JP2022176929A - ophthalmic composition - Google Patents

Abstract

To provide a new ophthalmic composition.SOLUTION: An ophthalmic composition contains (A) at least one selected from a group consisting of chondroitin sulfate and a salt thereof, (B) at least one selected from a group consisting of neostigmine and a salt thereof and cyanocobalamine and a salt thereof, (C) at least one selected from a group consisting of an imidazoline compound and an antihistamine, and (D) at least one selected from a group consisting of boric acid and a salt thereof, phosphoric acid and a salt thereof, citric acid and a salt thereof and ethylene diamine tetraacetic acid and a salt thereof. A content of the component (A) is 0.7-1.2 w/v% relative to a total amount of the ophthalmic composition.SELECTED DRAWING: None

Description

The present invention relates to ophthalmic compositions.

Chondroitin sulfate or its salt is a type of acidic mucopolysaccharide, and is used in ophthalmic preparations for the purpose of promoting energy metabolism, promoting metabolism and cell respiration to relieve eye fatigue, and replenishing tear components. are blended (for example, Patent Literature 1).

In addition, neostigmine or a salt thereof is blended in ophthalmic preparations for the purpose of improving focus adjusting function and relieving eye fatigue.

JP 2011-148791 A

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

An ophthalmic composition containing chondroitin sulfate or a salt thereof and neostigmine or a salt thereof or cyanocobalamin or a salt thereof at a high concentration (for example, 0.7 w/v% or more, preferably 1.0 w/v% or more) is It was confirmed that there was a large variation in the amount of dripping from the container. The present inventors have found that an ophthalmic composition further containing specific ingredients in addition to high-concentration chondroitin sulfate or a salt thereof and neostigmine or a salt thereof and/or cyanocobalamin or a salt thereof unexpectedly causes variation in the amount of drops. found to suppress

The present invention provides, for example, the following inventions.
[1]
(A) at least one selected from the group consisting of chondroitin sulfate and its salts, (B) at least one selected from the group consisting of neostigmine and its salts, and cyanocobalamin and its salts, and (C) an imidazoline compound. and at least one selected from the group consisting of antihistamines, and (D) at least selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts 1, wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition.
[2] The ophthalmic composition according to [1], wherein the component (C) is at least one selected from the group consisting of tetrahydrozoline and its salts, naphazoline and its salts, and chlorpheniramine and its salts.
[3]
(C) containing at least one selected from the group consisting of tetrahydrozoline and its salts and at least one selected from the group consisting of chlorpheniramine and its salts as the component [1] or [2] An ophthalmic composition as described.
[4]
(A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, (B1) at least one selected from the group consisting of neostigmine and salts thereof, and (B2) from the group consisting of cyanocobalamin and salts thereof and (D) at least one selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts. wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition.

According to the present invention, it is possible to provide an ophthalmic composition containing chondroitin sulfate or a salt thereof and neostigmine or a salt thereof and/or cyanocobalamin or a salt thereof at a high concentration while suppressing variation in the amount of drops.

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.

[(A) component]
The ophthalmic composition according to the present embodiment contains (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof (also referred to simply as "(A) component").

Chondroitin sulfate and salts thereof are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. The molecular weight of chondroitin sulfate and its salts is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, but usually the weight average molecular weight is 01,000 to 100,000. about 50,000 to 70,000, more preferably about 10,000 to 50,000, still more preferably about 20,000 to 45,000, particularly preferably about 20,000 to 30,000.

Salts of chondroitin sulfate include, for example, alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

Chondroitin sulfate and salts thereof are preferably chondroitin sulfate and alkali metal salts of chondroitin sulfate, more preferably chondroitin sulfate and sodium chondroitin sulfate, and still more preferably sodium chondroitin sulfate.

Commercially available chondroitin sulfate and salts thereof can also be used. Chondroitin sulfate and its salt may be used alone or in combination of two or more. Chondroitin sulfates and salts thereof can be used in combination with various weight average molecular weights of chondroitin sulfates and salts thereof. For example, sodium chondroitin sulfate with a weight average molecular weight of 56,000 and sodium chondroitin sulfate with a weight average molecular weight of 25,000 can be used in combination. When used in combination, chondroitin sulfate having a weight average molecular weight of 10,000 to 50,000, preferably 20,000 to 45,000, more preferably 20,000 to 30,000 and a salt thereof are used as starting materials. is preferred.

As used herein, the "weight average molecular weight" can be determined by using gel permeation chromatography in which a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) are connected online. . Specifically, the following conditions are presented.
<Standard sample preparation>
10 mL of 0.1 M sodium nitrate aqueous solution was added to 5 mg of chondroitin sulfate or its salt, and the mixture was gently stirred at room temperature to dissolve completely.
<Conditions for measuring weight average molecular weight>
Apparatus: Gel permeation chromatograph - multi-angle light scatterometer Detector: Differential refractive index detector (Optilab rEX manufactured by Wyatt Technology)
Multi-angle light scattering detector (DAWN HELEOS manufactured by Wyatt Technology)
Column: 2 Shodex OHpak SB-806M HQ (φ7.8 mm × 30 cm, manufactured by Showa Denko)
Solvent: 0.1 M sodium nitrate aqueous solution Flow rate: 0.7 mL/min
Column temperature: 23°C
Detector temperature: 23°C
Injection volume: 0.2 mL
Data processing: Wyatt Technology data processing system (ASTRA)
Although the weight-average molecular weight of chondroitin sulfate and its salt calculated by the above method is not particularly limited, the lower limit of the weight-average molecular weight is exemplified by 10,000 or more, 15,000 or more, and 20,000 or more. Examples of the upper limit of the weight average molecular weight include 50,000 or less, 45,000 or less, 40,000 or less, 35,000 or less, and 30,000 or less. Preferred weight average molecular weight ranges are 10,000 to 50,000, 20,000 to 45,000, and 20,000 to 30,000.

The content of component (A) in the ophthalmic composition according to this embodiment is 0.7 w/v% or more and 1.2 w/v% or less based on the total amount of the ophthalmic composition. Although the lower limit of the content of component (A) is not particularly limited as long as it is 0.7 w/v% or more, it is, for example, 0.8 w/v% or more from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferred, and 0.9 w/v% or more is more preferred. The upper limit of the content of component (A) is not particularly limited as long as it is 1.2 w/v% or less. is preferred. Moreover, the content of the component (A) in the ophthalmic composition according to this embodiment may be 1.0 w/v% based on the total amount of the ophthalmic composition.

[(B) component]
In addition to the component (A), the ophthalmic composition according to the present embodiment is selected from the group consisting of (B) neostigmine and salts thereof (also referred to as "component (B1)"), and cyanocobalamin and salts thereof. It contains at least one type (also referred to as "(B2) component") (these are collectively referred to simply as "(B) component").

[Neostigmine and its salt]
Neostigmine and its salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Salts of neostigmine include, for example, neostigmine methyl sulfate. As neostigmine and its salt, neostigmine methyl sulfate is preferred.

Commercially available neostigmine and salts thereof can also be used. Neostigmine and salts thereof may be used singly or in combination of two or more.

When neostigmine and its salt are used as the component (B), the content of neostigmine and its salt in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of neostigmine and its salt, and the type and content of other compounding ingredients. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of neostigmine and its salts is preferably 0.0001 to 0.05 w/v%, preferably 0.0005 to 0.05 w/v%, based on the total amount of the ophthalmic composition. 01 w/v%, more preferably 0.0008 to 0.008 w/v%, even more preferably 0.001 to 0.005 w/v%.

When neostigmine and its salt are used as the component (B), the content ratio of the neostigmine and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of neostigmine and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of neostigmine and salts thereof is preferably 0.0001 to 0.05 parts by mass, more preferably 0.0005 to 0.01 parts by mass, and more preferably 0.0008 to 0.01 part by mass. 008 parts by mass, more preferably 0.001 to 0.005 parts by mass.

[Cyanocobalamin and its salt]
Cyanocobalamin and its salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Cyanocobalamin and its salts are preferably cyanocobalamin.

Cyanocobalamin and its salt can also use what is marketed. Cyanocobalamin and its salt may be used alone or in combination of two or more.

When cyanocobalamin and its salt are used as the component (B), the content of cyanocobalamin and its salt in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of cyanocobalamin and its salt, and the type and content of other compounding ingredients. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of cyanocobalamin and its salts is 0.0001 to 5 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.0005 to 1 w/v%, more preferably 0.001 to 1 w/v%, even more preferably 0.002 to 0.1 w/v% Preferably, 0.004 to 0.02 w/v% is particularly preferred.

When cyanocobalamin and its salt are used as the component (B), the content ratio of the cyanocobalamin and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of cyanocobalamin and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of cyanocobalamin and its salts is preferably 0.0001 to 5 parts by mass, more preferably 0.0005 to 1 part by mass, and 0.001 to 1 part by mass. is more preferable, 0.002 to 0.1 parts by mass is even more preferable, and 0.004 to 0.02 parts by mass is particularly preferable.

[(C) component]
In addition to components (A) and (B), the ophthalmic composition according to the present embodiment includes at least one selected from the group consisting of (C) imidazoline compounds and antihistamines (also referred to simply as "(C) component"). ).

[Imidazoline compound and its salt]
The imidazoline compound and its salt are compounds and its salt having an imidazoline ring in the molecule. The imidazoline compound and its salt are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

Specific examples of imidazoline compounds and salts thereof include tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, tramazoline, timazoline, methizoline and salts thereof. As the imidazoline compound and its salt, tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride), tetrahydrozoline nitrate (tetrahydrozoline nitrate), and naphazoline hydrochloride (naphazoline hydrochloride) are preferable, and tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride) is more preferable.

Commercially available imidazoline compounds and salts thereof can also be used. An imidazoline compound and its salt may be used individually by 1 type, or may be used in combination of 2 or more type.

When an imidazoline compound and its salt are used as the component (C), the content of the imidazoline compound and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type and content, the application and formulation form of the ophthalmic composition, and the like. The content of the imidazoline compound and its salt is 0.00001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.00005 to 0.5 w/v%, more preferably 0.0001 to 0.1 w/v%, even more preferably 0.0002 to 0.1 w/v% is even more preferable, and 0.0006 to 0.05 w/v% is particularly preferable.

When an imidazoline compound and its salt are used as the component (C), the content ratio of the imidazoline compound and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. and the type of salt thereof, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. The content ratio of the imidazoline compound and its salt to the component (A) is, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of the imidazoline compound and its salt is preferably 0.00001 to 1 part by mass, more preferably 0.00005 to 0.5 part by mass, more preferably 0.0001 to 0.5 part by mass. It is more preferably 1 part by mass, even more preferably 0.0002 to 0.1 part by mass, and particularly preferably 0.0006 to 0.05 part by mass.

When tetrahydrozoline and its salt are used as the component (C), the content of the tetrahydrozoline and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of tetrahydrozoline and its salts is 0.0001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.0005 to 0.5 w/v%, more preferably 0.001 to 0.1 w/v%, and 0.002 to 0.1 w/v% is even more preferred.

When tetrahydrozoline and its salt are used as the component (C), the content ratio of the tetrahydrozoline and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of tetrahydrozoline and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of tetrahydrozoline and its salt is preferably 0.0001 to 1 part by mass, more preferably 0.0005 to 0.5 part by mass, and 0.001 to 0.1 part by mass. parts, and even more preferably 0.002 to 0.1 parts by mass.

(C) When using naphazoline and its salt as the component, the content of naphazoline and its salt in the ophthalmic composition according to the present embodiment is not particularly limited, the type of naphazoline and its salt, the type and content of other ingredients It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of naphazoline and its salts is 0.00001 to 0.1 w/v%, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.00005 to 0.05 w/v%, more preferably 0.0001 to 0.01 w/v%, even more preferably 0.0002 to 0.005 w/v% is even more preferred.

When naphazoline and its salt are used as the component (C), the content ratio of the naphazoline and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the component (A) and the naphazoline and its salt type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of naphazoline and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of naphazoline and its salts is preferably 0.00001 to 0.1 parts by mass, more preferably 0.00005 to 0.05 parts by mass, and more preferably 0.0001 to 0.05 parts by mass. 01 parts by mass, and even more preferably 0.0002 to 0.005 parts by mass.

[Antihistamine]
Antihistamines are compounds and salts thereof that have antihistamine action. Antihistamines are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

Specific examples of antihistamines include chlorpheniramine, iproheptine, diphenhydramine, ketotifen, olopatadine, levocabastine, and salts thereof. As the antihistamine, diphenhydramine, chlorpheniramine and salts thereof are preferred, diphenhydramine, diphenhydramine hydrochloride and chlorpheniramine maleate are more preferred, and diphenhydramine hydrochloride and chlorpheniramine maleate are more preferred.

A commercially available antihistamine can also be used. One type of antihistamine may be used alone, or two or more types may be used in combination.

The content of the antihistamine in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of antihistamine, the type and content of other ingredients, the application and formulation form of the ophthalmic composition, and the like. The content of the antihistamines is preferably 0.001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effect of the present invention more remarkably. 003 to 0.5 w/v%, more preferably 0.005 to 0.1 w/v%, even more preferably 0.01 to 0.05 w/v%, Particularly preferred is 0.02 to 0.04 w/v% (eg 0.03 w/v%).

The content ratio of the antihistamine to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the formulation form and the like. From the viewpoint of further enhancing the effect of the present invention, the content ratio of the antihistamine to the component (A) is, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment. It is preferably 0.001 to 1 part by mass, more preferably 0.003 to 0.5 part by mass, even more preferably 0.005 to 0.1 part by mass, and 0.01 to 0 0.05 parts by weight is even more preferred, and 0.02 to 0.04 parts by weight (eg 0.03 parts by weight) is particularly preferred.

(C) When chlorpheniramine and its salt are used as the component, the content of chlorpheniramine and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type and content of the compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. From the viewpoint of exhibiting the effects of the present invention more remarkably, the content of chlorpheniramine and its salts is 0.001 to 1 w/w based on the total amount of the ophthalmic composition. v%, more preferably 0.003 to 0.5 w/v%, even more preferably 0.005 to 0.1 w/v%, and 0.01 to 0.05 w/v% v% is even more preferred, and 0.02 to 0.04 w/v% (eg 0.03 w/v%) is particularly preferred.

When chlorpheniramine and its salt are used as the component (C), the content ratio of the chlorpheniramine and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type of chlorpheniramine and its salt, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of chlorpheniramine and its salt to component (A) is, for example, 1 mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. part, the total content of chlorpheniramine and its salts is preferably 0.001 to 1 part by mass, more preferably 0.003 to 0.5 part by mass, and 0.005 to It is more preferably 0.1 parts by mass, even more preferably 0.01 to 0.05 parts by mass, and 0.02 to 0.04 parts by mass (for example, 0.03 parts by mass). Especially preferred.

When diphenhydramine and its salt are used as the component (C), the content ratio of the diphenhydramine and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of diphenhydramine and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of diphenhydramine and its salt is preferably 0.001 to 1 part by mass, more preferably 0.003 to 0.5 part by mass, and 0.005 to 0.1 part by mass. parts by weight, even more preferably 0.01 to 0.05 parts by weight, and particularly preferably 0.02 to 0.04 parts by weight (eg, 0.03 parts by weight).

In addition to components (A), (B) and (C), the ophthalmic composition according to this embodiment includes (D) boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and It contains at least one selected from the group consisting of ethylenediaminetetraacetic acid and salts thereof (also referred to as "component (D)").

Examples of boric acid or salts thereof include boric acid, alkali metal borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), alkaline earth metal borates, and the like. Phosphoric acid or its salt includes phosphoric acid, alkali metal phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, etc.), alkali phosphate Examples include earth metal salts (calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.). Citric acid or salts thereof include citric acid, alkali metal citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), alkaline earth metal citrate salts, etc. is mentioned. Examples of ethylenediaminetetraacetic acid (EDTA) or salts thereof include EDTA, EDTA alkali metal salts (EDTA disodium, etc.), and the like.

Component (D) is preferably boric acid or a salt thereof, more preferably boric acid or borax.

(D) Component may use what is marketed. (D) Component may be used individually by 1 type, or may be used in combination of 2 or more type.

The content of component (D) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of component (D), 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 (D), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of the component (D) is 0.01 to 10 w/v based on the total amount of the ophthalmic composition. %, more preferably 0.05 to 5 w/v %, even more preferably 0.1 to 3 w/v %.

The content ratio of component (D) 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. From the viewpoint of further enhancing the effect of the present invention, the content ratio of component (D) to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. The total content of component (D) is preferably 0.01 to 100 parts by mass, more preferably 0.05 to 50 parts by mass, and 0.1 to 30 parts by mass. is more preferred.

(D) When using boric acid and its salts, phosphoric acid and its salts, citric acid and its salts as the component, boric acid and its salts, phosphoric acid and its salts, citric acid and The content of the salt is not particularly limited, boric acid and its salts, phosphoric acid and its salts, citric acid and its salts types, types and contents of other ingredients, use and formulation form of the ophthalmic composition, etc. is set as appropriate. The contents of boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts are 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 acid and its salts, citric acid and its salts is preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, 0.1 to 3 w /v% is more preferred.

(D) When using boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts as the component, boric acid and its salts, phosphoric acid and The content ratio of its salt, citric acid and its salt is not particularly limited, type of component (A) and boric acid and its salt, phosphoric acid and its salt, citric acid and its salt, type and content of other ingredients It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The content ratio of boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts to the component (A) is, for example, included in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts is 0.01 to 10 parts by mass with respect to 1 part by mass of the total content of the component (A) It is preferably from 0.05 to 5 parts by mass, and even more preferably from 0.1 to 3 parts by mass.

When ethylenediaminetetraacetic acid (EDTA) or a salt thereof is used as the component (D), the content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof in the ophthalmic composition according to the present embodiment is not particularly limited. ) or its salt, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. The content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, based on the total amount of the ophthalmic composition, is such that the total content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof is It is preferably 0.001 to 0.5 w/v%, more preferably 0.005 to 0.1 w/v%, even more preferably 0.01 to 0.05 w/v%.

When ethylenediaminetetraacetic acid (EDTA) or a salt thereof is used as component (D), the content ratio of ethylenediaminetetraacetic acid (EDTA) or a salt thereof to component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. , types of component (A) and ethylenediaminetetraacetic acid (EDTA) or salts thereof, types and contents of other compounding components, application and formulation form of the ophthalmic composition, and the like. The content ratio of ethylenediaminetetraacetic acid (EDTA) or a salt thereof to component (A) is, for example, the total content of component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof is preferably 0.001 to 0.5 parts by mass, more preferably 0.005 to 0.1 parts by mass, per 1 part by mass. is more preferable, and more preferably 0.01 to 0.05 parts by mass

Another embodiment of the ophthalmic composition according to the present invention comprises (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, and (B1) at least one selected from the group consisting of neostigmine and salts thereof. (B2) at least one selected from the group consisting of cyanocobalamin and its salts; and (D) boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts. and at least one selected from the group consisting of, wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition be. In the said embodiment, the kind, content, etc. of each component are as having demonstrated above.

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 preferable, more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, 5.3 ~7.5 is more particularly preferred, and 5.5 to 7.0 is most 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 17th 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. As the viscosity of the ophthalmic composition according to the present embodiment, for example, the viscosity at 20 ° C. measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34' × R24) is 1 It is preferably from 1 to 10,000 mPa s, more preferably from 1 to 8,000 mPa s, still more preferably from 1 to 1,000 mPa s, even more preferably from 1 to 100 mPa s, and from 1 to 20 mPa. · s is particularly preferred, and 1.5 to 10 mPa·s is most preferred.

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 2017 edition of the Standards for Manufacturing and Marketing Approval of Over-the-Counter Drugs (supervised by the Japanese Society of Regulatory Science). Specific examples of components used in ophthalmic drugs include the following components.
Antiallergic agents: for example, cromoglycate sodium, tranilast, pemirolast potassium, acitazanolast, amlexanox, ibudilast and the like.
Antihistamines: e.g. diphenhydramine or salts thereof (e.g. diphenhydramine hydrochloride), iproheptine or salts thereof (e.g. iproheptine hydrochloride), levocabastine or salts thereof (e.g. levocabastine hydrochloride), ketotifen or salts thereof (e.g. ketotifen fumarate), mirolast potassium, olopatadine or a salt thereof (eg, olopatadine hydrochloride), and the like.
Steroid agents: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide and the like.
Decongestants: For example, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Ocular muscle modulating drug: For example, a cholinesterase inhibitor having an active center similar to that of acetylcholine, specifically tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride and the like.
Anti-inflammatory agents: for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon- aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizic acid or its salts (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate and the like.
Vitamins: for example, retinol acetate, retinol palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate and the like.
Amino acids: for example, L-arginine, glutamic acid, glycine, alanine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine, taurine, aspartic acid and salts thereof.
Astringent: For example, zinc white and the like.
Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and salts thereof 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 Pharmaceutical Excipient Encyclopedia 2016 (edited by 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 (EDDA), ethylenediaminetriacetic acid, 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: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine and the like.
Surfactants: nonionic surfactants such as tyloxapol, polyoxyethylene sorbitan fatty acid esters, polyoxyl stearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamers; polyoxyethylene alkyl ether phosphate salt, anionic surfactants such as polyoxyethylene alkyl ether sulfates, alkylbenzenesulfonates, alkyl sulfates, N-acyl taurine salts; zwitterionic surfactants such as betaine lauryldimethylaminoacetate;
Perfumes or cooling agents: e.g. menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchen , nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be d-, l- or dl-isomers.
Thickeners: cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; guar gum; hydroxypropylguar gum; gum arabic; karaya gum; xanthan gum; Heparin-like substances, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and mucopolysaccharides thereof (such as sodium salts); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan;
(D) Buffers other than component: For example, carbonate buffer, acetate buffer, lactate buffer, succinate buffer, Tris buffer, AMPD buffer and the like.
Stabilizers: For example, sodium formaldehyde sulfoxylate (Rongalite), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium bisulfite, sodium pyrosulfite and the like.
Preservatives: e.g. quaternary ammonium salts of alkylpolyaminoethylglycines (e.g. benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydronium chloride, 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 ), Alexidine, etc.), Glokill (trade name of Rhodia), etc.
Tonicity agents: e.g. potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium bisulfite, sodium sulfite etc.
Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin and the like. These may be d-, l- or dl-isomers.
Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil; animal oils such as squalane; mineral oils such as liquid paraffin and petrolatum.

From the viewpoint that the effects of the present invention can be remarkably exhibited, the ophthalmic composition according to the present embodiment contains petrolatum, polyvinyl alcohol, flavin adenine dinucleotide sodium, epsilon-aminocaproic acid, alexidine, zinc chloride, menthol, and azulene sulfonic acid. and salts thereof, and at least one selected from the group consisting of berberine and salts thereof.

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. Their definitions are based on the 17th revision of the Japanese Pharmacopoeia.

The ophthalmic composition according to the present embodiment contains desired amounts of component (A), component (B), component (C), component (D), and, if necessary, other components at desired concentrations. and blending. 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 sterilization 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 cleaning agent, contact lens cleaning and preserving agent), contact lens packaging solution, 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).

The ophthalmic composition according to this embodiment is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses), since the effects of the present invention can be exhibited more remarkably. 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 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times, or 5 to 6 times a day can be exemplified.

The ophthalmic composition according to this embodiment is provided in an arbitrary container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of plastics include polyethylene terephthalate (PET), polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of these monomers, and mixtures of two or more thereof. Preferred is polyethylene terephthalate. Further, the container containing the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container is visible, or an opaque container in which the inside of the container is difficult to be seen. A transparent container is preferred. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

A nozzle may be attached to the container containing the ophthalmic composition according to the present embodiment. The material of the nozzle is not particularly limited, and may be, for example, glass or plastic. It is preferably made of plastic. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, the nozzle material is preferably polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, or polyethylene naphthalate, and more preferably polyethylene.

The container containing the ophthalmic composition according to the present embodiment may be of a multi-dose type that accommodates multiple doses, or may be of a unit dose type that accommodates a single dose.

The ophthalmic composition according to the present embodiment is preferably filled in a container having an internal volume of 4 to 30 mL, more preferably filled in a container having an internal volume of 5 to 20 mL. More preferably, it is packed in a container of 6 to 16 mL, and even more preferably packed in a container with an internal volume of 10 to 15 mL. Also, it may be filled in a container with an internal volume of 0.1 to 3 mL, or may be filled in a container with an internal volume of 0.2 to 1 mL.

As confirmed in the test examples described later, the ophthalmic composition according to the present embodiment has the effect of suppressing variations in the amount of drops, and is independent of the viscosity when the formulation is applied to the eye (high viscosity formulations). Effect of making it easier to blink and / or effect of suppressing discomfort when blinking, effect of reducing liquid residue in the container after use, effect of suppressing viscosity change due to daylight, ultraviolet rays and heat and ultraviolet rays There is an effect of suppressing the coloring of the formulation due to.

The present invention will be specifically described below based on test examples, but the present invention is not limited to these. In addition, the total amount of the test solution in the table is 100 mL. Hydrochloric acid or sodium hydroxide was used as a pH adjuster. In addition, the pH was adjusted using the minimum amount of pH adjuster. In the subsequent test examples, EDTA disodium was used.

[Test Example 1: Evaluation of Variation in Dropping Amount]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Tables 1 and 2, and used as a test solution. The unit of each component in Tables 1 and 2 is w/v%. In Test Example 1 and the following Test Examples and Formulation Examples, the sodium chondroitin sulfate used was sodium chondroitin sulfate (weight average molecular weight of about 25,000, manufactured by Maruha Nichiro Co., Ltd.). Next, 5 mL of each of the prepared ophthalmic compositions was filled in a polyethylene terephthalate eye drop container having an inner volume of 10 mL, and a polyethylene nozzle was attached to the container. As a polyethylene nozzle, a nozzle suitable for dropping 30 to 50 μL was used. The drop weight of each drop was measured when the eye drops contained in the container were dropped in the horizontal direction. From the average drop amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 10 times, the dispersion of the drop amount (variation coefficient CV: %) was calculated by the following formula 1. Using the obtained coefficients of variation, the variation improvement rate of the dropping amount of the test solutions 2 to 9 relative to the test solution 1 is calculated based on the following formula 2, and the variation in the dropping amount of the test solutions 11 to 14 relative to the test solution 10 is improved. The ratio was calculated based on Equation 3 below. Results are shown in Tables 1 and 2.
Each ophthalmic composition having the composition shown in Tables 3 and 4 was prepared according to a conventional method and used as a test solution. The unit of each component in Tables 3 and 4 is w/v%. Next, 5 mL of each of the prepared ophthalmic compositions was filled in a polyethylene terephthalate eye drop container having an inner volume of 10 mL, and a polyethylene nozzle was attached to the container. As a polyethylene nozzle, a nozzle suitable for dropping 30 to 50 μL was used. The drop weight of each drop was measured when the eye drops contained in the container were dropped in the horizontal direction. From the average drop amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 10 times, the dispersion of the drop amount (variation coefficient CV: %) was calculated by the following formula 1. Using the obtained coefficients of variation, the variation improvement rate of the drop amount of the test solutions 18 to 21 relative to the test solution 17 is calculated based on the following formula 2', and the test solutions 11 to 14 and 22 to 30 relative to the test solution 10. The rate of improvement in variation in the drip amount was calculated based on Equation 3 below. Results are shown in Tables 3 and 4.
[Formula 1] Variation in dropping amount (variation coefficient CV: %) = (SD / AVG) × 100
[Formula 2] Drop amount variation improvement rate (%) = {(variation coefficient of test solution 1-variation coefficient of test solutions 2 to 9)/variation coefficient of test solution 1} × 100
[Formula 2′] Drop amount variation improvement rate (%) = {(variation coefficient of test solution 17−variation coefficient of test solutions 18 to 21)/variation coefficient of test solution 17} × 100
[Formula 3] Drop amount variation improvement rate (%) = {(variation coefficient of test solution 10 - coefficient of variation of test solutions 11 to 14 and 22 to 30) / coefficient of variation of test solution 10} × 100

In addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solutions 2 and 5 further containing chlorpheniramine maleate or tetrahydrozoline hydrochloride, and sodium hydrogen phosphate hydrate instead of boric acid and borax in test solution 2 Alternatively, it was confirmed that test solutions 3, 4, 6 and 8 containing EDTA significantly improved the variability of the drop amount compared to test solution 1 containing sodium chondroitin sulfate and neostigmine methylsulfate. In addition, it was confirmed that test solutions 7 and 9 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride in addition to sodium chondroitin sulfate and neostigmine methylsulfate significantly improved the variation in the drop amount. .

Test solution 18, which further contains diphenhydramine in addition to sodium chondroitin sulfate and neostigmine methylsulfate, was confirmed to significantly improve the variation in the drop amount compared to test solution 17, which contains sodium chondroitin sulfate and neostigmine methylsulfate. was done. This tendency was also observed in test solutions 17 and 18 when boric acid and borax were changed to sodium hydrogen phosphate hydrate, EDTA, or sodium citrate (test solutions 19-21).

In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11 to 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine sulfate, or naphazoline hydrochloride were dropped compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin. It was confirmed that the variation in amount was remarkably improved. This tendency was also confirmed in test solutions 10 and 14 in formulations using sodium hydrogen phosphate hydrate, EDTA, and citric acid instead of boric acid and borax.

[Test Example 2: Measurement test of the amount of residual liquid in the eyedropper bottle]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 5 and used as a test solution. The unit of each component in Table 5 is w/v%. A 10 mL PET eye dropper bottle was tared and filled with 5 mL of each ophthalmic composition. Next, the weight of each ophthalmic composition filled in each ophthalmic composition was drained, and the weight of each eyedropper bottle was measured. (%) was calculated. Table 5 shows the results.
(Formula 4) Remaining liquid amount (g) = Weight of eyedropper bottle after the ophthalmic composition has been drained - Tare weight of eyedropper bottle (Formula 5) Improvement rate of residual liquid amount (%) = {1 - (each test Remaining liquid volume of solution/Remaining liquid volume of test solution 1)} × 100

In addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solution 2 further containing chlorpheniramine maleate, and test solution 3 containing EDTA instead of boric acid and borax in test solution 2, sodium chondroitin sulfate and Compared to test solution 1 containing neostigmine methylsulfate, the amount of residual liquid was reduced, and it was confirmed that the ophthalmic composition in the eyedropper bottle can be used up easily. In addition, in addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solutions 9, 15 and 16 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride, or cyanocobalamin significantly reduced the residual liquid volume, It was confirmed that the ophthalmic composition in the eyedropper bottle is much easier to use up.

[Test Example 3: Viscosity stability test by light irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Tables 6 and 7, and used as a test solution. The unit of each component in Tables 6 and 7 is w/v%. 10 mL of each ophthalmic composition was filled in a 10 mL capacity glass headspace vial (GL Sciences Inc.) and tested with a photostability tester (LT-120A-WCD (manufactured by Nagano Sciences)) using a D65 fluorescent lamp as a light source. , at a room temperature of 25° C., irradiation was performed at an illuminance of 4000 lx/h until an integrated illuminance of 1,200,000 lx. Each ophthalmic composition (600 μL) before and after irradiation was subjected to shearing at 34° C. using a cone-plate measuring jig (CP50-1, d: 0.102 mm) with a rheometer (MCR302 (AntonPaar)). Viscosity was measured against speed (1-10000 (1/s)). Then, using the viscosity (mPa·s) at a shear rate of 10000 (1/s), the viscosity stability before and after the test was evaluated according to Equations 6 and 7 below. Results are shown in Tables 6 and 7. The smaller the absolute value of the viscosity change rate, the less the viscosity change due to light irradiation, and the more the ophthalmic composition maintains the same physical properties.
(Formula 6) Viscosity change rate (%) = {(Viscosity of each ophthalmic composition before light irradiation - Viscosity of each ophthalmic composition after light irradiation)/Viscosity of each ophthalmic composition before light irradiation} x 100
(Formula 7) Viscosity change improvement rate (%) = {(viscosity change rate of test solution 1 (test solution 10 in Table 5) - viscosity change rate of each test solution) / test solution 1 (test solution 10 in Table 5) Viscosity change rate} × 100

In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2 and 4, which also contain chlorpheniramine maleate, were compared to test solution 1, which contained sodium chondroitin sulfate and neostigmine methylsulfate, using a D65 fluorescent lamp as the light source. It was confirmed that the viscosity change rate when used as is reduced and the stability of the ophthalmic composition due to light (daylight) irradiation is improved. In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11, 12, 13 and 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine methylsulfate or naphazoline hydrochloride were tested with sodium chondroitin sulfate and cyanocobalamin. It was confirmed that the viscosity change rate was lower when a D65 fluorescent lamp was used as the light source compared to solution 10, and the stability of the ophthalmic composition against light (daylight) irradiation was improved.

[Test Example 4: Viscosity stability test by UV irradiation]
A glass bottle (10 mL) was filled with 10 mL of each ophthalmic composition having the composition shown in Tables 8 and 9 and prepared according to a conventional method. Light intensity of 765 (W/m2), irradiation for 48 hours (test solutions 10, 12, 14) or 96 hours (test solutions 1, 2, 3, 4, 5, 7, 15). After sufficiently isothermalizing each ophthalmic composition at 25 ° C., the viscosity was measured in the same manner as above, and the viscosity (mPa s) at a shear rate of 1000 (1 / s) was used to determine the viscosity stability before and after the test. evaluated the sex. Results are shown in Tables 8 and 9.

In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2 and 4, which also contain chlorpheniramine maleate, were compared to test solution 1, which contained sodium chondroitin sulfate and neostigmine methylsulfate, using a D65 fluorescent lamp as the light source. It was confirmed that the viscosity change when used as is suppressed, and the stability of the ophthalmic composition due to light (daylight) irradiation is improved. In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2, 3, 4 and 15 further containing chlorpheniramine maleate, and sodium chondroitin sulfate and neostigmine methylsulfate further containing tetrahydrozoline hydrochloride In addition to test solution 5, sodium chondroitin sulfate and neostigmine methylsulfate, test solution 7 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride compared to test solution 1 containing sodium chondroitin sulfate and neostigmine methylsulfate. It was confirmed that the viscosity change is suppressed when a xenon lamp is used as a light source, and the stability of the ophthalmic composition is improved by light (ultraviolet) irradiation. Furthermore, in addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 12 and 14 further containing chlorpheniramine maleate and naphazoline hydrochloride, respectively, were compared with test solution 10 containing sodium chondroitin sulfate and cyanocobalamin using a xenon lamp as a light source. It was confirmed that the change in viscosity when used was suppressed, and the stability of the ophthalmic composition against light (ultraviolet) irradiation was improved.

[Test Example 5: Thermal Viscosity Stability Test]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Tables 11 and 12, and used as a test solution. The unit of each component in Tables 11 and 12 is w/v%. 10 mL of each ophthalmic composition was filled in a 10-mL glass headspace vial (GL Sciences) and stored in a 60° C. thermostat for 3 weeks. Each ophthalmic composition (600 μL) before and after standing was measured at 34° C. with a rheometer (MCR302 (AntonPaar)) using a cone-plate measuring jig (CP50-1, d: 0.102 mm). Viscosity against shear rate (1 to 10000 (1/s)) was measured. Using the viscosity (mPa·s) at a shear rate of 10000 (1/s) or 1000 (1/s), the viscosity stability before and after the test was evaluated according to Equations 8 and 9 below. Results are shown in Tables 11 and 12. Here, the reference test solution is the test solution 48 for the test solutions 49-63 and the test solution 64 for the test solutions 65-70. Incidentally, the smaller the absolute value of the viscosity change rate, the less viscosity change occurs, indicating that the ophthalmic composition maintains the same physical properties.
(Formula 8) Viscosity change rate (%) = {(Viscosity of each ophthalmic composition before storage in a constant temperature storage at 60°C - Viscosity of each ophthalmic composition after storage in a constant temperature storage at 60°C)/Storage of each ophthalmic composition in a constant temperature storage at 60°C Pre-viscosity}×100
(Formula 9) Viscosity change improvement rate (%) = {(viscosity change rate of reference test solution - viscosity change rate of each test solution) / viscosity change rate of reference test solution} x 100

[Test Example 6: Appearance (color) change suppression test due to ultraviolet irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 13 and used as a test solution. The unit of each component in Table 13 is w/v %. 10 mL of each ophthalmic composition was filled in a glass bottle (10 mL) and irradiated at 35° C. for 48 hours at an ultraviolet light illuminance of 765 (W/m ² ) using SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source). . After that, each ophthalmic composition was sufficiently thermostated at 25° C., and the color difference (L, a, b values) of each ophthalmic composition before and after ultraviolet irradiation was measured using a spectrophotometer (CM3500d: manufactured by Konica Minolta Co., Ltd.). was measured, the change in appearance (color) of the ophthalmic composition before and after UV irradiation (ΔE*ab) was calculated according to the following formula 10, and the color difference change reduction rate was calculated according to the following formula 11. Note that the smaller the ΔE value, the more suppressed the change (coloring) in the appearance (color) of the ophthalmic composition. The results are shown in Table 13.
(Formula 10) ΔE * ab = [(ΔL *) × 2 + (Δa *) × 2 + (Δb *) × 2] × 1/2
(Formula 11) Color difference change reduction rate (%) = {1-(ΔE*ab of each test solution)/ΔE*ab of test solution 10} × 100
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 14 and used as a test solution. The unit of each component in Table 14 is w/v%. 10 mL of each ophthalmic composition was filled in a glass bottle (10 mL) and irradiated at 35° C. for 48 hours at an ultraviolet light illuminance of 765 (W/m ² ) using SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source). . After that, each ophthalmic composition was sufficiently thermostated at 25° C., and the color difference (L, a, b values) of each ophthalmic composition before and after ultraviolet irradiation was measured using a spectrophotometer (CM3500d: manufactured by Konica Minolta Co., Ltd.). was measured, the change in appearance (color) of the ophthalmic composition before and after UV irradiation (ΔE*ab) was calculated according to the following formula 10, and the color difference change reduction rate was calculated according to the following formula 11′. Here, the reference test solution is the test solution 71 for the test solution 72, the test solution 73 for the test solution 74, and the test solution 75 for the test solutions 76-79. Note that the smaller the ΔE value, the more suppressed the change (coloring) in the appearance (color) of the ophthalmic composition. The results are shown in Table 14.
(Formula 10) ΔE * ab = [(ΔL *) × 2 + (Δa *) × 2 + (Δb *) × 2] × 1/2
(Formula 11′) Color difference change reduction rate (%) = {1-(ΔE*ab of each test solution)/ΔE*ab of reference test solution} × 100

In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11 to 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine sulfate, or naphazoline hydrochloride compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin: It was confirmed that the coloring of the formulation due to ultraviolet irradiation was suppressed.

[Test Example 7: Appearance (color) change suppression test due to light irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 15 and used as a test solution. The unit of each component in Table 15 is w/v% unless specified in the table. 10 mL of each ophthalmic composition was filled in a 10-mL glass headspace vial, and stored in a thermostat at 60°C for 3 weeks. After that, each ophthalmic composition was sufficiently thermostated at 25° C., and a spectrophotometer (CM3500d: manufactured by Konica Minolta) was used to measure the color difference (L, a, b values) ) was measured, the change (ΔE*ab) in the appearance (transparency) of the ophthalmic composition before and after the thermal acceleration test was calculated according to the following formula 12, and the transparency difference change reduction rate was calculated according to the following formula 13. Table 15 shows the results. It should be noted that the smaller the ΔE*ab value, the more suppressed the change in appearance (transparency) of the formulation.
(Formula 12) ΔE * ab = [(ΔL *) × 2 + (Δa *) × 2 + (Δb *) × 2] × 1/2
(Formula 13) Transparency difference change reduction rate (%) = {1-(ΔE*ab of corresponding test solution)/ΔE*ab of test solution 10} × 100
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 16 and used as a test solution. The unit of each component in Table 16 is w/v% unless specified in the table. 10 mL of each ophthalmic composition was filled in a 10-mL glass headspace vial, and stored in a thermostat at 60°C for 3 weeks. After that, each ophthalmic composition was sufficiently thermostated at 25° C., and a spectrophotometer (CM3500d: manufactured by Konica Minolta) was used to measure the color difference (L, a, b values) ) was measured, the change (ΔE*ab) in the appearance (transparency) of the ophthalmic composition before and after the thermal acceleration test was calculated according to the following formula 12, and the transparency difference change reduction rate was calculated according to the following formula 13'. Here, the reference test solution is the test solution 80 for the test solutions 81 and 82 and the test solution 83 for the test solution 84 . The results are shown in Table 16. It should be noted that the smaller the ΔE*ab value, the more suppressed the change in appearance (transparency) of the formulation.
(Formula 12) ΔE * ab = [(ΔL *) × 2 + (Δa *) × 2 + (Δb *) × 2] × 1/2
(Formula 13') Transparency difference change reduction rate (%) = {1-(ΔE*ab of corresponding test solution)/ΔE*ab of reference test solution} × 100

In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11-14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine methylsulfate, or naphazoline hydrochloride compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin. , It was confirmed that the coloring of the formulation due to heat load was suppressed. Furthermore, in addition to sodium chondroitin sulfate, cyanocobalamin and neostigmine methylsulfate, test solutions further containing tetrahydrozoline hydrochloride or chlorpheniramine maleate compared to test solutions containing sodium chondroitin sulfate, cyanocobalamin and neostigmine methylsulfate. , it was confirmed that the coloration of the formulation due to heat load was suppressed (comparison between test solution 80 and test solutions 81 and 82, and comparison between test solution 83 and test solution 84).

[Formulation example]
Eye drops were prepared by a conventional method according to the formulations shown in Tables 17 and 18 below. In addition, the unit of each component amount is w/v % except for those specified in the table. All of them are packed in a container made of polyethylene terephthalate, and each formulation has a low-density polyethylene nozzle attached, and all the walls that may come into contact with the content liquid when the cap is attached (during storage) Those with polybutylene terephthalate nozzles, those with polyethylene terephthalate nozzles on the part of the wall that may come in contact with the liquid content, and the part of the wall that may come in contact with the liquid was equipped with a nozzle made of polyethylene naphthalate.

Claims (4)

(A) at least one selected from the group consisting of chondroitin sulfate and its salts, (B) at least one selected from the group consisting of neostigmine and its salts, and cyanocobalamin and its salts, and (C) an imidazoline compound. and at least one selected from the group consisting of antihistamines, and (D) at least selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts 1, wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition. 2. The ophthalmic composition according to claim 1, wherein component (C) is at least one selected from the group consisting of tetrahydrozoline and its salts, naphazoline and its salts, and chlorpheniramine and its salts. 2. The ophthalmology according to claim 1, which contains at least one selected from the group consisting of tetrahydrozoline and its salts and at least one selected from the group consisting of chlorpheniramine and its salts as the component (C). Composition. (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, (B1) at least one selected from the group consisting of neostigmine and salts thereof, and (B2) from the group consisting of cyanocobalamin and salts thereof and (D) at least one selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts. wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition.