JPH05139955A - Stable instillation - Google Patents

Abstract

PURPOSE:To obtain an instillation excellent in long-term storage stability and appearance causing no precipitation by formulating a glycyrrhizic acid salt with each specified amount of epsilon-aminocaproic acid and liposoluble substance. CONSTITUTION:The objective instillation can be obtained by formulating (A) (1) pref. 0.05-0.5wt.% of an ester-based nonionic surfactant like water-soluble polyoxyethylene hardened castor oil and (2) pref. 0.01-5.0wt.% of glycyrrhizic acid salt like dipotassium glycyrrhizate with (B) 5-100 pts.wt., based on 100 pts.wt. of the salt, of epsilon-aminocaproic acid and (C) 0.3-5 pts.wt., based on 100 pts.wt. of the salt, of a liposoluble substance like dibutylhydroxytoluene or vitamin A.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for stabilizing eye drops containing an ester type nonionic surfactant and glycyrrhizinates for a long period of time without causing precipitation.

[0002]

2. Description of the Related Art Glycyrrhizin, which is a conjugate of glycyrrhetin and two molecules of glucuronic acid, and which is the main component of licorice, has an anti-inflammatory action but no anti-granulation action. Also its salts,
For example, dipotassium glycyrrhizinate or the like is often used as an eye drop because it is well soluble in water, has an anti-inflammatory action even in a small amount, and causes little irritation even when instilled. Furthermore, glycyrrhizinates are often used in combination with ester-type nonionic surfactants because they easily form a gel structure in an acidic aqueous solution. However, it is difficult to keep the appearance stable for a long period of time, for example, when both are mixed at the same time, the above-mentioned surfactant is mainly hydrolyzed to cause precipitation.

[0003]

DISCLOSURE OF THE INVENTION The present invention is to suppress decomposition of an ester nonionic surfactant in an eye drop containing an ester nonionic surfactant and glycyrrhizinates and improve appearance stability. With the goal.

[0004]

The stable eye drop of the present invention is an eye drop containing an ester nonionic surfactant and glycyrrhizinate, in which ε-aminocaproic acid is added in an amount of 5 to 100 relative to glycyrrhizinate. Weight ratio and fat-soluble substance to glycyrrhizinate are 0.3
It is characterized by being blended in a weight ratio of up to 5%.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the ester nonionic surfactant of the present invention include higher fatty acid esters such as water-soluble polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, polyethylene glycol fatty acid esters and the like. , For example, polyoxyethylene (p = 60) hydrogenated castor oil, polyoxyethylene (p =
20) There are sorbitan monooleate and polyethylene glycol (p = 10) monostearate. In addition, p shows the average addition mole number of ethylene oxide. Usually, 0.05 to 0.5% by weight can be added to the composition.

Examples of the glycyrrhizinates include dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, and the like, which may be commonly used in medicines, quasi-drugs, cosmetics, and the like. Specifically, they are manufactured by Maruzen Pharmaceutical Co., Ltd. Examples thereof include dipotassium glycyrrhizinate. Usually, 0.01 to 5.0% by weight can be added to the composition.

The ε-aminocaproic acid may be one generally used in medicine and the like, and specific examples thereof include epsilon aminocaproic acid for pharmaceuticals manufactured by Kyowa Hakko Kogyo Co., Ltd.

Examples of fat-soluble substances include dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHT).
HA), tocopherols, long chain fatty acids, vitamin A
Examples thereof include higher alcohols, paraffins, and the like, and one or more of these are used. As tocopherols, tocopherol, tocopherol acetate,
Examples thereof include tocopherol succinate. Also, as long-chain fatty acids, palmitic acid, stearic acid,
Examples thereof include oleic acid. More vitamin A
Examples of the class include vitamin A, vitamin A acetate, vitamin A palmitate, vitamin A oil and the like. As higher alcohols, cetyl alcohol,
Stearyl alcohol etc. can be mentioned. Examples of paraffins include liquid paraffin. The compounding ratios of these ε-aminocaproic acid and the fat-soluble substance to the glycyrrhizic acid salts are shown in Table 1 below.
Is the street.

[0009]

[Table 1]

The stable eye drops of the present invention include, if necessary, drugs such as water-soluble vitamins, chlorpheniramine maleate, tetrahydrozoline hydrochloride, allantoin, lysozyme chloride and naphazoline hydrochloride; chlorhexidine gluconate and chloride. Benzalkonium, sorbic acid,
Preservatives such as chlorobutanol; isotonic agents such as propylene glycol, sodium chloride, potassium chloride, buffers such as citric acid, glutamic acid, boric acid, sodium hydrogen phosphate, glacial acetic acid, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose. Polymer additives such as hydroxypropyl cellulose and the like can also be added.

The method for preparing the stable eye drop of the present invention is not particularly limited. For example, a fat-soluble substance such as BHT is mixed with polyoxyethylene hydrogenated castor oil, an ester nonionic interface such as polyoxyethylene sorbitan mono higher fatty acid ester. Solubilized in water by an activator. Then, glycyrrhizinates such as dipotassium glycyrrhizinate and ε-aminocaproic acid are added and dissolved in water.
By adjusting H, an eye drop having a stable appearance can be obtained. The pH of the eye drop of the present invention is usually 4.5 to 8.
It is preferably in the range of 5, and more preferably 5.0.
Is about 7.5. When the pH of the eye drop is extremely outside the above range, the appearance such as precipitation is remarkably deteriorated.

[0012]

According to the present invention, by adding epsilon aminocaproic acid and a fat-soluble substance in combination to an eye drop containing an ester nonionic surfactant and glycyrrhizinates, the surfactant is hydrolyzed. Suppress
The appearance can be stable over a long period of time. Less than,
The decomposition rates of the surfactants in the accelerated tests described in Examples 1 to 6 and Comparative Examples 1 to 6 are as follows. The decomposition products of fatty acids such as polyoxyethylene (20) sorbitan monooleate are oleic acid and poly Oxyethylene (6
0) The content of 12-hydroxystearic acid and the like in hydrogenated castor oil was quantified and calculated using a high speed chromatographic method.

[0013]

【Example】

Example 1 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), d-α-tocopherol acetate 0.
Dissolve 5 g by heating. 1.3 g of citric acid, 0.1 g of benzethonium chloride, 5 g of sodium chondroitin sulfate, 1 g of dipotassium glycyrrhizinate, 30 g of ε-aminocaproic acid, 3 g of chlorobutanol, 0.3 g of 1-menthol, 5 g of propylene glycol, 1 g of allantoin, bread. 0.2 g of tenol is mixed, the total amount is made 1000 ml (pH = 5.8) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of 6 months of accelerated test at 40 ° C, this preparation showed that the decomposition rate of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) was about 1%.
The appearance was stable without precipitation.

Comparative Example 1 4 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) and 0.3 g of vitamin A palmitate (1.7 million units) are dissolved by heating. 1.3 g of citric acid, 10 g of sodium citrate, 10 g of potassium aspartate, 1.0 g of dipotassium glycyrrhizinate, 2 g of 10% benzalkonium chloride solution, 10 g of mannitol, 5 g of propylene glycol, 0.1 g of 1-menthol and chloro. 4 g of butanol is mixed, the total amount is made up to 1000 ml (pH = 5.5) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. This formulation showed that polyoxyethylene (2
0) Sorbitan monooleate (Nikkor TO-1
The decomposition rate of 0) was 40% and the appearance was cloudy.

Example 2 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 3.5 g, d-α-tocopherol acetate 1 g, vitamin A palmitate (1.7 million units) 0.0
Dissolve 3 g by heating. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 0.5 g of 10% benzalkonium chloride solution, 1 of ε-aminocaproic acid
2.5 g, sodium chloride 1 g, pyridoxine hydrochloride 0.
5 g, dipotassium glycyrrhizinate 2.5 g, mannitol 20 g, ethylenediaminetetraacetic acid sodium 0.0
5 g were mixed, and the total amount was 1000 ml with purified water (pH =
7.0), aseptically filter and fill in an eye drop container to give an eye drop. As a result of 6 months of accelerated test at 40 ° C., this formulation showed that polyoxyethylene (60) hydrogenated castor oil (Nikkor H
The decomposition rate of CO-60) was about 2%, and the appearance was stable without precipitation.

Example 3 5 g of polyoxyethylene (40) hydrogenated castor oil (Nikkor HCO-40) and 1 g of stearic acid were dissolved by heating. 40 g of ε-aminocaproic acid, 2.5 g of potassium chloride, 0.25 g of 10% benzalkonium chloride solution,
Pyridoxine hydrochloride 1 g, dipotassium glycyrrhizinate 0.5 g, and chlorpheniramine maleate 0.3 g are mixed, the total volume is adjusted to 1000 ml (pH = 6.0) with purified water, sterile filtered, and filled in an eye drop container to be an eye drop. And As a result of 6 months of accelerated test at 40 ° C., this formulation showed that polyoxyethylene (40) hydrogenated castor oil (Nikkor HCO-4
The decomposition rate of 0) was about 2%, and the appearance was stable without precipitation.

Comparative Example 2 4 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), d-α-tocopherol acetate 1.
Dissolve 0 g by heating. 2.6 g of citric acid, 1.8 g of sodium citrate, 10 parts of potassium aspartate
g, dipotassium glycyrrhizinate, 0.1 g of benzethonium chloride, 1 g of allantoin, 0.3 g of chlorpheniramine maleate, 20 g of ε-aminocaproic acid, 5 g of propylene glycol, and 4 g of chlorobutanol, and the total amount is 1000 m with purified water ( pH = 4.0),
Aseptically filter and fill in an eye drop container to obtain an eye drop. As a result of 2 months of accelerated test at 40 ° C, this formulation showed that polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60)
The decomposition rate was about 15% and a white precipitate appeared.

Comparative Example 3 2 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) was dissolved by heating. Mix 1.3 g of citric acid, 10 g of sodium citrate, 10 g of potassium aspartate, 2.5 g of dipotassium glycyrrhizinate, 2 g of 10% benzalkonium chloride solution, 25 g of ε-aminocaproic acid, 4 g of sodium chloride, 3 g of chlorobutanol. Then, add 1000 ml of purified water.
(PH = 5.5), aseptically filter and fill an eye drop container to obtain an eye drop. As a result of the accelerated test at 40 ° C. for 6 months, this preparation had a decomposition rate of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) of 45% and had an opaque appearance.

Example 4 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 3 g, acetic acid d-α-tocopherol 0.
5 g and 0.15 g of BHT are dissolved by heating. To this, 2.2 g of sodium dihydrogen phosphate, 1 disodium hydrogen phosphate
2 g, 10% benzalkonium chloride solution 0.5 g, sodium chloride 1 g, pyridoxine hydrochloride 0.5 g, dipotassium glycyrrhizinate 1.25 g, mannitol 10 g, sodium ethylenediaminetetraacetate 0.05 g, and ε-aminocaproic acid 25 g are mixed. , 1000 with purified water
It is made up to pH (7.0), sterile filtered, and filled in an eye drop container to give an eye drop. As a result of the accelerated test at 40 ° C. for 6 months, this preparation had a decomposition rate of 2% of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), and was stable in appearance without causing precipitation.

Example 5 3 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) and 0.4 g of d-α-tocopherol acetate were dissolved under heating. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1
0% benzalkonium chloride solution 1 g, ε-aminocaproic acid 20 g, sodium chloride 1 g, pyridoxine hydrochloride 0.
5 g, dipotassium glycyrrhizinate 1 g, and sodium ethylenediaminetetraacetate 0.05 g are mixed, the total amount is adjusted to 1000 ml (pH = 7.0) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of the accelerated test at 40 ° C. for 6 months, this preparation had a decomposition rate of 5% of polyoxyethylene (20) sorbitan monooleate and (Nikkor TO-10), and the appearance was stable without precipitation. It was

Comparative Example 4 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) and 0.25 g of BHT were dissolved by heating. 1.3 g of citric acid and 10 parts of sodium citrate
g, potassium aspartate 10 g, dipotassium glycyrrhizinate 1 g, benzethonium chloride 0.2 g, ε-aminocaproic acid 3 g, propylene glycol 5 g, 1-
Mix 0.1 g menthol and 4 g chlorobutanol,
The total volume is made 1000 ml (pH = 5.5) with purified water, sterile filtered and filled in an eye drop container to give an eye drop. This formulation is
As a result of the accelerated test at 40 ° C. for 6 months, the decomposition rate of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) was 9%, and the appearance was clouded.

Comparative Example 5 5 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10), 2 g of d-α-tocopherol acetate and 0.25 g of BHA were dissolved under heating. 1.3 g of citric acid, 10 g of sodium citrate, 10 g of potassium aspartate, 0.3 g of dipotassium glycyrrhizinate, 2 g of 10% benzalkonium chloride solution, 40 g of ε-aminocaproic acid, 4 g of sodium chloride, 3 g of propylene glycol, and chloro. 2 g of butanol is mixed, the total amount is made up to 1000 ml (pH = 5.5) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. This formulation is 4
As a result of one month of 0 ° C accelerated test, polyoxyethylene (20) sorbitan monooleate (Nikkor TO-
The decomposition rate of 10) was 4%, but the appearance was cloudy.

Comparative Example 6 2 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) and 0.25 g of BHA were dissolved by heating. 1.3 g of citric acid and 10 parts of sodium citrate
g, potassium aspartate 10 g, dipotassium glycyrrhizinate 2.5 g, benzethonium chloride 0.2 g, 6
-Aminocaproic acid 2.5 g, sodium chloride 4 g, chlorobutanol 3 g, mannitol 10 g, propylene glycol 5 g, and 1-menthol 0.3 g were mixed, and the total volume was adjusted to 1000 ml (pH = 5.5) with purified water, and sterile filtered. Fill into an eye drop container to obtain an eye drop. This formulation is 4
As a result of the accelerated test at 0 ° C. for 3 months, the decomposition rate of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) was 9%, and the appearance caused precipitation.

Example 6 2 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) and 0.015 g of BHA were dissolved by heating. 1.3 g of citric acid, 1.
8 g, potassium aspartate 10 g, dipotassium glycyrrhizinate 3 g, benzethonium chloride 0.1 g, allantoin 1 g, chlorpheniramine maleate 0.3
g, ε-aminocaproic acid 20 g, propylene glycol 5 g, and chlorobutanol 4 g are mixed, the total amount is adjusted to 1000 ml (pH = 5.0) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of the accelerated test at 40 ° C. for 6 months, this preparation had a decomposition rate of 7% of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), and was stable in appearance without causing precipitation.

Claims (1)

[Claims] 1. In an eye drop containing an ester nonionic surfactant and glycyrrhizinates, ε-aminocaproic acid is added in an amount of 5 to 100 relative to glycyrrhizates.
A stable eye drop comprising a glycyrrhizic acid salt in a weight ratio of 0.3 to 5 and a fat-soluble substance.