JP2003119120A - Method for producing liposome, cosmetic containing the liposome, and skin care preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an aqueous solution of liposome stably including a hydrophilic medicinal component and a lipophilic medicinal component in high concentrations without damaging the quality of them, and further to provide a skin cosmetic, a skin care preparation and a hair cosmetic obtained by formulating the liposome. SOLUTION: The liposome is prepared by using carbon dioxide in a critical state or a subcritical state, optionally in combination with a solubilizing agent such as a lower alcohol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention uses a carbon dioxide gas in a critical or subcritical state without deteriorating the quality of a hydrophilic drug component or hydrophilic physiologically active component, a lipophilic drug component or a lipophilic rearrangement active component. The present invention relates to a method for producing liposomes containing these in a stable and high concentration, and a liposome preparation, and further a skin cosmetic containing these.
It relates to a skin external preparation and a hair cosmetic.

[0002]

2. Description of the Related Art Generally, liposomes are closed vesicles composed of a single layer or multiple layers of phospholipids obtained by mixing phospholipids with water. Can be included. For example, the water-soluble active ingredient is
It can be present in the core or between the bilayers, while the lipophilic active ingredient is contained in the bilayer.

Since liposomes are composed of lipids similar to biological membranes, they easily bind to cell membranes and can transport water and various medicinal components to the stratum corneum. In addition, by liposome formation, a medicinal component that is originally unstable and easily deactivated can be kept stable for a long period of time. For the above reasons, in recent years, liposomes encapsulating medicinal components have been applied as a formulation itself to skin cosmetics such as skin creams, hair cosmetics such as hair-growth agents, and skin external preparations such as ointments, or in these products. Is required to be blended with.

The liposome in which the medicinal component is encapsulated can be prepared by a thin film method, a reverse phase evaporation method, or an ethanol injection method. Furthermore, the liposome can be obtained by secondary treatment with an emulsifying machine such as a high-pressure homogenizer or an ultrasonic emulsifying machine that can apply high energy. These preparation methods are described, for example, in "Cosmetic Handbook".
(Nikko Chemicals et al., 1996).

However, the methods for preparing these liposomes and the liposome preparations obtained by these liposomes, especially when used as cosmetics or external preparations for skin,
The following problems have been pointed out. That is, (1) it is difficult to completely remove phospholipids from the final product because they use an organic solvent, and when applied to cosmetics and skin external preparations, there is a safety problem. Cause (2) In the method using an organic solvent, the organic solvent scatters during the preparation and affects the environment. Further, a solvent recovery device or the like for avoiding this is costly. (3) The process is complicated and manufacturing on an industrial scale is difficult. In particular, in the thin film method, the step of removing the organic solvent to obtain a phospholipid thin film is practically impossible on an industrial scale. (4) Using a strong mechanical force such as an ultrasonic emulsifier or a high-pressure homogenizer, a method of directly dispersing an phospholipid and an oil phase, in which a lipophilic inclusion is optionally mixed therein, directly into an aqueous phase is The process is simple and suitable for industrial scale production, but the liposome production rate is not sufficient and the encapsulation rate is small. Also, due to the heat and high shearing force generated during stirring,
When encapsulating an unstable medicinal component, problems of decomposition and denaturation occur.

These methods are widely used because they are simple and suitable for industrial scale production, but the liposomes obtained have low stability and can be directly applied as cosmetics or external preparations for skin. It is difficult. In particular, when this liposome is blended with a cosmetic or an external preparation for skin, there is a problem that the stability is significantly lowered due to the influence of other components such as an emulsifier.

On the other hand, as a suitable method for producing liposomes, a technique of using supercritical carbon dioxide gas for the preparation of liposomes is disclosed in JP-A-6-315624. However, in these methods, the phospholipid that can be preferably used as the lipid membrane is limited to 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine. It is pointed out that this product is unsuitable for production on an industrial scale because it is complicated to synthesize and purify unlike phospholipid obtained industrially.

[0008]

DISCLOSURE OF THE INVENTION The present invention aims to obtain a liposome which has practical stability as a cosmetic or an external preparation for skin, and which contains a hydrophilic drug component or a lipophilic drug component in a stable and high ratio. As a purpose, to find a method suitable for production on an industrial scale that does not impair the stability of the medicinal ingredient, and to increase the liposome production rate and the encapsulation rate of the medicinal ingredient, and to secure the stability of the liposome and the medicinal ingredient. Another object was to find a preparation method that does not use an organic solvent that may remain in the product.

[0009]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to solve the above-mentioned problems, the method of preparing liposomes using supercritical or subcritical carbon dioxide gas is more effective than conventional methods. It has been found that the production rate of the drug and the encapsulation rate of the medicinal component are high, and the residual ratio of the medicinal component is higher than that of the liposome prepared by the conventional method. Further, it was confirmed that the production method can be applied on an industrial scale substantially without using an organic solvent, and the present invention was completed.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The preferred pressure of carbon dioxide in the supercritical or subcritical state used in the present invention is 50 kg.
/ Cm ^{2 to} 500 Kg / cm ² , preferably 75 Kg
/ Cm ^{2 to} 500 kg / cm ² , more preferably 10
It is 0 Kg / cm ^{2 to} 400 Kg / cm ² . The temperature of carbon dioxide gas in a suitable supercritical state or subcritical state is 25 ° C to 200 ° C, preferably 31 ° C to 100 ° C.
C, more preferably 35 to 80 ° C.

The preferred method for preparing the liposome of the present invention is as follows. That is, phospholipid as a lipid membrane component and, if necessary, a lipophilic medicinal component are added to carbon dioxide in a supercritical state or a subcritical state at the above suitable pressure and temperature, and stirred and dissolved. Further, if necessary, a solvent acceptable for cosmetics and the like can be used together in order to enhance the solubility of phospholipids and the like. Subsequently, the predetermined aqueous phase is continuously added. By adding the water phase, a water / carbon dioxide gas emulsion is formed, and a phase transition of the system occurs with an increase in the amount of the water phase added, resulting in an excess of water / carbon dioxide gas emulsion + carbon dioxide gas / water emulsion two-phase system. Carbon dioxide becomes a two-phase system separated from the carbon dioxide / water emulsion. If desired, the desired liposomes can be obtained by reducing the pressure and vaporizing and recovering carbon dioxide.

Further, the continuous method disclosed in JP-A-6-315624 and JP-A-9-502644 can also be preferably prepared.

As a component of the lipid membrane used in the present invention, phospholipid or glycolipid can be preferably used. These may be used alone or in combination.

The phospholipid used in the present invention is not particularly limited to its type, and is not limited to fatty acid composition regardless of saturated fatty acid or unsaturated fatty acid.

Specific examples of phospholipids include lecithin and lysolecithin obtained from soybean, egg yolk and the like and / or their hydrogenated products and derivatives such as hydroxides. Further, phosphatidylcholine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin and the like can be mentioned. At that time,
The constituent phospholipid is not particularly limited, and the constituent fatty acid is not particularly limited, and may be either saturated fatty acid or unsaturated fatty acid.

Specific examples of glycolipids include glycerolipids such as digalactosyl diglyceride and galactosyl diglyceride sulfate, galactosylceramide, galactosylceramide sulfate, lactosylceramide, ganglioside G7, ganglioside G6, ganglioside G.
Glycosphingolipids such as 4 can be preferably used.

To prepare the liposome of the present invention, these lipid membrane components are dissolved, dispersed or mixed in the above-mentioned supercritical or subcritical fluid containing carbon dioxide in the supercritical state and / or subcritical state. It is preferable. At that time, one or two of lower alcohol, glycol, glycol ether, glycol ester, alkyl carbonate
The combined use of two or more species is more preferable because the solubility of the lipid membrane component in the above-mentioned supercritical or subcritical fluid is improved.

Preferred lower alcohols include methanol, ethanol, isopropanol and the like, and ethanol is particularly desirable from the viewpoint of safety.

Preferred glycols, glycol ethers and glycol esters include ethylene glycol, propylene glycol, dipropylene glycol,
1,3-butanediol, ethyl carbitol, butyl carbitol, diethylene glycol diethyl ether, alkyl esters of these glycols and the like can be mentioned.

Preferred alkyl carbonates include alkyl carbonates such as propylene carbonate and diethyl carbonate.

The liposome of the present invention contains a hydrophilic drug component and / or a lipophilic drug component,
It can be suitably used for cosmetics and external preparations for skin. Suitable medicinal components include antioxidants, antibacterial agents, anti-inflammatory agents, blood circulation promoters, whitening agents, skin roughening inhibitors, anti-aging agents, hair growth promoters, moisturizers, hormones, vitamins, pigments, And proteins.

Suitable antioxidants include tocopherols, natural vitamin Es and fatty acid esters thereof, BHT, BHA, hydroxyanisole, t-butylhydroquinone, nordihydroguaiaretin, alkyl gallates and thiols. Dilauryl dipropionate,
Triyl biguanide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, erythorbic acid and its salts, L-ascorbic acid and its salts, fatty acid ascorbyl, catechins such as tea extract and apple extract, catechin derivatives, and polyphenols Is mentioned. Further, amino acids having a reducing group such as thiotaine, glutathione, thiotaurine, and hypotaurine are also preferable.

Suitable antibacterial agents include organic acids such as benzoic acid, undecylenic acid, salicylic acid, sorbic acid, dehydroacetic acid, paraoxybenzoic acid alkyl ester and salts and derivatives thereof, isopropylmethylphenol, chlorhexidine, chlorhexidine gluconate, Phenol, cresol, thymol, phenols such as triclosan, hinokitiol, hiba oil, plant extracts such as tea extract, apple extract, grapefruit seed extract, plant extracts, catechins, catechin derivatives, and polyphenols. To be Also, chloramine T, zinc pyrithione and the like are preferable.

Suitable anti-inflammatory agents include ε-aminocaproic acid, tranexamic acid, tranexamic acid alkyl ester, glutyrrhizinic acid, glycyrrhizinic acid alkyl ester, glycyrrhetinic acid, glycyrrhetinic acid alkyl ester, lysozyme chloride, guaiazulene, hydrocortisone, perilla extract, ginkgo biloba. Examples include plant extracts such as extracts and seaweed extracts.

Examples of suitable blood circulation promoters include plant extracts such as ginkgo biloba extract, senburi extract, sericoside and horse chestnut extract, tocopherols, vitamin E and its derivatives, γ-oryzanol and the like.

Suitable whitening agents include L-ascorbic acid, sodium L-ascorbate, sodium ascorbyl phosphate, magnesium ascorbate phosphate, sodium ascorbate sulfate, glyceryl ascorbate (polyglyceryl) ethers, Glyceryl ascorbate (polyglyceryl)
Esters, Ascorbic acid glucoside (glycoside)
, Vitamin Cs such as alkyl esters of ascorbic acid, alkyl ethers of ascorbic acid and derivatives thereof, kojic acid, arbutin, placenta extract, sulfur and the like.

Further, plant extracts such as oil-soluble licorice extract, mulberry extract, peony extract, touki extract, oleander extract, horse chestnut bark extract, chamomile extract and the like, and further linoleic acid, linolenic acid, lactic acid, tranexamic acid and the like are also preferable.

Examples of suitable skin roughening preventives and moisturizers are polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol and sorbitol, saccharides such as trehalose and maltose,
Sodium hyaluronate, sodium chondroitin sulfate, biopolymers such as chitin and chitosan, sodium pyrrolidonecarboxylate, amino acids such as hydroxyproline, sodium lactate, urea, sphingolipids, ceramides, cholesterol and its fatty acid ester and polyoxyethylene addition Derivatives such as the thing are mentioned. Hydrocarbon oils such as squalane and squalene, glycerides such as kukui nut oil, borage oil, and rosehip oil can also be preferably used.

Suitable antiaging agents include the above-mentioned antioxidants, moisturizers, blood circulation promoters, and skin roughness inhibitors. Further, α-hydroxy acid, vitamin A and its derivative, vitamin A alcohol and its derivative can be preferably used.

Suitable hair growth accelerators include botanical extracts such as capsicum tincture, quince extract, pearl extract, and gerbil extract, sterols and sterol glycosides, fatty acids such as linoleic acid, linolenic acid, and pentadecanoic acid. And derivatives thereof such as glyceride, hormones such as ethinyl estradiol, and minoxidil.

Suitable hormonal agents include corticosterone, andosterone, hydrocortisone, steroid hormones such as β-estrandiol, prostaglandins and the like.

Suitable vitamins include vitamin A
Group, vitamin B group, vitamin C group, vitamin E group, and vitamin K group can be used alone or in combination, and lipophilic and hydrophilic derivatives thereof are also suitable.

Further, coenzymes such as ubiquinones, carnitine, ferulic acid, γ-oryzanol, α-lipoic acid,
Vitamin agents such as orotic acid can also be preferably used.

Suitable dyes include legal dyes (tar dyes), flavonoids, carotenoids, quinones,
One kind or two kinds or more arbitrarily selected from natural pigments having a skeleton such as porphyrin, diketone, bioflavonoid, flavin, and betacyanidine can be preferably used.

Suitable proteins include amino acids, hydrolyzed elastin, water-soluble elastin,
Hydrolyzed collagen, wheat peptides, soybean peptides, cationized peptides, modified proteins such as acyl peptides, casein, glutathione and the like can be mentioned.

The liposome of the present invention can be used as a cosmetic or an external preparation for the skin by itself or by mixing it with an existing preparation. When mixed with an existing formulation, they may be mixed at the final stage of the formulation, or may be mixed in the middle of the formulation, for example, when the aqueous phase is added. As the mixing conditions, the conditions for producing ordinary cosmetics and external preparations for skin can be applied as they are.

The liposome encapsulating the medicinal component according to the present invention keeps the liposome stable even when mixed with existing preparations, and does not impair the stability of the medicinal component.

The cosmetics and external preparations for skin to which the present invention can be applied are not particularly limited as long as they are generally acceptable cosmetics and external preparations for skin. Specific examples thereof include emulsions, lotions, creams and sunscreens. Basic cosmetics, facial cleansers, body soaps and other cleaning products, shampoos, hair rinses, hair conditioners, hair restorers, hair styling products, hair tonics, permanent wave agents, hair color cosmetics such as hair bleaches, liquid foundations, Examples include makeup cosmetics such as lipsticks and external skin preparations such as ointments.

[0039]

The present invention will be specifically described below with reference to examples, but the technical scope of the present invention is not limited thereto.

As the phospholipid, hydrogenated soybean lecithin (Recinol S10: Nikko Chemicals) was used. The phospholipid composition was analyzed by thin-phase chromatography / fluorescence detection method to determine phosphatidylcholine 31.8% by weight, phosphatidylethanolamine 31.2% by weight,
The content was 7.8% by weight of phosphatidic acid and 15.1% by weight of phosphatidylinositol. <Preparation of liposomes according to the present invention>: Examples 1-10

(1) Method for preparing liposomes encapsulating hydrophilic medicinal components Hydrogenated soybean lecithin and carbon dioxide were put together with ethanol in a stainless steel autoclave equipped with a metering pump and a stirrer for supplying an aqueous phase. I prepared it. After charging, the inside of the autoclave was stirred at 40 ° C. and 200 Kg / cm ² , and hydrogenated soybean lecithin was dissolved in a supercritical carbon dioxide gas together with a solvent as needed. After uniform dissolution,
While continuing stirring, green tea catechins, L-ascorbic acid, L-ascorbyl magnesium phosphate, L-ascorbic acid glucoside shown in Table 1 as water-soluble active ingredients,
The aqueous phase containing dipotassium glycyrrhizinate and glutathione was continuously injected into the autoclave by a metering pump. After injecting a predetermined amount, the system was depressurized and carbon dioxide gas was discharged to obtain a liposome containing a water-soluble drug component.

(2) Method for preparing liposome encapsulating lipophilic medicinal ingredient Hydrogenated soybean lecithin and carbon dioxide, and vitamin A alcohol, β-carotene, natural vitamin E and ceramide shown in Table 1 as lipophilic medicinal ingredients III, cholesterol, squalene, rosehip oil, stearyl glycyrrhetinate, and hinokitiol were charged together with ethanol into a stainless steel autoclave equipped with a metering pump and a stirring device for supplying an aqueous phase. After the charging, the inside of the autoclave was stirred at 60 ° C. and 200 kg / cm ² to dissolve the hydrogenated soybean lecithin and the lipophilic medicinal component in supercritical carbon dioxide. After uniform dissolution, the aqueous phase was continuously injected into the autoclave by a metering pump under the same conditions while continuing stirring. After injecting a predetermined amount, the pressure in the system was reduced and carbon dioxide gas was discharged to obtain a liposome containing a water-soluble drug component.

(3) Method for preparing liposome containing hydrophilic medicinal ingredient and lipophilic medicinal ingredient, method for preparing liposome encapsulating hydrophilic medicinal ingredient,
And a method for preparing a liposome encapsulating a lipophilic medicinal component are used together to prepare a liposome encapsulating a hydrophilic medicinal component and a lipophilic medicinal component. (Comparative example)

<Preparation of Liposomes Using High-Pressure Homogenizer>: Comparative Examples 1 to 10 Hydrogenated soybean lecithin and lipophilic medicinal ingredients and / or hydrophilic medicinal ingredients and water were previously mixed with a homomixer at 80 ° C., The mixture was stirred at 8000 rpm for 30 minutes to obtain a uniform dispersion liquid. Furthermore, this liquid
The treatment was repeated 5 times with a high-pressure homogenizer under the pressure of 500 Kg / cm ² to obtain a liposome containing a hydrophilic or lipophilic medicinal component. In addition,
When treated with a high-pressure homogenizer, the temperature of the treatment liquid was about 80 ° C.

(Evaluation of stability of medicinal component and liposome)
Regarding the stability of the medicinal components, the respective components were quantified by high performance liquid chromatography, and the stability was evaluated from the residual ratio with respect to the initial addition amount. The stability of the liposome was measured by measuring the particle size distribution with a particle size distribution measuring device (Coulter Counter N4MD: Coulter, Inc.) and evaluating the stability from the increase in particle size. Example 1 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
% By weight, 0.2% by weight of Vitamin A alcohol as lipophilic medicinal ingredient, and 0.1% of stearyl glycyrrhetinate.
Liposomes were prepared by the method of the present invention using 01% by weight and water as the balance. Table 1 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0046]

[Table 1] Example 2 Cerebroside 3.0% by weight, β-as lipophilic medicinal ingredient
Carotene 0.15% by weight, and hinokitiol 0.05
Liposomes were prepared by the method of the present invention using wt% and water as the balance. Table 2 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0047]

[Table 2] Example 3 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
% By weight, natural vitamin E as lipophilic medicinal ingredient 0.2
Liposomes were prepared by the method of the present invention using 1% by weight, 0.01% by weight of ceramide III, and water as the balance. Table 3 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0048]

[Table 3] Example 4 A liposome was prepared by the method of the present invention using 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of squalene as a lipophilic drug, and water as the balance. Table 4 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0049]

[Table 4] Example 5 Hydrogenated soybean lecithin 3.0% by weight, cerebroside 3.
Liposomes were prepared by the method of the present invention using 0% by weight, 7.0% by weight of ethanol, 0.01% by weight of cholesterol, 0.2% by weight of rosehip oil as a lipophilic drug component, and water as the balance. 1 at 0 ° C and 50 ° C
Table 5 shows the quantitative values of the medicinal components after months and the measured values of the average particle size of liposomes.

[0050]

[Table 5] Example 6 A liposome was prepared by the method of the present invention using 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of green tea catechin as a hydrophilic medicinal component, and water as the balance. Table 6 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0051]

[Table 6] Example 7 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared by the method of the present invention, using wt%, 0.2 wt% L-ascorbic acid as the hydrophilic drug component, and water as the balance. Table 7 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0052]

[Table 7] Example 8 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of magnesium L-ascorbyl phosphate as a hydrophilic drug component, and 0.1% by weight of dipotassium glycyrrhizinate, Liposomes were prepared by the method of the present invention using water as the balance. Table 8 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0053]

[Table 8] Example 9 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared according to the method of the present invention by using, by weight, L-ascorbic acid glucoside (0.1% by weight) as a hydrophilic active ingredient, dipotassium glycyrrhizinate (0.1% by weight) and water as the balance. 1 at 0 ° C and 50 ° C
Table 9 shows the quantitative values of the medicinal components after months and the measured values of the average particle size of liposomes.

[0054]

[Table 9] Example 10 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared by the method of the present invention, using wt%, glutathione 0.2 wt% as a hydrophilic drug component, urea 0.1 wt% and water as the balance. Table 10 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0055]

[Table 10] The liposomes of Examples 1 to 10 had extremely little decomposition or damage of the medicinal component contained therein during preparation, and were stable over time. Furthermore, the average change in the average particle size of the liposomes was small, and no aggregation, separation, or precipitation was observed, and the liposomes were extremely stable. Comparative Example 1 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
% By weight, 0.2% by weight of Vitamin A alcohol as lipophilic medicinal ingredient, and 0.1% of stearyl glycyrrhetinate.
A liposome was prepared by the method of Comparative Example using 01% by weight and water as the balance. Table 11 shows the quantitative values of the medicinal components after 1 month at 0 ° C and 50 ° C, and the measured values of the average particle size of liposomes.

[0056]

[Table 11] Comparative Example 2 Cerebroside 3.0% by weight, β-as lipophilic medicinal ingredient
Carotene 0.15% by weight, and hinokitiol 0.05
Liposomes were prepared by the method of Comparative Example using water as a weight percentage and the balance as water. Table 12 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0057]

[Table 12] Comparative Example 3 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
% By weight, natural vitamin E as lipophilic medicinal ingredient 0.2
Liposomes were prepared by the method of the comparative example using 1% by weight, 0.01% by weight of ceramide III, and water as the balance. Table 13 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C., and the measured values of the average particle size of liposomes.

[0058]

[Table 13] Comparative Example 4 A liposome was prepared by the method of Comparative Example using 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of squalene as a lipophilic drug component, and water as the balance. Table 14 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0059]

[Table 14] Comparative Example 5 Hydrogenated soybean lecithin 3.0% by weight, cerebroside 3.
Liposomes were prepared by the method of Comparative Example using 0% by weight, 7.0% by weight of ethanol, 0.01% by weight of cholesterol, 0.2% by weight of rosehip oil as a lipophilic drug component, and water as the balance. 1 at 0 ° C and 50 ° C
Table 15 shows the quantitative values of the medicinal components and the measured values of the average particle size of liposomes after months.

[0060]

[Table 15] Comparative Example 6 A liposome was prepared by the method of Comparative Example using 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of green tea catechin as a hydrophilic medicinal component, and water as the balance. Table 16 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C., and the measured values of the average particle size of liposomes.

[0061]

[Table 16] Comparative Example 7 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared by the method of Comparative Example, using wt%, 0.2 wt% of L-ascorbic acid as the hydrophilic drug component, and water as the balance. Table 17 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0062]

[Table 17] Comparative Example 8 3.0% by weight of hydrogenated soybean lecithin, 0.01% by weight of cholesterol, 0.2% by weight of magnesium L-ascorbate phosphate as a hydrophilic drug component, and 0.1% by weight of dipotassium glycyrrhizinate, Liposomes were prepared by the method of Comparative Example using water as the balance. Table 18 shows the quantitative values of the medicinal components after 1 month at 0 ° C and 50 ° C, and the measured values of the average particle size of liposomes.

[0063]

[Table 18] Comparative Example 9 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared by the method of Comparative Example, using wt%, L-ascorbic acid glucoside 0.1 wt% as a hydrophilic drug component, dipotassium glycyrrhizinate 0.1 wt%, and water as the balance. 1 at 0 ° C and 50 ° C
Table 19 shows the quantitative values of the medicinal components and the measured values of the average particle size of liposomes after months.

[0064]

[Table 19] Comparative Example 10 Hydrogenated soybean lecithin 6.0% by weight, ethanol 7.0
Liposomes were prepared by the method of Comparative Example, using wt%, glutathione 0.2 wt% as a hydrophilic drug component, urea 0.1 wt% and water as the balance. Table 20 shows the quantitative values of the medicinal components after 1 month at 0 ° C. and 50 ° C. and the measured values of the average particle size of liposomes.

[0065]

[Table 20] In the liposomes of Comparative Examples 1 to 10, the medicinal component contained therein was decomposed or damaged by the mechanical force at the time of preparation or the heat generated, and the residual rate was decreased immediately after the preparation, and it was unstable over time. It was Furthermore, changes in the average particle size of liposomes with time were extremely large, and in addition, precipitation of components and destruction of the system were confirmed. In particular, when L-ascorbic acid, magnesium L-ascorbyl phosphate, and L-ascorbic acid glucoside were included as encapsulating components, these liposomes were extremely unstable.

Further, specific formulations of cosmetics and external preparations for skin using the liposome of the present invention will be shown. Example 11: Emollient cream (formulation) Oil phase wt% Polyoxyethylene monostearate 40 2.0 Self-emulsifying glyceryl monostearate 5.0 Stearic acid 2.0 Cetanol 2.0 Squalane 12.0 Macadamia nut oil 4. 0 Methylpolysiloxane 0.2 Preservative Amount Aqueous phase 1,3-Butanediol 7.0 Purified water Residual liposome Liposome of Example 1 50.0 (Preparation method)

Both the oil phase and the water phase are dissolved by heating at 80 ° C., and the water phase is gradually added to the oil phase while stirring to emulsify. After further stirring, the mixture was cooled, liposomes were added at 40 ° C. or lower, and the mixture was further stirred and uniformly mixed. Example 12: Emulsion (formulation) Oil phase wt% Polyoxyethylene 20 sorbitan monostearate 1.0% Polyoxyethylene 40 sorbitol tetraoleate 0.5 Sorbitan monostearate 1.0 Stearic acid 0.5 Behenyl alcohol 0. 5 Beeswax 0.5 Squalane 10.0 Glyceryl triisooctanoate 10.0 Decaglyceryl dekaoleate 3.0 1,3-Butanediol 7.0 Preservative Amount of water phase Xanthan gum 0.04 Triethanolamine 0.05 Purified water balance Liposomes Liposomes of Example 3 50.0 (Preparation method) Prepared according to the method of Example 11. Example 13: Lotion 1 (formulation) Phase A weight% sodium citrate 0.1 sodium pyrrolidonecarboxylate 1.0 1,3-butanediol 5.0 purified water balance B phase polyoxyethylene 30 polyoxypropylene 6 decyl Tetradecyl ether 0.6 Preservative Appropriate amount Ethanol 10.0 Liposomes Liposomes of Example 6 50.0 (Preparation method) Both phase A and phase B are dissolved by heating at 50 ° C., and phase B is gradually stirred into phase A. And solubilize. The mixture was further stirred and cooled, the liposome was added at 40 ° C. or lower, and the mixture was further stirred and uniformly mixed. Example 14: Lotion 2 (formulation) Phase A weight% sodium citrate 0.1 sodium pyrrolidonecarboxylate 1.0 1,3-butanediol 5.0 purified water balance B phase polyoxyethylene 30 polyoxypropylene 6 decyl Tetradecyl ether 0.6 Preservative Appropriate amount Ethanol 10.0 Liposomes Liposomes of Example 8 50.0 (Preparation method) Prepared according to the method of Example 13. (Stability evaluation)

Regarding the cosmetic formulations of Examples 11 to 14,
It was left for 6 months in a constant temperature bath at 50 ° C. and evaluated by visually observing its appearance.

As a result, all of these cosmetic formulations were extremely stable without causing aggregation, separation or precipitation.

[0070]

INDUSTRIAL APPLICABILITY As described in detail above, according to the present invention, it is possible to produce a liposome aqueous solution containing a hydrophilic drug component and a lipophilic drug component in a stable and high concentration without impairing the quality thereof. Also provided are skin cosmetics, skin external preparations, and hair cosmetics containing these liposomes.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 45/00 A61K 45/00 47/24 47/24 47/26 47/26 A61P 17/00 101 A61P 17 / 00 101 (72) Inventor Masahiko Abe 58-71 Odonoi, Noda City, Chiba Prefecture (72) Inventor Katsuhito Otake Ibaraki Matter 1-1 Tsukuba City East (72) Inventor Satoru Hashimoto 3-chome Hasune, Itabashi-ku, Tokyo 24th No. 3 F-term in Japan Surfactant Co., Ltd. (reference) 4C076 AA19 BB31 CC18 DD15 DD37 DD45 DD63 DD67 FF63 4C083 AA121 AC021 AC071 AC101 AC121 AC241 AC301 AC401 AC441 AC851 AD151 AD201 AD351 AD571 CC04 CC05 DD45 4C084 AA17 MA10 MA63 NA03 NA03 ZA89 4C086 AA01 BA03 MA24 NA03 ZA89

Claims (10)

[Claims] 1. A method for producing a liposome, which comprises using phospholipid and / or glycolipid as a membrane lipid and using carbon dioxide gas in a critical or subcritical state, and the liposome. 2. The method for producing a liposome according to claim 1, wherein the membrane lipid is dissolved or mixed in advance in a supercritical or subcritical carbon dioxide gas, and the liposome. 3. A carbon dioxide gas in a critical or subcritical state, 1
One or two or more solubilizing agents are added, and the method for producing the liposome according to claim 1 or 2, and the liposome. 4. The method for producing a liposome according to any one of claims 1 to 3, wherein one or more of the hydrophilic drug active ingredient and / or the lipophilic drug active ingredient is included, and the liposome. 5. The liposome according to claim 4, wherein an aqueous solution in which a hydrophilic drug component is dissolved or mixed is added to carbon dioxide gas in a critical or subcritical state in which membrane lipid is dissolved or mixed. Preparation method and the liposome. 6. The method for preparing liposomes according to claim 4, wherein the lipophilic medicinal component is dissolved or mixed in carbon dioxide in a critical or subcritical state in which membrane lipid is dissolved or mixed. The liposome. 7. A method for preparing liposomes, characterized in that the solubilizing agent according to claim 2 is one or more of lower alcohols, glycols, glycol ethers, glycol esters and alkyl carbonates, and Liposomes. 8. The hydrophilic drug component and / or the lipophilic drug component according to claim 4, wherein the hydrophilic drug component and / or the lipophilic drug component is an antioxidant, an antibacterial agent, an anti-inflammatory agent, a blood circulation promoter, a whitening agent, a skin roughening preventive agent, and aging. Inhibitor,
One or two selected from hair growth promoter, moisturizer, hormone, vitamins, pigments and proteins
A liposome characterized in that it is more than one species. 9. The medicinal ingredient according to claims 4 to 6 and 8,
Ascorbic acid, and any of the ascorbic acid derivatives
A liposome, which is one kind or two or more kinds. 10. A cosmetic or external preparation for skin, which comprises the liposome according to any one of claims 1 to 9.