JPH05163136A - Fat-soluble substance-containing aqueous solution - Google Patents

Abstract

PURPOSE:To obtain a fat-soluble-substance-containing aqueous solution useful for medicines, cosmetics, foods, etc. CONSTITUTION:A fat-soluble-substance-containing aqueous solution comprising a fat-soluble substance, lecithin and ethanol, isopropanol or a mixed solution of ethanol and isopropanol as essential components. In the case where the volume of ethanol, isopropanol or the mixed solution of ethanol and isopropanol is <=50V/V% of the aqueous solution, a fat-soluble-substance-containing aqueous solution contains 0.002-0.05 pt.wt. lecithin when the amount of ethanol blended is <=24 pts.wt. By adjusting the blending ratio of ethanol or isopropanol and lecithin as mentioned above, the fat-soluble-substance-containing aqueous solution having externally excellent clarity is obtained.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fat-soluble substance-containing aqueous liquid used for applications such as medicines, cosmetics, and foods.

[0002]

BACKGROUND ART For the purpose of transparently dissolving or emulsifying a fat-soluble substance in water, an example in which a large amount of a nonionic surfactant is used has heretofore been known. However, as is well known, nonionic surfactants cause some damage to the human body by any of various administration methods. From this point of view, a technique has been developed in which lecithin, which is a natural substance and relatively safe, is used in place of the synthetic surfactant. For example, JP-A-55-62
010, JP-A-55-147228, JP-A-55-38.
314, JP-A-52-83912, and JP-A-52-839.
11, JP-A-49-50124, JP-A-50-1268
21. However, in these techniques, strong mechanical stress needs to be applied in order to supplement the weak emulsifying power of lecithin, and the average particle size of the particles in the obtained emulsion is as large as 0.5 μm or more. In addition, the stability over time is not sufficient due to the large particle size distribution. From this point of view, some of the present inventors have studied a system in which ethanol is added in addition to the fat-soluble substance and lecithin, and as a result, 1 part by weight of the fat-soluble substance and 0.1-10 parts by weight of lecithin. A system in which water was added to 1 to 50 parts by weight of ethanol to emulsify was found, and a patent application was previously filed as an invention disclosed in JP-A-53-56315.

After that, the present inventor further studied a system which contains a fat-soluble substance, lecithin and alcohol as essential components and which becomes a stable emulsion or solubilized solution by a simple and simple method. In particular, for the purpose of using the emulsion or solubilizing solution as a lotion, lotion, emulsion, etc., a system such as a high alcohol concentration of 20 to 50% is required in the emulsion or solubilizing solution. And I searched for it. That is, in general, adding a large amount of alcohol to a system in which a fat-soluble substance is emulsified or solubilized with a surface-active substance such as lecithin is a difficult technique because it damages the emulsified system or the solubilized system. ing. For example, BBA 298 (1973) 1015
1019 is an ethanol solution of lecithin 0.16M
It has been reported that the maximum concentration of ethanol in the resulting solution when added to an aqueous KCl solution was 7.5%. Therefore, in order to form a stable emulsified system or solubilized system by adding a fat-soluble substance and lecithin to a high-concentration alcohol aqueous solution, it is necessary to set certain numerical limits on the composition ratio between these compounded substances. It seems that there is. As described above, the present inventor starts from a system containing a high concentration of alcohol in response to a request for a lotion, a lotion, an emulsion, etc., to be an emulsion or solubilizing solution containing fat-soluble substances, lecithin and alcohol as essential components. Various component systems were investigated.

As a result, it has been found that by using ethanol or isopropanol and lecithin under specific blending conditions, a fat-soluble substance-containing aqueous liquid having excellent clarity can be obtained. The present invention is based on such findings. That is, the present invention is a fat-soluble substance,
A fat-soluble substance-containing aqueous liquid containing lecithin and ethanol, isopropanol, or ethanol isopropanol mixed solution as an essential component, wherein the volume of ethanol, isopropanol, or ethanol isopropanol mixed solution is 50 V / V% or less of the aqueous solution. The present invention provides a fat-soluble substance-containing aqueous liquid containing lecithin in an amount of 0.002 to 0.05 parts by weight when ethanol is mixed in an amount of 24 parts by weight or less with respect to 1 part by weight of a soluble substance.
Therefore, an object of the present invention is to provide a stable emulsion or solubilized solution containing fat-soluble substances, lecithin and ethanol or isopropanol as essential components by blending each component with a composition of specific requirements.

Next, the present invention will be described. In the fat-soluble substance-containing aqueous liquid of the present invention, the aqueous liquid means an emulsion or a solubilizing liquid. The aqueous liquid contains a fat-soluble substance, lecithin, ethanol, isopropanol or a mixed solution of ethanol and isopropanol as essential components.

In the present invention, the fat-soluble substance is one or more mixtures of fat-soluble substances used in pharmaceuticals, cosmetics, foods, etc. which are soluble in ethanol or isopropanol, and specifically, for example, vitamin A. , E, K and other fat-soluble vitamins and their derivatives or CoQ
_8. Coenzymes such as CoQ ₁₀ , gefarnate, ethyl decaprenate, isoprenoids such as vitamin A retinoids and their derivatives, methyl salicylate, monoglycol salicylate, 1-menthol,
Examples thereof include camphor, α-bisabolol, glycyrrhetinic acid and its derivatives. In addition, paraaminobenzoic acid and its derivatives such as octyldimethylparaaminobenzoic acid and ethylbenzoic acid for cosmetics, squalane, isopropyl myristate, myristyl octyldodecyl, octyldodecanol, vegetable oil and the like can be mentioned. Here, vegetable oil refers to sesame oil, soybean oil, olive oil and the like.

The lecithin according to the present invention means a phospholipid-containing substance extracted from egg yolk or vegetable oil and optionally further purified, or a hydrogenated product thereof, or a synthetic glycerophosphate ester represented by the following general formula and a mixture thereof. Say

[0008]

[Chemical 1] [In the formula, R ₁ and R ₂ are hydrogen or a saturated or unsaturated hydrocarbon having 8 to 20 carbon atoms, and R ₃ is hydrogen, choline,
Represents ethanolamine, serine, inositol, glycerol, etc.]

Next, ethanol and isopropanol are used either individually or as a mixture of both. When used as a mixture, the ratio of the two may be arbitrary. The volume of ethanol, isopropanol, or a mixture of ethanol and isopropanol is 50% or less of the fat-soluble substance-containing aqueous liquid of the present invention. Here,% represents V / V%.

In the present invention, in preparing the fat-soluble substance-containing aqueous liquid, 1 part by weight of the fat-soluble substance is used when the volume of the ethanol, isopropanol or ethanol-isopropanol mixed liquid is 50 V / V% or less of the aqueous liquid. On the other hand, when ethanol is blended in an amount of 24 parts by weight or less, the content of lecithin is 0.002 to 0.05 parts by weight, but these requirements have been experimentally confirmed by the present inventors. It was obtained by These will be described with reference to Experimental Examples 1 to 4 and Examples described later.

Experimental Example 1 was prepared by using 1 part by weight of tocopherol acetate as a fat-soluble substance, using 15 parts by weight of lecithin and changing the amount of ethanol used in the range of 4 to 2,400 parts by weight. The stability and appearance of various aqueous liquids were examined. The results of this experiment show that the amount of ethanol used is 40 parts by weight (1.0 V / V%).
In the case of, the emulsion state was the largest, and it became clear that the clarity gradually increased with the increase and decrease of the amount of ethanol used (see the numerical value of transmittance T ₆₄₀ (%) in Table 1). ..

Next, in Experimental Example 2, 1 part by weight of squalane was used as the fat-soluble substance, the amount of ethanol used was changed to 32 parts by weight, and the amount of lecithin used was varied within the range of 0.002 to 0.1 part by weight. The stability and the appearance of various aqueous liquids prepared by the above method were examined. According to the experimental results and Experimental Example 1 and Example 2, at least 24 parts by weight of ethanol and 0.002 parts by weight of lecithin were obtained. ~
It is found that the combination of 0.05 gives an aqueous solution having excellent clarity and stability.

Next, in Experimental Example 4, 1 part by weight of squalane was used as the fat-soluble substance, the amount of ethanol was 200 parts by weight, and the amount of lecithin used was varied from 0.01 to 60 parts by weight. The stability and appearance of each of the various aqueous liquids tested were examined. According to the results of this experiment and Experimental Example 1 and Reference Example 2, at least 51.4 to 1,600 parts by weight of ethanol and at least 1 part by weight of lecithin were used. It is found that the combination of 0.01 to 15 gives an aqueous solution having excellent clarity and stability.

Next, in Experimental Example 3, 1 part by weight of squalane was used as the fat-soluble substance, the amount of lecithin used was 0.3 part by weight, and the amount of isopropanol used was varied in the range of 4 to 480 parts by weight. The stability and appearance of each of the various aqueous liquids examined were examined. According to the experimental results and Reference Example 5, at least isopropanol part by weight was 6.6 to 320, and lecithin part by weight was 0.17 to.
It is found that the combination of 0.3 gives an aqueous solution having excellent clarity and stability.

In the aqueous liquid of the present invention, an emulsifier, a tensioning agent, a buffering agent, in addition to the essential components, as shown in Examples below.
A solubilizing agent, a flavoring agent, a preservative, and a stabilizer can be appropriately added, and the combination is free and does not limit the present invention.

The aqueous liquid of the present invention is used for medicines, cosmetics, foods and the like, and specific forms thereof include injections, liquid preparations for internal use, lotions, hair tonics, emulsions for cosmetics and drinks.

The aqueous liquor of the present invention may be produced according to a general conventional method for producing an aqueous liquor. For example, a fat-soluble substance and lecithin are dissolved in ethanol, isopropanol or a mixture of ethanol and isopropanol, and this is dissolved in another desired solution. The components may be added to an aqueous solution in which the components have been previously dissolved, and ordinary stirring may be performed. Upon stirring, pressure treatment or ultrasonic treatment can be freely performed.

The effects of the present invention will be described with reference to the following experimental examples.

Experimental Example 1 Sample and Method 0.02 g of tocopherol acetate was added to ethanol (0.1-60 ml) having the concentration shown in the ethanol concentration column of Table 1.
Dissolve 0.3 g of purified hydrogenated egg yolk lecithin, about 40
The mixture was heated to 0 ° C., and was poured under pressure into purified water heated to about 35 ° C. with stirring to give an emulsion or a solubilized liquid. Tocopherol acetate in the sample is 1 part by weight, purified hydrogenated lecithin is 15 parts by weight, and ethanol is 4 to 2400 parts by weight. For each sample, the appearance and 640 nm at the time of preparation and after storage at 5 ° C and 45 ° C for 30 days. Transmittance T of
₆₄₀ (%) was calculated.

Results The results are shown in Table 1. From Table 1, ethanol concentration is 50V /
It was found that a stable aqueous liquid can be obtained at V% or less, particularly 40 V / V% or less.

[0021]

[Table 1]

Experimental Example 2 Samples and Methods 0.5 ml of squalane in 20 ml of ethanol and purified hydrogenated egg yolk lecithin (0.001 to 0.05 g) in the parts by weight described in the part by weight column of the purified hydrogenated egg yolk lecithin in Table 2. Dissolve and heat to about 40 ° C, pressurize it into purified water heated to about 35 ° C with stirring under pressure to make an emulsion, and add 1 volume of purified water.
The sample was set to 00 ml. In the sample, 1 part by weight of squalane and 0.002 parts of purified hydrogenated egg yolk lecithin were used.
0.1 parts by weight, ethanol is 32 parts by weight, and the ethanol concentration in the sample is 20 V / V%. 45 samples
After leaving it at 30 ° C., 5 ° C. and room temperature for 30 days, the appearance change and the transmittance T ₆₄₀ (%) at ₆₄₀ nm were obtained.

Results Table 2 shows the results after standing for 30 days at room temperature. No separation was observed in any of the samples after standing at 45 ° C. and 5 ° C. for 30 days. When 32 parts by weight of ethanol is used for 1 part by weight of squalane, it is proved that the purified hydrogenated egg yolk lecithin may be 0.1 part by weight or less.

[0024]

[Table 2]

In the table, parts by weight of purified hydrogenated egg yolk lecithin represent parts by weight per 1 part by weight of squalane.

Experimental Example 3 Sample and method Squalane 0.1 was added to isopropanol (0.5 to 60 ml) having the concentration described in the isopropanol concentration column of Table 3.
g and purified soybean lecithin 0.03 g were dissolved and prepared according to the following Experimental Example 1 to prepare a sample. In the sample, squalane is 1 part by weight, purified soybean lecithin is 0.3 part by weight, and isopropanol is 4 to 480 parts by weight. The stability was determined by the same method as described in Experimental Example 1 below.

Results The results are shown in Table 3. From Table 3, the isopropanol concentration is 5
It is found that a stable aqueous liquid can be obtained at 0 V / V% or less.

[0028]

[Table 3]

Experimental Example 4 Sample and Method Squalane (0.1 g) and purified hydrogenated egg yolk lecithin (0.001 to 6 g) in parts by weight shown in Table 4 were dissolved in 20 ml of ethanol. The sample was prepared according to the description of Experimental Example 2. In the sample, 1 part by weight of squalane and 0.1% of purified hydrogenated egg yolk lecithin were used.
01-60 parts by weight, ethanol is 200 parts by weight,
The ethanol concentration in the sample is 20 V / V%. The sample was left at room temperature for 30 days, and the appearance change and the transmittance T ₆₄₀ (%) at ₆₄₀ nm were determined.

Results The results are shown in Table 4. From Table 4, it is clear that when 200 parts by weight of ethanol is used for 1 part by weight of squalane, the amount of purified hydrogenated egg yolk lecithin is 50 parts by weight or less.

[0031]

[Table 4]

In the table, parts by weight of purified hydrogenated egg yolk lecithin represent parts by weight per 1 part by weight of squalane.

The present invention will be described in more detail with reference to the following examples and reference examples.

Example 1 Drinking agent Tocopherol acetate 1.0 g Purified soybean lecithin 0.02 g Hydrogenated egg yolk lecithin 0.03 g Ascorbic acid 1.0 g Sodium citrate 0.3 g Sorbit 50.0 g Sucrose 80.0 g Flavor 0.2 g Ethyl paraben 0.1 g Ethanol 10.0 ml Propylene glycol 25.0 g Purified water Total volume 1,000 ml

Tocopherol acetate, purified soybean lecithin,
Hydrogenated egg yolk lecithin and flavor were added to ethanol, dissolved and kept at about 40 ° C. (solution I). This was pressure-injected into purified water heated to about 35 ° C. according to the method described in the method of Experimental Example 1 to obtain a uniform bluish white clear solution. A propylene glycol solution in which ascorbic acid, sodium citrate, sorbit, sucrose, and ethylparaben were dissolved was added to this solution and uniformly dissolved to obtain an internal solution.

The solution had a uniform, bluish white clear appearance and was stable.

Example 2 Lotion Squalane 4.0 g dl-α-tocopherol 1.0 g Purified hydrogenated egg yolk lecithin 0.25 g Ethanol 150.0 ml Glycerin 40.0 g Sorbit 40.0 g Perfume 0.5 g Purified water Total amount 1,000 ml

Squalane, dl-α-tocopherol, purified hydrogenated egg yolk lecithin, and flavor were added to ethanol, dissolved by heating, and kept at about 55 ° C. (solution I). Separately, glycerin and sorbit were uniformly dissolved in purified water and kept at about 45 ° C (solution II). Hereinafter, a lotion was prepared according to the production method of Reference Example 3. The obtained lotion had a uniform, slightly transparent milky white appearance and was stable.

Reference Example 1 Ubidecarenone Injection Ubidecarenone 1.0 g Purified egg yolk lecithin 0.4 g Ethanol 65.0 ml Macrogol 400 50.0 g Sorbitol 45.0 g Distilled water for injection Total 1,000 ml

Ubidecarenone and purified egg yolk lecithin were added to ethanol and dissolved, and Macrogol 400 was added and dissolved, and the resulting solution (solution I) was heated to about 45 ° C.

Sorbitol was added to distilled water for injection to dissolve it, and this solution (solution II) was heated to about 40 ° C. Then I
The previously prepared solution I was poured into solution I under stirring of solution II to prepare a solubilized solution of ubidecarenone, which was cooled to room temperature and then filtered using a membrane having a pore size of 0.22 μm to obtain a filtrate. After dispensing and sealing in an ampoule, it was heat sterilized at 115 ° C. for 30 minutes to give a ubidecarenone injection. The obtained injection was clear and stable in appearance.

Reference Example 2 Menatetrenone Injection Menatetrenone 1.0 g Purified sesame oil 0.4 g Purified egg yolk lecithin 0.4 g Purified soybean lecithin 0.2 g Ethanol 90.0 ml Macrogol 400 50.0 g Glucose 50.0 g Distilled water for injection Total amount 1 1,000 ml

Menatetrenone, purified sesame oil, purified egg yolk lecithin and purified soybean lecithin were dissolved in a mixed solution of ethanol and macrogol and kept at about 50 ° C. (solution I). Glucose was dissolved in distilled water for injection and kept at about 45 ° C (I
Liquid I).

Then, according to the production method of Reference Example 1, a menatetrenone injection solution was prepared.

The obtained injection was almost transparent in appearance,
It was stable over time.

Reference Example 3 Toner lotion Purified hydrogenated soybean lecithin 2.0 g Tocopherol acetate 1.0 g Squalane 1.0 g Ethanol 140.0 ml Glycerin 40.0 g Sorbit 40.0 g Fragrance 0.7 g Purified water Total volume 1,000 ml

Purified hydrogenated soybean lecithin, tocopherol acetate, perfume and squalane were dissolved in ethanol to give about 4
The temperature was kept at 5 ° C (solution I). On the other hand, glycerin and sorbit were dissolved in purified water and kept at about 40 ° C (solution II). Next, the liquid I was poured into the liquid II with stirring to obtain a lotion.
The obtained lotion had a uniform, slightly hazy blue-white appearance and was stable.

Reference Example 4 Medicinal hair tonic dl-α-tocopherol nicotinate 1.0 g squalane 2.0 g Irgasan DP-300 0.5 g Cholesterol 0.2 g 1-menthol 0.5 g Purified hydrogenated egg yolk lecithin 1.0 g Ethanol 350 ml Propylene glycol 60.0 g Perfume 2.0 g Purified water Total volume 1,000 ml

Dl-α-tocopherol nicotinic acid ester, isopropyl myristate, irgasan DP-3
00, cholesterol, 1-menthol, fragrance and purified hydrogenated egg yolk lecithin were dissolved in a mixed solution of ethanol and propylene glycol and kept at about 45 ° C (solution I). The purified water was heated and kept at about 40 ° C (solution II). Hereinafter, according to the method for producing a lotion of Reference Example 3, a hair tonic having a uniform bluish white clear appearance was obtained. The obtained hair tonic was stable over time.

Reference Example 5 Sun Protection Lotion Octylparadimethylparaaminobenzoic acid 10.0 g Squalane 1.0 g Saturated fatty acid (C ₈ -C ₁₂ ) triglyceride 1.0 g Purified hydrogenated egg yolk lecithin 2.0 g Isopropanol 100.0 ml Perfume 0 .7 Macrogol 400 50.0 g Propylene glycol 50.0 g Purified water Total volume 1,000 ml

Octyl para-dimethyl para-aminobenzoic acid, squalane, saturated fatty acid (C ₈ -C ₁₂ ) triglyceride, fragrance and purified hydrogenated egg yolk lecithin were dissolved in a mixed solution of isopropanol and Macrogol 400 to give about 50 parts.
The temperature was kept at (° C) (solution I). Separately, propylene glycol was dissolved in purified water and kept at about 40 ° C (solution II). Hereinafter, a sunscreen lotion was prepared according to the production method of Reference Example 3. The obtained lotion had a uniform, slightly transparent milky white appearance and was stable.

Reference Example 6 Hair Tonic Tocopherol acetate 1.0 g Squalane 2.0 g Hinokitiol 0.5 g Cholesterol 0.1 g Benzyl nicotinate 0.05 g 1-Menthol 0.5 g Purified soybean lecithin 4.0 g Isopropanol 50.0 ml Ethanol 300. 0 ml Glycerin 60.0 g Perfume 2.0 g Purified water Total volume 1,000 ml

Tocopherol acetate, squalane, hinokitiol, cholesterol, benzyl nicotinate, 1-
Dissolve menthol, fragrance, and purified soy lecithin in a mixture of ethanol and isopropanol, add glycerin,
The temperature was kept at 5 ° C (solution I). The purified water was heated and kept at about 40 ° C (solution II). Hereinafter, according to the method for producing a lotion of Reference Example 3, a hair tonic having a uniform bluish white clear appearance was obtained. The obtained hair tonic was stable over time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 9/08 H 7329-4C 31/07 8413-4C 31/12 8413-4C 31/195 8413- 4C 31/20 8413-4C 31/23 8413-4C 31/245 8413-4C 31/355 7252-4C 31/59 7252-4C 31/60 7252-4C 47/10 G 7329-4C 47/18 G 7329- 4C

Claims (3)

[Claims] 1. A fat-soluble substance-containing aqueous liquid containing a fat-soluble substance, lecithin and ethanol, isopropanol or an ethanol isopropanol mixture as an essential component, wherein the volume of the ethanol, isopropanol or ethanol isopropanol mixture is 50 V of the aqueous liquid. / V
% Or less, the fat-soluble substance-containing aqueous liquid contains lecithin in an amount of 0.002 to 0.05 parts by weight when 24 parts by weight or less of ethanol is mixed with 1 part by weight of the fat-soluble substance. 2. The fat-soluble substance is vitamin A, vitamin E,
A combination of one or more selected from the group consisting of vitamin D, vitamin K, ubidecarenone and derivatives thereof, bisabolol, salicylate, para-aminobenzoic acid and derivatives thereof, squalane, isopropyl myristate, and vegetable oil. An aqueous liquid containing the fat-soluble substance described. 3. The fat-soluble substance-containing aqueous liquid according to claim 1, wherein the aqueous liquid is any one of an injection, an oral liquid preparation, a lotion, a hair tonic, and a cosmetic emulsion.