AN AQUEOUS LIQUID CONTAINING A FAT-SOLUBLE SUBSTANCE

Abstract: A clear and stable aqueous liquid containing as essential components a fat-soluble substance and lecithin, as well as ethanol and/or iso-propanol. The volume of the alcohol is not more than 50 V/V % of the aqueous liquid, and the amount of lecithin is determined from the following: (1) not more than 0.1 part by weight when less than 50 parts by weight of ethanol is used per part by weight of the fat-soluble substance; (2) not more than 50 parts by weight when at least 50 parts by weight of ethanol is used per part by weight of the fat-soluble substance; or (3) not more than 50 parts by weight when iso­ propanol or a mixture of ethanol and iso-propanol is used.

Description: This invention relates to an aqueous liquid containing as essential components a fat-soluble substance selected from vitamin A, vitamin E, vitamin D, vitamin K, ubidecarenone, derivatives of these substances, bisabolol, salicylic acid esters, squalane, isopropyl myristate and vegetable oils, furthermore lecithin and at least one alcohol selected from ethanol and isopropanol. Examples have heretofore been known in which large amounts of nonionic surface-active agents are used in order to clearly dissolve or emulsify fat-soluble substances in water It is well known, however, that by any of various administration methods, nonionic surface-active agents cause some undesirable trouble to humans. In view of this, techniques were developed for using lecithin, a natural substance with relatively high safety, instead of synthetic surfactants, as seen, for example, in Japanese Patent Applications Laid-Open Nos. 62010/1980, 147228/1980, 38314/1980, 83912/1977, 83911/1977, 50124/1974 and 126821/1975. With these techniques, exertion of a strong mechanical stress is required in order to supplement the weak emulsifying power of lecithin. Furthermore, since the average particle diameter of particles in the resulting emulsion is as large as 0.5 µm or more and the particle size distribution is broad, the stability of the emulsion with the lapse of time is not sufficient. With this background, some of the present inventors studied a system composed of a fat-soluble substance, lecithin and ethanol, and discovered a system composed of 1 part by weight of a fat-soluble substance, 0.1 to 10 parts by weight of lecithin and 1 to 50 parts by weight of ethanol, which can be emulsified by addition of water. An invention based on this discovery was applied for a patent in Japanese Patent Application Laid-Open No. 56315/1978 (= JP-A-53-56315A). Subsequently, the present inventors studied a system consisting essentially of a fat-soluble substance, lecithin and an alcohol, which can be converted to a stable emulsion or solution by a simple convenient method. It is necessary that the concentration of alcohol in the emulsion or solution should be as high as 20 to 50% for example, in order to use the emulsion or solution as a lotion, a skin lotion or a milky lotion. The present inventors made investigations in order to obtain such a system. Generally, the addition of a large amount of an alcohol to an emulsion or solution of a fat-soluble substance prepared by emulsifying or dissolving it with the aid of a surface-active substance such as lecithin adversely affects the emulsion or solution, and such an addition, without adverse effects, has been considered to be a difficult technique. For example, BBA 298 (1973) 1015-1019 reported that when an ethanol solution of lecithin was added to a 0.16M aqueous solution of KCl, the concentration of ethanol in the resulting solution was 7.5% at the highest. In order, therefore, to prepare a stable emulsified or solubilized system by adding a fat-soluble substance and lecithin to an aqueous solution of an alcohol at a high concentration, it is considered necessary to set certain numerical limitations on the proportions of these ingredients to be blended. The present inventors studied systems containing various components starting with a system containing an alcohol at a high concentration, in view of the need to use an emulsified or solubilized liquid containing a fat-soluble substance, lecithin and an alcohol as essential components as a lotion, a skin lotion or a hair tonic. It was first found that besides ethanol, isopropanol can be used as the alcohol, and ethanol can be incorporated at a concentration of up to 50% by volume. It was also found that when the alcohol is ethanol to be incorporated at a concentration of not more than 50 V/V% of the aqueous liquid and when it is added in an amount of less than 50 parts by weight per part by weight of the fat-soluble substance, the amount of lecithin should be less than 0.1 part by weight per part by weight of the fat-soluble substance; when ethanol is incorporated in an amount of 50 parts by weight or more per part by weight of the fat-soluble substance, the amount of lecithin should be not more than 50 parts by weight per part by weight of the fat-soluble substance; and when the alcohol is isopropanol in a concentration of 10 to 30 V/V% in the aqueous liquid, the amount of lecithin should be not more than 50 parts by weight per part by weight of the fat-soluble substance. The foregoing findings have led to the present invention. It is an object of this invention to provide a stable aqueous liquid containing a fat-soluble substance, lecithin and ethanol or isopropanol as essential components. This object is solved by an aqueous liquid containing as essential components a fat-soluble substance selected from vitamin A, vitamin E, vitamin D, vitamin K, ubidecarenone, derivatives of these substances, bisabolol, salicylic acid esters, squalane, isopropyl myristate and vegetable oils, furthermore lecithin and at least one alcohol selected from ethanol and isopropanol a) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being less than 0.1 part by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of less than 50 parts by weight per part by weight of the fat-soluble substance, or b) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of at least 50 parts by weight per part by weight of the fat-soluble substance, or c) the volume of isopropanol being 10 to 30 V/V% of the aqueous liquid and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance. The aqueous liquid containing a fat-soluble substance in accordance with this invention denotes an emulsion or solution. The aqueous liquid contains a fat-soluble substance, lecithin as well as ethanol or iso-propanol as essential components. The fat-soluble substance used in this invention denotes one or more of fat-soluble substances for medicines, cosmetics and foodstuffs, which are soluble in ethanol or iso-propanol. The fat-soluble substance is selected from vitamins A, E, D and K, ubidecarenone and derivatives of these substances, coenzymes such as CoQ₈ and CoQ₁₀, salicyclic acid esters, methyl salicylate, monoglycol salicylate, bisabolol, α-bisabolol, squalane and isopropyl myristate and vegetable oils. The vegetable oils denote for instance sesame oil, soybean oil and olive oil. Lecithin used in this invention denotes a phospholipid-containing substance extracted from egg yolk or from a vegetable oil and optionally purified, or a hydrogenation product thereof. It also denotes synthetic glycerophosphoric acid esters of the following general formula, or mixtures thereof. In the formula, R₁ and R₂ each represent a hydrogen atom or a saturated or unsaturated hydrocarbon having 8 to 20 carbon atoms, and R₃ represents for instance a hydrogen atom, choline, ethanolamine, serine, inositol, glycerol. Ethanol and iso-propanol are used either singly or in combination. When they are used in combination, the ratio between the two may be any desired one. The volume of ethanol is not more than 50% of the aqueous liquid of this invention containing a fat-soluble substance. The percentage here expresses V/V%. In the aqueous liquid of this invention, the proportions of the fat-soluble substance, lecithin and the alcohol are limited. They differ whether the alcohol used is ethanol or iso-propanol. When ethanol is used in an amount of less than 50 parts by weight per part by weight of the fat-soluble substance, the amount of lecithin is less than 0.1 part by weight. When ethanol is used in an mount of at least 50 parts by weight per part by weight of the fat-soluble substance, the amount of lecithin is not more than 50 parts by weight. When iso-propanol or the ethanol-isopropanol mixture is used as the alcohol, the amount of lecithin is not more than 50 parts by weight. The aqueous liquid of this invention may optionally contain for instance emulsifiers, isotonizing agent, buffers, dissolution aids, corrigents, antiseptics and stabilizers in addition to the essential components, as shown in Examples given hereinafter. The addition of these optional substances is free and does not limit the present invention. The aqueous liquid of this invention is used for medicines, cosmetics and foodstuffs. Specific forms of the aqueous liquid include, for example, an injectable preparation, an orally administrable liquid preparation, a lotion, a hair tonic and a drink preparation. The aqueous liquid of this invention may be prepared by general ordinary methods for the production of aqueous liquids. For example, the fat-soluble substance and lecithin are dissolved in ethanol or iso-propanol. The solution is added to an aqueous solution containing optional components, and the mixture is stirred in an ordinary manner. The stirring may, for example, be carried out by applying a pressurizing treatment or an ultrasonication treatment. The following Experimental Examples illustrate the effects of the present invention. Experimental Example 1 Sample and method:- Tocopherol acetate (0.02 g) and purified hydrogenated egg yolk lecithin (0.3 g) were dissolved in ethanol (0.1 - 60 ml) having each the concentrations shown in Table 1. The solution was heated to about 40 o C, and purified water warmed at about 35 o C was injected under pressure into the solution with stirring to form an emulsion or solution. Purified water was added to adjust the total amount of the emulsion or solution to 100 ml and thus provide a sample. In these samples containing 1 part by weight of tocopherol acetate, 15 parts by weight of purified hydrogenated lecithin and 4 to 2400 parts by weight of ethanol were prepared, and their appearances and percent transmittances at 640 nm (T₆₄₀) were determined upon preparation and after storage for 30 days at 5 o C and 45 o C respectively. Results:- The results are summarised in Table 1. It is seen from Table 1 that stable aqueous liquids can be obtained when the concentration of ethanol is not more than 50 V/V %, particularly not more than 40 V/V %. Experimental Example 2 Sample and method:- Squalane (0.5 g) and purified hydrogenated egg yolk lecithin (0.001 to 0.35 g) in the weight parts shown in Table 2 were dissolved in 20 ml of ethanol. The solution was heated to about 40 o C. The solution was injected under pressure into purified water warmed at about 35 o C with stirring to form an emulsion. The purified water was added to the emulsion to adjust its total amount to 100 ml and thus provide a sample. The resulting samples contained 1 part by weight of squalane, 0.002 to 0.1 part by weight of purified hydrogenated egg yolk lecithin and 32 parts by weight of ethanol, and the concentration of ethanol in each of the samples was 20 V/V %. The samples were left to stand for 30 days at 45 o C, 5 o C and room temperature, and changes in appearance and percent transmittances at 640 nm, T₆₄₀(%), were determined. Results:- Table 2 shows the results obtained with samples left to stand at room temperature for 30 days. No separation was observed in any of the samples after standing for 30 days at 45 o C and 5 o C, respectively. It is thus seen that when 32 parts by weight of ethanol is used per part by weight of squalane, the amount of purified hydrogenated egg yolk lecithin may be not more than 0.1 part by weight. Parts by weight of purified hydrogenated egg yolk lecithin After standing for 30 days at room temperature Stability Appearance T₆₄₀(%) 0.002 Uniform emulsion 52.2 Nearly good 0.004 Uniform emulsion 56.0 Good 0.01 Uniform, slightly bluish white emulsion 68.0 Good 0.02 Uniform, slightly bluish white emulsion 75.0 Good 0.1 Uniform emulsion 15.0 Nearly good In the table, the parts by weight of purified hydrogenated egg yolk lecithin are per part by weight of squalane. Experimental Example 3 Sample and method:- Squalane (0.1 g) and purified soybean lecithin (0.03 g) were dissolved in iso-propanol (0.5 to 60 ml) having each of the concentrations shown in Table 3. Then, samples were prepared by the same procedure as in Experimental Example 1. Each of the samples contained 1 part by weight of squalane, 0.3 part by weight of purified soybean lecithin and 5 to 600 parts by weight of iso-propanol. By the same method as in Experimental Example 1, the stabilities of the samples were determined. Results:- The results are summaried in Table 3. It is seen from Table 3 that stable aqueous liquids can be obtained when the concentration of iso-propanol is 10 to 30 V/V% of the aqueous liquid according to the invention. Experimental Example 4 Squalane (0.1 g) and purified hydrogenated egg yolK lecithin (0.001 to 6 g) corresponding to the weight parts indicated in Table 4 were dissolved in 20 ml of ethanol, followed by the same procedure as in Experimental Example 2, to prepare samples. Each of the samples contained 1 part by weight of squalane, 0.01 to 60 parts by weight of purified hydrogenated egg yolk lecithin and 200 parts by weight of ethanol, and the concentration of ethanol in each of the samples was 20 V/V %. The samples were left to stand for 30 days at room temperatures, and changes in appearance and percent transmittances at 640 nm, T₆₄₀(%), were determined. Results:- The results are shown in Table 4. It is seen from Table 4 that when 200 parts by weight of ethanol is used per part by weight of squalane, the amount of purified hydrogenated egg yolk lecithin may be not more than 50 parts by weight. Parts by weight of purified hydrogenated egg yolk lecithin After standing at room temperature for 30 days Stability Appearance T₆₄₀ (%) 0.01 Clear solution 99.5 Good 0.02 Clear solution 97.5 Good 0.05 Clear solution 95.1 Good 0.1 Clear solution 96.7 Good 0.2 Clear solution 97.8 Good 0.5 Clear solution 98.8 Good 1.0 Clear solution 98.1 Good 2.0 Nearly clear solution 90.1 Good 10.0 Uniform emulsion 66.8 Good 30.0 Uniform emulsion 31.9 Good 50.0 Nearly uniform emulsion 6.3 Good The parts by weight of the purified hydrogenated egg yolk lecithin in the table are per part by weight of squalane. The following Examples illustrate the present invention more specifically. Example 1 Ubidecarenone injectable preparation:- 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 ad. 1,000 ml Ubidecarenone and purified egg yolk lecithin were dissolved in ethanol, and then Macrogol 400 (Macrogol 400 is a general name for "polyethylene glycol". The figure of "400" represents the mean polymerization degree). was dissolved in the solution. The resulting solution (solution I) was heated to about 45 o C. Sorbitol was dissolved in distilled water for injection, and the resulting solution (solution II) was heated to about 40 o C. The solution I prepared earlier was injected into the stirred solution II to prepare a solution of ubidecarenone. The solution was cooled to room temperature and filtered through a membrane having a pore diameter of 0.22 µm. The filtrate was dividedly put in ampoules. The ampoules were sealed up by melting and heat-sterilized at 115 o C for 30 minutes to form ubidecarenone injectable preparations. The injectable preparations were clear in appearance and stable. Example 2 Menatetrenone Injectable preparation:- 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 ad. 1,000 ml Menatetrenone, purified sesame oil, purified egg yolk lecithin and purified soybean lecithin were dissolved in a mixture of ethanol and Macrogol 400, and the solution was maintained at about 50 o C (solution I). Glucose was dissolved in distilled water for injection, and the solution was maintained at about 45 o C (solution II). Thereafter, a menatetrenone injectable preparation was formed from the solution I and the solution II, by the same procedure as in Example 1. The injectable preparation obtained was nearly clear in appearance and remained stable with time. Example 3 Skin lotion:- Purified hydrogenated soybean lecithin 2.0 g Tocopherol acetate 1.0 g Squalane 1.0 g Ethanol 140.0 ml Glycerol 40.0 g Sorbitol 40.0 g Perfume 0.7 g Purified water ad. 1,000 ml Purified hydrogenated soybean lecithin, tocopherol acetate, the perfume and squalane were dissolved in ethanol, and the solution was maintained at about 45 o C (solution I). Separately, glycerol and sorbitol were dissolved in purified water, and the solution was maintained at about 40 o C (solution II). Then, the solution I was injected into the stirred solution II to form a skin lotion which was uniform and bluish white with slight turbidity and stable. Example 4 Medicated hair tonic:- dℓ-α-tocopherol nicotinate 1.0 g Squalane 2.0 g Irgasan DP-300® 0.5 g Cholesterol 0.2 g ℓ-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 ad. 1,000 ml dℓ-α-Tocopherol nicotinate, Irgasan DP-300®, cholesterol, ℓ-menthol, the perfume and purified hydrogenated egg yolk lecithin were dissolved in a mixture of ethanol and propylene glycol, and the solution was maintained at about 45 o C (solution I). Purified water was heated and maintained at about 40 o C (liquid II). Thereafter, a hair tonic having a uniform, clear, bluish white appearance was obtained from the solution I and the liquid II, by the same procedure as in Example 3. The resulting hair tonic remained stable with time. Example 5 Drink preparation:- 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 Sorbitol 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 ad. 1,000 ml Tocopherol acetate, purified soybean lecithin, hydrogenated egg yolk lecithin and the flavor were dissolved in ethanol, and the solution was maintained at about 40 o C (solution I). The solution I was injected under pressure into purified water warmed at about 35 o C by the same procedure as in Experimental Example 1 to give a uniform, bluish white, clear solution. To the solution was added propylene glycol having dissolved therein ascorbic acid, sodium citrate, sorbitol, sucrose and ethyl paraben. They were dissolved uniformly to obtain a liquid preparation for oral administration. This solution showed a uniform, bluish white, clear appearance and was stable. 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 ℓ-Menthol 0.5 g Purified soybean lecithin 4.0 g iso-Propanol 50.0 ml Ethanol 300.0 ml Glycerol 60.0 g Perfume 2.0 g Purified water ad. 1,000 ml Tocopherol acetate, squalane, hinokitiol, cholesterol, benzyl nicotinate, ℓ-menthol, the perfume and purified soybean lecithin were dissolved in a mixture of ethanol and isopropanol, followed by adding glycerol thereto. The solution was maintained at about 45 o C (solution I). Purified water was heated and maintained at about 40 o C (solution II). Thereafter, by the same procedure as in the preparation of the skin lotion in Example 3, a hair tonic having a uniform, bluish white, clear appearance was obtained. The resulting hair tonic remained stable with time.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE An aqueous liquid containing as essential components a fat-soluble substance selected from vitamin A, vitamin E, vitamin D, vitamin K, ubidecarenone, derivatives of these substances, bisabolol, salicylic acid esters, squalane, isopropyl myristate and vegetable oils, furthermore lecithin and at least one alcohol selected from ethanol and isopropanol a) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being less than 0.1 part by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of less than 50 parts by weight per part by weight of the fat-soluble substance, or b) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of at least 50 parts by weight per part by weight of the fat-soluble substance, or c) the volume of isopropanol being 10 to 30 V/V% of the aqueous liquid and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance. The aqueous liquid of claim 1 which is an injectable preparation, an orally administratable liquid preparation, a lotion or a hair tonic. The aqueous liquid of claim 1 wherein the lecithin is selected from a phospholipid-containing substance extracted from egg yolk or from a vegetable oil and optionally purified; a hydrogenation product thereof; synthetic glycerophosphoric acid esters of the following formula; and mixtures thereof: wherein R₁ and R₂ each represent hydrogen atom or a saturated or unsaturated hydrocarbon having 8 to 20 carbon atoms, and R₃ represents hydrogen atom, choline, ethanolamine, serine, inositol or glycerol. Claims for the following Contracting State : AT A process for preparing an aqueous liquid containing as essential components a fat-soluble substance selected from vitamin A, vitamin E, vitamin D, vitamin K, ubidecarenone, derivatives of these substances, bisabolol, salicylic acid esters, squalane, isopropyl myristate and vegetable oils, furthermore lecithin and at least one alcohol selected from ethanol and isopropanol, wherein the respective components are mixed in the following ratios: a) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being less than 0.1 part by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of less than 50 parts by weight per part by weight of the fat-soluble substance, or b) the volume of ethanol being not more than 50 V/V% of the aqueous liquid, and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance, when ethanol is used as the alcohol in an amount of at least 50 parts by weight per part by weight of the fat-soluble substance, or c) the volume of isopropanol being 10 to 30 V/V% of the aqueous liquid and the amount of lecithin being not more than 50 parts by weight per part by weight of the fat-soluble substance. A process according to claim 1 wherein the aqueous liquid is an injectable preparation, an orally administratable liquid preparation, a lotion or a hair tonic. A process according to claim 1 wherein the lecithin is selected from a phospholipid-containing substance extracted from egg yolk or from a vegetable oil and optionally purified; a hydrogenation product thereof; synthetic glycerophosphoric acid esters of the following formula; and mixtures thereof: wherein R₁ and R₂ each represent hydrogen atom or a saturated or unsaturated hydrocarbon having 8 to 20 carbon atoms, and R₃ represents hydrogen atom, choline, ethanolamine, serine, inositol or glycerol.

Inventors: IWAO, AMADA, SHIGEMITSU, OSAWA
Applicants: EISAI CO., LTD.
Application year: 1983
Main classification: A61K47
IPC codes: A61K31, A61K9, A61K8, A61Q90