JPH06340525A - Stable eye lotion containing solubilized vitamin a and having low stimulation to eye - Google Patents

Abstract

PURPOSE:To prepare an eye lotion capable of improving the aging stability of vitamin A compounds and decreasing the stimulation to the eye. CONSTITUTION:This eye lotion containing solubilized vitamin A compound is produced by compounding a vitamin A compound, a hydrogenated lecithin such as hydrogenated soybean lecithin and hydrogenated yolk lecithin and a nonionic surfactant such as polyoxyethylene hardened castor oil higher fatty acid ester and polyoxyethylene sorbitan higher fatty acid ester at ratios falling in the shadowed region encircled by the lines connecting the points A, B, C and D on the triangular diagram shown by the figure.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an eye drop containing solubilized vitamins A, more specifically, hydrogenated lecithin, a nonionic surfactant and vitamins A are mixed in a specific ratio. Thus, the present invention relates to a vitamin A solubilized eye drop which not only prevents the vitamin A from degrading over time but also reduces irritation to the eye.

[0002]

2. Description of the Related Art Vitamin A, including vitamin A oil and vitamin A fatty acid ester, has the function of maintaining normal vision of humans or animals, and its deficiency causes night blindness, keratoconjunctival dryness, etc. It is an essential fat-soluble vitamin for the eye. On the other hand, since vitamins A useful for the eye have remarkably low solubility in water, it has been indispensable to solubilize them with a nonionic surfactant or the like when used as an aqueous eye drop. However, an aqueous eye drop containing only a nonionic surfactant which is commonly used as a solubilizer has the following drawbacks or problems. It is difficult to sufficiently prevent the decomposition of vitamins A over time, especially the decomposition due to oxidation, without further adding other additives such as antioxidants. When an eye irritation sensation caused by other compounding ingredients such as a preservative typified by a quaternary ammonium type cationic surfactant occurs, it is impossible to reduce it. As a proposal that partially considers these points, Japanese Patent Laid-Open No. 4-2
No. 70218 and the like are listed, but in eye drops containing solubilized vitamin A's, those having good stability over time of vitamin A's and extremely reduced eye irritation have been found at all. There wasn't.

[0003]

The present invention is directed to vitamin A
It is an object of the present invention to not only improve the stability of vitamin A compounds over time, but also reduce the irritation to the eye in an eye drop containing a solubilized compound.

[0004]

[Means for Solving the Problems] As a result of intensive studies conducted by the present inventors for the purpose of improving the stability of vitamins A and reducing irritation to the eyes, vitamin A solubilized eye drops were solubilized. By adding hydrogenated lecithin which is an auxiliary agent, nonionic surfactant which is a solubilizing agent and vitamins A in a specific ratio, the stability of vitamins A with time is extremely high, and the eye irritation is high. It was found that a vitamin A solubilized eye drop having a low viscosity can be obtained, and the present invention was completed. That is, the vitamin A solubilizing eye drop of the present invention is a diagonal line formed by connecting hydrogenated lecithin, a nonionic surfactant and vitamin A to points A, B, C and D on the triangular chart shown in FIG. It is characterized in that it is blended in a specific ratio within the range represented by the region. Furthermore, the more preferable range of effect is that points A ', B', C'and D'on the same triangular chart.
It is a specific range expressed by the double mesh area formed by connecting the.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Vitamin A which is the first essential component of the present invention means vitamin A in addition to vitamin A itself.
Also included are vitamin A-containing mixtures such as oils and vitamin A derivatives such as vitamin A fatty acid esters. In particular,
Examples include 1.7 million international units (I.U.) of retinol palmitate manufactured by Nippon Roche Co., Ltd. Vitamin A is
Usually, 0.003 to 0.1% by weight can be added to the eye drop composition, and preferably 0.01 to 0.05% by weight.

The hydrogenated lecithin which is the second essential component of the present invention may be any lecithin whose oxidation resistance is improved by hydrogenation, specifically, hydrogenated soybean lecithin and hydrogenated egg yolk lecithin. Etc. A hydrogenation amount of 60% or more is preferable for stabilizing vitamins A, but the present invention is not limited to this. However, lecithin without any hydrogen added markedly reduces the stabilizing effect of vitamins A. The hydrogenated lecithin preferably contains 80% or more phospholipid component, more preferably 80 to 95% phosphatidylcholine as a phospholipid component, and as a result, a stabilizing effect of vitamin A is obtained. It is further improved, but the present invention is not particularly limited thereto.
Examples of hydrogenated lecithin that satisfies all the above conditions include, for example, Recinol S- manufactured by Nikko Chemicals Co., Ltd.
10E, Resinol Y-10E, Resinol S-10E
There are X etc. Hydrogenated lecithin can be usually added to the eye drop composition in an amount of 0.001 to 0.1% by weight, preferably 0.003 to 0.05% by weight.

Examples of the nonionic surfactant which is the third essential component of the present invention include higher fatty acid esters such as water-soluble polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, and the like. There are polyoxyethylene (p = 60) hydrogenated castor oil and polyoxyethylene (p = 20) sorbitan monooleate. In addition, p shows the average addition mole number of ethylene oxide. Specifically, Nikkor H manufactured by Nikko Chemicals Co., Ltd.
CO-40, HCO-50, HCO-60, TO-10
Etc. The nonionic surfactant can be usually added to the eye drop composition in an amount of 0.01 to 1.0% by weight, preferably 0.05 to 0.2% by weight.

The above three essential components of the present invention must be blended in a ratio within the shaded area surrounded by points A, B, C and D in the triangular diagram shown in FIG. It is blended in proportions within the double-hatched area surrounded by A ', B', C'and D '. In the triangular diagram of FIG. 1, the apex indicates the 100% position of each component, and the coordinates of each point are represented by (hydrogenated lecithin, nonionic surfactant, vitamin A) and are as follows. Point A (4.8, 47.6, 47.6) Point B (33.3, 33.3, 33.3) Point C (8.3, 83.3, 8.3) Point D (0. 9, 90.1, 9.0) Point A '(4.4, 66.9, 28.7) Point B' (20.8, 55.4, 23.8) Point C '(8.0, 8.0 82.8, 9.2) Point D '(1.5, 88.6, 9.9)

The vitamin A solubilized eye drops of the present invention may contain other vitamins, epsilon-aminocaproic acid, dipotassium glycyrrhizinate, chlorpheniramine maleate, naphazoline hydrochloride, potassium aspartate, if necessary. Drugs such as zinc sulfate, sulfamethoxazole and allantoin; preservatives such as benzalkonium chloride, chlorobutanol and paraoxybenzoates; isotonic agents such as potassium chloride, sodium chloride, propylene glycol, polyethylene glycol and glycerin. Agents; citric acid, boric acid, sodium hydrogen phosphate, glacial acetic acid and other buffers; mannitol and other sugars; l-menthol and other flavors and the like can be added.

The method for preparing the vitamin A solubilized eye drop of the present invention is not particularly limited. For example, vitamin A such as vitamin A acetate and hydrogenated lecithin are mixed with nonionic surface such as polyoxyethylene hydrogenated castor oil 60. Dissolves in water with an activator. Then, if necessary, epsilon-
A vitamin A solubilized ophthalmic solution that prevents the decomposition of vitamin A with the passage of time and reduces irritation to the eye by adjusting the pH by adding a drug such as aminocaproic acid and a buffer such as citric acid. Can be obtained.

PH of the eye drops for solubilizing vitamin A compounds of the present invention
Is preferably in the range of 4 to 9, and more preferably 5 to 8.5. If the pH of the eye drop is out of the above range, the stability of vitamins A with time will be significantly lowered, and the irritation to the eye will be increased.

[0012]

EFFECTS OF THE INVENTION According to the present invention, by adding hydrogenated lecithin, a nonionic surfactant and vitamins A in a specific ratio, only the stability of vitamins A over time is improved. Moreover, irritation to the eyes can be reduced.

[0013]

【Example】

Examples 1 to 2 and Comparative Examples 1 to 3 Eye drops having the formulations shown in Table 1 were prepared, filled in a container, and evaluated for eye irritation and stability of vitamin A palmitate with time. The results are shown. In addition, the pH of eye drops is 5.5 with sodium dihydrogen phosphate and disodium hydrogen phosphate, and the osmotic pressure is 290 mOsm with sodium chloride.
Adjusted to each.

[0014]

Table 1 Examples Examples Examples Comparative Examples Comparative Examples Comparative Examples 1 2 1 2 3 Blending amount (g / 100ml): Vitamin A palmitate 0.02 0.02 0.02 0.02 0.02 Hydrogenated soybean lecithin * 0.005 0.015 − 0.025 0.04 Polyoxyethylene (20) 0.1 0.1 0.1 0.4 0.1 Sorbitan monooleate 10% Benzalkonium chloride solution 0.05 0.05 0.05 0.05 0.05 Distilled water Suitable quantity Suitable quantity Suitable quantity Suitable quantity Suitable quantity Coordinate position of triangle chart: Hydrogenated soybean lecithin 4.0 11.1 0 5.6 25.0 Polyoxyethylene (20) 80.0 74.1 83.3 89.9 62.5 Sorbitan monooleate Vitamin A palmitate 16.0 14.8 16.7 4.5 12.5 Evaluation results: Eye irritation ○ ○ △ × ○ Vitamin A palmitate 83 81 39 78 26 Survival rate(%) * Nikko Chemicals Resinol S-10EX

The evaluation of eye irritation was carried out according to the short-term test method of the eye mucosal irritation test of the preservative for eye drops in the Ministry of Health and Welfare Scientific Research Report (1965). Table 1 and Table 2 below
The legend inside is as follows. ◯: Average score by Draize method is 0 or more and less than 2 points Δ: Average score by Draize method is 2 points or more and less than 5 points ×: Average score by Draize method is 5 points or more The stability was evaluated by measuring the vitamin A content immediately after production and after storage at 40 ° C.-75% RH for 2 months using a high performance liquid chromatographic method, and calculating the vitamin A residual ratio by the formula 1. It was

[0016]

[Equation 1]

Example 3 2 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), 0.1 g of hydrogenated egg yolk lecithin
(Nikko Chemicals Recinol Y-10E) and vitamin A palmitate 0.4 g (1.7 million international units) are dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol,
Propylene glycol 5 g, allantoin 1 g, panthenol 0.2 g, epsilon-aminocaproic acid 10
g and 0.05 g of disodium ethylenediaminetetraacetate are mixed, the pH is adjusted to 7.0 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. The coordinates of the triangular diagram in FIG. 1 are (4.0, 80.0, 16.0). The stability of the vitamin A palmitate of this preparation was extremely high, and the irritation to the eyes was low.

Comparative Example 5 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 3 g, vitamin A palmitate 0.4 g
(1.7 million international units) 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 1 g, panthenol 0.2 g, epsilon-aminocaproic acid 10 g, and ethylenediaminetetraacetic acid disodium 0.05 g are mixed, and the pH is adjusted to 7.0 with sodium hydroxide. After adjusting, bring the total volume to 100 with purified water.
Make up 0 ml, filter aseptically and fill in an eye drop container to obtain an eye drop. Vitamin A palmitate of this preparation was significantly decomposed over time, and its irritation to the eye was rather high.

Example 4 1.5 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), 0.05 g of hydrogenated soybean lecithin (Nikko Chemicals Recinol S-10EX), 0.2 g of vitamin A palmitate (1.7 million) (International units) are dissolved by heating. Tetrahydrozoline hydrochloride 0.5
g, benzethonium chloride 0.1 g, 1-menthol 0.
05g, propylene glycol 5g, allantoin 1
g, panthenol 0.2 g, epsilon-aminocaproic acid 10 g, ethylenediaminetetraacetic acid disodium 0.
After mixing 05 g and adjusting the pH to 7.0 with sodium hydroxide, 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 coordinates of the triangular diagram in FIG. 1 are (2.9, 85.7, 11.4).
The stability of the vitamin A palmitate of this preparation was extremely high, and the irritation to the eyes was low.

Comparative Example 6 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 1.5 g, vitamin E acetate 0.0
5 g and 0.2 g of vitamin A palmitate (1.7 million international units) 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, 1 g of allantoin, 0.2 g of panthenol, 10 g of epsilon-aminocaproic acid, and 0.05 g of disodium ethylenediaminetetraacetate are mixed. And adjust the pH to 7.0 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 stability of the vitamin A palmitate of this preparation was low, and the irritation to the eye was slight.

Example 5 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 1.5 g, hydrogenated soybean lecithin (Nikko Chemicals Recinol S-10EX) 0.05 g, vitamin A palmitate 0.2 g (1.7 million) International units),
Vitamin E acetate (0.25 g) is dissolved by heating. 0.5 g of tetrahydrozoline hydrochloride, 0.1 g of benzethonium chloride, 0.05 g of 1-menthol, 5 g of propylene glycol, 1 g of allantoin, 0.2 of panthenol.
g, 10 g of epsilon-aminocaproic acid, and 0.05 g of disodium ethylenediaminetetraacetate were mixed, the pH was adjusted to 7.0 with sodium hydroxide, the total volume was adjusted to 1000 ml with purified water, and sterile filtered and filled in an eyedrop container. To make eye drops. The coordinates of the triangular chart in Fig. 1 are (2.9, 8
5.7, 11.4). The stability of the vitamin A palmitate of this preparation was extremely high, and the irritation to the eyes was low.

Comparative Example 7 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 0.2 g, egg yolk lecithin 0.1 g (Nikko Chemicals Recinol Y-10E), vitamin A palmitate 0.4 g (1.7 million international units) ) Is 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, 1 g of allantoin, 0.2 g of panthenol, 10 g of epsilon-aminocaproic acid, and 0.05 g of disodium ethylenediaminetetraacetate are mixed. Then, after adjusting the pH to 7.0 with sodium hydroxide, 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. Although this preparation had low eye irritation, vitamin A palmitate was significantly decomposed over time.

Table 2 shows the evaluation results of Examples 3 to 5 and Comparative Examples 5 to 7 for eye irritation and stability of vitamin A palmitate.

[0024]

[Table 2] Evaluation results: Implementation Comparison Implementation Comparison Implementation Comparison Comparison Evaluation Item Example 3 Example 5 Example 4 Example 6 Example 5 Example 7 Eye irritation ○ △ ○ △ ○ ○ Vitamin A palmitate 88 47 86 65 93 38 Persistence rate (%)

[Brief description of drawings]

FIG. 1 is a triangular chart showing the blending ratio of hydrogenated lecithin, nonionic surfactant and vitamin A's. The coordinates of each point indicating the ratio of (hydrogenated lecithin, nonionic surfactant, vitamins A) are as follows. Point A (4.8, 47.6, 47.6) Point B (33.3, 33.3, 33.3) Point C (8.3, 83.3, 8.3) Point D (0. 9, 90.1, 9.0) Point A '(4.4, 66.9, 28.7) Point B' (20.8, 55.4, 23.8) Point C '(8.0, 8.0 82.8, 9.2) Point D '(1.5, 88.6, 9.9)

Claims (1)

[Claims] 1. Vitamin A, hydrogenated lecithin, nonionic surfactant, points A and B on the triangular chart shown in FIG.
A vitamin A solubilized eye drop characterized by being blended in a ratio of a shaded area formed by connecting C and D.