WO2001013888A1

WO2001013888A1 - Liposome preparations for external use

Info

Publication number: WO2001013888A1
Application number: PCT/JP1999/004563
Authority: WO
Inventors: Kohsaku Kawakami; Yoshitaka Nishihara; Koichiro Hirano
Original assignee: Shionogi & Co., Ltd.
Priority date: 1998-08-20
Filing date: 1999-08-24
Publication date: 2001-03-01
Also published as: JP2000063265A

Abstract

Preparations for external use for protecting or treating the skin characterized by containing liposomes having a fat-soluble drug enclosed therein, a water-soluble humidifying component and a polymer compound located outside the liposomes. These preparations attain a high ratio of holding the fat-soluble drug in the liposomes and an excellent humidifying effect.

Description

Specification

Liposome external preparation Technical field

The present invention relates to an external preparation containing ribosome (hereinafter also referred to as a ribosome external preparation). The external preparation is useful, for example, as a skin protective agent / treatment agent. Background art

Since ribosomes can incorporate drugs into their internal aqueous phase and lipid membrane, they are useful as drug carriers for any hydrophilic, hydrophobic, or amphiphilic drug. In recent years, attempts have been made to use liposomes as a base for external preparations, because liposomes generally have very low skin permeability, and drugs retained in ribosomes can be used on the skin. This is because they are excellent in terms of retention in the case. There is also a reason that a drug absorption promoting effect can be expected depending on the composition of the lipid membrane. In any case, it is considered that increasing the retention rate of the drug in the liposome results in an external preparation with improved retention or absorption of the drug on the skin. As a means for improving the retention rate of a drug to ribosomes by using a polymer compound, for example, Japanese Patent Application Laid-Open No. 4-126545 describes a method of adding an amphipathic polymer compound. The purpose of this study is to improve the liposome membrane by solubilizing the polymer compound into the liposome lipid bilayer.

In addition, the abstracts of the Chemical Society of Japan Spring Meeting (March 1996, Lecture No. 2C540) show that the release of a marker contained in ribosomes is based on methylcellulose as a polymer compound. It has been reported that it is suppressed by being present outside the liposome. However, this marker is a water-soluble substance, lucine, and its target is not a fat-soluble substance.

JP-A 64-3114 discloses a liposome containing a polyhydric alcohol and / or a saccharide. Aqueous dispersions are described. In this technology, the stability of the ribosome is measured by adding a polyhydric alcohol and Z or a saccharide, but no improvement in the liposomal retention of the encapsulated drug has been studied. In addition, since the temporal change in the particle size of ribosomes was examined, it is presumed that the aqueous dispersion was supposed to be exclusively used as an injection solution, and a skin protective agent and treatment There is no description or suggestion about the use of the agent as an external preparation or the pharmaceutical effect at that time, for example, improvement of moisture retention.

Although liposomal preparations using polymer compounds have been studied in this way, studies to increase the retention of fat-soluble drugs in liposomes as external preparations to improve the retention on the skin have been made. It has not been done, and there is no example of successful commercialization. In addition, as a skin protective agent / therapeutic agent, a substance having a high moisturizing property is generally preferred, but there is no report specifically examining the improvement of the moisturizing property by ribosome formation. In other words, there has been a demand for the development of external preparations that make the most of the properties of ribosomes. Disclosure of the invention

In view of the above problems, the present inventors have conducted intensive studies.As a result, if a polymer compound is already present outside a liposome holding a fat-soluble drug, an external preparation having an increased drug retention rate in the liposome can be obtained. (Japanese Patent Application No. 9-1126692), but this time, if water-soluble moisturizing components are retained in ribosomes, the moisturizing properties when used on skin etc. will be improved. The present invention shown below has been completed.

(1) An external preparation comprising a liposome containing a fat-soluble drug, a water-soluble moisturizing component, and a polymer compound existing outside the ribosome.

(2) The external preparation according to the above (1), wherein the water-soluble moisturizing component is present inside and outside the ribosome.

(3) The external preparation according to the above (1) or (2), which is a skin protective or therapeutic agent. (4) Fat-soluble drugs include vitamins, glycyrrhetinic acids, glycyrrhizic acids, The external preparation according to any one of (1) to (3), which is one or more selected from the group consisting of azulene and steroids.

(5) The high molecular compound is at least one selected from the group consisting of polysaccharides, polyvinyl derivatives, polyacrylic acid derivatives, polyoxyethylene polyoxypropylene glycols, and polyethylene glycols. An external preparation according to any one of the above (1) to (3).

(6) The external preparation according to any one of the above (1) to (3), wherein the water-soluble moisturizing component is a polyol.

(7) The external use according to (6), wherein the polyol is at least one selected from the group consisting of propylene glycol, polyethylene glycol, 1,3-butanediol, glycerin, and ethylene glycol. Agent.

(8) The fat-soluble drugs are vitamins and glycyrrhetinic acids, the polymer compound is uncharged celluloses, and the water-soluble moisturizing component is a polyol.

An external preparation according to any one of (I) to (3).

(9) The fat-soluble drugs are vitamin E and glycyrrhetinic acid, the polymer compound is uncharged cellulose, and the water-soluble moisturizing component is glycerin, propylene glycol, and 1,3-butane. The external preparation according to any one of (1) to (3), which is one or more selected from the group consisting of evening diols.

(10) The fat-soluble drugs are vitamin E and glycyrrhetinic acid, the polymer compound is uncharged cellulose, and the water-soluble moisturizing components are glycerin, propylene glycol, and 1,3-butane. The external preparation according to any one of the above (1) to (3), which is at least one member selected from the group consisting of diols, and wherein the liposome membrane component is a phospholipid.

(I I) The external preparation according to any one of (1) to (10) above, wherein the polymer compound is contained in an amount of 0.01 to 10 parts by weight with respect to 1 part by weight of the liposome membrane component.

(1 2) 0.01 to 5 weight of polymer compound per 1 weight part of liposome membrane component The external preparation according to any one of the above (1) to (10), which comprises:

(13) The external preparation according to any of (1) to (10) above, wherein the water-soluble moisturizing component is contained in an amount of 0.1 to 10 parts by weight based on 1 part by weight of the liposome membrane component. .

(14) The external preparation according to any of (1) to (10), wherein the water-soluble moisturizing component is contained in an amount of 0.5 to 5 parts by weight based on 1 part by weight of the ribosome membrane component.

(15) Any one of the above (1) to (10), which contains 0.01 to 5 parts by weight of a polymer compound and 0.5 to 5 parts by weight of a water-soluble moisturizing component with respect to 1 part by weight of a ribosome membrane component. An external preparation according to any of the above items.

(16) 1 part by weight of the external preparation, 0.001 to 0.05 parts by weight of the fat-soluble drug, 0.01 to 0.9 parts by weight of the water-soluble moisturizing component, and 0.005 to 0.9 parts by weight of the liposome membrane component 0.

The external preparation according to any one of the above (1) to (10), comprising 5 parts by weight and 0.001 to 0.9 parts by weight of the polymer compound.

(17) A group consisting of vitamin E and glycyrrhetinic acid in a total amount of 0.0005 to 0.01 part by weight, glycerin, propylene glycol, and 1,3-butanediol with respect to 1 part by weight of the external preparation (5) containing at least one selected from the group consisting of 0.05 to 0.5 parts by weight, phospholipids at 0.01 to 0.1 parts by weight, and uncharged celluloses at 0.05 to 0.5 parts by weight. The external preparation according to any one of ~ (10).

(18) The external preparation according to any one of the above (1) to (17), wherein the retention rate of the fat-soluble drug in liposomes is increased and the moisture retention property is excellent.

(19) The method according to any of (1) to (18) above, wherein the ribosome containing the fat-soluble drug, the water-soluble moisturizing component, and the polymer compound are mixed in the presence of water, and then, if necessary, the pressure is reduced. The method for producing an external preparation according to any one of the above.

(20) A mixture of a liposome containing a fat-soluble drug and an aqueous medium containing a water-soluble moisturizing component, and an aqueous medium containing a polymer compound are mixed, and if necessary, the pressure is reduced. The method according to (19).

(21) The above (1) obtained by the method described in the above (19) or (20). An external preparation according to any one of (1) to (18).

(22) A method for improving the moisturizing effect of an external preparation, which comprises retaining the water-soluble moisturizing ingredient in a liposome in an external preparation containing a water-soluble moisturizing ingredient.

(23) The method according to (22), wherein the water-soluble moisturizing component is contained in an amount of 0.1 to 10 parts by weight based on 1 part by weight of the ribosome membrane component.

(24) An external preparation having an improved moisturizing property, characterized in that a water-soluble moisturizing component is held by ribosomes.

(25) The external preparation according to the above (24), which is a skin protective or therapeutic agent.

(26) The external preparation according to the above (24) or (25), wherein the water-soluble moisturizing component is a polyol.

(27) The method according to (26), wherein the polyol is at least one selected from the group consisting of propylene glycol, polyethylene glycol, 1,3-butanediol, glycerin, and ethylene glycol. External preparation.

(28) The external preparation according to the above (27), wherein the polyol is glycerin.

(29) The external preparation according to any of (24) to (28), wherein the water-soluble moisturizing component is contained in an amount of 0.1 to 10 parts by weight with respect to 1 part by weight of the ribosome membrane component. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of fat-soluble drugs that can be retained by the ribosome contained in this external preparation include fat-soluble vitamins (A, D, E, K), glycyrrhetinic acids (eg, glycyrrhetic acid or its salts (Κ salt, ammonium salt) )), Glycyrrhizic acids (eg, glycyrrhizic acid or its salts (eg, salt, ammonium salt, etc.)), azulenes (eg, guaiazulene, etc.), steroids (eg, betamethasone, dexamethasone, alclomethasone, prechloride) Etc.), but preferably vitamin A (eg, vitamin A palmitate, vitamin A acetate, etc.), vitamin E (eg, vitamin E acetate, vitamin E succinate, etc.) or glycyrrhetin Is an acid. These can be used alone or in combination.

Pharmaceuticals are exemplified by drugs expected to have anti-inflammatory action, antioxidant action, and the like. The drug content is not particularly limited, but is usually about 0.0001 to 0.05 parts by weight, preferably about 0.0005 to 0.01 parts by weight, per 1 part by weight of the external preparation.

Examples of the water-soluble moisturizing component contained in this external preparation include polyols.For example, propylene glycol, polyethylene glycol, 1,3-butanediol, glycerin, ethylene glycol, etc. may be used alone or in combination. However, glycerin, propylene glycol, or 1,3-butanediol is preferable, and glycerin is particularly preferable. The content of the water-soluble moisturizing component is not particularly limited, but is usually about 0.1 to 10 parts by weight, preferably about 0.5 to 5 parts by weight, per 1 part by weight of the liposome membrane component. The amount is about 0.01 to 0.9 part by weight, preferably about 0.05 to 0.5 part by weight, based on 1 part by weight of the external preparation. The water-soluble moisturizing component is present both inside and outside the liposome, and usually several to about 20% by weight is present inside the liposome. From the viewpoint of the moisturizing effect and its persistence, it is considered preferable that about 10% by weight or more of the water-soluble moisturizing component is present in the ribosome. The type of ribosome contained in this topical formulation is not particularly limited, and may be any type such as multilamellar vesicles (MLV) and single lamellar vesicles (SUV, LUV). Any known method such as freeze-drying, spray-drying, reverse-phase evaporation, surfactant removal, and ethanol injection may be used. Further, the particle size of the obtained ribosome may be adjusted using an extruder, a high-pressure emulsifier, ultrasonic waves, or the like. As the liposome membrane component, various known phospholipids can be used.For example, egg yolk, soybean or other naturally occurring phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, Ceramide, sphingomyelin, hydrogenated products of these, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, and dicetylphos, a charged lipid obtained by synthesis Examples include phytate, dihexadecyl phosphate, dioctadecyl dimethyl ammonium salt, stearylamine and the like, and these can be used alone or as a mixture. The content of the liposome membrane component is usually about 0.05 to 0.5 parts by weight, preferably about 0.01 to 0.1 parts by weight, per part by weight of the external preparation. is there.

In addition, steroid compounds such as cholesterol may be added to the ribosome membrane component, for example, as a membrane stabilizer, and any stabilizer (preservative, antioxidant, chelating agent, etc.) may be contained in the preparation. Etc.) can be added.

In the present external preparation, the retention of the fat-soluble drug in the ribosome can be increased by the presence of the polymer compound outside the liposome. That is, a direct interaction between the polymer compound and the liposome membrane as in the conventional ribosome preparation in which the polymer compound is solubilized in the ribosome membrane is not particularly required. However, as long as the drug retention rate on the liposome is not significantly adversely affected, a polymer compound of the same or different type as the polymer compound existing outside or inside the ribosome may be accidentally or differently from the present invention. It may exist for the purpose.

The high molecular compound which can be added to the external preparation generally means a compound having a molecular weight of several thousands or more, for example, cellulose as a polysaccharide, preferably methylcellulose, carboxymethylcellulose, or hydroxy. Uncharged celluloses such as methylcellulose, hydroxycetyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starches, dextran, pullulan, alginic acids, chondroitin sulfates, hyaluronic acids, etc .; Polyvinyl acetate acetylethyl acetate, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, etc .; polyacrylic acid derivatives as polyacrylates, carboxyvinyl polymers, water-soluble Metaak Latex copolymers (eg, Eudragit LD, Rohm Pharma Co., Ltd.), etc. Polyoxyethylenepolyoxypropylene glycol (eg, pull mouth nick L-61, L-64, Asahi Denka Kogyo, etc.), polyethylene glycol Etc., but are preferably non-charged cell ports. Species. These can be used alone or in combination. The content of the high molecular compound is generally about 0.01 to 10 parts by weight, preferably about 0.01 to 5 parts by weight, per 1 part by weight of ribosome. The amount is usually about 0.01 to 0.9 part by weight, preferably about 0.05 to 0.5 part by weight, per part by weight of the external preparation.

The method for producing the external preparation is not particularly limited, but it can be usually produced by mixing a liposome containing a fat-soluble drug, a water-soluble moisturizing component, and a polymer compound in the presence of water, and then reducing the pressure if desired. . Preferably, the external preparation is prepared by mixing a mixture of a liposome containing a fat-soluble drug and an aqueous medium containing a water-soluble humectant with an aqueous medium containing a polymer compound, and then reducing the pressure if necessary. It can be manufactured by Preferably, it can be produced by the following method.

(1) A predetermined amount of all fat-soluble components (lipid-soluble drugs, phospholipids and other additives, if necessary) is dissolved in an organic solvent (eg, porcine form, t-butanol, etc.), and then rotary evaporated. In the evening, the solvent is distilled off using a spray dryer or freeze dryer to prepare a lipid powder or lipid thin film containing a fat-soluble component.

(2) The lipid powder or lipid thin film of (1) above is added to an aqueous medium in which a water-soluble moisturizing component is dissolved (eg, phosphate buffer: preferable pH is about 4 to 7), and the phospholipid is added. The liposomal dispersion is obtained by high-speed stirring at a temperature not lower than the phase transition temperature (eg, preferably about 60 ° C in the case of hydrogenated phosphatidylcholine of natural origin). The content of the phospholipid in the total amount of the dispersion is preferably about 0.1 to 30% by weight, more preferably about 1 to 15% by weight.

(3) Prepare an aqueous medium containing a polymer compound (eg, phosphate buffer: preferable pH is about 4 to 7). The content of the polymer compound is preferably about 0.1 to 30% by weight, more preferably about 0.5 to 10% by weight, based on the whole preparation.

(4) The external preparation can be obtained by mixing the above liquids (2) and (3) at an arbitrary ratio (for example, 1: 1), and further mixing under reduced pressure (preferably, less than or equal to lOKPa). . The mixing time varies depending on the amount of the mixture, etc., and cannot be specified unconditionally. To tens of hours, for example, about 5 to 30 minutes. The same applies to the decompression time, but is usually about several minutes to several tens of hours, for example, about 5 to 30 minutes.

The present invention further provides a method for improving a moisturizing effect, wherein a water-soluble moisturizing component is retained in liposomes in an external preparation containing a water-soluble moisturizing component, and that the liposome retains the water-soluble moisturizing component. The present invention also provides an external preparation having an improved moisturizing property. Here, “retaining” means a state in which the water-soluble moisturizing component is encapsulated in ribosomes or adsorbed outside the liposome membrane. That is, in the external preparation, the water-soluble moisturizing component can be present both inside and outside the liposome. However, from the viewpoint of the expression of the moisturizing effect and its persistence, etc., It may be preferred that about 10% or more by weight be present in the ribosome. The kind and content of the water-soluble moisturizing ingredient ゃ liposomal in the method and the external preparation are as described above. In the external preparation, the fat-soluble drug and the high molecular compound need not necessarily be contained. The external preparation can be produced by a method according to the above. Reference Examples, Examples, Test Examples and the like are given below, but these do not limit the present invention in any way. The definitions of the abbreviations are as follows.

VA: vitamin A palmitate, VE: vitamin E acetate, HSL: hydrogenated soybean phospholipid, EL: egg yolk phospholipid, Choi: cholesterol, GT: glycyrrhetinic acid, AZ: guaiazulene, AEA: poly Vinyl acetal acetylaminoacetate, PLU: Pull mouth nick L-64, PEG: Polyethylene glycol 600, HPC: Hydroxypropyl cellulose, HE C: Hydroxypropyl cellulose, MC: Methyl cellulose, PVP: polyvinylpyrrolidone K90, Alg: sodium alginate, BHT: dibutylhydroxytoluene, EDTA-2Na: ethylenediamine tetraacetate 2 sodium, M-paraben: methylparaben, G1y: Glycerin Examples 1 to 5 and Reference Examples 1 to 2

After preparing the external preparation of the composition shown in Table 1 below and the liposomal external preparation to which no polymer compound was added as a control by the following methods, the lipid-soluble drug from the ribosome was prepared for each external preparation. Was measured. VA, VE and GT were used as fat-soluble drugs.

(Preparation method of ribosome external preparation)

(1) After dissolving a predetermined amount of all fat-soluble components (lipid-soluble drug, phospholipid and other additives as required) in chloroform, the solvent is distilled off using a rotary evaporator to make the fat-soluble components uniform. Obtain a mixed thin film.

(2) The above thin film is added to an aqueous medium containing a water-soluble moisturizing component (phosphate buffer or distilled water for injection, about 50 ml, pH 7), and the phospholipid is rapidly stirred at 60 ° C ( (10000 rpm, 10 minutes) to obtain a ribosome dispersion.

(3) Dissolve the polymer compound in the same aqueous medium as in (2) above (about 50 ml). (4) The external preparation is obtained by mixing the above liquids (2) and (3) and slowly stirring for 30 minutes under reduced pressure (5 Kpa) (Example).

Further, by adding an aqueous medium to the solution of (2) and then performing a mixing treatment in the same manner as in (4), a liposome external preparation to which no polymer compound is added can be obtained (Reference Example). (Measurement method of drug release rate from ribosome)

(1) Sample about 100 mg of each ribosome external preparation obtained by the above method, and dissolve in 10 ml with isopropanol. If the sample contains high molecules, perform pretreatment with a syringe filter, and then quantify the concentration of each drug by HPLC (drug concentration of the entire formulation).

(2) Prepare an appropriate amount (3-5 g) of the ribosome external preparation and perform ultracentrifugation (100,000 GX for 1 hr, 25 V) (all liposomes are precipitated by this treatment). Sample the entire non-precipitated part, weigh it, and dissolve in isopropanol to make 10 ml. If the sample contains high polymers, pre-treat with a syringe filter After that, each drug concentration is quantified by HPLC (drug concentration in non-precipitated part). (3) From the above weight and concentration values, calculate the ratio of the amount of drug contained in the non-precipitated part, that is, the amount of drug not retained in the liposome, to the total drug amount, and determine the release rate. Table 1 shows the results.

table 1

(Note) Type of dispersion medium

Reference Example 1 and Examples 1-2: distilled water for injection

Reference Example 2 and Examples 3 to 5: 10 mM phosphate buffer The above results show that the external preparation containing a polymer compound had a higher drug release rate from liposomes than the external preparation of Reference Example. Indicates low. From this, it can be seen that the addition rate of the high-molecular-weight compound of this external preparation increased the retention rate of the drug in the liposome. Test Example 1 (Comparison of properties between liposomal and non-liposomal preparations)

The characteristics of this external preparation and a non-liposomal preparation (mixed preparation and control preparation without phospholipids) prepared by simply mixing each component were compared. Table 2 shows the composition of each formulation, and Table 3 shows the test results. The test method is as follows.

(1) Inner aqueous phase volume

It can be proved by evaluating the volume of the internal aqueous phase to evaluate whether the prototype formulation is liposomal (K. Kawakami et al., Anal Biochem. Vol. 209, No.l , 139-142, 1999). The internal aqueous phase volume was determined from the amount of fluorescent dye incorporated. That is, a ribosome dispersion was prepared using a buffer in which CF was dissolved according to a conventional method. This was diluted 80-fold with a buffer solution containing no CF, the liposome was removed with a syringe filter, and the fluorescence intensity of the external aqueous phase was measured (Em = 517nDi, Ex = 494nm). At this time, the dilution ratio of the outer aqueous phase was 80 times or more because the inner aqueous phase was not diluted, and the volume of the inner aqueous phase was calculated from the difference in the dilution ratio.

(2) In vitro moisture retention rate and moisture absorption rate

37 Save the ° C 70% RH in humidity with (NaN0 ₃₎ was (added 2Omm0, 23 mm to about 1 ml specimen glass Rasuseru of H) desiccator Ichita analyte in each was determined over time by weight, moisturizing The speed was calculated. The sample was vacuum dried in a silica gel / desiccator, stored at 70% RH, weighed over time, and the moisture absorption rate was calculated. The moisture retention rate means the degree of transpiration of water from the preparation.The smaller the value, the higher the moisture retention.On the other hand, the rate of moisture absorption means the degree of moisture absorption from the atmosphere after the preparation is dried. This can be interpreted as high hygroscopicity.

(3) In vivo moisture retention (water absorption and retention)

(A) Long time application test

Hachiro Tagami (Skin, No.27 (6), 1985, Evaluation of the moisturizing properties of Nutrogen Naked Dream) was measured according to the method described in the above.

(1) The test site (three places on the left forearm flexion side of the human) was marked with a 35 mm ø mark (application site), and the center was marked with a magic mark as the measurement site.

(2) The electric conductivity (〃mho) was measured using a SKIC0N-200 (SKIN SURFACE HYDROMETER: IBS) before applying the area marked with the magic mark (measurement site).

(3) Apply 20 mg of the sample to the application site (approximately 20 mg 80 cm ^: apply thinly with a hand wrapped with Saran wrap), and set it to Ohr, and conduct the conductivity 0.5, 1, 2, 4, and 6 hours after application. Was measured with SKIC0N-200. The measurement was carried out on different days and sites.

As an analysis method, the moisturizing effect was compared by the change in conductivity over time or its AUC, and the continuity (water retention capacity) was compared by the MRT of the same change over time. (B) Water load test

After the long-term application test was completed, the water load test was performed by Kumiko Kumasaka (FRAGRANCE

JOURNAL extra edition No.13, 1994, skin moisturizing effect measurement method),

(1) The application site (three places on the flexed side of the left forearm) was wiped with a dry tissue to remove the specimen.

(2) 100〃1 of distilled water was placed on the measurement site, and after 10 seconds, water droplets were completely wiped off with a dry tissue.

(3) Conductivity was measured immediately after wiping (Wmax) and after 30, 60, 90 and 120 seconds. The conductivity at the end of the long-term coating test was W0.

(4) The above-mentioned) to (3) were repeated by changing the test site.

As an analysis method, the water absorption capacity was evaluated by calculating Wmax-W0, and the larger the numerical value, the greater the ability to absorb moisture. Since the water holding ability of the curve exit release moisture matching exponential function of W = Wmax · e- ^{A 1,} human i.e. moisture release constants

(30 seconds to 120 seconds). The smaller the value of the water release constant, the slower the water release speed, that is, the better the water retention ability.

(Table 2) (Unit: mg / g)

(Note) ^ As a certain person, ¾ ^? F ^^^^^ ¾ ^^^ ii] ¾ ¾a¾¾.

(Table 3)

From the above results, it was found that by ribosome formation, an external preparation excellent in physical stability and moisture retention was obtained. Industrial applicability

This external preparation is usually a liquid or semi-solid mouthwash having a viscosity of about 0.0510 Pa · s, and can be used after being applied to the skin. This external preparation is advantageous in terms of sustained drug efficacy because the lipid-soluble drug is efficiently retained in the liposome due to the presence of the polymer compound. Various drug effects are expected by selecting the type of drug, and it can be used, for example, as a skin protective agent, a therapeutic agent, an anti-inflammatory agent, and the like. In addition, since the water-soluble moisturizing component is held in the ribosome, a high moisturizing effect is secured. Compared with a commercially available topical preparation, it showed the same or better effects in terms of retention on the skin and moisturizing properties.

Claims

The scope of the claims

1. An external preparation comprising a liposome containing a fat-soluble drug, a water-soluble moisturizing component, and a polymer compound present outside the liposome.

2. The external preparation according to claim 1, wherein the water-soluble moisturizing component is present inside and outside the liposome.

3. The external preparation according to claim 1 or 2, which is a skin protective agent or a therapeutic agent.

4. The external use according to any one of claims 1 to 3, wherein the fat-soluble drug is at least one selected from the group consisting of vitamins, glycyrrhetinic acids, glycyrrhizic acids, azulene, and steroids. Agent.

5. The high molecular compound is one or more selected from the group consisting of polysaccharides, polyvinyl derivatives, polyacrylic acid derivatives, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol. The external preparation according to any one of 1 to 3.

6. The external preparation according to any one of claims 1 to 3, wherein the water-soluble moisturizing component is a polyol.

7. The external preparation according to claim 6, wherein the polyol is at least one selected from the group consisting of propylene glycol, polyethylene glycol, 1,3-butanediol, glycerin, and ethylene glycol.

8. The fat-soluble drug is a vitamin or glycyrrhetinic acid, the polymer compound is an uncharged cellulose, and the water-soluble moisturizing component is a polyol.

4. The external preparation according to any one of to 3 above.

9. The fat-soluble drugs are vitamin E and glycyrrhetinic acid, the polymer compound is uncharged cellulose, and the water-soluble moisturizing component is glycerin, propylene glycol, and 1,3-butanediol. The external preparation according to any one of claims 1 to 3, which is at least one selected from the group.

10. The fat-soluble drugs are vitamin Es and glycyrrhetinic acid, the polymer compound is uncharged cellulose, and the water-soluble moisturizing component is glycerin, propylene glycol, and 1,3-butanediol. 4. The external preparation according to claim 1, which is at least one selected from the group, and wherein the ribosome membrane component is a phospholipid.

11. The external preparation according to any one of claims 1 to 10, wherein the polymer compound is contained in an amount of 0.01 to 10 parts by weight based on 1 part by weight of the ribosome membrane component.

12. The external preparation according to any one of claims 1 to 10, wherein the polymer compound is contained in an amount of 0.01 to 5 parts by weight based on 1 part by weight of the liposome membrane component.

1 3. The external preparation according to any one of claims 1 to 10, wherein the water-soluble moisturizing component is contained in an amount of 0.1 to 10 parts by weight based on 1 part by weight of the ribosome membrane component.

14. The external preparation according to any one of claims 1 to 10, wherein the water-soluble moisturizing component is contained in an amount of 0.5 to 5 parts by weight based on 1 part by weight of the ribosome membrane component.

1 5. The composition according to any one of claims 1 to 10, wherein the polymer compound is contained in an amount of 0.01 to 5 parts by weight and a water-soluble moisturizing component is contained in an amount of 0.5 to 5 parts by weight based on 1 part by weight of the liposome membrane component. External preparations.

1 6. For the external preparation 1 part by weight, the fat-soluble drug is 0.01-0.15 parts by weight, the water-soluble moisturizing component is 0.01-0.9 parts by weight, and the liposome membrane component is 0.05-0.5. The external preparation according to any one of claims 1 to 1, wherein the external preparation contains 0.01 to 0.9 parts by weight of a polymer compound.

1 7. Total amount of vitamin Es and glycyrrhetinic acid 0.01 to 0.01 parts by weight per 1 part by weight of external preparation selected from the group consisting of glycerin, propylene glycol, and 1,3-butanediol 0.1 to 0.5 parts by weight of at least one of the above, 0.01 to 0.1 parts by weight of a phospholipid, and 0.05 to 0.5 parts by weight of an uncharged cellulose. An external preparation according to any one of the above.

1 8. The retention rate of fat-soluble drugs in ribosomes is increased and moisture retention is excellent. The external preparation according to any one of claims 1 to 17, wherein

19. The liposome containing a fat-soluble drug, a water-soluble moisturizing component, and a polymer compound are mixed in the presence of water, and then, if necessary, the pressure is reduced. 3. The method for producing an external preparation according to item 1.

20. After mixing a mixture of a liposome containing a fat-soluble drug and an aqueous medium containing a water-soluble moisturizing component with an aqueous medium containing a polymer compound, the pressure is reduced as required. Item 19. The manufacturing method according to Item 19.

21. The external preparation according to any one of claims 1 to 18, which is obtained by the method according to claim 19 or 20.

22. A method for improving the moisturizing effect of an external preparation, wherein the external preparation contains a water-soluble moisturizing component, wherein the water-soluble moisturizing component is retained in a liposome.

23. The method according to claim 22, wherein the water-soluble moisturizing component is contained in an amount of 0.1 to 10 parts by weight based on 1 part by weight of the liposome membrane component.

24. An external preparation with improved moisture retention, characterized in that the water-soluble moisture retention component is retained in the liposome.

25. The external preparation according to claim 24, which is an agent for protecting or treating skin.

26. The external preparation according to claim 24 or 25, wherein the water-soluble moisturizing component is a polyol.

27. The external preparation according to claim 26, wherein the polyol is at least one selected from the group consisting of propylene glycol, polyethylene glycol, 1,3-butanediol, glycerin, and ethylene glycol. .

28. The external preparation according to claim 27, wherein the polyol is glycerin.

29. The external preparation according to any one of claims 24 to 28, comprising 0.1 to 10 parts by weight of a water-soluble moisturizing component per 1 part by weight of a liposome membrane component.