JPH07316060A - Stable eye drop - Google Patents

Abstract

PURPOSE:To obtain an eye drop, capable of improving the stability of an ester- based nonionic surfactant and excellent in long-term stability by blending the ester-based nonionic surfactant with glycyrrhetinic acid and cyclodextrin. CONSTITUTION:This eye drop is obtained by blending (A) 0.01-2.0wt.%, preferably 0.05-0.5wt.% ester-based nonionic surfactant (e.g. polyoxyethylene hardened castor oil 60, polyoxyl 40 stearate or polysorbate 80) with (B) preferably 0.01-5.0wt.% glycyrrhetinic acid or its salts and (C) 0.01-10.0wt.%, preferably 0.05-5.0wt.% one or more selected from cyclodextrin or its derivatives (alpha-,beta- or gamma-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin). Furthermore, the pH of the eye drop is preferably 4-9, especially preferably 4.5-8.5.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a technique for stabilizing eye drops containing an ester nonionic surfactant, glycyrrhizic acid or salts thereof for a long period of time.

[0002]

2. Description of the Related Art Glycyrrhizin, which is a conjugate of glycyrrhetin and two molecules of glucuronic acid and is a main component of licorice, has an anti-inflammatory action but no anti-granulation action. Its salts, especially dipotassium glycyrrhizinate, which is a potassium salt, are well used in eye drops because they dissolve well in water and cause little irritation even when instilled.

On the other hand, the ester type nonionic surfactant is
It is widely used in eye drops as an anti-gelling agent for the above-mentioned glycyrrhizinates, which easily forms a gel structure in an acidic aqueous solution, and as a solubilizer for glycyrrhizic acid itself, which is a poorly water-soluble substance, and perfume.

However, when this ester nonionic surfactant and glycyrrhizic acid or its salts are mixed in eye drops at the same time, the hydrolysis of the above surfactants is significantly accelerated by glycyrrhizic acid or its salts, resulting in turbidity or precipitation. It was extremely difficult to keep the resulting eye drops sufficiently stable for a long period of time. As an invention considering this,
JP-A-5-139955 and JP-A-5-27105
Although it is reported in Japanese Patent No. 3, etc., the acceleration of hydrolysis of the ester nonionic surfactant by glycyrrhizic acid or its salts has not been sufficiently suppressed.

[0005]

DISCLOSURE OF THE INVENTION The present invention relates to an eye drop containing an ester nonionic surfactant, glycyrrhizic acid or a salt thereof, which accelerates hydrolysis of the ester nonionic surfactant by glycyrrhizic acid or a salt thereof. The purpose is to prevent the above and improve the stability of the eye drop over a long period of time.

[0006]

Means for Solving the Problems The present inventors have aimed to improve the stability of an ester nonionic surfactant in an eye drop containing an ester nonionic surfactant, glycyrrhizic acid or a salt thereof. As a result of diligent research, by incorporating cyclodextrin or a derivative thereof, it is possible to obtain a stable eye drop sufficiently suppressing the accelerated hydrolysis of the ester nonionic surfactant by glycyrrhizic acid or its salts. Found out. That is, the stable eye drop of the present invention is characterized by containing the following components (a), (b) and (c). (A) Ester-based nonionic surfactant. (B) Glycyrrhizic acid or salts thereof. (C) Cyclodextrin or a derivative thereof.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION As the ester-based nonionic surfactant which is the first essential component of the present invention, higher fatty acid ester such as water-soluble polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid ester and the like can be used. For example, polyoxyethylene hydrogenated castor oil 60
(Listed as pharmaceutical additive standard), polyoxyethylene (p =
40) There are monostearate (also known as "polyoxyl 40 stearate" listed in Japanese Pharmacopoeia) and polyoxyethylene (p = 20) sorbitan monooleate (also known as "polysorbate 80" listed in Japanese Pharmacopoeia). Where p
Represents the average number of moles of ethylene oxide added. Specifically, Nikkor HCO-40 manufactured by Nikko Chemicals Co., Ltd.,
HCO-50, HCO-60, MYS-25, MYS-
40, MYL-10, TO-10, TS-10 and the like. The ester nonionic surfactant can be usually added to the eye drop composition in an amount of 0.01 to 2.0% by weight, preferably 0.05 to 0.5% by weight.

Examples of the glycyrrhizic acid or salts thereof, which is the second essential component of the present invention, include glycyrrhizinic acid itself, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, and the like.
It may be one commonly used in quasi-drugs, cosmetics and the like, and specific examples thereof include dipotassium glycyrrhizinate manufactured by Maruzen Pharmaceutical Co., Ltd. Glycyrrhizic acid or a salt thereof can be usually compounded in the eye drop composition in an amount of 0.01 to 5.0% by weight, but there is no particular limitation on the compounding amount in the present invention.

The cyclodextrin or its derivative which is the third essential component of the present invention includes α-cyclodextrin (polymerization degree 6), β-cyclodextrin (polymerization degree 7) and γ-cyclodextrin (polymerization degree 8). , Methylated-β-cyclodextrin such as trimethyl-β-cyclodextrin and dimethyl-β-cyclodextrin, and hydroxypropylated-β-cyclodextrin such as hydroxypropyl-β-cyclodextrin. Specifically, for example, β- manufactured by Shimizu Minato Sugar Co., Ltd.
There are cyclodextrins, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin. In particular, cyclodextrin derivatives such as methylated products and hydroxypropylated products are excellent in stability, especially in long-term stability.

The cyclodextrin derivative may be a cyclodextrin which is methylated or hydroxypropylated by a conventional method. For example, when a known methylating agent is used, the hydroxyl groups of glucose residues are at the 6-, 2-, and 3-positions. In this order, a mixture of methylated cyclodextrins substituted with methyl groups is produced, but in the present invention, any one may be substituted as long as at least one methyl group is introduced.

The degree of polymerization of cyclodextrins is 6
Those with α-cyclodextrin, those with 7 are β-cyclodextrin, those with 8 are γ-cyclodextrin,
9 is called delta-cyclodextrin. Cyclodextrin or a derivative thereof can be usually added to the eye drop composition in an amount of 0.01 to 10.0% by weight, preferably 0.05 to 5.0% by weight.

In addition, the stable eye drop of the present invention may optionally contain retinol palmitate, tocopherol acetate,
Vitamins such as pyridoxine hydrochloride; drugs such as neostigmine methylsulfate, chlorpheniramine maleate, tetrahydrozoline hydrochloride, potassium aspartate, zinc sulfate, sulfamethoxazole, allantoin, lysozyme chloride; potassium chloride, sodium chloride, propylene glycol, Isotonic agents such as polyethylene glycol and glycerin; buffering agents such as citric acid, boric acid, sodium hydrogen phosphate, glacial acetic acid; sugars such as mannitol;
-A fragrance such as menthol or the like can be added.

The method for preparing the stable eye drop of the present invention is not particularly limited, and examples thereof include cyclodextrin such as trimethyl-β-cyclodextrin or a derivative thereof, glycyrrhizic acid such as dipotassium glycyrrhizinate or a salt thereof, and polyoxyethylene. An ester type nonionic surfactant such as (p = 20) sorbitan monooleate is dissolved in water as it is. Then, by adding a preservative such as benzethonium chloride or the like, a drug such as neostigmine methylsulfate or the like, and a buffer such as citric acid to adjust the pH, glycyrrhizic acid or a salt thereof as an ester nonionic surfactant. It is possible to obtain a stable eye drop which is prevented from accelerating decomposition over time.

Glycyrrhizic acid or salts thereof,
The ester nonionic surfactant is easily included by simply stirring and mixing it with cyclodextrin or its derivative in an aqueous solution, but the above-mentioned inclusion substance may be treated with cyclodextrin or its derivative in advance. Absent. The method is not particularly limited. For example, glycyrrhizic acid or a salt thereof, an ester nonionic surfactant, cyclodextrin or a derivative thereof, and water are physically kneaded by using a kneader or the like. A kneading method, a saturated aqueous solution method in which glycyrrhizic acid or a salt thereof and an ester nonionic surfactant are added to an aqueous solution of saturated cyclodextrin or a derivative thereof, and the like can be used.

The pH of the stable eye drop of the present invention is preferably in the range of 4 to 9, more preferably 4.5 to 8.
It is 5. When the pH of the eye drop is out of the above range, the stability of the ester nonionic surfactant with time particularly deteriorates.

[0016]

INDUSTRIAL APPLICABILITY According to the present invention, an eye drop containing an ester nonionic surfactant, glycyrrhizic acid or a salt thereof is mixed with sylodextrins to give an ester nonionic surfactant glycyrrhizic acid. Alternatively, it is possible to prevent the hydrolysis from being accelerated by the salts thereof, and to significantly improve the stability of the eye drop over a long period of time.

[0017]

【Example】

<Stability evaluation method> After filling the prepared eye drops into a container,
It was stored at 40 ° C. for 6 months or at 50 ° C. for 3 months or 6 months, and the stability of the ester nonionic surfactant over time was evaluated.

The stabilizing effect of the ester-type nonionic surfactant by cyclodextrin or its derivative was evaluated using the hydrolysis inhibition rate of the ester-type nonionic surfactant as an index. This inhibition rate was calculated by measuring the production amount of each higher fatty acid, which is a hydrolysis product, by a high performance liquid chromatography method and using the following formula 1.

[0019]

[Equation 1]

A in the above formula 1 is the content of higher fatty acid after storage in the eye drop containing cyclodextrin or its derivative, and B is the eye drop in which only cyclodextrin or its derivative is deleted from the above eye drop composition. Means the higher fatty acid content after storage. Appearance is 40 ℃
After storage for 6 months or 50 ° C. for 3 months or 6 months, the evaluation was performed according to the following criteria. ○: clear ×: precipitate formation

Examples 1 to 5 and Comparative Example 1 Eye drops having the formulations shown in Table 1 were prepared and their stability was evaluated. The results are shown in Table 1. The pH was adjusted to 5.0 with sodium citrate and citric acid, and the osmotic pressure was adjusted to 290 mOsm with sodium chloride.

[0022]

[Table 1]Table 1: Composition and evaluation results IngredientsExample Comparative example Example 1 2 3 1 4 5 Composition (g / 100ml) Glycyrrhizic acid 0.1 0.1 0.1 0.1 0.1 0.1 Dipotassium Polyoxyethylene 0.2 0.2 0.2 0.2 0.2 0.2 Hydrogenated castor oil 60 γ-Cyclodextrin 0.1 0.5 1.0 − − − β-Cyclodextrin − − − − 1.0 − α -Cyclodextrin − − − − − 1.0 10% benzal chloride 0.05 0.05 0.05 0.05 0.05 0.05 Conium solution Chlorobutanol 0.1 0.1 0.1 0.1 0.1 0.1Purified water Suitable quantity Suitable quantity Suitable quantity Suitable quantity Suitable quantity Suitable quantity Evaluation results Appearance (3 months) ○ ○ ○ × ○ ○ Hydrolysis suppression rate *¹71 85 90 − 81 72 (Three months) * 1) Water content of polyoxyethylene hydrogenated castor oil 60
Solution suppression rate

Examples 6 to 10 Eye drops having the formulations shown in Table 2 were prepared and their stability was evaluated. The results are shown in Table 2. The pH was adjusted in the same manner as in Example 1. It can be seen that the methylated and propylated forms of cyclodextrin are superior to β-cyclodextrin in the stability effect, particularly in the long-term stability effect.

[0024]

[Table 2]Table 2: Composition and evaluation results IngredientsExample Comparative example Example 4 6 7 1 8 9 10 Compounding amount (g / 100ml) Dipotassium glycyrrhizinate 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Polyoxyethylene 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Hydrogenated castor oil 60 β-Cyclodextrin 1.0 − − − − − − Dimethyl-β-sic − 1.0 − − 1.0 0.1 − Rodextrin Hydroxypropyl-β- − − 1.0 − 1.0 − 0.1 Cyclodextrin 10% Benzalkonium chloride solution 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Chlorobutanol 0.1 0.1 0.1 0.1 0.1 0.1 0.1Purified water Suitable quantity Suitable quantity Suitable quantity Suitable quantity Suitable quantity Suitable quantity Evaluation results Appearance 3 months ○ ○ ○ × ○ ○ ○ 6 months × ○ ○ × ○ ○ ○ Hydrolysis suppression rate *¹(%) 3 months 81 93 94 − 95 90 90 6 months 59 87 89 − 90 81 80 * 1) Hydrolysis of polyoxyethylene hydrogenated castor oil 60
Suppression rate

Example 11 10 g of β-cyclodextrin, 2.5 g of dipotassium glycyrrhizinate, and 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkole HCO-60) were dissolved by heating.
To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, After adjusting the pH to 5.5 with diluted hydrochloric acid, the total amount is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to give an eye drop. 4 in this formulation
Hydrolysis inhibition rate after storage for 6 months at 0 ° C and 75% RH is 8
3%, and the appearance was extremely stable.

Comparative Example 2 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (60) hydrogenated castor oil (Nikkole HCO-60)
Dissolve 3 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, After adjusting the pH to 5.5 with dilute hydrochloric acid, the total volume is adjusted to 100 with purified water.
Make up 0 ml, filter aseptically and fill in an eye drop container to obtain an eye drop. This formulation was stored at 40 ° C. and 75% RH for 6 months, and as a result, a white precipitate was formed.

Example 12 20 g of γ-cyclodextrin, 2.5 g of dipotassium glycyrrhizinate, and 1 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) were dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 of 1-menthol
g, propylene glycol 5 g, allantoin 2 g, panthenol 0.8 g, boric acid 8 g, ethylenediaminetetraacetic acid disodium 0.05 g were mixed, and the pH was adjusted to 5.5 with dilute hydrochloric acid, and the total amount was adjusted to 1000 ml with purified water. Then, aseptically filter and fill in an eye drop container to obtain an eye drop. The hydrolysis inhibitory rate of this preparation after storage at 40 ° C. and 75% RH for 6 months was 91%, and the appearance was extremely stable.

Comparative Example 3 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (20) sorbitan monooleate (Nikkor T
O-10) 1 g is dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, l-
Menthol 0.05 g, propylene glycol 5 g, allantoin 2 g, panthenol 0.8 g, boric acid 8 g,
After mixing 0.05 g of disodium ethylenediaminetetraacetate and adjusting the pH to 5.5 with dilute hydrochloric acid, the total amount is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of storing this preparation at 40 ° C. and 75% RH for 6 months, it became cloudy.

Example 13 40 g of α-cyclodextrin, 5 g of dipotassium glycyrrhizinate, and 5 g of polyoxyethylene (25) monostearate (Nikkor MYS-25) are dissolved by heating.
To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, After adjusting the pH to 8 with sodium hydroxide, the total volume is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to give an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 74%, and the appearance was extremely stable.

Comparative Example 4 Dipotassium glycyrrhizinate 5 g, polyoxyethylene (25) monostearate (Nikkor MYS-25)
Dissolve 5 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, After adjusting the pH to 8 with sodium hydroxide, the total volume is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to give an eye drop. As a result of storing this preparation at 40 ° C. and 75% RH for 3 months, a white precipitate was formed.

Example 14 γ-cyclodextrin 40 g, β-cyclodextrin 10 g, dipotassium glycyrrhizinate 10 g, tocopherol acetate 0.5 g, retinol palmitate 0.1
5 g (1.7 million international units), polyoxyethylene (6
0) 1.5 g of hydrogenated castor oil (Nikkor HCO-60)
Dissolve by heating. Tetrahydrozoline hydrochloride 0.5
g, benzethonium chloride 0.1 g, 1-menthol 0.
05g, propylene glycol 5g, allantoin 2
g, panthenol 0.8 g, boric acid 8 g, and disodium ethylenediaminetetraacetate 0.05 g were mixed, and after adjusting the pH to 6.5 with sodium hydroxide, the total volume was adjusted to 1000 ml with purified water, and sterile filtration was performed. Fill the container to make eye drops. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 89%, and the appearance was extremely stable.

Example 15 10 g of α-cyclodextrin, 10 g of β-cyclodextrin, 0.5 g of dipotassium glycyrrhizinate, 0.5 g of tocopherol acetate, retinol palmitate 0.
15 g (1.7 million international units), polyoxyethylene (6
0) 1.5 g of hydrogenated castor oil (Nikkor HCO-60)
Dissolve by heating. Tetrahydrozoline hydrochloride 0.5
g, benzethonium chloride 0.1 g, 1-menthol 0.
05 g, propylene glycol 5 g, allantoin 2
g, panthenol 0.8 g, boric acid 8 g, and disodium ethylenediaminetetraacetate 0.05 g were mixed, and the pH was adjusted to 5 with dilute hydrochloric acid, and then the total amount was 1000 ml with purified water.
Then, aseptically filter and fill in an eye drop container to obtain an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 94%, and the appearance was extremely stable.

Example 16 50 g of dimethyl-β-cyclodextrin, 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (6
0) 3 g of hydrogenated castor oil (Nikkole HCO-60) is dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride,
Benzethonium chloride 0.1 g, l-menthol 0.05
g, propylene glycol 5 g, allantoin 2 g, panthenol 0.8 g, boric acid 8 g, ethylenediaminetetraacetic acid disodium 0.05 g were mixed, and the pH was adjusted to 5.5 with dilute hydrochloric acid, and the total amount was adjusted to 1000 ml with purified water. , Aseptically filter and fill in an eye drop container to obtain an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 95%, and the appearance was extremely stable.

Example 17 0.5 g of dimethyl-β-cyclodextrin, 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (2
0) Sorbitan monooleate (Nikkor TO-1
0) Dissolve 3 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetic acid were mixed. After adjusting the pH to 5.5 with diluted hydrochloric acid, the total amount is adjusted to 100 with purified water.
Make up 0 ml, filter aseptically and fill in an eye drop container to obtain an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 89%, and the appearance was extremely stable.

Example 18 0.08 g of dimethyl-β-cyclodextrin, 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (20) sorbitan monooleate (Nikkor TO-
10) Dissolve 3 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed,
After adjusting the pH to 5.5 with dilute hydrochloric acid, bring the total volume to 1 with purified water.
Make up to 000 ml, aseptically filter and fill in an eye drop container to obtain an eye drop. The formulation had a hydrolysis inhibition rate of 59% after being stored at 40 ° C. and 75% RH for 6 months, and the appearance was slightly cloudy.

Comparative Example 5 2.5 g of dipotassium glycyrrhizinate, polyoxyethylene (20) sorbitan monooleate (Nikkor T
3g of O-10) is dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, l-
Menthol 0.05 g, propylene glycol 5 g, allantoin 2 g, panthenol 0.8 g, boric acid 8 g,
After mixing 0.05 g of disodium ethylenediaminetetraacetate and adjusting the pH to 5.5 with dilute hydrochloric acid, the total amount is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of storing this preparation at 40 ° C. and 75% RH for 6 months, it became cloudy.

Example 19 40 g of hydroxypropyl-β-cyclodextrin,
Dipotassium glycyrrhizinate 5 g, polyoxyethylene (25) monostearate (Nikkor MYS-25)
Dissolve 5 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 g of panthenol, 8 g of boric acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, After adjusting the pH to 8 with sodium hydroxide, the total volume is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to give an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 94%, and the appearance was extremely stable.

Example 20 Hydroxypropyl-β-cyclodextrin 0.4
g, dipotassium glycyrrhizinate 0.5 g, polyoxyethylene (25) monostearate (Nikkor MYS
-25) Dissolve 0.5 g by heating. 0.5g of tetrahydrozoline hydrochloride, 0.1g of benzethonium chloride,
-0.05 g menthol, 5 g propylene glycol,
Allantoin 2g, panthenol 0.8g, boric acid 8
g, and 0.05 g of disodium ethylenediaminetetraacetate are mixed, the pH is adjusted to 8 with sodium hydroxide, the total amount is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. 40 ℃ ・ 75% in this formulation
RH · hydrolysis inhibition rate after storage for 6 months is 93%,
The appearance was extremely stable.

Example 21 5 g of trimethyl-β-cyclodextrin, 10 g of hydroxypropyl-β-cyclodextrin, 10 g of dipotassium glycyrrhizinate, and 0.5 tocopherol acetate.
g, 0.15 g of retinol palmitate (1.7 million international units), and 1.5 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) are dissolved by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 2 g of allantoin, 0.8 of panthenol.
g, boric acid 8 g, and ethylenediaminetetraacetic acid disodium 0.05 g are mixed, and the pH is adjusted to 6.5 with sodium hydroxide.
Then, the total volume is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. The hydrolysis inhibition rate after storage for 6 months at 40 ° C. and 75% RH in this preparation was 95%, and the appearance was extremely stable.

Example 22 5 g of trimethyl-β-cyclodextrin, dimethyl-
β-Cyclodextrin 10 g, dipotassium glycyrrhizinate 0.5 g, tocopherol acetate 0.5 g, retinol palmitate 0.15 g (1.7 million international units), polyoxyethylene (60) hydrogenated castor oil (Nikkor H
1.5 g of CO-60) is dissolved by heating. To this, tetrahydrozoline hydrochloride 0.5 g, benzethonium chloride 0.1
g, 1-menthol 0.05 g, propylene glycol 5 g, allantoin 2 g, panthenol 0.8 g, boric acid 8 g, ethylenediaminetetraacetic acid disodium 0.05
After mixing g and adjusting the pH to 5 with dilute hydrochloric acid, the total volume is adjusted to 1000 ml with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. 40 ℃ ・ 75% RH in this formulation
The hydrolysis inhibition rate after storage for 6 months was 96%, and the appearance was extremely stable.

Claims (2)

[Claims] 1. A stable eye drop comprising (a) an ester nonionic surfactant, (b) glycyrrhizic acid or a salt thereof, and (c) at least one or more of cyclodextrin or a derivative thereof. . 2. Cyclodextrin or a derivative thereof is at least one selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methylated-β-cyclodextrin and hydroxypropylated-β-cyclodextrin. The eye drop preparation according to claim 1, which is