JPH05132421A - Aqueous eye drop containing solubilized vitamin a - Google Patents

Abstract

PURPOSE:To provide an aqueous eye drop containing a quarternary ammonium- type cationic surfactant, sodium sulfite and vitamin A solubilized by a nonionic surfactant. CONSTITUTION:Sodium sulfite and 0.001-0.1wt.% quaternary ammonium-type cationic surfactant (e.g. benzalconium chloride) are contained. To an aqueous vitamin A solution solubilized by a nonionic surfactant, two or more kinds of substances selected from a liposoluble antioxidant, an anionic substance and a cationic substance except the quaternary ammonium-type surfactant are blended. Deterioration of vitamin A due to oxidation in the aqueous eye drop can be prevented and the blended vitamin A can be kept stably over a long period.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous eye drop in which vitamin A is stably solubilized for a long period of time.

[0002]

2. Description of the Related Art Vitamin A including vitamin A oil and vitamin fatty acid ester has a normal function of maintaining visual and mucous membranes for humans or animals, and its deficiency causes night blindness, keratosis, etc. It is an indispensable substance. However, it is known that vitamin A, which is a fat-soluble vitamin, is extremely easily oxidized and is extremely unstable especially in an aqueous solution. As a conventional technique for stabilizing unstable vitamin A, dibutylhydroxytoluene (BH) has been used as an emulsion system or powder system.
T), fat-soluble antioxidants such as butylhydroxyanisole (BHA), nordihydroguaiaretic acid (NDGA) and tocopherol, water-soluble antioxidants such as ascorbic acid, hydroquinone and cysteine, or both antioxidants. A method of adding or mixing
No. 8-48617, JP-A-58-41813), a method of coating vitamin A with gelatin, casein, dextrin, etc., and stabilizing it by cutting off contact with air in the form of particles or powder (JP-A No. 8-48317). Sho 61-212322
No. publication) is known. Especially when using eye drops,
Of the above water-soluble antioxidants, a system in which sodium sulfite, which has the highest stabilizing effect on vitamin A, and a quaternary ammonium type cationic surfactant, which is a preservative with high antibacterial activity and which is most commonly used, are simultaneously mixed. Then, since vitamin A becomes extremely unstable, it was difficult to obtain a stable vitamin A-solubilized aqueous eye drop.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to improve the stability of a water-soluble eye drop in which vitamin A is solubilized in a system in which a quaternary ammonium type cationic surfactant and sodium sulfite coexist. And

[0004]

The aqueous solution of vitamin A solubilized according to the present invention contains a quaternary ammonium type cationic surfactant and sodium sulfite, and is used in an aqueous solution of vitamin A solubilized by a nonionic surfactant. ,(I)
One or more kinds of compounds of at least two groups out of three groups of fat-soluble antioxidants, (b) anionic substances, and (c) cationic substances other than quaternary ammonium type cationic surfactants are blended. Characterize.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The vitamin A of the present invention includes, in addition to vitamin A itself, a vitamin A-containing mixture such as vitamin A oil and a vitamin A derivative such as vitamin A fatty acid ester. It is possible to add 0.01 to 0.05% by weight.

Examples of the quaternary ammonium type cationic surfactant include benzalkonium chloride and benzethonium chloride, which can be usually added in an amount of 0.001 to 0.1% by weight in the composition.

Examples of nonionic surfactants that solubilize vitamin A include higher fatty acid esters such as water-soluble polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, and the like. For example, polyoxyethylene (p = 60) hydrogenated castor oil, polyoxyethylene (p = 20) sorbitan monooleate,
Usually, 0.05 to 0.5% by weight can be added to the composition. In addition, p shows the average addition mole number of ethylene oxide.

Examples of the fat-soluble antioxidant (a) include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), nordihydroguaiaretic acid, and tocopherols.

Examples of the (b) anionic substance include dipotassium glycyrrhizinate and sodium chondroitin sulfate.

(C) Examples of the cationic substance other than the quaternary ammonium type cationic surfactant include naphazoline hydrochloride, chlorpheniramine maleate, pyridoxine hydrochloride and the like.

In the present invention, at least two groups are selected from the above three groups of additives (a) to (d), and at least one compound selected from these selected groups is added in combination. Compound. Further, by using these three groups together, a further stabilizing effect can be obtained. The amounts of these additives to be added are shown in Table 1 below, for example, for vitamin A of about 1.5 million units (1 g).

[0012]

[Table 1]

The vitamin A-solubilized aqueous eye drop of the present invention may contain other vitamins, if necessary; lysine and salts thereof, glycine, epsilon aminocaproic acid, aminoethylsulfonic acid, L-arginine, aspartic acid. And amino acids such as salts thereof; drugs such as zinc sulfate, sulfamethoxazole, allantoin, and lysozyme chloride;
Preservatives such as chlorhexidine gluconate, sorbic acid, chlorobutanol; potassium chloride, sodium chloride,
An isotonicity agent such as propylene glycol; a buffering agent such as citric acid, boric acid, sodium hydrogen phosphate, glacial acetic acid, or the like can be added.

The method for preparing the vitamin A-solubilized aqueous eye drop of the present invention is not particularly limited. For example, vitamin A may be added to BHT.
Solubilized in water by a nonionic surfactant such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan higher fatty acid ester together with a fat-soluble antioxidant such as. Then, an anionic substance such as dipotassium glycyrrhizinate and / or a cationic substance other than a quaternary ammonium type cationic surfactant such as naphazoline hydrochloride,
By adding a quaternary ammonium type cationic surfactant and sodium sulfite and dissolving them in water, and adding a buffer to adjust the pH, a vitamin A-solubilized aqueous eye drop which is stable against oxidation can be obtained. ..

The p of the vitamin A-solubilized aqueous eye drop of the present invention is
H is preferably in the range of 5 to 9, more preferably 6 to 8.5. When the pH of the eye drop is out of the above range, the stabilizing effect of vitamin A decreases.

[0016]

INDUSTRIAL APPLICABILITY According to the present invention, an aqueous eye drop containing a quaternary ammonium type cationic surfactant and sodium sulfite and having vitamin A solubilized by a nonionic surfactant is used. By adding at least one compound in combination of at least two groups out of the three groups of the oxidizing agent, the (b) anionic substance, and the (c) cationic substance other than the quaternary ammonium type cationic surfactant,
It is possible to prevent deterioration of vitamin A due to oxidation in an aqueous eye drop, and stabilize and mix vitamin A for a long period of time.

[0017]

【Example】

Example 1 2 g of polyoxyethylene (40) hydrogenated castor oil (Nikkor HCO-40), d-α-tocopherol acetate 0.
3 g, vitamin A palmitate (1.7 million units) 0.1
g is dissolved by heating. 1.3 g of citric acid, 1 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 g of benzethonium chloride, 5 dipotassium glycyrrhizinate.
g, chlorobutanol 3 g, 1-menthol 0.3 g,
Propylene glycol 5g, allantoin 1g, panthenol 0.2g are mixed, and the total amount is 1000ml with purified water.
(PH = 5.5), aseptically filter and fill an eye drop container to obtain an eye drop. As a result of 1 month of the accelerated test at 50 ° C., the residual ratio of vitamin A palmitate was 60%.

Comparative Example 1 4 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) and 0.2 g of vitamin A palmitate (1.7 million units) are dissolved by heating. 1.3 g of citric acid, 8 g of boric acid, 5 g of sodium sulfite,
10 g of potassium aspartate, 2 g of 10% benzalkonium chloride solution, and 2 g of chlorobutanol are mixed, and 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. As a result of 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 0%.

Example 2 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 2.5 g, d-α-tocopherol acetate 0.5 g, vitamin A palmitate (1.7 million units)
Dissolve 0.1 g by heating. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, 30 g of ε-aminocaproic acid, 0.5 g of 10% benzalkonium chloride solution, and pyridoxine hydrochloride of 0.
5 g, 20 g of mannitol and 0.05 g of sodium ethylenediaminetetraacetate are mixed, and the total amount is 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 1 month of the accelerated test at 50 ° C., the residual ratio of vitamin A palmitate was 68%.

Example 3 5 g of polyoxyethylene (40) hydrogenated castor oil (Nikkor HCO-40), d-α-tocopherol acetate 1.
0g, Vitamin A palmitate (1.7 million units) 0.2
g is dissolved by heating. 1.3 g of citric acid, 2 g of sodium sulfite, 10 g of potassium aspartate, 0.1 g of benzethonium chloride, 5 g of sodium chondroitin sulfate, 2.5 g of dipotassium glycyrrhizinate, 0.2 g of panthenol, 5 g of propylene glycol, 4 g of chlorobutanol, Sodium ethylenediaminetetraacetate 0.0
2 g were mixed, and the total amount was 1000 ml with purified water (pH =
5.5), aseptically filter and fill in an eye drop container to give an eye drop. As a result of one month of the accelerated test at 50 ° C., the formulation had a residual rate of vitamin A palmitate of 58%.

Example 4 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), d-α-tocopherol acetate of 0.
5g, Vitamin A palmitate (1.7 million units) 0.1
Dissolve 5 g by heating. To this, 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, 20 g of ε-aminocaproic acid, 0.5 g of 10% benzalkonium chloride solution, 0.5 g of pyridoxine hydrochloride.
g, dipotassium glycyrrhizinate 2.5 g, mannitol 20 g, sodium ethylenediaminetetraacetate 0.03
g and mixed with purified water to a total volume of 1000 ml (pH = 7.
0), aseptically filter and fill in an eye drop container to obtain an eye drop. As a result of 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate was 81%.

Example 5 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), d-α-tocopherol acetate of 0.
5g, Vitamin A palmitate (1.7 million units) 0.1
Dissolve 5 g by heating. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, 5 g of ε-aminocaproic acid, 0.25 g of 10% benzalkonium chloride solution, 1 g of pyridoxine hydrochloride,
5.0 g of dipotassium glycyrrhizinate, 0.3 g of chlorpheniramine maleate, 30 g of mannitol, and 0.05 g of sodium ethylenediaminetetraacetate were mixed, and the total volume was adjusted to 1000 ml (pH = 7.0) with purified water. Fill a container to make eye drops. This formulation is 50
As a result of one month of the accelerated test of degree C, the residual rate of vitamin A palmitate was 90%.

Comparative Example 2 Polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60) 2 g, BHA 0.015 g, vitamin A
0.15 g of acetate (1.7 million units) is dissolved by heating. 2 g of citric acid, 2 g of sodium sulfite, 0.1 g of benzethonium chloride, 1 g of allantoin, 0.3 g of chlorpheniramine maleate, 1 pyridoxine hydrochloride.
g, 12 g of boric acid are mixed, and the total amount is 1000 m with purified water.
1 (pH = 4.0), aseptically filter and fill an eye drop container to obtain an eye drop. As a result of 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A acetate in this preparation was 15%.

Comparative Example 3 3 g of polyoxyethylene (20) sorbitan monooleate (Nikkor TO-10) and 0.1 g of vitamin A palmitate (1.7 million units) are dissolved under heating. 1.3 g of citric acid, 5 g of sodium sulfite, 10 g of potassium aspartate, 5 sodium chondroitin sulfate.
g, 10% benzalkonium chloride solution 2 g, chlorobutanol 2 g, 1-menthol 0.2 g, and propylene glycol 5 g are mixed, and the total amount is 1000 ml with purified water (pH
= 5.5), aseptically filter and fill in an eye drop container to obtain an eye drop. This formulation, as a result of one month of accelerated test of 50 degrees C,
The residual rate of vitamin A palmitate was 3%.

Example 6 3 g of polyoxyethylene (60) hydrogenated castor oil (Nikkor HCO-60), vitamin A palmitate (170
Dissolve 0.15 g by heating. 2.2 g of sodium dihydrogen phosphate, 12 sodium phosphates
g, sodium sulfite 1 g, ε-aminocaproic acid 5
g, 10% benzalkonium chloride solution 0.25 g, pyridoxine hydrochloride 1 g, dipotassium glycyrrhizinate 5.0
g, chlorpheniramine maleate 0.3 g, mannitol 30 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 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 55%.

Example 7 2 g of polyoxyethylene (40) hydrogenated castor oil (Nitsukol HCO-40), 0.25 g of BHT and 0.1 g of vitamin A palmitate (1.7 million units) were dissolved under heating.
1.3 g of citric acid, 1 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 of benzethonium chloride.
g, dipotassium glycyrrhizinate 5 g, chlorobutanol 3 g, 1-menthol 0.3 g, propylene glycol 5 g, allantoin 1 g, panthenol 0.2 g were mixed, and the total volume was adjusted to 1000 ml (pH = 5.5) with purified water, and aseptic. It is filtered and filled in an eye drop container to obtain an eye drop. As a result of the accelerated test at 50 ° C. for 1 month, this preparation showed that the residual rate of vitamin A palmitate was 65%.

Example 8 3 g of polyoxyethylene (60) hydrogenated castor oil (Nitsukol HCO-60), d-α-tocopherol acetate of 0.
5g, BHA0.05g, Vitamin A palmitate (1
0.15 g (700,000 units) is dissolved by heating. To this, 2.2 g of sodium dihydrogen phosphate, 1 disodium hydrogen phosphate
2 g, sodium sulfite 1 g, ε-aminocaproic acid 5
g, 10% benzalkonium chloride solution 0.25 g, pyridoxine hydrochloride 1 g, dipotassium glycyrrhizinate 5.0
g, chlorpheniramine maleate 0.3 g, mannitol 30 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 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 92%.

Example 9 Polyoxyethylene (60) hydrogenated castor oil (Nitsukol HCO-60) 3 g, BHA 0.015 g, vitamin A
0.15 g of palmitate (1.7 million units) is dissolved by heating. To this, 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, 20 g of ε-aminocaproic acid, 0.5 g of 10% benzalkonium chloride solution, 0.5 g of pyridoxine hydrochloride, 2 potassium diglycyrrhizinate 2 0.5 g, mannitol 20 g, and sodium ethylenediaminetetraacetate 0.03 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 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 75%.

Example 10 3 g of polyoxyethylene (60) hydrogenated castor oil (Nitsukol HCO-60), d-α-tocopherol acetate of 0.
5g, Vitamin A palmitate (1.7 million units) 0.1
Dissolve 5 g by heating. To this, 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, 20 g of ε-aminocaproic acid, 0.05 g of benzethonium chloride, 0.5 g of pyridoxine hydrochloride, 2.5 g of dipotassium glycyrrhizinate, 20 of mannitol.
g, and 0.03 g of sodium ethylenediaminetetraacetate are mixed, the total amount is made 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 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 85%.

Comparative Example 4 Polyoxyethylene (20) sorbitan monooleate (Nitsukol TO-10) (4 g), BHT (0.25 g), and vitamin A palmitate (1.7 million units) (0.2 g) were dissolved under heating. 1.3 g of citric acid, 8 g of boric acid, 5 g of sodium sulfite, 10 g of potassium aspartate, 1
0% benzalkonium chloride solution 2g, chlorobutanol 2
g and mixed with purified water to a total volume of 1000 ml (pH = 5.
5), aseptically filter and fill in an eye drop container to obtain an eye drop. As a result of the accelerated test at 50 ° C. for 1 month, this preparation had a residual rate of vitamin A palmitate of 12%.

Example 11 5 g of polyoxyethylene (40) hydrogenated castor oil (Nitzcol HCO-40), d-α-tocopherol acetate 1.
0g, Vitamin A palmitate (1.7 million units) 0.2
g is dissolved by heating. 1.3 g of citric acid, 2 g of sodium sulfite, 10 g of potassium aspartate, 10%
1 g of benzalkonium chloride solution, 5 g of sodium chondroitin sulfate, 1 g of pyridoxine hydrochloride, panthenol.
2 g, propylene glycol 5 g, chlorobutanol 4
g, and 0.02 g of sodium ethylenediaminetetraacetate are mixed, the total amount is adjusted to 1000 ml (pH = 5.5) with purified water, sterile filtered and filled in an eye drop container to obtain an eye drop. As a result of 1 month of the accelerated test at 50 ° C., the residual rate of vitamin A palmitate of this preparation was 73%.

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Claims (1)

[Claims] 1. A vitamin A aqueous solution containing a quaternary ammonium type cationic surfactant and sodium sulfite and solubilized by a nonionic surfactant, wherein (a) a fat-soluble antioxidant and (b) an anionic substance. (C) A vitamin A-solubilized aqueous eye drop comprising at least one compound selected from at least two groups out of three groups of cationic substances other than quaternary ammonium type cationic surfactants.