Examples of salts of substituted azulene include alkali metal salts of azulene sulfonic acid, such as sodium azulene sulfonate. The above azulene derivatives may be used individually or in combination of two or more.

[0011] The content of azulene or azulene derivative in the ophthalmic composition may be 0.001 w / v% or more, 0.002 w / v% or more, or 0.004 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.03 w / v% or less. The content of azulene or azulene derivative in the ophthalmic composition may be 0.001 to 1 w / v%, 0.001 to 0.05 w / v%, 0.002 to 0.05 w / v%, 0.004 to 0.03 w / v%, 0.004 to 0.02 w / v%, or 0.01 to 0.02 w / v%, based on the total amount of the ophthalmic composition.

[0012] The ophthalmic composition may further contain at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, allantoin, vitamin E, berberine and its salts, terpenoids, and vegetable oils.

[0013] When an ophthalmic composition further contains, in addition to azulene or an azulene derivative, at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, and allantoin, the stability of azulene or an azulene derivative tends to decrease particularly. However, in the case of the above-mentioned containerized ophthalmic composition, because the filling rate of the ophthalmic composition in the container is within a specific range, the stability of azulene or an azulene derivative is excellent even when the ophthalmic composition contains both azulene or an azulene derivative and at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, and allantoin.

[0014] If the ophthalmic composition contains cyanocobalamin, the cyanocobalamin content in the ophthalmic composition may be 0.001 w / v% or more, 0.002 w / v% or more, or 0.004 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.03 w / v% or less. If the ophthalmic composition contains cyanocobalamin, the cyanocobalamin content in the ophthalmic composition may be 0.001-1 w / v%, 0.001-0.1 w / v%, 0.001-0.05 w / v%, 0.002-0.05 w / v%, 0.004-0.03 w / v%, 0.004-0.02 w / v%, or 0.01-0.02 w / v%, based on the total amount of the ophthalmic composition.

[0015] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains cyanocobalamin, the content of cyanocobalamin per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.01 parts by mass or more, 0.1 parts by mass or more, or 0.2 parts by mass or more, and may be 100 parts by mass or less, 10 parts by mass or less, or 5 parts by mass or less. When the ophthalmic composition contains cyanocobalamin, the content of cyanocobalamin per 1 part by mass of azulene or azulene derivative may be 0.01 to 100 parts by mass, 0.1 to 10 parts by mass, or 0.2 to 5 parts by mass.

[0016] If the ophthalmic composition contains aminoethylsulfonic acid, the content of aminoethylsulfonic acid in the ophthalmic composition may be 0.0001 w / v% or more, 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, 0.05 w / v% or more, or 0.1 w / v% or more, based on the total amount of the ophthalmic composition, and may be 5 w / v% or less, 4 w / v% or less, 3 w / v% or less, 2 w / v% or less, or 1 w / v% or less. If the ophthalmic composition contains aminoethylsulfonic acid, the content of aminoethylsulfonic acid in the ophthalmic composition may be 0.0001 to 5 w / v%, 0.001 to 4 w / v%, 0.05 to 3 w / v%, or 0.1 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0017] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains aminoethylsulfonic acid, the content of aminoethylsulfonic acid per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 0.1 parts by mass or more, 1 part by mass or more, or 5 parts by mass or more, and may be 1000 parts by mass or less, 500 parts by mass or less, or 250 parts by mass or less. When the ophthalmic composition contains aminoethylsulfonic acid, the content of aminoethylsulfonic acid per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 0.1 to 1000 parts by mass, 1 to 500 parts by mass, or 5 to 250 parts by mass.

[0018] Vitamin A may be retinol and its derivatives. Specific examples of retinol derivatives include retinyl palmitate, retinyl acetate, retinal, and retinoic acid. Vitamin A is preferably a retinol derivative, more preferably retinyl palmitate or retinyl acetate, and even more preferably retinyl palmitate.

[0019] If the ophthalmic composition contains vitamin A, the total vitamin A content in the ophthalmic composition may be 0.0005 w / v% or more, 0.0015 w / v% or more, 0.0025 w / v% or more, 0.004 w / v% or more, or 0.005 w / v% or more, based on the total amount of the ophthalmic composition, and may be 0.15 w / v% or less, 0.09 w / v% or less, 0.08 w / v% or less, 0.06 w / v% or less, or 0.03 w / v% or less. If the ophthalmic composition contains vitamin A, the total vitamin A content in the ophthalmic composition may be 0.0005-0.15 w / v%, 0.0015-0.15 w / v%, 0.0025-0.09 w / v%, 0.004-0.08 w / v%, 0.005-0.06 w / v%, or 0.005-0.03 w / v%, based on the total amount of the ophthalmic composition.

[0020] When the ophthalmic composition contains vitamin A, the total content of vitamin A in the ophthalmic composition may be 1,000 units / 100 mL or more, 3,000 units / 100 mL or more, 5,000 units / 100 mL or more, 8,000 units / 100 mL or more, or 10,000 units / 100 mL or more, based on the total amount of the ophthalmic composition, and may be 250,000 units / 100 mL or less, 180,000 units / 100 mL or less, 150,000 units / 100 mL or less, 130,000 units / 100 mL or less, 100,000 units / 100 mL or less, or 50,000 units / 100 mL or less. Also, when the ophthalmic composition contains vitamin A, the total content of vitamin A in the ophthalmic composition may be 1,000 - 250,000 units / 100 mL, 3,000 - 180,000 units / 100 mL, 5,000 - 150,000 units / 100 mL, 8,000 - 130,000 units / 100 mL, 10,000 - 100,000 units / 100 mL, or 10,000 - 50,000 units / 100 mL. Here, the "unit" means the international unit (IU) determined by the method described in the method for quantifying vitamin A in the 17th revised Japanese Pharmacopoeia, etc. For example, in each article of pharmaceuticals in the 17th revised Japanese Pharmacopoeia, in the case of retinol acetate, it is described that it contains 2.5 million units or more of vitamin A per 1 g, and in the case of retinol palmitate, it contains 1.5 million units or more of vitamin A per 1 g.

[0021] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains vitamin A, the total content of vitamin A relative to 1 part by mass of the content of azulene or an azulene derivative in the ophthalmic composition may be 0.1 part by mass or more, 0.5 part by mass or more, or 1 part by mass or more, and may be 200 parts by mass or less, 100 parts by mass or less, or 75 parts by mass or less. When the ophthalmic composition contains vitamin A, the total content of vitamin A relative to 1 part by mass of the content of azulene or an azulene derivative in the ophthalmic composition may be 0.1 - 200 parts by mass, 0.5 - 100 parts by mass, or 1 - 75 parts by mass.

[0022] Furthermore, if the ophthalmic composition contains vitamin A, the total vitamin A content (International Units (IU)) per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 10,000 units or more, 100,000 units or more, or 500,000 units or more, and may be 50 million units or less, 20 million units or less, 12.5 million units or less, 5 million units or less, or 2.5 million units or less. Furthermore, if the ophthalmic composition contains vitamin A, the total vitamin A content (International Units (IU)) per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 10,000 to 20 million units, 100,000 to 12.5 million units, or 500,000 to 2.5 million units.

[0023] In chondroitin sulfate and its salts, the salt of chondroitin sulfate (chondroitin sulfate ester) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of chondroitin sulfate salts include alkali metal salts and alkaline earth metal salts of chondroitin sulfate. Examples of alkali metal salts of chondroitin sulfate include sodium salt and potassium salt. Examples of alkaline earth metal salts of chondroitin sulfate include magnesium salt and calcium salt. The above chondroitin sulfate and its salts may be used individually or in combination of two or more. It is preferable that chondroitin sulfate and its salts contain sodium chondroitin sulfate (sodium chondroitin sulfate ester).

[0024] When the ophthalmic composition contains at least one of chondroitin sulfate and its salts, the content of chondroitin sulfate and its salts in the ophthalmic composition may be 0.01 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more, 0.3 w / v% or more, 0.5 w / v% or more, or 0.8 w / v% or more, based on the total amount of the ophthalmic composition, and may be 4 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, or 1 w / v% or less. When the ophthalmic composition contains at least one of chondroitin sulfate and its salts, the content of chondroitin sulfate and its salts may be 0.01 - 4 w / v%, 0.05 - 4 w / v%, 0.1 - 3 w / v%, 0.3 - 2 w / v%, 0.5 - 1.5 w / v%, or 0.8 - 1.3 w / v%, based on the total amount of the ophthalmic composition, and may also be 0.05 - 0.5 w / v% or 0.05 - 1 w / v%.

[0025] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains at least one of chondroitin sulfate and its salts, the content of chondroitin sulfate and its salts relative to 1 part by mass of the content of azulene or an azulene derivative in the ophthalmic composition may be, for example, 0.1 part by mass or more, 1 part by mass or more, 5 parts by mass or more, 10 parts by mass or more, 25 parts by mass or more, 50 parts by mass or more, or 80 parts by mass or more, and may be 1000 parts by mass or less, 500 parts by mass or less, or 250 parts by mass or less. When the ophthalmic composition contains chondroitin sulfate and its salts, the content of chondroitin sulfate and its salts relative to 1 part by mass of the content of azulene or an azulene derivative may be 0.1 - 1000 parts by mass, 1 - 500 parts by mass, 5 - 250 parts by mass, or 10 - 125 parts by mass.

[0026] In aspartic acid and its salts, the salt of aspartic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of aspartic acid salts include alkali metal salts and alkaline earth metal salts of aspartic acid. Examples of alkali metal salts of aspartic acid include sodium salts and potassium salts, and examples of alkaline earth metal salts of aspartic acid include magnesium salts and calcium salts. The above aspartic acid and its salts may be used individually or in combination of two or more. Preferably, the aspartic acid and its salts contain at least one selected from the group consisting of potassium aspartate, magnesium aspartate, and magnesium-potassium aspartate (equal mixture).

[0027] If the ophthalmic composition contains at least one of aspartic acid and its salts, the content of aspartic acid and its salts in the ophthalmic composition may be 0.01 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more, 0.2 w / v% or more, 0.3 w / v% or more, 0.5 w / v% or more, or 0.8 w / v% or more, based on the total amount of the ophthalmic composition, and may be 4 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, or 1 w / v% or less. If the ophthalmic composition contains at least one of aspartic acid and its salts, the content of aspartic acid and its salts may be 0.01-4 w / v%, 0.05-4 w / v%, 0.1-3 w / v%, 0.3-2 w / v%, 0.5-1.5 w / v%, or 0.8-1.3 w / v%, based on the total amount of the ophthalmic composition.

[0028] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains at least one of aspartic acid and its salt, the content of aspartic acid and its salt per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.1 parts by mass or more, 1 part by mass or more, 10 parts by mass or more, 25 parts by mass or more, or 40 parts by mass or more, and may be 1000 parts by mass or less, 500 parts by mass or less, 300 parts by mass or less, 100 parts by mass or less, or 50 parts by mass or less. When the ophthalmic composition contains at least one of aspartic acid and its salt, the content of aspartic acid and its salt per 1 part by mass of azulene or azulene derivative may be 0.1 to 1000 parts by mass, 1 to 500 parts by mass, or 10 to 300 parts by mass.

[0029] If the ophthalmic composition contains allantoin, the allantoin content in the ophthalmic composition may be 0.005 w / v% or more, 0.01 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more, or 0.2 w / v% or more, based on the total amount of the ophthalmic composition, and may be 5 w / v% or less, 4 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1 w / v% or less, or 0.3 w / v% or less. If the ophthalmic composition contains allantoin, the allantoin content in the ophthalmic composition may be 0.005 to 5 w / v%, 0.01 to 4 w / v%, 0.03 to 3 w / v%, 0.06 to 0.3 w / v%, or 0.1 to 0.3 w / v%, based on the total amount of the ophthalmic composition.

[0030] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains allantoin, the content of allantoin per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 0.1 parts by mass or more, 1 part by mass or more, 3 parts by mass or more, 5 parts by mass or more, or 10 parts by mass or more, and may be 1000 parts by mass or less, 500 parts by mass or less, 100 parts by mass or less, or 50 parts by mass or less. When the ophthalmic composition contains allantoin, the content of allantoin per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be 0.1 to 1000 parts by mass, 1 to 500 parts by mass, 5 to 75 parts by mass, or 5 to 30 parts by mass.

[0031] The stability of azulene or azulene derivative can be further improved by including, in addition to azulene or an azulene derivative, at least one selected from the group consisting of vitamin E, berberine and its salts, terpenoids, and vegetable oils in the ophthalmic composition.

[0032] Vitamin E may be tocopherol and its derivatives. Specific examples of tocopherol derivatives include tocopherol acetate, tocopherol succinate, and tocopherol nicotinate. Vitamin E preferably contains a tocopherol derivative, and more preferably contains tocopherol acetate.

[0033] If the ophthalmic composition contains vitamin E, the vitamin E content in the ophthalmic composition may be 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, or 0.03 w / v% or more, based on the total amount of the ophthalmic composition, and may be 2 w / v% or less, 1 w / v% or less, 0.5 w / v% or less, 0.1 w / v% or less, or 0.05 w / v% or less. If the ophthalmic composition contains vitamin E, the vitamin E content in the ophthalmic composition may be 0.001 to 2 w / v%, 0.005 to 1 w / v%, 0.005 to 0.5 w / v%, or 0.01 to 0.05 w / v%, based on the total amount of the ophthalmic composition.

[0034] From the viewpoint of further enhancing the effects of the present invention, if the ophthalmic composition contains vitamin E, the amount of vitamin E per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.01 parts by mass or more, 0.1 parts by mass or more, or 0.25 parts by mass or more, and may be 100 parts by mass or less, 10 parts by mass or less, or 2.5 parts by mass or less. If the ophthalmic composition contains vitamin E, the amount of vitamin E per 1 part by mass of azulene or azulene derivative may be 0.01 to 100 parts by mass, 0.25 to 12.5 parts by mass, or 1 to 5 parts by mass.

[0035] In berberine and its salts, the salt of berberine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The salt of berberine may be, for example, an acid addition salt of berberine. Examples of acid addition salts of berberine include berberine chloride and berberine sulfate. The above berberine and its salts may be used individually or in combination of two or more. It is preferable that the berberine and its salts contain berberine chloride.

[0036] If the ophthalmic composition contains at least one of berberine and its salts, the content of berberine and its salts in the ophthalmic composition may be 0.001 w / v% or more, 0.0025 w / v% or more, 0.005 w / v% or more, or 0.01 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.1 w / v% or less, 0.08 w / v% or less, 0.05 w / v% or less, or 0.025 w / v% or less. If the ophthalmic composition contains at least one of berberine and its salts, the content of berberine and its salts in the ophthalmic composition may be 0.001 to 1 w / v%, 0.005 to 0.1 w / v%, 0.005 to 0.05 w / v%, or 0.01 to 0.025 w / v%, based on the total amount of the ophthalmic composition.

[0037] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains at least one of berberine and its salt, the content of berberine and its salt per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.01 parts by mass or more, 0.1 parts by mass or more, 0.5 parts by mass or more, or 1 part by mass or more, and may be 100 parts by mass or less, 30 parts by mass or less, or 10 parts by mass or less. When the ophthalmic composition contains at least one of berberine and its salt, the content of berberine and its salt per 1 part by mass of azulene or azulene derivative may be 0.01 to 100 parts by mass, 0.1 to 30 parts by mass, 0.5 to 10 parts by mass, or 1 to 10 parts by mass.

[0038] Examples of terpenoids include menthol, menthone, camphor (also known as "camphor"), borneol (also known as "borneol"), geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchene, nerol, myrcene, myrcenol, linalool acetate, and lavandulol. Each terpenoid may be in d-, l-, or dl-form. For example, menthol may be l-menthol, d-menthol, or dl-menthol; camphor may be dl-camphor or d-camphor; and borneol may be dl-borneol or d-borneol. Furthermore, in this specification, terpenoids also include essential oils containing terpenoid compounds (for example, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc.). Terpenoids may be used individually or in combination of two or more.

[0039] From the viewpoint of further enhancing the effects of the present invention, the terpenoid preferably contains at least one selected from the group consisting of menthol, camphor, borneol, menthone, geraniol, terpenoids contained in eucalyptus oil, and terpenoids contained in bergamot oil, more preferably contains at least one selected from the group consisting of menthol, camphor, and borneol, even more preferably contains menthol, and even more preferably contains l-menthol.

[0040] If the ophthalmic composition contains terpenoids, the terpenoid content in the ophthalmic composition may be 0.001 w / v% or more, 0.005 w / v% or more, or 0.008 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.5 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.03 w / v% or less. If the ophthalmic composition contains menthol, the terpenoid content in the ophthalmic composition may be 0.001 to 1 w / v%, 0.001 to 0.5 w / v% or less, 0.005 to 0.1 w / v%, 0.005 to 0.05 w / v%, or 0.008 to 0.03 w / v%, based on the total amount of the ophthalmic composition. Furthermore, if an ophthalmic composition contains an essential oil as a terpenoid, the terpenoid content shall refer to the amount of terpenoid compounds (e.g., menthol) in the essential oil.

[0041] From the viewpoint of further enhancing the effects of the present invention, when the ophthalmic composition contains a terpenoid, the content of the terpenoid per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.01 parts by mass or more, 0.1 parts by mass or more, 0.5 parts by mass or more, or 0.8 parts by mass or more, and may be 100 parts by mass or less, 10 parts by mass or less, or 5 parts by mass or less. When the ophthalmic composition contains a terpenoid, the content of the terpenoid per 1 part by mass of azulene or azulene derivative may be 0.01 to 100 parts by mass, 0.1 to 10 parts by mass, 0.5 to 10 parts by mass, or 0.8 to 5 parts by mass.

[0042] The vegetable oil may include, for example, an oil in which fatty acids are bonded to glycerin. Examples of vegetable oils containing oils in which fatty acids are bonded to glycerin include sesame oil, castor oil, soybean oil, peanut oil, olive oil, avocado oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, and coconut oil. The vegetable oil may be used alone or in combination of two or more types. From the viewpoint of further enhancing the effects according to the present invention, the vegetable oil preferably contains at least one of sesame oil and castor oil, and more preferably contains sesame oil.

[0043] If the ophthalmic composition contains vegetable oil, the vegetable oil content in the ophthalmic composition may be 0.001 w / v% or more, 0.005 w / v% or more, or 0.01 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.5 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.03 w / v% or less. If the ophthalmic composition contains vegetable oil, the vegetable oil content in the ophthalmic composition may be 0.001 to 1 w / v%, 0.001 to 0.5 w / v% or less, 0.005 to 0.1 w / v%, 0.005 to 0.05 w / v%, or 0.008 to 0.03 w / v%, based on the total amount of the ophthalmic composition.

[0044] From the viewpoint of further enhancing the effects of the present invention, if the ophthalmic composition contains vegetable oil, the content of vegetable oil per 1 part by mass of azulene or azulene derivative in the ophthalmic composition may be, for example, 0.01 parts by mass or more, 0.1 parts by mass or more, 0.5 parts by mass or more, or 0.8 parts by mass or more, and may be 100 parts by mass or less, 10 parts by mass or less, or 5 parts by mass or less. If the ophthalmic composition contains vegetable oil, the content of vegetable oil per 1 part by mass of azulene or azulene derivative may be 0.01 to 100 parts by mass, 0.1 to 10 parts by mass, 0.5 to 10 parts by mass, or 0.8 to 5 parts by mass.

[0045] The ophthalmic composition may further contain a buffering agent. Examples of buffering agents include inorganic buffering agents derived from inorganic acids, and organic buffering agents derived from organic acids or organic bases.

[0046] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid and its salts (alkali metal borate, alkaline earth metal borate, etc.). Examples of phosphate buffers include phosphoric acid and its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of carbonate buffers include carbonic acid and its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.). Borates, phosphates, and carbonates may each be in hydrate form.

[0047] Examples of boric acid salts include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Examples of phosphoric acid salts include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, and calcium dihydrogen phosphate. Examples of carbonate salts include sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate.

[0048] Examples of organic buffers include citrate buffers, acetate buffers, lactic acid buffers, succinate buffers, Tris buffers, and AMPD buffers.

[0049] Examples of citrate buffers include citric acid and its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid and its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of lactic acid buffers include lactic acid and its salts (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of succinate buffers include succinic acid and its salts (alkali metal succinate, etc.). Citrates, acetates, lactates, and succinates may each be in hydrate form.

[0050] Examples of citric acid salts include sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate. Examples of acetic acid salts include ammonium acetate, sodium acetate, potassium acetate, and calcium acetate. Examples of lactic acid salts include sodium lactate, potassium lactate, and calcium lactate. Examples of succinic acid salts include monosodium succinate and disodium succinate.

[0051] Examples of Tris buffers include trometamol and its salts (such as trometamol hydrochloride). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol and its salts.

[0052] As a buffering agent, the above-mentioned components can be used individually or in combination of two or more. The buffering agent may, for example, contain boric acid and borax, and may also contain disodium hydrogen phosphate and sodium dihydrogen phosphate. Commercially available buffering agents may also be used.

[0053] The buffering agent content is set appropriately according to the type of buffering agent, the types and amounts of other ingredients, the use of the ophthalmic composition, and the formulation form. The buffering agent content may be 0.01 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more, 0.3 w / v% or more, 0.5 w / v% or more, 0.8 w / v% or more, or 1 w / v% or more, based on the total amount of the ophthalmic composition, and may be 4 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1.3 w / v% or less, or 1 w / v% or less. The buffering agent content may be 0.01 to 4 w / v%, 0.05 to 3 w / v%, 0.1 to 2 w / v%, or 0.3 to 1 w / v%, based on the total amount of the ophthalmic composition.

[0054] The ophthalmic composition may further contain inorganic salts. In this specification, inorganic salts are excluded from those corresponding to the azulene derivatives or buffering agents. The inorganic salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0055] Inorganic salts include metal salts and ammonium salts. Examples of metal salts include metal chlorides and metal sulfides. Examples of metal chlorides include alkali metal chlorides such as sodium chloride and potassium chloride, and alkaline earth metal chlorides such as calcium chloride and magnesium chloride. Examples of metal sulfides include alkali metal sulfides such as sodium sulfate and potassium sulfate, and alkaline earth metal sulfides such as calcium sulfate and magnesium sulfate.

[0056] Examples of ammonium salts include ammonium chloride and ammonium sulfate. Inorganic salts may be used individually or in combination of two or more.

[0057] The inorganic salt content is set appropriately according to the type of inorganic salt, the type and content of other ingredients, the use of the ophthalmic composition, and the formulation form. The inorganic salt content may be 0.0001 w / v% or more, 0.001 w / v% or more, 0.01 w / v% or more, 0.05 w / v% or more, 0.07 w / v% or more, or 0.1 w / v% or more, based on the total amount of the ophthalmic composition, and may be 1 w / v% or less, 0.8 w / v% or less, 0.5 w / v% or less, or 0.3 w / v% or less. The inorganic salt content may also be 0.001 to 1 w / v%, 0.01 to 0.8 w / v%, or 0.1 to 0.5 w / v%, based on the total amount of the ophthalmic composition.

[0058] The ophthalmic composition may further contain a pH adjuster. Examples of pH adjusters include hydrochloric acid (e.g., dilute hydrochloric acid), acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, and diisopropanolamine.

[0059] The ophthalmic composition may further contain a surfactant. If the ophthalmic composition contains at least one selected from the group consisting of vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, allantoin, vitamin E, berberine and its salts, terpenoids, and vegetable oils, it is preferable that it further contains a surfactant.

[0060] Examples of surfactants include nonionic surfactants such as polyoxyethylene polyoxypropylene glycol (poloxamer), polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, tyroxapole, polyoxyethylene sorbitan fatty acid esters (polysorbate), polyoxyl stearate, and polyethylene glycol monostearate; anionic surfactants such as polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, and N-acyl taurine salts; and amphoteric surfactants such as lauryldimethylaminoacetic acid betaine.

[0061] The surfactant may be a nonionic surfactant, and may be one or more selected from the group consisting of polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol monostearate. It is particularly preferable that the surfactant be one or more selected from the group consisting of polysorbate 80, poloxamer 407, POE hydrogenated castor oil 60, POE castor oil 10, and polyoxyl stearate 40. As surfactants, one of these may be used alone, or two or more may be used in combination.

[0062] Examples of polyoxyethylene polyoxypropylene glycols include POE(20)POP(20) glycol (Pluronic® L44), POE(54)POP(39) glycol (Pluronic® P85), POE(120)POP(40) glycol (Pluronic® F87), POE(160)POP(30) glycol (Poloxamer 188, Pluronic® F68), POE(196)POP(67) glycol (Poloxamer 407, Pluronic® F127), and POE(200)POP(70) glycol (Lutrol F127).

[0063] Examples of polyoxyethylene (POE) hydrogenated castor oil include polyoxyethylene (5) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 5), polyoxyethylene (10) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 10), polyoxyethylene (20) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 20), polyoxyethylene (30) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 30), polyoxyethylene (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), polyoxyethylene (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), polyoxyethylene (80) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 80), and polyoxyethylene (100) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 100).

[0064] Examples of polyoxyethylene (POE) castor oil include polyoxyethylene (3) castor oil (polyoxyethylene castor oil 3), polyoxyethylene (10) castor oil (polyoxyethylene castor oil 10), polyoxyethylene (35) castor oil (polyoxyethylene castor oil 35), and polyoxyethylene (70) castor oil (polyoxyethylene castor oil 70).

[0065] Examples of polyoxyethylene sorbitan fatty acid esters include POE(20) sorbitan monolaurate (Polysorbate 20), POE(20) sorbitan monopalmitate (Polysorbate 40), POE(20) sorbitan monostearate (Polysorbate 60), POE(20) sorbitan tristearate (Polysorbate 65), and POE(20) sorbitan oleate (Polysorbate 80). Examples of polyethylene glycol monostearate include polyoxyl 10 stearate and polyoxyl 40 stearate. In the compound names listed above, the number in parentheses indicates the number of moles added.

[0066] The surfactant content in the ophthalmic composition may be 0.01 w / v% or more, 0.05 w / v% or more, 0.1 w / v% or more, or 0.3 w / v% or more, based on the total amount of the ophthalmic composition, and may be 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1 w / v% or less, or 0.5 w / v% or less. The surfactant content may be 0.01 to 3 w / v%, 0.05 to 2 w / v%, 0.1 to 1.0 w / v%, or 0.2 to 0.5 w / v%, based on the total amount of the ophthalmic composition.

[0067] The ophthalmic composition may contain, in addition to the above-mentioned components, an appropriate amount of components selected from various pharmacologically active and physiologically active components, provided that the effects of the present invention are not impaired. The components are not particularly limited, and examples include the active ingredients in ophthalmic drugs listed in the 2017 edition of the Standards for Approval of Manufacturing and Marketing of Over-the-Counter Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, examples of components used in ophthalmic drugs include the following: Antiallergic agents: For example, cromoglycic acid or its salts (e.g., sodium cromoglycate), tranilast, pemirolast potassium, acitazanolest, anlexanox, ibudilast, etc. Antihistamines: For example, chlorpheniramine or its salt (e.g., chlorpheniramine maleate), diphenhydramine or its salt (e.g., diphenhydramine hydrochloride), iproheptine or its salt (e.g., iproheptine hydrochloride), levocabastine or its salt (e.g., levocabastine hydrochloride), ketotifen or its salt (e.g., ketotifen fumarate), pemirolast potassium, olopatadine or its salt (e.g., olopatadine hydrochloride), epinastine or its salt (e.g., epinastine hydrochloride), etc. Anti-inflammatory agents other than azulene or azulene derivatives, allantoin, and berberine and its salts: for example, methyl salicylate, glycol salicylate, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, glycyrrhizic acid or its salts (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate, etc. Steroids: For example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. Ocular muscle modulating agents: For example, cholinesterase inhibitors that have an active site similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc. Vitamins other than cyanocobalamin, vitamin A, and vitamin E: for example, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc. Amino acids other than aminoethylsulfonic acid, and aspartic acid and its salts: for example, L-arginine, glutamic acid, glycine, alanine, lysine, gamma-aminobutyric acid, gamma-aminovaleric acid, trimethylglycine, or their salts. Astringent agents: For example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine, and their salts.

[0068] In ophthalmic compositions, as long as the effects of the present invention are not impaired, various additives may be appropriately selected in addition to the above-mentioned components, according to conventional methods, and one or more may be used in combination in appropriate amounts, depending on the formulation. Examples of such additives include the various additives listed in the 2021 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). The following are examples of typical additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: For example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Base: For example, octyldodecanol, titanium dioxide, potassium bromide, Plastibase, etc. Thickeners: For example, cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides other than chondroitin sulfate and its salts, such as heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. Stabilizers: For example, dibutylhydroxytoluene, butylhydroxyanisole, sodium formaldehyde sulfoxylate (Longalit), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, sodium pyrosulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, potassium iodide, etc. Preservatives, disinfectants, or antibacterial agents: for example, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), Glokill (a trade name of Rhodia Corporation), etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. Glycols: For example, propylene glycol, ethylene glycol, etc. Oils other than vegetable oils: for example, animal oils such as squalane, liquid paraffin, mineral oils such as petrolatum, etc.

[0069] When an ophthalmic composition contains water, the water may be any form that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 17th edition of the Japanese Pharmacopoeia.

[0070] The pH of the ophthalmic composition is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, 4.0 to 9.0, 4.5 to 9.0, 4.5 to 8.5, 5.0 to 8.5, 5.5 to 8.0, 6.0 to 8.0, or 6.0 to 7.5.

[0071] Ophthalmic compositions can be adjusted to an osmotic pressure ratio within a range acceptable to the body, as needed. The osmotic pressure ratio can be appropriately set depending on the application site, dosage form, etc., of the ophthalmic composition, but may be, for example, 0.5-6, 0.4-5, 0.6-3, or 0.8-2. The osmotic pressure ratio is defined as 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 18th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured by referring to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0072] The viscosity of an ophthalmic composition is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. For example, the viscosity of an ophthalmic composition at 20°C, as measured with a rotational viscometer (TV-20 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24), may be 0.1 to 10000 mPa·s, 1 to 3000 mPa·s, 1 to 1000 mPa·s, 1 to 100 mPa·s, 1 to 50 mPa·s, 1 to 10 mPa·s, 1.3 to 5 mPa·s, or 1.5 to 3 mPa·s. The ophthalmic composition may be a liquid, a gel, or a semi-solid (ointment, etc.).

[0073] Ophthalmic compositions can be used, for example, as eye drops (also called eye solutions or eye medicines; eye drops include artificial tears; eye drops also include eye drops that can be used while wearing contact lenses), eye washes (also called eye washes or eye medicines; eye washes also include eye washes that can be used while wearing contact lenses), and contact lens compositions [contact lens insertion solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning and preservation agents), contact lens insertion eye drops used for both contact lens insertion solutions and eye drops used while wearing contact lenses, etc.]. Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic lenses, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0074] The above-mentioned ophthalmic composition is contained in a container, and the filling rate of the ophthalmic composition in the container is 80% by volume or more. In this specification, the filling rate refers to the ratio (%) of the amount of ophthalmic composition (mL) to the volume (mL) of the container in which the ophthalmic composition is contained. In other words, it is calculated by the following formula. Filling rate (%) = Amount of ophthalmic composition filled (mL) / Capacity of the container (mL) × 100 Furthermore, the capacity of the container refers to the maximum volume of the ophthalmic composition that can be contained in the container, as it is sold in its current state, and not to the sales volume indicated on the product. Here, "as sold in its current state" means that, if there are any parts attached to the container at the time of sale (e.g., a nozzle), all such parts are attached.

[0075] The filling rate of the ophthalmic composition in the container may be 85% by volume or more, 88% by volume or more, or 90% by volume or more, and may be 100% by volume or less, or 98% by volume or less, or 95% by volume or less, from the viewpoint of further improving the stability of azulene or azulene derivative.

[0076] The container may be made of glass or plastic, for example. Examples of plastics include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, cyclic olefin copolymers and copolymers of their constituent monomers, and mixtures of two or more of these. The container may be transparent, allowing the contents to be seen, or opaque, making it difficult to see the contents. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0077] The above container may be a multi-dose type that contains enough for multiple uses, or a unit-dose type that contains enough for a single use.

[0078] The container capacity may be, for example, 1 mL or more, 5 mL or more, or 10 mL or more, and may be 30 mL or less, 25 mL or less, or 20 mL or less. The container capacity may be 1 to 30 mL, 5 to 25 mL, or 10 to 20 mL. A container capacity within the above numerical range is more suitable as a multi-dose container.

[0079] Furthermore, the container capacity may be 0.1 mL or more, or 0.2 mL or more, and 3 mL or less, or 1 mL or less. The container capacity may be 0.1 to 3 mL, or 0.2 to 1 mL. A container capacity within the above numerical range is more suitable as a unit dose type container.

[0080] An ophthalmic composition contained in a container may be further contained in a packaging body. One aspect of this disclosure can be considered as a product comprising an ophthalmic composition, a container for containing the ophthalmic composition (primary packaging body), and packaging body for containing the container (secondary packaging body). The packaging body (secondary packaging body) may be, for example, a bag-shaped packaging body. An example of a bag-shaped packaging body is a pillow packaging bag. The packaging body may contain, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride, or mixtures thereof as constituent materials. The packaging body may be formed of a film made of the above constituent materials, or it may be formed of an aluminum laminate film containing the above constituent materials (e.g., polyethylene and polyethylene terephthalate). The packaging body may be formed of a multilayer film made by laminating two or more layers containing the above constituent materials. Furthermore, it is preferable that the volume of the space formed between the enclosing body and the container is 300 V / V% or less, 200 V / V% or less, or 150 V / V% or less, based on the volume of the container.

[0081] The ophthalmic composition, contained in a container, may be packaged together with an oxygen absorber. Examples of oxygen absorbers include oxygen absorbers such as Ageless® (manufactured by Mitsubishi Gas Chemical Company, Inc.).

[0082] The above-mentioned containerized ophthalmic composition can be manufactured by a manufacturing method comprising preparing the ophthalmic composition and filling the ophthalmic composition into a container. The ophthalmic composition can be prepared, for example, by adding and mixing azulene or an azulene derivative and the above-mentioned components, as used as needed, in desired amounts. Preparing the ophthalmic composition may include, for example, dissolving or suspending the above components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

[0083] The above-mentioned ophthalmic composition in a container exhibits excellent stability of azulene or azulene derivative as a component. One aspect of this disclosure is to provide a method for improving the stability of azulene or azulene derivative in an ophthalmic composition containing azulene or an azulene derivative, the method comprising filling the ophthalmic composition into a container, wherein the filling rate of the ophthalmic composition in the container is 80% by volume or more. Specific embodiments of this method can be applied without particular limitation to the specific embodiments described above. [Examples]

[0084] The present invention will be described in more detail below based on the examples. However, the present invention is not limited to these examples.

[0085] <Test 1> 1. Manufacturing of ophthalmic compositions in containers Ophthalmic compositions were prepared according to conventional methods using the types and quantities of each component shown in Table 1, so that the pH was as shown in Table 1. The prepared ophthalmic compositions were filled into eye drop bottles (capacity: 14.0 mL, constituent material: polyethylene terephthalate) at the filling rates shown in Table 2, and the lids were closed to produce the containerized ophthalmic compositions of Test Examples 1 to 5. Each containerized ophthalmic composition was then pillow-packaged (constituent material of the packaging: polyethylene terephthalate and polypropylene (manufactured by TOPPAN Corporation, GL Pillow Film)) together with an oxygen absorber (manufactured by Mitsubishi Gas Chemical Company, Inc., Ageless® FL-10).

[0086] 2. Stability evaluation It is known that the absorption spectrum of an aqueous solution of sodium azulene sulfonate shows an absorption maximum around wavelengths of 368-372 nm. Therefore, each ophthalmic composition in its respective container was stored for one month in a 50°C environment (in a constant temperature bath) in the pillow packaging described above. The stability improvement rate of azulene or azulene derivative (sodium azulene sulfonate) was calculated by measuring the absorbance of light at 370 nm for each ophthalmic composition before and after storage. Specifically, first, the absorption spectra of each ophthalmic composition before and after one month of storage under the above conditions were measured using a spectrophotometer, and the absorbance of light at a wavelength of 370 nm was determined. At this time, the absorbance of the ophthalmic composition in Test Example 1 (100% filling rate) was set to 100, and the absorbance (relative absorbance) of each ophthalmic composition was determined. Using this relative absorbance, the remaining rate of each aqueous ophthalmic composition was calculated as an index for stability evaluation using the following formula 1. [Formula 1] Survival rate (%) = (Relative absorbance after storage / Relative absorbance before storage) × 100 Furthermore, the stability improvement rate due to increased filling density was calculated using Equation 2 below. The results are shown in Table 2. [Formula 2] Stability improvement rate (%) = 100 × (Decrease rate at 70% filling rate - Decrease rate at each filling rate) / Decrease rate at 70% filling rate Note that the rate of decrease in Equation 2 refers to the rate of decrease in content calculated by the following formula. Content reduction rate (%)=100-residual rate

[0087] [Table 1]

[0088] [Table 2]

[0089] <Exam 2> 1. Manufacturing of ophthalmic compositions in containers Ophthalmic compositions were prepared according to conventional methods using the types and quantities of each component shown in Tables 3 to 10. The prepared ophthalmic compositions were filled into eye drop bottles (capacity: 14.0 mL (ophthalmic compositions shown in Tables 3 to 6), 13.6 mL (ophthalmic compositions shown in Tables 7 to 10), constituent material: polyethylene terephthalate) at the filling rates shown in Tables 3 to 10, and the lids were closed to produce the containerized ophthalmic compositions of each comparative example and example. Unless otherwise specified, the units of the formulation amounts shown in Tables 3 to 10 are w / v%, and the amount of retinol palmitate means the amount per 100 mL (IU). Furthermore, each containerized ophthalmic composition was pillow-packaged (constituent material of the packaging: polyethylene terephthalate and polypropylene (TOPPAN Corporation, GL Pillow Film)) together with an oxygen absorber (Mitsubishi Gas Chemical Co., Ltd., Ageless® FL-10).

[0090] 2. Stability evaluation Each container of ophthalmic composition was stored for two months in a 50°C environment (in a constant temperature bath) in the pillow packaging described above. The sodium azulene sulfonate content in each ophthalmic composition before and after storage was quantified by HPLC. The sodium azulene sulfonate content (remaining percentage) in each ophthalmic composition after storage was determined, based on the total mass of each ophthalmic composition, with the sodium azulene sulfonate content in the ophthalmic composition before storage set to 100% by mass. Furthermore, the stability improvement rate due to increased packing density was calculated using the following formula. In the following formula, "decrease rate at 70% packing density" refers to the decrease rate of a comparative example in which the composition of the ophthalmic composition at the time of preparation is the same as that of the example, and the packing density is 70% (volume %). For example, "decrease rate at 70% packing density" refers to the decrease rate of Comparative Example 1 for Examples 1-1 to 1-3, and to the decrease rate of Comparative Example 2 for Examples 2-1 to 2-2. The results are shown in Tables 3 to 6. The percentage decrease for each example or comparative example = 100 - the remaining percentage for each example or comparative example. Stability improvement rate due to increased filling rate (%) = 100 × (Decrease rate at 70% filling rate - Decrease rate for each example) / Decrease rate at 70% filling rate

[0091] Furthermore, for the ophthalmic compositions shown in Tables 4 to 10, the rate of decrease due to the addition of component B to the ophthalmic composition was calculated using the following formula, based on the decrease rate values ​​of two comparative examples that differed only in the presence or absence of component B shown in the table. For example, for Comparative Examples 2 and 3, the "rate of decrease due to component B" was calculated by using the decrease rates of Comparative Examples 2 and 3 as the "rate of decrease after adding component B," and the decrease rate of Comparative Example 1 as the "rate of decrease before adding component B." Similarly, for Comparative Example 5, the "rate of decrease due to component B" was calculated by using the decrease rate of Comparative Example 5 as the "rate of decrease after adding component B," and the decrease rate of Comparative Example 4 as the "rate of decrease before adding component B." A "rate of decrease due to component B" greater than 1 means that in the ophthalmic composition of that composition, the presence of component B together with sodium azulene sulfonate made the stability of azulene more susceptible to decrease. Rate of decrease due to component B = Decrease rate after adding component B / Decrease rate before adding component B

[0092] Similarly, for the ophthalmic compositions shown in Tables 7-10, the rate of decrease resulting from adding component B to the ophthalmic composition was calculated using the above formula, with the decrease rates of two comparative examples differing in the presence or absence of component B shown in the table. For example, the "rate of decrease due to component B" for Comparative Examples 7-10 was calculated by using the decrease rates of Comparative Examples 7-10 as the "rate of decrease after adding component B" and the decrease rate of Comparative Example 6 as the "rate of decrease before adding component B".

[0093] [Table 3]

[0094] [Table 4]

[0095] [Table 5]

[0096] [Table 6]

[0097] [Table 7]

[0098] [Table 8]

[0099] [Table 9]

[0100] [Table 10]

[0101] <Exam 3> 1. Manufacturing of ophthalmic compositions in containers Ophthalmic compositions were prepared according to conventional methods using the types and quantities of each component shown in Table 11. The prepared ophthalmic compositions were filled into eye drop bottles (capacity: 13.6 mL, constituent material: polyethylene terephthalate) at the filling rates shown in Table 11, and the lids were closed to produce the containerized ophthalmic compositions for each comparative example and example. Unless otherwise specified, the units of the blending amounts shown in Table 11 are w / v%. Each containerized ophthalmic composition was then pillow-packaged (constituent material of the packaging: polyethylene terephthalate and polypropylene (manufactured by TOPPAN Corporation, GL Pillow Film)) together with an oxygen absorber (manufactured by Mitsubishi Gas Chemical Company, Inc., Ageless® FL-10).

[0102] 2. Stability evaluation Each container of ophthalmic composition was stored for one month in a 50°C environment (in a constant temperature bath) in the pillow packaging described above. The sodium azulene sulfonate content in each ophthalmic composition before and after storage was quantified by HPLC. The sodium azulene sulfonate content (remaining percentage) in each ophthalmic composition after storage was determined, based on the total mass of each ophthalmic composition, with the sodium azulene sulfonate content in the ophthalmic composition before storage set to 100% by mass. Furthermore, the stability improvement rate due to the addition of component B and the stability improvement rate due to increased filling rate, as shown in the table, were determined using the following formula. In the following formula, "decrease rate at 70% filling rate" refers to the decrease rate of the comparative example, where the composition of the ophthalmic composition at the time of preparation is the same as that of the example, and the filling rate is 70% (volume %). For example, "decrease rate at 70% filling rate" refers to the decrease rate of Comparative Example 11 for Example 11, and to the decrease rate of Comparative Example 12 for Example 12. The results are shown in Table 11. The percentage decrease for each example or comparative example = 100 - the remaining percentage for each example or comparative example. Stability improvement rate due to the addition of component B (%) = 100 × (Decrease rate of Comparative Example 6 - Decrease rate of each comparative example) / Decrease rate of Comparative Example 6 Stability improvement rate due to increased filling rate (%) = 100 × (Decrease rate at 70% filling rate - Decrease rate for each example) / Decrease rate at 70% filling rate

[0103] [Table 11]

[0104] <Examples of formulations> The ophthalmic compositions shown in Tables 12 and 13 were prepared according to conventional methods. The units for the amounts shown in Table 13 are g / 100 mL. The prepared ophthalmic compositions were filled to 80%, 90%, and 95% volume, respectively, and the lids were closed to produce containerized ophthalmic compositions. Each containerized ophthalmic composition was then pillow-packaged with an oxygen absorber.

[0105] [Table 12]

[0106] Table 13

Claims

1. An ophthalmic composition contained in a container, The ophthalmic composition contains azulene or an azulene derivative. An ophthalmic composition in which the filling rate of the ophthalmic composition in the container is 80% by volume or more.

2. The ophthalmic composition according to claim 1, further comprising at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, allantoin, vitamin E, berberine and its salts, terpenoids, and vegetable oils.

3. The ophthalmic composition according to claim 1, further comprising at least one selected from the group consisting of cyanocobalamin, aminoethylsulfonic acid, vitamin A, chondroitin sulfate and its salts, aspartic acid and its salts, and allantoin.

4. The ophthalmic composition according to claim 1, further comprising at least one selected from the group consisting of vitamin E, berberine and its salts, terpenoids, and vegetable oils.

5. A method for improving the stability of azulene or azulene derivative in an ophthalmic composition containing azulene or an azulene derivative, A method comprising filling the ophthalmic composition into a container, wherein the filling rate of the ophthalmic composition in the container is 80% by volume or more.

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