JPH05331056A - Stable vitamin A solubilization solution - Google Patents

Abstract

(57) [Summary] [Composition] 100-600% HL for Vitamin A
Hydrogenated castor oil with B of 10 or more and H of 10 to 250%
Nonionic surfactant having LB of 2 to 9 or further 1
Ophthalmic solution, injection solution containing 0 to 500% of HLB10 or more polyoxyethylene sorbitan fatty acid ester,
Vitamin A solubilization liquid such as drinks. The nonionic surfactant is polyethylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, or the like. [Effect] The instability of vitamins A can be prevented and the appearance can be stably maintained for a long period of time.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aqueous solution in which vitamins A are stably solubilized for a long period of time without causing turbidity or precipitation.

[0002]

BACKGROUND OF THE INVENTION Vitamin A including vitamin A oil and vitamin A fatty acid ester has a normal function of maintaining visual and mucous membranes for humans or animals, and due to their deficiency, night blindness, keratoconjunctival dryness, and growth disorders. It is an essential substance because it causes Conventionally, as a method of solubilizing vitamin A, which is a fat-soluble vitamin, for example, sucrose fatty acid monoester as a solubilizer (Japanese Patent Publication No. 34-
6746), polyoxyethylene sorbitan fatty acid ester (Japanese Patent Publication No. 39-3044), polyoxyethylene hydrogenated castor oil (Japanese Patent Publication No. 40-21998), and the like are known. However, in each case, there are problems such that a large amount of the above-mentioned solubilizing agent is required and it is unstable over time.

[0003]

The present invention is directed to vitamin A
The purpose is to improve the stability of the appearance of the aqueous solution in which the compounds are solubilized.

[0004]

[Means for Solving the Problems] The present inventors have conducted earnest research on stabilization of a solubilized solution of vitamin A using a nonionic surfactant such as polyoxyethylene hydrogenated castor oil as a solubilizer. As a result, by blending a polyoxyethylene hydrogenated castor oil having a specific HLB value with a nonionic surfactant having a specific HLB value, a small amount of a solubilizing agent and a stable appearance over a long period of time can be obtained. It has been found that a certain vitamin A solubilized solution can be obtained.

Further, in the present invention, a further stabilizing effect can be obtained by blending a polyoxyethylene sorbitan fatty acid ester having a specific HLB value.

That is, the stable solution of vitamin A solubilizing liquid of the present invention is characterized by containing the following components (a) to (c) or further component (d). (A) Vitamin A. (B) Polyoxyethylene hydrogenated castor oil having an HLB value of 10 or more: 100 to 600% by weight with respect to vitamins A. (C) Nonionic surfactant having an HLB value of 2 to 9: 10 to 250% by weight with respect to vitamin A. (D) Polyoxyethylene sorbitan fatty acid ester having an HLB value of 10 or more: 10 to 500 relative to vitamins A
weight%.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION (a) Vitamin A, which is the first essential requirement of the present invention, includes, in addition to vitamin A itself,
Also included are vitamin A-containing mixtures such as vitamin A oil and vitamin A derivatives such as vitamin A fatty acid esters.

A specific example of the vitamin A derivative is 1.7 million international units (I.U.) of retinol palmitate manufactured by Nippon Roche Co., Ltd. Vitamin A as the component (a) is usually added to the composition in an amount of 0.00
3 to 0.1 wt% can be blended, and preferably,
It is in the range of 0.01 to 0.05% by weight.

(B) HL which is the second essential requirement of the present invention
Examples of the polyoxyethylene hydrogenated castor oil having a B value of 10 or more include polyoxyethylene (p = 40) hydrogenated castor oil, polyoxyethylene (p = 60) hydrogenated castor oil, and the like. There are Nikkor HCO-40, HCO-50, and HCO-60 manufactured by the company. In addition, p shows the average addition mole number of ethylene oxide.

(C) HL which is the third essential requirement of the present invention
Examples of the nonionic surfactant having a B value of 2 to 9 include polyethylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, and the like.
Specifically, Nikkor MYS manufactured by Nikko Chemicals Co., Ltd.
-2, MGS-A, MGO, MYO-6, SS-30.

If necessary, the stable vitamin A solubilizing solution of the present invention contains (d) HLB value 1 as the fourth essential component.
A polyoxyethylene sorbitan fatty acid ester having 0 or more can be blended. As a concrete example of this,
Examples thereof include polyoxyethylene (p = 20) sorbitan monostearate and polyoxyethylene (p = 20) sorbitan monooleate. Specifically, Nikkor TS-10, TO-10, TP- manufactured by Nikko Chemicals Co., Ltd.
There is 10.

In the present invention, polyoxyethylene hydrogenated castor oil having the above-mentioned second essential component (b) HLB value of 10 or more and the third essential component (c) HLB value 2
Each of them is used in combination with at least one kind selected from the group of nonionic surfactants containing

Further, if necessary, the stable vitamin A solubilizing solution of the present invention is further compounded with the fourth essential component (d) polyoxyethylene sorbitan fatty acid ester to further improve the stabilizing effect. Is obtained.

The second to third essential components of the present invention and optionally the fourth essential component of the solubilizing agent are blended in amounts of, for example, about 1.5 million international units of vitamin A (I.U.). Each is as shown in Table 1 below.

[0015]

[Table 1]  Addition amount Preferred addition amount  (a) 100 to 600% by weight having an HLB value of 10 or more 200 to 500% by weight Polyoxyethylene hydrogenated castor oil (c) 10 to 250% by weight having an HLB value of 2 to 9 10 to 200% by weight Nonionic surfactant Agent (d) Polyoxyethylene sol having HLB value of 10 or more 10 to 500% by weight 100 to 300% by weight Bitan fatty acid ester

The vitamin A solubilizing solution of the present invention may further contain other vitamins, agents such as zinc sulfate, sulfamethoxazole, allantoin, and lysozyme chloride; chlorhexidine gluconate. , Sorbic acid, chlorobutanol, paraoxybenzoate, sodium benzoate and other preservatives; isotonic agents such as potassium chloride, sodium chloride, propylene glycol, polyethylene glycol, glycerin; citric acid, boric acid, phosphorus Buffering agents such as sodium hydrogen hydrate and glacial acetic acid; glucose,
Saccharose such as sucrose, mannitol, and xylitol; flavoring agents such as glutamic acid; and flavors such as 1-menthol can be added.

The method for preparing the solubilized solution of vitamin A of the present invention is not particularly limited. For example, the vitamin A is first added to a nonionic surfactant such as polyoxyethylene hydrogenated castor oil and polyethylene glycol fatty acid ester. A solubilized solution of vitamin A can be obtained by solubilizing it in water, and then adding a drug such as naphazoline hydrochloride or a buffering agent such as citric acid as necessary to adjust the pH.

The pH of the vitamin A solubilizing solution of the present invention is 2
Is preferably in the range of 9 to 9, more preferably 3 to
It is 8.5. When the pH of the liquid agent is out of the above range, the stabilizing effect of vitamins A decreases.

[0019]

According to the present invention, (a) vitamins A,
(B) 100 to 600% by weight of HL with respect to vitamins A
A solubilizing solution by blending a polyoxyethylene hydrogenated castor oil having a B value of 10 or more and (c) a nonionic surfactant having an HLB value of 2 to 9 of 10 to 250% by weight with respect to vitamins A. It is possible to prevent destabilization of vitamins A in the interior and maintain a stable appearance over a long period of time. In addition, (d) for vitamins A, 10 to
By adding a polyoxyethylene sorbitan fatty acid ester having an HLB value of 10 or more at 500% by weight, this stabilizing effect can be further improved.
Such vitamin A solubilized liquid can be used in the fields of pharmaceuticals such as eye drops and injections, foods such as drinks, and the like.

[0020]

【Example】

Example 1 0.5 g of polyoxyethylene (p = 40) hydrogenated castor oil (Nikkole HCO-40, HLB12.5), glyceryl monostearate (Nikkor MGS-A, HLB)
4.0) 0.05 g, acetic acid d-α-tocopherol 0.
1g, vitamin A palmitate (1.7 million international units)
Dissolve 0.1 g 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 g of dipotassium glycyrrhizinate, 3 g of chlorobutanol, 1-menthol.
3 g, propylene glycol 5 g, allantoin 1 g,
0.2 g of panthenol, neostigmine methylsulfate 0.
05 g and flavin adenine dinucleotide sodium 0.25 g were mixed, and the total amount was 1000 ml (p
H = 5.5), sterile filter and fill an eye drop container to obtain an eye drop. This formulation is the result of accelerated test at 50 ° C for 3 months,
The appearance was stable with no turbidity or precipitation.

Comparative Example 1 4 g of polyoxyethylene (p = 20) sorbitan monooleate (Nikkole TO-10, HLB15.0),
Vitamin A palmitate (1.7 million international units) 0.2 g
Dissolve by heating. To this, the following components of citric acid described in Example 1 were added in the same amount as in Example 1 and mixed, and the total amount was adjusted to 1 with purified water.
000 ml (pH = 5.5), aseptically filter and fill an eye drop container to obtain an eye drop. This formulation produced turbidity and precipitation as a result of the accelerated test at 50 ° C. for 1 month.

Example 2 0.4 g of polyoxyethylene (p = 60) hydrogenated castor oil (Nikkole HCO-60, HLB14.0), glyceryl monooleate (Nikkor MGO, HLB2.
5) 0.2 g, polyoxyethylene (p = 20) sorbitan monooleate (Nikkole TO-10, HLB1)
5.0) 0.1 g, acetic acid d-α-tocopherol 0.1
g, Vitamin A palmitate (1.7 million international units) 0.
Dissolve 1 g by heating. To this, 0.5 g of tetrahydrozoline hydrochloride, 1 g of 10% benzalkonium chloride solution, 5 g of dipotassium glycyrrhizinate, 0.05 of 1-menthol.
g, propylene glycol 5 g, allantoin 1 g, panthenol 0.2 g, epsilon-aminocaproic acid 2
After mixing 0 g and adjusting the pH 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. As a result of the accelerated test at 50 ° C. for 3 months, this formulation had a stable appearance without causing turbidity or precipitation.

Example 3 1 g of polyoxyethylene (p = 60) hydrogenated castor oil (Nikkole HCO-60, HLB14.0), polyethylene glycol (p = 2) monostearate (Nikkor MYS-2, HLB4.0) ) 0.05 g and vitamin A acetate (1.7 million international units) 0.2 g are dissolved by heating. 2.6 g of citric acid and 0.0 of naphazoline hydrochloride
3 g, pyridoxine hydrochloride 0.5 g, cyanocobalamin 0.1 g, sodium chondroitin sulfate 1 g, chlorpheniramine maleate 0.3 g, benzethonium chloride 0.05 g, chlorobutanol 3 g, and propylene glycol 5 g were mixed, and purified water was added. 1000 ml (pH)
= 4.5), 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 3 months, this formulation had a stable appearance without causing turbidity or precipitation.

Example 4 2 g of polyoxyethylene (p = 50) hydrogenated castor oil (Nikkole HCO-50, HLB13.5), sorbitan tristearate (Nikkor SS-30, HLB2.
1) 0.5 g, tocopherol 1 g, vitamin A oil (1
Dissolve 1 g of 1,000,000 international units by heating. D-sorbitol solution (70%) (1.5 g) and propylene glycol (5 g) were mixed with the mixture, and the total amount was adjusted to 50 ml with distilled water to give 0.2 μm.
It is filtered with a membrane filter of m and filled in a container to make a drink. As a result of the accelerated test at 50 ° C. for 3 months, this formulation had a stable appearance without causing turbidity or precipitation.

Comparative Example 2 Polyoxyethylene (p = 60) hydrogenated castor oil (Nikkole HCO-60, HLB14.0) 8 g, tocopherol 1 g, vitamin A oil (1 million international units) 1 g were dissolved under heating. To do. D-sorbitol solution (70%) 1.
5 g and propylene glycol 5 g are mixed, the total amount is made up to 50 ml with distilled water, filtered through a 0.22 μm membrane filter and filled in a container to prepare a drink. This formulation produced turbidity and precipitation as a result of the accelerated test at 50 ° C. for 1 month.

EXAMPLE 5 0.3 g of polyoxyethylene (p = 50) hydrogenated castor oil (Nikkole HCO-50, HLB13.5), polyethylene glycol (p = 2) monostearate (Nikkor MYS-2, HLB4) 0.0) 0.15 g, tocopherol 0.05 g, vitamin A (1 million international units)
Dissolve 0.075 g by heating. 5.0 of lemon juice
g, sodium l-glutamate 0.5 g, white sugar 10
g, glucose 10 g, thiamine hydrochloride 0.01 g, riboflavin 0.03 g, pyridoxine hydrochloride 0.05 g, aminoethylsulfonic acid 0.5 g, sodium benzoate 0.
05 g, adipic acid 0.5 g, ethanol 5 g, and an appropriate amount of perfume were mixed, and the total amount was made 100 ml with distilled water, and 0.22
Filter with a membrane filter of μm and fill the container to make a drink. As a result of the accelerated test at 50 ° C. for 3 months, this formulation had a stable appearance without causing turbidity or precipitation.

Example 6 0.1 g of polyoxyethylene (p = 40) hydrogenated castor oil (Nikkole HCO-40, HLB12.5), polyethylene glycol (p = 6) monooleate (Nikkor MYO-6, HLB8.5) ) 0.2 g, polyoxyethylene (p = 20) sorbitan monopalmitate (Nikkole TP-10, HLB15.6) 0.1 g, vitamin A (1.5 million international units) 0.1 g are dissolved by heating. To do. 2.2 g of sodium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 1 g of sodium sulfite, epsilon-
30 g of aminocaproic acid, 0.5 g of 10% benzalkonium chloride solution, 20 g of mannitol, and 0.05 g of sodium ethylenediaminetetraacetate are mixed, and the total amount is 1 with purified water.
Make 000 ml (pH = 7.0), 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 3 months, this formulation had a stable appearance without causing turbidity or precipitation.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical display location A61K 47/14 G 7433-4C J 7433-4C 47/44 G 7433-4C J 7433-4C

Claims (2)

[Claims] 1. (a) Vitamin A, (b) Polyoxyethylene hydrogenated castor oil having an HLB value of 10 or more: 100 to 600% by weight relative to vitamin A, (c) an HLB value of 2 to 9 Nonionic surfactant: A stable solubilized solution of vitamin A, which contains 10 to 250% by weight of vitamin A. 2. Further, (d) a polyoxyethylene sorbitan fatty acid ester having an HLB value of 10 or more: 10 to 500 relative to vitamins A
The stable vitamin A solubilizing solution according to claim 1, wherein the solubilizing solution contains vitamin%.