JP3199475B2 - Stabilization method of solubilized aqueous solution of vitamin A - Google Patents

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 an aqueous solution containing solubilized vitamin A for a long period of time.

[0002]

2. Description of the Related Art Vitamin A, including vitamin A oil and fatty acid esters of vitamin A, have a function of maintaining normality of humans and animals such as visual and mucous membranes, and deficiency causes night blindness, keratoconjunctiva, and growth disorders. It is an indispensable substance because it causes such things as:

However, vitamin A, which is a fat-soluble vitamin,
Classes are known to be extremely susceptible to oxidation and particularly unstable in aqueous solutions. As a technique for stabilizing such unstable vitamin A, conventionally, dibutylhydroxytoluene (BHT),
Fat-soluble antioxidants such as butylhydroxyanisole (BHA), nordihydroguaiaretic acid (NDGA) and tocopherols, ascorbic acid, hydroquinone,
A method of adding or mixing a water-soluble antioxidant such as cysteine or both of these antioxidants (JP-A-48-4)
8617, JP-A-58-41813), a method of coating vitamin A with gelatin, casein, dextrin, etc., and stabilizing it by cutting off contact with air as granules or powder (JP-A-58-41813). No. 61-212322) is known.

[0004] However, even in the above emulsified or powdered systems, the stability of vitamin A is not satisfactory, and even more, in a transparent and homogeneous solubilizing system, a method for stabilizing vitamin A for a long period of time is not enough. unknown.

On the other hand, when a solubilized solution of vitamin A is stored, a plastic container is often used, for example, for eye drops and nasal drops. However, since many plastic containers have high oxygen permeability, vitamin A and the like are used. The easily oxidizable substance solution is liable to be oxidized and unstable. As a stabilizing method, there is a method in which a solution of an easily oxidizable substance is filled in an oxygen-permeable plastic container, sealed, and sealed with an oxygen-impermeable enclosure together with a deoxidizer (Japanese Patent Application Laid-Open No. 62-138438). However, there are drawbacks such as high cost due to the envelope having high characteristics, and a sudden deterioration in stability after opening the envelope.

[0006]

An object of the present invention is to improve the stability of a solubilized aqueous solution of vitamin A filled in a container.

[0007]

According to the present invention, a method for stabilizing a solubilized aqueous solution of vitamin A is provided by adding a fat-soluble antioxidant and a water-soluble antioxidant to an aqueous solution of vitamin A solubilized by a nonionic surfactant. After at least one compound is mixed and filled in a container, the container is hermetically sealed, and then sealed with an enclosure together with a deoxidizer.

[0008]

DETAILED DESCRIPTION OF THE INVENTION Vitamin A, which is the first essential requirement of the present invention, includes vitamin A itself and vitamin A itself.
Vitamin A-containing mixtures such as oils and vitamin A derivatives such as vitamin A fatty acid esters are also included. In particular,
Nippon Roche Co., Ltd. retinol palmitate 1.7 million international units (IU). Vitamin A is
Usually, 0.003 to 0.1% by weight can be blended in the composition, preferably 0.01 to 0.05% by weight.

Vitamin A which is the second essential requirement of the present invention
Nonionic surfactants for solubilizing the compounds include higher fatty acid esters such as water-soluble polyoxyethylene hydrogenated castor oil, and higher fatty acid esters of polyoxyethylene sorbitan. For example, polyoxyethylene (p = 6)
0) Hardened castor oil and polyoxyethylene (p = 20) sorbitan monooleate. Specifically, there are Nikkol HCO-60 and TO-10 manufactured by Nikko Chemicals Corporation. Usually, it can be incorporated in the composition in an amount of 0.01 to 1.0% by weight, preferably 0.05 to 0.5% by weight. Here, p represents the average number of moles of ethylene oxide added.

As a fat-soluble antioxidant which is one of the third essential requirements of the present invention, dibutylhydroxytoluene (B
HT), butylhydroxyanisole (BHA), nordihydroguaiaretic acid, tocopherols, etc., and specifically, Riken E acetate α manufactured by Riken Vitamin Co., Ltd. is exemplified. When using a fat-soluble antioxidant,
Usually, 0.005 to 0.2% by weight can be added to the composition, and preferably 0.01 to 0.1% by weight.

The water-soluble antioxidant which is one of the third essential requirements of the present invention includes ascorbic acid, hydroquinone,
Examples include cysteine and sulfites, and specific examples include anhydrous sodium sulfite manufactured by Wako Pure Chemical Industries, Ltd. When a water-soluble antioxidant is used, it can be usually added in the composition in an amount of 0.001 to 10% by weight, preferably 0.01 to 5.0% by weight.

In the present invention, at least one of the two groups of the above-mentioned fat-soluble antioxidants and water-soluble antioxidants is selected, and at least one or more of the selected compounds is added, Mix. Further, by using a fat-soluble antioxidant and a water-soluble antioxidant in combination, a further stabilizing effect can be obtained. The blending amounts of these additives are as shown in Table 1 below, for example, for those having about 1.5 million international units (IU) of vitamin A.

[0013]

[Table 1] The preferred amount more preferred amount lipophilic antioxidant 10-1000 wt% 50 to 500% by weight of a water-soluble antioxidant 50-10000 wt% 300-6000 wt%

As the plastic container which is the fourth essential requirement of the present invention, a material such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials is used. be able to.

As the oxygen absorber which is the fifth essential requirement of the present invention, for example, those containing iron and an iron compound as main components can be used. Specifically, Ageless manufactured by Mitsubishi Gas Chemical Co., Ltd. is available. .

The envelope material which is the sixth essential requirement of the present invention includes, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, and aluminum-deposited polyvinyl. Examples thereof include an alcohol-based / polyamide-based film, a polyvinylidene chloride-coated film or a laminated film thereof, and a composite or multilayer film thereof.

The solubilized solution of vitamin A of the present invention may contain, if necessary, other vitamins, drugs such as zinc sulfate, sulfamethoxazole, allantoin, and lysozyme chloride; chlorhexidine gluconate. Preservatives such as sorbic acid, chlorobutanol, paraoxybenzoate, sodium benzoate; tonicity agents such as potassium chloride, sodium chloride, propylene glycol, polyethylene glycol, glycerin; citric acid, boric acid, phosphorus Buffers such as sodium hydrogen oxyacid and glacial acetic acid; glucose,
Sugars such as sucrose, mannitol and xylitol; flavoring agents such as glutamic acid; flavors such as l-menthol and the like can be added.

The method for preparing the solubilized aqueous solution of vitamin A of the present invention is not particularly limited. For example, vitamin A is mixed with a fat-soluble antioxidant such as BHT, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan higher fatty acid ester. Solubilized in water by a nonionic surfactant such as.

Next, a water-soluble antioxidant such as sodium sulfite is dissolved in water, and a buffer is added to adjust the pH.
By filling the container, sealing the container, and sealing the container together with the oxygen scavenger with an enclosure, it is possible to obtain an aqueous solution of solubilized vitamin A stable against oxidation.

[0020] pH of the solubilized aqueous solution of vitamin A of the present invention
Is preferably in the range of 4 to 9, more preferably 5 to 8.5. When the pH of the solution is out of the above range, the stabilizing effect of vitamins A decreases.

[0021]

According to the present invention, at least one of a fat-soluble antioxidant and a water-soluble antioxidant is added to an aqueous solution in which vitamin A is solubilized by a nonionic surfactant, and then added to a container. Filling, sealing, and sealing with the envelope together with the oxygen scavenger, the stabilization effect of vitamin A is sufficiently high until the envelope is opened, and even after the envelope is opened, it is resistant to oxidation. Therefore, the aqueous solution of solubilized vitamin A can be stably maintained for a long period of time without suddenly deteriorating the stability. Such a solubilized solution of vitamin A can be used, for example, in medicines such as eye drops, nasal drops, injections, etc.
It can be used in the field of foods such as drinks.

[0022]

【Example】

Examples 1 to 3 and Comparative Examples 1 to 3 Liquid preparations having the formulations shown in Table 2 were prepared, filled in a plastic container made of polyethylene terephthalate, and, if necessary, combined with a deoxidizer (Ageless ZJ-PK) to form a polyvinylidene chloride composite. After sealing with a film, it was stored at 50 ° C. for one month, and the residual ratio of vitamin A palmitate immediately after the completion of the storage was examined. Furthermore, for those sealed with a film, the vitamin A palmitate was allowed to stand at room temperature for another week after opening.
The residual rate of the sample was also examined, and the results are shown in the same table. The pH was adjusted to 5.8 with sodium dihydrogen phosphate and disodium hydrogen phosphate. Further, the content of vitamin A palmitate in the liquid preparation was measured by using a high performance liquid chromatography method.

[0023]

[Table 2]  Blending amount (%) Comparative example Comparative example Example Example Comparative example Example Example  1 2 1 3 2 3 Vitamin A palmitate 0.03 0.03 0.03 0.03 0.03 0.03 Tocopherol acetate--0.025 0.025-0.025 Sodium sulfite----0.1 0.1 POE (60) hydrogenated castor oil 0.3 0.3 0.3 0.3 0.3 0.3 Chlorobutanol 0.3 0.3 0.3 0.3 0.3 0.3 Distilled water balance Oxygen absorber (Ageless ZJ-PK) No Yes Yes No Yes Yes Vitamin A palmitate residual rate (50 ℃ -1 month) Immediately after storage 10% 38% 70% 49% 75% 86% Leave for 1 week at room temperature-7% 70%-72% 82%

Example 4 2 g of polyoxyethylene (20) sorbitan monooleate (Nicol TO-10), 0.25 g of BHT,
Vitamin A acetate (1.7 million international units) 0.15g
Is heated and dissolved. This was mixed with 8 g of boric acid, 10 g of potassium aspartate, and 2 g of 10% benzalkonium chloride solution, adjusted to a total volume of 1000 ml (pH = 6.5) with purified water, sterile filtered, and filled in a polycarbonate ophthalmic container. It sealed with the polyvinylidene chloride composite film with the oxygen scavenger (Ageless ZJ-PK). The formulation has 50
As a result of leaving the film at room temperature for one month after the accelerated test at 1 ° C. and opening the film, the residual ratio of vitamin A acetate was 60% and 59%, respectively.

Comparative Example 4 2 g of polyoxyethylene (20) sorbitan monooleate (Nicol TO-10), 0.25 g of BHT,
Vitamin A acetate (1.7 million international units) 0.15g
Is heated and dissolved. To this, 8 g of boric acid, 10 g of potassium aspartate, and 2 g of 10% benzalkonium chloride solution were mixed, and the total amount was made up to 1,000 ml (pH = 6.5) with purified water, aseptically filtered, and filled in a polycarbonate ophthalmic container. As a result of an accelerated test at 50 ° C. for one month, the residual ratio of vitamin A acetate was 28%.

Comparative Example 5 2 g of polyoxyethylene (20) sorbitan monooleate (Nicol TO-10) and 0.15 g of vitamin A acetate (1.7 million international units) were dissolved by heating. 8g of boric acid, 10g of potassium aspartate, 10%
2 g of benzalkonium chloride solution was mixed, the total volume was adjusted to 1000 ml (pH = 6.5) with purified water, sterile-filtered, filled into a polycarbonate ophthalmic container, and polyvinylidene chloride together with an oxygen scavenger (Ageless ZJ-PK). Sealed with composite film. The preparation was left at room temperature for one month after an accelerated test at 50 ° C. for one month and after opening the film. As a result, the residual ratio of vitamin A acetate was 56% and 24%, respectively.

Example 5 Polyoxyethylene (50) hydrogenated castor oil (Nicol HCO-50) 2 g, vitamin A (1.7 million international units)
0.1 g is dissolved by heating. 1.3 g of citric acid, 2 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 g of benzethonium chloride, 5 g of dipotassium glycyrrhizinate, 3 g of chlorobutanol and 0.1 g of l-menthol.
3 g, propylene glycol 5 g, allantoin 1 g,
0.2 g of panthenol was mixed, and the total amount was 100
0 ml (pH = 5.5), sterile-filtered, filled into a polypropylene ophthalmic container, and then treated with an oxygen scavenger (Ageless ZJ).
-PK) and sealed with a polyethylene composite film. The preparation was left at room temperature for one week after an accelerated test at 50 ° C. for one month and after opening the film. As a result, the residual ratio of vitamin A was 65% and 59%, respectively.

Comparative Example 6 Polyoxyethylene (50) hydrogenated castor oil (Nicol HCO-50) 2 g, vitamin A (1.7 million international units)
0.1 g is dissolved by heating. 1.3 g of citric acid, 2 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 g of benzethonium chloride, 5 g of dipotassium glycyrrhizinate, 3 g of chlorobutanol and 0.1 g of l-menthol.
3 g, propylene glycol 5 g, allantoin 1 g,
0.2 g of panthenol was mixed, and the total amount was 100
The volume was adjusted to 0 ml (pH = 5.5), aseptically filtered, and filled in a polypropylene ophthalmic container. As a result of an accelerated test at 50 ° C. for 1 month, the residual ratio of vitamin A was 32%.

Example 6 Polyoxyethylene (60) hydrogenated castor oil (Nicol HCO-60) 3 g, d-α-tocopherol acetate 0.1 g
5g, Vitamin A palmitate (1.7 million international units)
0.15 g is dissolved by heating. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 30 g of ε-aminocaproic acid, 0.5 g of 10% benzalkonium chloride solution, 0.5 g of pyridoxine hydrochloride, mannitol 2
0 g and 0.05 g of sodium ethylenediaminetetraacetate are mixed, and the whole amount is 1000 ml with purified water (pH = 7.0).
After aseptic filtration and filling in a polyethylene terephthalate ophthalmic container, it was sealed with a polyvinylidene chloride composite film together with an oxygen scavenger (Ageless ZJ-PK). This preparation was left for one month at room temperature after one month of an accelerated test at 50 ° C. and further after opening the film. As a result, the residual ratio of vitamin A palmitate was 81%.

Example 7 2 g of polyoxyethylene (50) hydrogenated castor oil (Nicol HCO-50), d-α-tocopherol acetate 0.1 g
5g, Vitamin A palmitate (1.7 million international units)
0.3 g is heated and dissolved. 1.3 g of citric acid, 1 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 g of benzethonium chloride, 3 g of chlorobutanol,
0.3 g of 1-menthol, 5 g of propylene glycol,
1 g of allantoin and 0.2 g of panthenol are mixed, the total amount is made up to 1000 ml (pH = 5.5) with purified water, sterile-filtered, filled into a polyethylene terephthalate eyedropper, and then an oxygen scavenger (Ageless ZJ-PK) Together with a polyvinylidene chloride composite film. This formulation has 5
As a result of 1 month of accelerated test at 0 ° C. and further left at room temperature for 1 week after opening the film, the residual ratio of vitamin A palmitate was 85% and 82%, respectively.

Example 8 3 g of polyoxyethylene (20) sorbitan monooleate (Nicol TO-10), 0.25 g of d-α-tocopherol acetate, vitamin A palmitate (1.7 million international units) ) 0.15 g is heated and dissolved. Boric acid 8
g, 10 g of potassium aspartate and 2 g of a 10% benzalkonium chloride solution, and the total amount was 1000 m with purified water.
1 (pH = 6.5), aseptically filtered, filled into a polyethylene terephthalate ophthalmic container, and sealed with a polyvinylidene chloride composite film together with an oxygen scavenger (Ageless ZJ-PK). The preparation was left at room temperature for one month after accelerated test at 50 ° C. for one month and after opening the film. As a result, the residual ratio of vitamin A palmitate was 58% and 56%, respectively.
Met.

Example 9 Polyoxyethylene (60) hydrogenated castor oil (Nicol HCO-60) 2 g, vitamin A palmitate (170)
0.15 g is dissolved by heating. 1.3 g of citric acid, 2 g of sodium sulfite, 0.03 g of naphazoline hydrochloride, 0.05 g of benzethonium chloride, 5 g of dipotassium glycyrrhizinate, 3 g of chlorobutanol, 1-
0.3 g of menthol, 5 g of propylene glycol, 1 g of allantoin, 0.5 g of pyridoxine hydrochloride, and sodium flavin adenine dinucleotide were mixed, adjusted to a total volume of 1000 ml (pH = 5.5) with purified water, sterile filtered, and polyethylene After filling in a terephthalate and polyarylate composite ophthalmic container, an oxygen scavenger (Ageless ZJ-PK)
Together with a polyvinylidene chloride composite film.
The preparation was left at room temperature for one week after accelerated test at 50 ° C. for one month and after opening the film, and the residual ratio of vitamin A was 72% and 69%, respectively.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ identification code FI A61K 47/22 A61K 47/22 (58) Investigated field (Int.Cl. ⁷ , DB name) A61K 31/232 A61K 9/08 A61K 31/07 A61K 31/203 A61K 47/10 A61K 47/22 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (1)

(57) [Claims] 1. An aqueous solution of vitamin A solubilized by a nonionic surfactant, at least one of a fat-soluble antioxidant and a water-soluble antioxidant is blended, and the mixture is filled in a container, sealed, and then deoxygenated. And a method of stabilizing a solubilized aqueous solution of vitamin A, which is sealed by an enclosure.