JP2006290894A - Liposome and liposome preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liposome whose substrate has high solubility in water and which can easily be prepared and is a temporally stable double membrane endoplasmic reticulum, etc. <P>SOLUTION: This liposome is characterized by comprising (A) one or more multi-chain multi-hydrophilic group type compounds each having two or more hydrophobic groups and two or more hydrophilic groups in the molecule and (B) water. The multi-chain multi-hydrophilic group type compounds include a compound in which n (m≥n) substituents [(n) is an integer of 2 to 20] represented by the general formula (2) [Z is a bond portion originated from the functional group of the hydrocarbon chain; R<SP>1</SP>CO is an acyl group derived from a 2 to 20C fatty acid; R<SP>2</SP>is H, OH, or the like; Y is carboxyl group, sulfonic group, sulfate group, or the like; (j) and (k) are each one of 0, 1, and 2, and are simultaneously not 0] are bound to a hydrocarbon chain having m functional groups. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a liposome that is a bilayer vesicle that can encapsulate various physiologically active substances such as cosmetics and pharmaceuticals and can be used as an external preparation. Alternatively, the present invention relates to a liposome preparation in which various physiologically active substances are encapsulated in the liposome.

  A technology that uses the concept of a drug delivery system to efficiently transport, absorb, or hold a drug to the affected area to increase or sustain the drug effect has been rapidly expanding in recent years and has been put into practical use. Many are also seen. Among drug delivery systems, fields such as sustained-release preparations, transdermal administration methods, targeting agents, and preparations for elderly people are attracting attention. Yes.

  Bases used in this transdermal administration method are polysaccharides, fatty acids (esters), vinyl polymers, peptides / proteins, etc., but are phospholipids and fatty acid glycerides, which are constituents of cell membranes, and main components of the stratum corneum. Liposomes using ceramide and the like are also used.

  However, since these phospholipids, ceramides and the like are hardly soluble in water, and advanced technology is required to form liposomes, many technological developments have been carried out. For example, Patent Document 1 and Patent Document 2 describe that liposomes containing fat-soluble drugs can be obtained using an organic solvent such as chloroform as an external preparation for skin protection or treatment. Many techniques for producing liposomes using various oil and fat derivatives are also known. For example, as in Patent Document 3, a method for producing a stable lamellar structure using a combination of a fatty acid monoglyceride and an alkyl glycerin ether is described. In addition, as described in Patent Document 4, by using a specific synthetic ceramide, an attempt is made to produce a safe and relatively inexpensive aqueous dispersion of lipid globules rather than raw materials derived from natural products such as bovine brain. It has been. Moreover, as a technique using phospholipid, a technique using hydrogenated lecithin as described in Patent Document 5 and Patent Document 6 is known.

However, in spite of these technological developments, it is still not easy to obtain a large amount of high-quality liposomes, and there are many problems. For example, the methods using chloroform described in Patent Document 1 and Patent Document 2 described above have a drawback that the influence on the human body becomes a problem and the operation becomes complicated. In the method described in Patent Document 3, it is essential to stir with a strong force using a special atomizer when preparing the liposome. If this is not done, stable liposomes cannot be obtained over time, Although the method described in Patent Document 4 shows a high moisturizing effect, the difficulty in preparing liposomes has not been solved at all. Moreover, when using a lecithin like patent document 5 and patent document 6, the smell and color derived from a lecithin have an unfavorable influence on the cosmetics and pharmaceutical which mix | blended the liposome. Furthermore, the liposome preparation which is a lyotropic liquid crystal also has a problem that the stability of the preparation is low because the crystallization of polar lipids easily progresses with time.
JP 10-316555 A JP 2000-63265 A JP-A-8-59449 JP 2000-186013 A JP-A-62-95134 JP-A-3-293024

  An object of the present invention is to obtain a liposome that is a bilayer vesicle that is easy to produce due to high solubility of the base in water and that is stable over time, or a liposome preparation using the liposome. To do.

1. (A) A liposome comprising one or more multi-chain polyhydrophilic group-type compounds each having two or more hydrophobic groups and hydrophilic groups in the molecule, and (B) water.
2. In the multi-chain polyhydrophilic group type compound, at least one of the hydrophobic groups is an acyl group, and the hydrophilic group is selected from a carboxyl group, a sulfonic acid group, a sulfate ester group, a phosphate ester group, or a salt thereof. 1. An anionic surfactant that is a species or more. The liposome according to 1.
3. The above-mentioned 1., wherein at least one of the multi-chain polyhydrophilic group type compounds further has an amino acid residue in the molecule. Or 2. The liposome according to 1.
4). At least one of the multi-chain polyhydrophilic group type compounds is a compound represented by the following general formula (1): ~ 3. The liposome according to any one of the above.

（上記一般式（１）において、Ｘは、ｍ個の官能基を有し、さらにそれ以外の置換基を有していてもよい分子量１００万以下の直鎖または分枝鎖または環状鎖または芳香族炭化水素鎖である。Ｘに結合しているｎ（ｍ≧ｎ）個のＱは、下記一般式（２）で表される置換基であり、それぞれ互いに同一でも異なっていてもよい。ｎは２〜２０の整数を示す。また、ｍはｍ≧ｎである整数を示す。

(In the above general formula (1), X is a linear, branched, cyclic, or aromatic group having a molecular weight of 1,000,000 or less, which may have m functional groups and further have other substituents. N (m ≧ n) Q bonded to X are substituents represented by the following general formula (2), which may be the same as or different from each other. Represents an integer of 2 to 20. m represents an integer satisfying m ≧ n.

上記一般式（２）において、ＺはＸの有する官能基に由来する結合部であり、Ｒ¹ＣＯは炭素原子数２〜２０の飽和または不飽和の脂肪酸から誘導されるアシル基を示し、Ｒ²は水素であるか、またはヒドロキシル基若しくはカルボキシル基が置換していてもよい炭素原子数１〜３の低級アルキル基を示し、Ｙはカルボキシル基、スルホン酸基、硫酸エステル基、リン酸エステル基またはそれらの塩の内のいずれかを示す。ｊ、ｋはそれぞれ独立に０，１，２のいずれかであり、かつｊ、ｋは同時に０ではない。）

In the general formula (2), Z is a bond derived from a functional group of X, R ¹ CO represents an acyl group derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms, R ² represents hydrogen, or a lower alkyl group having 1 to 3 carbon atoms which may be substituted with a hydroxyl group or a carboxyl group, and Y represents a carboxyl group, a sulfonic acid group, a sulfate group, or a phosphate group. Or any of their salts. j and k are each independently 0, 1, or 2, and j and k are not 0 at the same time. )

5. 3. The carbon number of X is 1 to 40, wherein The liposome according to 1.
6). The content of the multi-chain polyhydrophilic group type compound is 0.001% by mass or more and 50% by mass or less. ~ 5. The liposome according to any one of the above.
7). (C) A nonionic surfactant is contained, and (C) / (A) is 0.1 to 50 by mass ratio. ~ 6. The liposome according to any one of the above.
8). (D) A liposome forming aid is contained, and (D) / (A) is 0.01 to 10 by mass ratio. ~ 7. The liposome according to any one of the above.
9. The above-mentioned (D) liposome formation assistant is at least one selected from the group consisting of cholesterols, fatty acid esters of the cholesterols, alkyl ethers of the cholesterols, and fatty acids. The liposome according to 1.
10. Above 1. ~ 9. (E) The liposome formulation characterized by mix | blending (E) bioactive substance with the liposome in any one of these.
11. Above 1. ~ 9. 10. The liposome according to any one of the above or 10. An external preparation comprising the liposome preparation described in 1. above.

  Since the base is easily soluble in water, adjustment for obtaining liposomes is easy. In addition, liposomes that are stable over time can be obtained. In addition, high concentration liposomes can be easily and stably mass-produced without using an organic solvent such as chloroform.

  Embodiments of the present invention will be specifically described below. In the present invention, as a base constituting the liposome, (A) a multi-chain multi-hydrophilic group compound (hereinafter referred to as “multi-chain multi-hydrophilic group compound”) having two or more hydrophobic groups and hydrophilic groups in the molecule. May be omitted). This is a so-called gemini-type surfactant in which two or more hydrophobic groups and two or more hydrophilic groups are connected by an appropriate spacer (linking group). Furthermore, it is preferable to have a structure in which the hydrophilic groups of two or more molecules having one or more hydrophilic groups and one hydrophobic group are connected by an appropriate spacer.

  By using this product as a base with (B) water, a liposome as an excellent double membrane sachet can be obtained. Since this base is relatively easy to dissolve in water, the preparation of liposomes is relatively easy and can be mass-produced. Moreover, the obtained liposome has the characteristic which is excellent in stability over time. The liposomes referred to in the present invention are not limited to so-called lipid bilayer vesicles using phospholipids, and may be vesicles having a bilayer structure similar to that. Liposomes obtained by combining this (A) multi-chain polyhydrophilic group compound and (B) water are a kind of spherically lyotropic liquid crystals whose formation is a cross pattern called a Maltese cross in a polarizing microscope. Can be confirmed by the presence or absence of.

  In addition to (A) the multi-chain polyhydrophilic group type compound and (B) water, (C) a nonionic surfactant and (D) a liposome-forming aid are used in combination to form liposomes. It can be made easier. Component (C) and component (D) may be blended simultaneously, or only one of them may be blended. Hereinafter, each of these components will be described in order.

  First, (A) two or more hydrophobic groups possessed by a multi-chain polyhydrophilic group type compound are each independently a hydrophobic group having a saturated or unsaturated straight chain, branched chain or cyclic chain having 2 to 20 carbon atoms. It is preferably a group. Further, the two or more hydrophilic groups possessed by the multi-chain polyhydrophilic group type compound are each independently a carboxyl group, a sulfonic acid group, a sulfuric acid residue, a phosphoric acid residue or a salt thereof, or an oxyalkylene group, polyethylene A glycol group or the like, or an amino group, a quaternary ammonium group, a pyridinium group, a sulfonium group or a salt thereof is preferable.

  The number of hydrophobic groups or hydrophilic groups contained in the multi-chain polyhydrophilic group type compound is preferably 2 or more and 60 or less, respectively, from the viewpoint of relatively high solubility in water and the stability of the obtained liposome. More preferably, it is 2 or more and 40 or less. Further, it is particularly preferably 2 or more and 20 or less. More preferably, the number of hydrophilic groups is 3 or more and 10 or less.

  Preferred examples of the hydrophobic group of the polychain polyhydrophilic group compound include n-acetyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. , N-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, and their branches Examples of the chain isomers and unsaturated residues having an unsaturated moiety at one, two or three positions corresponding to these are given.

  Further, the hydrophobic group of the multi-chain polyhydrophilic group type compound is more preferably an acyl group derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms. That is, the multi-chain polyhydrophilic group-type compound is preferably an acyl compound having two or more acyl groups. By having this structure, the solubility in water becomes higher, and the temporal stability of the resulting liposome becomes higher. Two or more acyl groups may be independently different or the same. The acyl group is preferably derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms, and may be linear, branched or cyclic. However, the carboxyl group is not included.

  Examples of the acyl group include acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, Linear fatty acids such as margaric acid, stearic acid, nonadecanoic acid, arachidic acid; 2-butyl-5-methylpentanoic acid, 2-isobutyl-5-methylpentanoic acid, dimethyloctanoic acid, dimethylnonanoic acid, 2-butyl- 5-methylhexanoic acid, methylundecanoic acid, dimethyldecanoic acid, 2-ethyl-3-methylnonanoic acid, 2,2-dimethyl-4-ethyloctanoic acid, methyldocosanoic acid, 2-propyl-3-methylnonanoic acid, methyltridecane Acid, dimethyldodecanoic acid, 2-butyl-3-methylnonanoic acid, methyl Tradecanoic acid, ethyltridecanoic acid, propyldodecanoic acid, butylundecanoic acid, pentyldecanoic acid, hexylnonanoic acid, 2- (3-methylbutyl) -3-methylnonanoic acid, 2- (2-methylbutyl) -3-methylnonanoic acid, butyl Ethylnonanoic acid, methylpentadecanoic acid, ethyltetradecanoic acid, propyltridecanoic acid, butyldodecanoic acid, pentylundecanoic acid, hexyldecanoic acid, heptylnonanoic acid, dimethyltetradecanoic acid, butylpentylheptanoic acid, trimethyltridecanoic acid, methylhexadecanoic acid, ethyl Pentadecanoic acid, propyltetradecanoic acid, butyltridecanoic acid, pentyldodecanoic acid, hexylundecanoic acid, heptyldecanoic acid, methylheptylnonanoic acid, dipentylheptanoic acid, methylheptadecanoic acid, ethyl heptane Sadecanoic acid, ethylhexadecanoic acid, propylpentadecanoic acid, butyltetradecanoic acid, pentyltridecanoic acid, hexyldecanoic acid, heptylundecanoic acid, octyldecanoic acid, dimethylhexadecanoic acid, methyloctylnonanoic acid, methyloctadecanoic acid, ethylheptadecanoic acid, Branched fatty acids such as dimethylheptadecanoic acid, methyloctyldecanoic acid, methylnonadecanoic acid, methylnonadecanoic acid, dimethyloctadecanoic acid, butylheptylnonanoic acid;

  Octenoic acid, nonenoic acid, decenoic acid, caproleic acid, undecylenic acid, Lindellic acid, touric acid, lauroleic acid, tridecenoic acid, tuzuic acid, myristoleic acid, pentadecenoic acid, hexedenoic acid, palmitoleic acid, heptadecenoic acid, octadecenoic acid, Linear monoenoic acids such as oleic acid, nonadecenoic acid, gondonic acid; methylheptenoic acid, methylnonenoic acid, methylundecenoic acid, dimethyldecenoic acid, methyldodecenoic acid, methyltridecenoic acid, dimethyldodecenoic acid, dimethyltridecenoic acid, methyl Branched monoenoic acids such as octadecenoic acid, dimethylheptadecenoic acid, ethyloctadecenoic acid; linoleic acid, linoleic acid, eleostearic acid, linolenic acid, linolenic elaidic acid, pseudoeleostearic acid, parinaric acid, arachidone Di- or trienoic acids such as: ocetic acid, nonionic acid, decinic acid, undecinic acid, dodecinic acid, tridecinic acid, tetradecinic acid, pentadecinic acid, heptadesinic acid, octadecinic acid, nonadesinic acid, acetyloctenoic acid Methyleneoctadecenoic acid, methyleneoctadecanoic acid, aleprolic acid, alepresinic acid, allepuric acid, alepuric acid, hydnocarpic acid, sorghumulinic acid, gorulic acid, α-cyclopentylic acid, α-cyclohexylic acid, α-cyclopentylethylic acid And those derived from fatty acids such as cyclic acids;

  The acyl group may be a fatty acid-derived acyl group obtained from natural fats and oils, and is preferably a mixed fatty acid-derived acyl group containing 80% or more of the above saturated or unsaturated fatty acid having 2 to 20 carbon atoms. For example, acyl groups derived from palm oil fatty acid, palm oil fatty acid, linseed oil fatty acid, sunflower oil fatty acid, soybean oil fatty acid, sesame oil fatty acid, castor oil fatty acid, olive oil fatty acid, camellia oil fatty acid, rapeseed oil fatty acid, palm kernel oil fatty acid, etc. Etc. Two or more of these acyl compounds having an acyl group may be used in combination. The acyl group is preferably derived from a saturated or unsaturated fatty acid having 8 to 20 carbon atoms.

  The polychain polyhydrophilic group type compound can also be used as a salt, and examples of the salt include alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine salts, basic amino acid salts, and the like. Includes alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, metals such as aluminum and zinc, organic amines such as ammonia, monoethanolamine, diethanolamine, triethanolamine and triisopropanolamine, A salt with one or more kinds arbitrarily selected from basic amino acids such as arginine and lysine can be used. Among these, sodium salts, potassium salts, organic amine salts, and basic amino acid salts are particularly preferable.

  Furthermore, it is preferable that at least one of the multi-chain polyhydrophilic group type compounds is an acyl compound represented by the following general formulas (1) and (2). This acyl compound has a structure in which compounds each having at least one acyl group and a hydrophilic group in the molecule are connected by an appropriate spacer as shown in the general formulas (1) and (2). It has become. A compound having such a structure has higher solubility in water and higher stability over time of liposomes obtained therefrom.

（上記一般式（１）において、Ｘは、ｍ個の官能基を有し、さらにそれ以外の置換基を有していてもよい分子量１００万以下の直鎖または分枝鎖または環状鎖または芳香族炭化水素鎖である。Ｘに結合しているｎ（ｍ≧ｎ）個のＱは、下記一般式（２）で表される置換基であり、それぞれ互いに同一でも異なっていてもよい。ｎは２〜２０の整数を示す。また、ｍはｍ≧ｎである整数を示す。

(In the above general formula (1), X is a linear, branched, cyclic, or aromatic group having a molecular weight of 1,000,000 or less, which may have m functional groups and further have other substituents. N (m ≧ n) Q bonded to X are substituents represented by the following general formula (2), which may be the same as or different from each other. Represents an integer of 2 to 20. m represents an integer satisfying m ≧ n.

上記一般式（２）において、ＺはＸの有する官能基に由来する結合部であり、Ｒ¹ＣＯは炭素原子数２〜２０の飽和または不飽和の脂肪酸から誘導されるアシル基を示し、Ｒ²は水素であるか、またはヒドロキシル基若しくはカルボキシル基が置換していてもよい炭素原子数１〜３の低級アルキル基を示し、Ｙはカルボキシル基、スルホン酸基、硫酸エステル基、リン酸エステル基またはそれらの塩の内のいずれかを示す。ｊ、ｋはそれぞれ独立に０，１，２のいずれかであり、かつｊ、ｋは同時に０ではない。）

In the general formula (2), Z is a bond derived from a functional group of X, R ¹ CO represents an acyl group derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms, R ² represents hydrogen, or a lower alkyl group having 1 to 3 carbon atoms which may be substituted with a hydroxyl group or a carboxyl group, and Y represents a carboxyl group, a sulfonic acid group, a sulfate group, or a phosphate group. Or any of their salts. j and k are each independently 0, 1, or 2, and j and k are not 0 at the same time. )

In the general formula (2), the acyl groups represented by R ¹ CO may be independent from each other, that is, may be different or the same, and are derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms as described above. It is preferred that it be linear, branched or cyclic.

In general formula (2), R ² is hydrogen, or the number of carbon atoms that may be substituted by a hydroxyl group, a carboxyl group, a sulfonic acid group, a sulfate ester group, a phosphate ester group, or a salt thereof. 1 to 3 lower alkyl groups, and examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxy (iso) propyl group, and a dihydroxy (iso) propyl group. Group, carboxymethyl group, carboxyethyl group, carboxypropyl group, sulfoethyl group and the like.

  In the general formula (1), n substituents Q (formula (2)) bonded to X may be different from each other or the same. Moreover, Formula (2) shows what is called an acidic amino acid N-acylated, and it does not ask | require whether they are optical isomers, for example, D-form, L-form, and a racemate.

  The acidic amino acid is a monoaminodicarboxylic acid having 2 and 1 carboxyl groups and 1 amino group, respectively, in the molecule, and the amino group may be an N-methyl group or an N-ethyl group. It does not matter whether it is an optical isomer, for example, a D-form, an L-form, or a racemate. Examples of acidic amino acids include glutamic acid, aspartic acid, lanthionine, β-methyllanthionine, cystathionine, diencholic acid, ferrinin, aminomalonic acid, β-oxyaspartic acid, α-amino-α-methylsuccinic acid, β-oxyglutamic acid. , Γ-oxyglutamic acid, γ-methylglutamic acid, γ-methyleneglutamic acid, γ-methyl-γ-oxyglutamic acid, α-aminoadipic acid, α-amino-γ-oxyadipic acid, α-aminopimelic acid, α-amino- Examples thereof include γ-oxypimelic acid, β-aminopimelic acid, α-aminosuberic acid, α-aminosebacic acid, pantothenic acid and the like.

  The n substituents (formula (2)) attached to X are preferable because the acidic amino acid is an L-acidic amino acid molecule because it is excellent in biodegradability.

In the general formula (2), Z is a bonding part (—O) derived from m functional groups (hydroxyl group, amino group, thiol group) substituted with X (m ≧ n and an integer of 2 to 20). -, -NR < ³ >-, -S-). Here, R ³ is hydrogen or an alkyl group, alkenyl group, aryl group or alkylaryl group having 1 to 10 carbon atoms.

  In the general formula (1), X is a linear, branched or cyclic chain having a molecular weight of 1 million or less and having m functional groups composed of one or more selected from hydroxyl group, amino group and thiol group Or it is a spacer which is an aromatic hydrocarbon chain | strand, and X may have substituents other than a hydroxyl group, an amino group, and a thiol group.

  In the general formula (1), X is preferably a residue of an m-valent compound having a molecular weight of 1 million or less and having m functional groups of one kind or two or more kinds selected from a hydroxyl group, an amino group and a thiol group. And a compound residue that may have a substituent other than a hydroxyl group, an amino group, and a thiol group. Here, the m-valent compound means that a bond derived from m functional groups can be formed. It does not matter whether they are optical isomers such as D-form, L-form, and racemate.

  Examples of such m-valent compounds include amino acids such as serine, threonine, cysteine, cystine, cystine disulfoxide, cystathionine, methionine, arginine, lysine, tyrosine, histidine, tryptophan, and oxyproline; aminoethanol, aminopropanol , Aminobutanol, aminopentanol, aminohexanol, aminopropanediol, aminoethylethanolamine, aminoethylaminoethanol, aminocresol, aminonaphthol, aminonaphtholsulfonic acid, aminohydroxybenzoic acid, aminohydroxybutanoic acid, aminophenol, amino Compounds having amino and hydroxyl groups in the molecule such as phenethyl alcohol and glucosamine; mercaptoethanol, mercaptofe Lumpur, mercapto propanediol, compounds having a thiol group and a hydroxyl group in the molecule such as Gurukochiosu; aminothiophenol, compounds having a thiol group and an amino group in the molecule such as aminotriazole thiol; and the like. Further, proteins, peptides, etc., or those obtained by hydrolyzing them may be used.

  In the general formula (1), X is preferably an m-valent (m ≧ n) polyhydroxyl compound residue having a molecular weight of 1 million or less, which may have a substituent other than a hydroxyl group. Here, the m-valent polyhydroxyl compound means that m ester bonds can be formed. It does not matter whether they are optical isomers such as D-form, L-form, and racemate.

  Examples of such m-valent polyhydroxyl compounds include ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, and 1,4-butanediol. , Pentanediol, 1,6-hexanediol, cyclohexanediol, dimethylolcyclohexane, neopentyl glycol, 1,8-octanediol, 2,2,4-trimethyl-1,3-pentanediol, isoprene glycol, 3-methyl -1,5-pentanediol, sorbite, catechol, resorcin, hydroquinone, bisphenol A, bisphenol F, hydrogenated bisphenol A, hydrogenated bisphenol F, dimer diol, dimethylolpropionic acid, dimethylolbutanoic acid, tartaric acid, dihydro Shi tartaric, mevalonate, 3,4-dihydroxy cinnamic acid, 3,4-dihydroxy-hydro cinnamic acid, hydroxy benzoic acid, dihydroxy stearic acid, dihydroxyphenylalanine, and the like, and divalent hydroxyl compounds such as isomers thereof;

  Glycerin, trioxyisobutane, 1,2,3-butanetriol, 1,2,3-pentanetriol, 2-methyl-1,2,3-propanetriol, 2-methyl-2,3,4-butanetriol, 2-ethyl-1,2,3-butanetriol, 2,3,4-pentanetriol, 2,3,4-hexanetriol, 4-propyl-3,4,5-heptanetriol, 2,4-dimethyl- Trivalent poly, such as 2,3,4-pentanetriol, 1,2,4-butanetriol, 1,2,4-pentanetriol, trimethylolethane, trimethylolpropane, diethanolamine, triethanolamine, trihydroxystearic acid Hydroxyl compounds; pentaerythritol, erythritol, 1,2,3,4-pentanetetrol, , 3,4,5-hexanetetrol, 1,2,4,5-pentanetetrol, 1,3,4,5-hexanetetrol, diglycerin, sorbitan, and other tetravalent polyhydroxyl compounds; adonitol, arabitol , Pentavalent polyhydroxyl compounds such as xylitol, triglycerin; hexavalent polyhydroxyl compounds such as dipentaerythritol, sorbitol, mannitol, iditol, inositol, dulcitol, talose, allose; or their dehydration condensates, polyglycerin, etc. It is done.

  Also, sugars such as tetroses such as erythrose, sreose and erythrulose; pentoses such as ribose, arabinose, xylose, lyxose, xylulose and ribulose; allose, altrose, glucose, mannose, guylose, idose, galactose, talose, fructose, Monosaccharides such as hexoses such as sorbose, psicose and tagatose; maltose, isomaltose, cellobiose, gentiobiose, melibiose, lactose, turanose, trehalose, saccharose, mannitolose, cellotriose, gentianose, raffinose, meletetose, etc. Examples include sugars.

  In addition, other saccharides such as heptose, deoxy sugar, amino sugar, thio sugar, seleno sugar, aldone sugar, uronic acid, sugar acid, ketoaldonic acid, anhydro sugar, unsaturated sugar, sugar ester, sugar ether, glycoside, etc. It may be a group, and may be a polysaccharide such as starch, glycogen, cellulose, chitin, chitosan or the like, or a hydrolyzed product thereof.

  In general formula (1), X is preferably an m-valent polyamino compound residue having a molecular weight of 1,000,000 or less, which may have a substituent other than an amino group. Here, the m-valent polyamino compound means that m acid amide bonds can be formed. It does not matter whether they are optical isomers such as D-form, L-form, and racemate.

  Examples of such m-valent polyamino compounds include N, N′-dimethylhydrazine, ethylenediamine, N, N′-dimethylethylenediamine, diaminopropane, diaminobutane, diaminopentane, diaminohexane, diaminoheptane, diaminooctane, diaminononane, Aliphatic diamines such as diaminodecane, diaminododecane, diaminoadipic acid, diaminopropanoic acid, diaminobutanoic acid and their isomers; diethylenetriamine, triaminohexane, triaminododecane, 1,8-diamino-4-aminomethyl -Octane, 2,6-diaminocapric acid-2-aminoethyl ester, 1,3,6-triaminohexane, 1,6,11-triaminoundecane, di (aminoethyl) amine, and isomers thereof Aliphatic triamines;

  Alicyclic polyamines such as diaminocyclobutane, diaminocyclohexane, 3-aminomethyl-3,5,5-trimethylcyclohexylamine, triaminocyclohexane; diaminobenzene, diaminotoluene, diaminobenzoic acid, diaminoanthraquinone, diaminobenzenesulfonic acid, Aromatic polyamines such as diaminobenzoic acid and their respective isomers; aromatics such as diaminoxylene, di (aminomethyl) benzene, di (aminomethyl) pyridine, di (aminomethyl) naphthalene, and their respective isomers Aliphatic polyamines; polyaminos substituted with hydroxyl groups such as diaminohydroxypropane and isomers thereof.

  In general formula (1), X is preferably an m-valent polythiol compound residue having a molecular weight of 1,000,000 or less, which may have a substituent other than a thiol group. Here, the m-valent polythiol compound means that m thioester bonds can be formed. It does not matter whether they are optical isomers such as D-form, L-form, and racemate. Examples of such m-valent polythiol compounds include dithiol compounds such as dithioethylene glycol, dithioerythritol, and dithiothreitol.

  X preferably has 1 to 40 carbon atoms among the residues of the compounds listed above, and more preferably X has 1 to 20 carbon atoms. X is preferably a naturally occurring type from the viewpoint of excellent biodegradability.

  In the general formula (2), a carboxyl group, a sulfonic acid group, a sulfate ester group, a phosphate ester group represented by Y, and a carboxyl group, a sulfonic acid group, a sulfate ester group, a phosphate ester group, and the like that can be contained in X Can form salts with various basic substances. Examples of such salts include alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine salts, basic amino acid salts, polyvalent metal salts, and the like, specifically, alkalis such as sodium, potassium, and lithium. Metals, alkaline earth metals such as calcium and magnesium, metals such as aluminum, zinc, iron, cobalt, titanium and zirconium, organic amines such as ammonia, monoethanolamine, diethanolamine, triethanolamine and triisopropanolamine, arginine and lysine Or a salt with one or more kinds selected arbitrarily from basic amino acids and the like.

  As the method for producing the acyl compound represented by the general formula (1), an N-acyl acidic amino acid anhydride represented by the following general formula (3) and one kind selected from a hydroxyl group, an amino group and a thiol group in the molecule or By reacting two or more kinds of compounds having m functional groups in water or a mixed solvent of water and an organic solvent, or tetrahydrofuran, benzene, toluene, xylene, carbon tetrachloride, chloroform, acetone, etc. The reaction can be carried out using an inert solvent or by mixing at -5 ° C. to 200 ° C. at a temperature equal to or higher than any melting point without solvent.

  Alternatively, the acyl compound represented by the general formula (1) includes an N-acyl acidic amino acid mono-lower ester (for example, methyl ester, ethyl ester) and a polyhydroxyl compound, a polyamino compound, or a polythiol compound, or a hydroxyl group or an amino group in the molecule. , A compound having any two or three of the thiol groups is dissolved in a suitable solvent such as dimethylformamide, a catalyst such as potassium carbonate is added, and the reaction is performed at −5 ° C. to 250 ° C. under reduced pressure. Thereafter, it can be obtained by removing the reaction solvent. Alternatively, the acyl compound can be obtained by melting with heating without a solvent, adding a catalyst such as sodium hydroxide, and performing a transesterification reaction at room temperature to 250 ° C.

  Next, (B) water functions as a dispersion medium for the (A) multi-chain polyhydrophilic group type compound, and may be pure water or may contain some impurities. (B) Water is preferably used in the range of 30% by mass or more and 99.999% by mass or less with respect to the total mass of (A) the polychain polyhydrophilic group type compound and (B) water. More preferably, it is 50 mass% or more and 99.9 mass% or less, More preferably, it is 60 mass% or more and 99 mass% or less. Most preferably, it is 70 mass% or more and 95 mass% or less.

  Next, (C) the nonionic surfactant has a function of further enhancing the stability of the liposome. (C) Nonionic surfactants include POE (polyoxyethylene) octyl ether, POE lauryl ether, POE myristyl ether, POE cetyl ether, POE stearyl ether, POE oleyl ether, POE isostearyl ether, POE behenyl ether, Polyoxyethylene alkyl ethers such as POE octyl (2-ethyl-hexyl) ether; polyoxyethylene polyoxy such as POE · POP (polyoxypropylene) butyl ether, POE · POE lauryl ether, POE · POP cetyl ether POE · POP glycol, etc. Propylene glycol type; POE octyl phenyl ether, POE nonyl phenyl ether, POE chlorophenyl ether, polyoxyethylene naphthol ether Polyoxyethylene aryl ether; POE hydrogenated castor oil ether, POE castor oil ether; other POE lanolin alcohol ether, such as POE phytosterol;

  Polyoxyethylene glycerin fatty acid esters such as POE glyceryl monostearate and POE glyceryl oleate; polyoxyethylene sorbitan fatty acid esters such as POE sorbitan monolaurate, POE sorbitan monostearate, POE sorbitan tristearate, POE sorbitan monoisostearate; Polyoxyethylene sorbitol fatty acid esters such as POE sorbitol hexastearate, POE sorbitol tetrastearate, POE sorbitol tetraoleate, POE sorbitol monolaurate;

  Polyethylene glycol monolauric acid, polyethylene glycol monostearic acid, polyethylene glycol monooleic acid, polyethylene glycol distearic acid, polyethylene glycol dioleic acid, polyethylene glycol fatty acid esters such as polyethylene glycol diisostearic acid; and other ether ester systems such as polyethylene glycol lanolin fatty acid ester Glyceryl fatty acid esters such as glyceryl monostearate, glyceryl monostearate, glyceryl monohydroxystearate, glyceryl distearate; diglyceryl monostearate, diglyceryl monooleate, diglyceryl dioleate, diisostearate di Glyceryl, tetraglyceryl monostearate, tristeare Phosphate tetraglyceryl, penta monostearate tetraglyceryl monolaurate hexaglyceryl, monomyristate hexaglyceryl, decaglyceryl distearate, polyglycerol fatty acid esters such diisostearate decaglyceryl;

  Sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, sorbitan trioleate, sorbitan tristearate, sorbitan monoisostearate; ethylene glycol fatty acid esters such as ethylene glycol monolaurate; propylene glycol monostearate Propylene glycol fatty acid esters such as self-emulsifying propylene glycol monostearate; pentaerythritol fatty acid esters such as pentaerythritol monostearate and pentaerythritol monooleate; maltitol hydroxy fatty acid ethers, alkylated polysaccharides, alkyl (poly) glucosides, Sugar derivatives such as sugar esters; alkyl groups such as α-monoisostearyl glyceryl ether Glyceryl ether; acetyl - monoglyceride, lactic monoglyceride, organic acid monoglyceride and citric acid monoglyceride;

  Fatty acid alkanols such as coconut oil fatty acid monoethanolamide, lauroyl monoethanolamide, myristoyl monoethanolamide, lauroyl diethanolamide, coconut oil fatty acid diethanolamide, lauroyl isopropanolamide, myristoyl isopropanolamide, coconut oil fatty acid isopropanolamide, POE lauroyl monoethanolamide Amides; POE alkylamines such as POE laurylamine and POE stearylamine; amine oxides such as lauryldimethylamine oxide, cocodimethylamine oxide and cocoamidopropyldimethylamine oxide; and polyglycol diesters.

  Furthermore, the blending ratio of (C) / (A) is preferably in the range of 0.1 to 50, more preferably in the range of 0.5 to 30.0, by mass ratio. More preferably, it is in the range of 5 to 10.0.

  Next, (D) the liposome-forming aid has a function of (A) promoting the liposome formation of the multi-chain polyhydrophilic group-type compound and further improving the temporal stability of the resulting liposome, and (C) a nonionic When used in combination with a surfactant, the effect is drastically improved as compared with the case where each is added alone. (D) Liposomes include cholesterol, stigmasterol, lanosterol, ergosterol and other cholesterols, fatty acid esters of the cholesterols, and alkyl ethers of the cholesterols, lauric acid, myristic acid, palmitic acid, stearin Examples thereof include saturated and unsaturated linear and branched fatty acids such as acid and oleic acid.

  The alkyl group in the cholesterol fatty acid ester and the cholesterol alkyl ether preferably has 10 to 26 carbon atoms, and more preferably has a straight chain or branched chain having 12 to 22 carbon atoms in order to assist liposome formation.

  The fatty acid preferably has 10 to 26 carbon atoms, and particularly preferably a saturated and linear fatty acid having 12 to 22 carbon atoms, in order to assist liposome formation. Further, in order to form a liposome structure, (D) / (A) is preferably 0.01 to 10 in mass ratio, more preferably 0.5 to 4.0. More preferably, it is set to 0.0 to 3.0.

  (E) A physiologically active component means a chemical substance that acts on a living body in a very small amount and has some influence on the physiological function of the living body, and is an object to be transported by a liposome as a drug delivery system. A liposome preparation can be obtained by blending (E) a physiologically active ingredient with the above-mentioned liposome. (E) The physiologically active component may be water-soluble, oil-soluble, or amphiphilic, but is preferably safe for the skin and human body. Specifically, for example, a moisturizing agent; an anti-inflammatory agent; an antioxidant agent; an antibacterial agent; an astringent agent; a whitening agent; an anti-aging agent; a hair restoring agent; a blood flow promoting agent; a cell activator; Examples include active oxygen scavengers; physiologically active substances derived from natural substances or chemically synthesized substances such as 5α-reductase inhibitors.

  More specifically, for example, anti-dandruff and itching agents such as trichlorocarbanilide, salicylic acid, zinc pyrithione, isopropylmethylphenol; benzophenone derivatives, paraaminobenzoic acid derivatives, paramethoxycinnamic acid derivatives, salicylic acid derivatives and other ultraviolet absorbers Whitening agents such as arbutin, kojic acid, ascorbic acid, hinokitiol and derivatives thereof; blood circulation promoters such as assembly extract, cephalanthin, vitamin E and derivatives thereof, gamma oryzanol; red pepper tincture, ginger orchid tincture, cantharis tincture and nicotinic acid Local stimulants such as benzyl esters; Nutrients such as various vitamins and amino acids; Female hormone agents; Hair root activators; Glycyrrhetinic acid, Glycyrrhizic acid derivatives, Allantoin, Azulene, Ami Anti-inflammatory agents such as caproic acid and hydrocortisone; astringents such as zinc oxide, zinc sulfate, allantoin hydroxyaluminum, aluminum chloride, zinc sulfococolate and tannic acid; refreshing agents such as menthol and camphor; antihistamines; estradiol, estrone and ethinylestradiol Sebum suppressants such as; exfoliating and dissolving agents such as sulfur, salicylic acid and resorcin;

  Others, oyster extract, N-methyl-L-serine, whey, nicotinamide, diisopropylamine dichloroacetic acid, mevalonic acid, γ-aminobutyric acid (including γ-amino-β-hydroxybutyric acid), altea extract, aloe extract, Apricot kernel extract, turmeric extract, oolong tea extract, seawater dried product, hydrolyzed wheat powder, hydrolyzed silk, carrot extract, cucumber extract, gentian extract, yeast extract, rice germ oil, comfrey extract, savanna extract, ginger extract, lion extract , Birch extract, Atlantic mint extract, assembly extract, bisabolol, propolis, loofah extract, bodaiju extract, hop extract, marronnier extract, muroji extract, melissa extract, eucalyptus extract, yukinoshita extract, rosemary extract, Over Ma chamomile extract, royal jelly extract, seaweed, rice bran, licorice, citrus unshiu peel, angelica, pulverized Momonoha, sphingolipids, guaiazulene, vitamin C; and the like.

  (E) The physiologically active ingredient is preferably contained in the range of 0.0001 to 5% by mass in the liposome preparation, and more preferably in the range of 0.001 to 1% by mass. The physiologically active substance can be either internally added to the liposome, externally added, or a combination of both. However, in the case of internal addition, an oil-soluble or amphiphilic substance is preferable.

  Next, to the above-mentioned liposome or liposome preparation, an oil agent, a humectant, a viscosity modifier, a pH adjuster, an ultraviolet absorber, a preservative, a fragrance, a solvent, an inorganic or organic powder, a bactericidal agent, a colorant, etc. It can mix | blend suitably in the range which does not inhibit the effect of invention, Thereby, the external preparation containing a liposome or a liposome formulation is obtained. Examples of what can be blended in such an external preparation include the following.

  Alkane sulfonate, alpha-olefin sulfonate (AOS), alkylbenzene sulfonate, alkylnaphthalene sulfonate, alkyl sulfonate (SAS), sulfonate of higher fatty acid ester, alpha-sulfonated fatty acid salt, higher fatty acid Amide sulfonate, N-acyl-N-alkyl taurate, dialkyl sulfosuccinate, sulfated oil, alkyl sulfate ester (AS), alkyl ether sulfate, sulfate of higher fatty acid ester, higher fatty acid alkylol amide Sulfate, polyoxyalkylene alkyl ether sulfate (AES), polyoxyalkylene styrenated phenyl ether sulfate, alkyl phosphate, alkyl ether phosphate, polyoxyethylene alkyl ether phosphate, polyoxy Polyoxyethylene alkyl phenyl ether phosphates, naphthalenesulfonic acid salt formalin condensates, alkyl ether carboxylates, anionic surfactants such as ether carboxylic acid salts;

  In particular, N-acylamino acid type anionic surfactants are effective. Examples of the acyl group include those having 8 to 20 carbon atoms as described above, and examples of the constituent amino acids include glutamic acid and aspartic acid. Glycine, alanine, valine, leucine, isoleucine, proline, methionine, cysteine, tryptophan, tyrosine, phenylalanine, asparagine, glutamine, serine, threonine, oxyproline, β-aminopropionic acid, γ-aminobutyric acid, And amino acids such as anthranilic acid, m-aminobenzoic acid, and p-aminobenzoic acid.

  Alkylbetaines, alkylamidobetaines, alkylsulfobetaines, imidazolinium betaines, lecithins, and the like, specifically, amphoteric surfactants such as lauric acid amidopropylbetaine;

  Primary to tertiary fatty amine salts, alkylammonium chloride salts, tetraalkylammonium salts, trialkylbenzylammonium salts, alkylpyridinium salts, alkylhydroxyethylimidazolinium salts, dialkylmorpholinium salts, alkylisoquinolium salts, Cationic surfactants such as benzethonium salts and benzalkonium salts;

  Cationized cellulose derivative, cationic starch, cationized guar gum derivative, diallyl quaternary ammonium salt / acrylamide copolymer, quaternized polyvinylpyrrolidone derivative, quaternized vinylpyrrolidone / vinylimidazole polymer, polyglycol / amine condensate, Cationic compounds such as quaternized collagen polypeptides, polyethyleneimine, cationic silicone polymers, adipic acid / dimethylaminohydroxypropyldiethylenetriamine copolymers, polyaminopolyamides, cationic chitin derivatives, quaternized polymers and other cationic polymers;

  Natural rubbers such as gum arabic and tragacanth, glucosides such as saponin, cellulose derivatives such as methylcellulose, carboxycellulose, and hydroxymethylcellulose, natural polymers such as lignin sulfonate and shellac, polyacrylate, and styrene-acrylic acid Polymer salts, vinyl naphthalene-maleic acid copolymer salts, sodium salts of β-naphthalene sulfonic acid formalin condensates, anionic polymers such as phosphates, and nonions such as polyvinyl alcohol, polyvinyl pyrrolidone and polyethylene glycol Dispersing agents such as functional polymers;

  Polymeric surfactants such as sodium alginate, starch derivatives, tragacanth gum; natural surfactants such as lecithin, lanolin, saponin; avocado oil, almond oil, olive oil, cacao oil, sesame oil, safflower oil, soybean oil, coconut oil, permanent Oils, castor oil, mink oil, cottonseed oil, molasses, coconut oil, egg yolk oil, palm oil, palm kernel oil, synthetic triglyceride, jojoba oil, etc .; hydrocarbons such as liquid paraffin, petrolatum, ceresin, microcrystalline wax, isoparaffin; Waxes such as beeswax, whale wax, lanolin, carnauba wax, candelilla wax and derivatives thereof;

  Lauryl alcohol, cetanol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, lanolin alcohol, hydrogenated lanolin alcohol, hexyldecanol, octyldodecanol and other higher alcohols; other esters such as isopropyl myristate and butyl stearate Oil; silicones such as metal soap, dimethylpolysiloxane, polyether-modified silicone, alcohol-modified silicone, methylphenylpolysiloxane, epoxy-modified silicone, fluorine-modified silicone, alkyl-modified silicone, alkoxy-modified silicone, amino-modified silicone, and volatile silicone Volatile and non-volatile oils such as trimethylglycine, sorbitol, raffinose, pyrrolidone carboxylic acid and Salts, lactic acid and its salts, hyaluronic acid and salts thereof, ceramides, moisturizing agents such as polymethacryloylacetones oxyethyl phosphorylcholine;

  Hydroxyethylcellulose, carboxymethylcellulose, hydroxyethylcellulose hydroxypropyltrimethylammonium chloride ether, methylcellulose, ethylcellulose, hydroxypropylcellulose, methylhydroxypropylcellulose, soluble starch, carboxymethylstarch, methylstarch, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl Methyl ether, carboxyvinyl polymer, polyacrylate, guar gum, locust bin gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid, gelatin, casein , Rubumin, collagen, methoxyethylene maleic anhydride copolymer, amphoteric methacrylate copolymer, poly (dimethylmethylenepiperidinium chloride), polyacrylate copolymer, polyvinyl acetate, nitrocellulose, silicone resin, polyquaternium-1 , Polyquaternium-2, polyquaternium-4, polyquaternium-5, polyquaternium-6, polyquaternium-7, polyquaternium-10, polyquaternium-11, polyquaternium-16, polyquaternium-22, polyquaternium-24, polyquaternium-28, polyquaternium-30, polyquaternium-30 -32, polyquaternium-37, polyquaternium-39, polyquaternium-43, polyquaternium-44, polyquaternium-46, Water-soluble and oil-soluble such as Li-quaternium-47, polyquaternium-51, polyquaternium-52, polyquaternium-53, polyquaternium-54, polyquaternium-55, polyquaternium-56, polyquaternium-57, polyquaternium-61, polyquaternium-64, polyquaternium-65 High molecular;

  Polyethylene glycol fatty acid ester, polyoxyethylene fatty acid ester methyl glycoside, tetradecene sulfonate, etc., thickening and foam increasing components; ethylenediaminetetraacetic acid and its salts, hydroxyethylenediaminetriacetic acid and its salts, phosphoric acid, ascorbic acid, succinic acid Sequestering agents such as gluconic acid, polyphosphates, metaphosphates, hinokitiles; paraoxybenzoic acid esters, benzoic acid and salts thereof, preservatives such as phenoxyethanol, hinokitiol; citric acid, malic acid, adipic acid, PH adjusters such as glutamic acid and aspartic acid; silicone materials such as polymeric silicones and cyclic silicones; antioxidants such as tocopherols, BHA, BHT, gallic acid, and NDGA;

  Organic synthetic pigments (dyes, lakes, organic pigments), natural pigments, inorganic pigments (external pigments, colored pigments, white pigments), pearlescent pigments, polymer powders, functional pigments It can be used without being limited to the shape of needles, etc., the particle size of fumes, fine particles, pigment grades, etc., and the structure of particles such as porous and nonporous. For example, talc, kaolin, sericite, calcium carbonate, zinc oxide, aluminum oxide, magnesium oxide, zirconium oxide, magnesium carbonate, calcium carbonate, barium sulfate, chromium oxide, chromium hydroxide, tar dyes, mica, (synthetic) seric Site, silicon carbide, boron nitride, titanium dioxide, black titanium oxide, conger, red iron oxide, black iron oxide, yellow iron oxide, ultramarine, titanium coated mica, bismuth oxychloride, bengara, caking pigment, gunjo pink, gun Zou violet, chromium hydroxide, mica titanium, chromium oxide, aluminum cobalt oxide, carbon black, anhydrous silicic acid, magnesium silicate, bentonite, (synthetic) mica, zirconium oxide, magnesium (meth) silicate aluminate, aluminum silicate Calcium oxide, Liethylene powder, nylon powder, polymethyl methacrylate, polyethylene terephthalate-polymethyl methacrylate laminate powder, acrylonitrile-methacrylic acid copolymer powder, vinylidene chloride-methacrylic acid copolymer powder, wool powder, silk powder, crystalline cellulose, N-acyl lysine, poly Methyl silsesquioxane powder, plant fruit and skin powder, bismuth oxychloride, mica titanium, iron oxide coated mica, iron oxide mica titanium, organic pigment treated mica titanium, aluminum powder, fine particle titanium oxide, Fine zinc oxide, fine titanium oxide coated mica titanium, fine zinc oxide coated mica titanium, barium sulfate coated mica titanium, carmine, β-carotene, chlorophyll, sunset yellow FCF, Ponceau SX, eosin YS, TE Trabromofluorescein, rhodamine B, quinoline yellow SS, quinoline yellow WS, alizanin cyanine green, quinizarin green, resolbin BCA, resolbin BCA, permaton red, herringdon pink CN, phthalocyanine blue, β-apo-8-carotenal , Capsanthin, lylopine, bixin, crocin, canthaxanthin, shisonin, raphanin, ninocyanin, calsamine, safrole yellow, rutin, quercetin, cacao dye, lipoflavin, lacaic acid, carminic acid, kermesic acid, alizanin, shikonin, alkanine, niquinochrome, blood dye , Curcumin, betanin, and other cosmetic colorants;

  Next, the manufacturing method of a liposome, a liposome formulation, or an external preparation is demonstrated. For these productions, production methods usually used for the production of liposome preparations and the like may be used. Even when the components of the liposome are only the components (A) and (B), the components (C) and (D) Even when components are added, they can be produced in the same manner. Preferably, the following production methods can be exemplified.

  First, at 80 ° C., the components (A), (C) and (D) of the inner oil phase are completely uniformly dissolved and mixed. Among the components (E), the lipophilic or amphiphilic bioactive substance is added and mixed uniformly at this time. Next, an aqueous phase component such as a hydrophilic nonionic surfactant among the component (C) and water as the component (B) are added and heated to 80 ° C. again. Among the components (E), the hydrophilic physiologically active substance is uniformly dissolved at this time. After confirming that each component is completely dissolved, the system temperature is gradually cooled to around 40 ° C. while stirring. Thus, the target liposome or the like is obtained. The stirring device may be a propeller mixer that can uniformly stir the inside of the system. However, when the viscosity is high, stirring is performed uniformly using an adihomomixer or the like.

  In the liposome preparation or external preparation thus obtained, a water-soluble, oil-soluble, or amphiphilic physiologically active substance is encapsulated, so that cosmetics, quasi-drugs, pharmaceuticals, etc. are used as highly functional materials. It can be used for external preparations. Liposome preparations can also be applied to animals other than plants and humans as fertilizers, agricultural chemicals, and the like. In addition, a liposome preparation in which a physiologically active substance is encapsulated in liposomes has an effect of promoting uptake into a living body and a medicinal effect in a small amount. In addition, the effect of the physiologically active substance can be improved or enhanced.

Hereinafter, the present invention will be described based on examples. First, the manufacture example of the acyl compound which is an example of a polychain polyhydrophilic group type compound is shown.
(Production Example 1 of acyl compound)

  9.1 g (0.05 mol) of L-lysine hydrochloride was mixed with 57 g of water. While this solution was adjusted to a pH range of 10 to 11 with a 25% aqueous sodium hydroxide solution and the reaction temperature was maintained at 5 ° C., 31.1 g of N-lauroyl-L-glutamic anhydride (0. 1 mol) was added over 2 hours to carry out the reaction. After stirring for another 30 minutes, tertiary butanol was added to a concentration of 20% by mass in the liquid, 75% sulfuric acid was added dropwise to bring the pH value of the liquid to 2, and the liquid temperature to 65 ° C. It was adjusted. After completion of the dropwise addition, stirring was stopped, and the mixture was allowed to stand at 65 ° C. for 20 minutes. Tertiary butanol and water were added to the separated organic layer, the temperature was raised to 65 ° C., and the mixture was stirred for 20 minutes. After the stirring was stopped, the mixture was allowed to stand to separate into an organic layer and an aqueous layer. After repeating the same water washing operation for the obtained organic layer, the solvent was removed from the obtained organic layer and neutralized with sodium hydroxide to an aqueous solution having a solid content of 30% by mass and a pH of 6.5 (25 ° C.). After the preparation, this was dried to obtain a composition containing an acyl compound represented by the following formula (4).

（式４において、Ｘは、各々独立にＨまたはＮａ）
（アシル化合物の製造例２）

(In Formula 4, each X is independently H or Na)
(Production Example 2 of acyl compound)

In Production Example 1, except that N-lauroyl-L-glutamic acid anhydride was changed to N-cocoyl-L-glutamic acid anhydride, the same procedure as in Production Example 1 was performed to obtain a composition containing an acyl compound. It was.
(Acyl Compound Production Example 3)

In the manufacture example 1, it implemented on the same conditions as the method of the manufacture example 1 except having implemented the neutralization process with potassium hydroxide, and obtained the composition containing an acyl compound.
[Examples 1-9, Comparative Examples 1-9]

  Based on the production method of the liposome or liposome preparation exemplified above, the compositions of Examples 1 to 9 and Comparative Examples 1 to 9 were prepared with the compositions shown in Table 1 and Table 2, and the presence or absence of formation of the liposome structure. The stability of the composition was confirmed.

The presence or absence of liposome structure formation was judged by whether or not a cross pattern called a Maltese cross could be observed with a polarizing microscope. Those in which the Maltese cross was confirmed had a liposome structure, and it was judged that the rest had no liposome structure. The evaluation criteria are as follows.
◯: Maltese cloth was entirely confirmed immediately after preparation.
Δ: Maltese cloth was partially confirmed immediately after preparation.
X: Maltese cloth was not able to be confirmed at all immediately after preparation.

Moreover, the prepared composition was preserve | saved at 40 degreeC, 25 degreeC, and -5 degreeC, respectively, and the same polarizing microscope observation was performed after one month. At this time, those in which the same state as that of the Maltese cloth immediately after preparation was confirmed were regarded as having good stability, and those other than that were regarded as having poor stability.
The evaluation criteria are as follows.
○: After one month, the Maltese cloth was confirmed as a whole.
X: Maltese cloth was not confirmed at all after one month.

［実施例１０］

[Example 10]

A lotion, which is an external preparation using the acyl compound of Production Example 1, was prepared according to the following formulation by a commonly performed method. Based on the above production method, a lipophilic and amphiphilic material was added to the oil phase, and a hydrophilic material was added to the aqueous phase to obtain a composition. This composition was evaluated by observing with a polarizing microscope in the same manner as used in Example 1. The results are shown in Table 3. Maltese cloth was observed by polarizing microscope observation and was stable over time.
Ingredient name Mass%
Acyl compound of Production Example 1 0.8
Cholesterol 0.4 (Riken Vitamin Co., Ltd., trade name: RIKEN Cholesterol)
Ceramide 2 0.1 (manufactured by CRODA JAPAN)
Citric acid 0.1
Sodium benzoate 0.1
Ethanol 5.0
Glycerin 5.0
Aloe extract 1.0 (Ichimaru Falcos, trade name: Aloe extract vera)
Chamomile extract 1.0 (Product name: Chamomile Liquid, manufactured by Ichimaru Falcos)
Purified water Total amount to be 100 [Example 11]

An emulsion, which is an external preparation using the acyl compound of Production Example 2, was prepared according to the following formulation by a commonly performed method. The obtained composition was evaluated by observing with a polarizing microscope in the same manner as used in Example 1. The results are shown in Table 3. Maltese cloth was observed by polarizing microscope observation and was stable over time.
Ingredient name Mass%
Acyl compound of Production Example 2 1.0
Dipropylene glycol 4.0
PEG400 5.0
Edetic acid 2Na 0.1
Stearyl alcohol 0.5
Hardened palm oil 3.0 (Nisshin Oilio Co., Ltd., trade name: Nomucote PHS)
Squalane 35.0 (Nikko Chemicals, trade name: NIKKOL Squalane)
Lauric acid 0.3
Stearic acid 0.3
Sorbitan sesqui
Oleic acid ester 1.5
POE (20) oleyl
Alcohol ether 2.5
Carbomer aqueous solution (1%) 15.0 (Nikko Chemicals, trade name: Carbopol 934)
Sodium hydroxide 0.1
Butylparaben 0.3
Purified water Total amount to be 100 [Example 12]

A cream which is an external preparation using the acyl compound of Production Example 3 was prepared according to the following formulation by a commonly performed method. The obtained composition was evaluated by observing with a polarizing microscope in the same manner as used in Example 1. The results are shown in Table 3. Maltese cloth was observed by polarizing microscope observation and was stable over time.
Ingredient name Mass%
Behenyl alcohol 2.0 (trade name: Lanette 22, manufactured by Cognis Japan)
Stearyl alcohol 4.0
Stearic acid 2.0
Hydrogenated Lanolin 4.0 (Nippon Seika Co., Ltd., trade name: Hard Lanolin)
Squalane 9.0 (Nikko Chemicals, trade name: NIKKOL Squalane)
Octyldodecanol 10.0
Vitamin E 0.1
Acyl compound of Production Example 3 1.2
Polyquaternium-51 0.2 (Nippon Yushi Co., Ltd., trade name: Lipidure-PMB)
1,3 butylene glycol 6.0
PEG1500 4.0
Vitamin C 2.0
POE (25) cetyl
Alcohol ether 3.0
Glycerol monostearate 2.0
Butylparaben 0.2
Purified water Total amount to be 100 [Example 13]

An ointment that is an external preparation using the acyl compound of Production Example 3 was prepared according to the following formulation by a commonly performed method. The obtained composition was evaluated by observing with a polarizing microscope in the same manner as used in Example 1. The results are shown in Table 3. Maltese cloth was observed by polarizing microscope observation and was stable over time.
Ingredient name Mass%
Acylated product of Example 1 2.0
Cetyl alcohol 3.0
Stearyl alcohol 5.0
Behenyl alcohol 5.0 (manufactured by Cognis Japan, trade name: Lanette 22)
Sorbitan monostearate 8.0
POE (20) sorbitan
Monostearate 25.0
Cholesteryl isostearate 6.0
Vitamin E 0.1
Vitamin A oil 0.2
Vitamin D oil 0.1
Glycerin 8.0
Methylparaben 0.1
Sodium chloride 0.02
Phytosterol 0.1 (trade name: β-sitosterol, manufactured by Eisai Co., Ltd.)
Glycyrrhetinic acid 0.4
Purified water Total amount to be 100

Claims (11)

  (A) A liposome comprising one or more multi-chain polyhydrophilic group-type compounds each having two or more hydrophobic groups and hydrophilic groups in the molecule, and (B) water.   In the multi-chain polyhydrophilic group type compound, at least one of the hydrophobic groups is an acyl group, and the hydrophilic group is selected from a carboxyl group, a sulfonic acid group, a sulfate ester group, a phosphate ester group, or a salt thereof. The liposome according to claim 1, wherein the liposome is an anionic surfactant that is a species or more.   The liposome according to claim 1 or 2, wherein at least one of the multi-chain polyhydrophilic group type compounds further has an amino acid residue in the molecule. The liposome according to any one of claims 1 to 3, wherein at least one of the multi-chain polyhydrophilic group type compounds is a compound represented by the following general formula (1).

(In the above general formula (1), X is a linear, branched, cyclic, or aromatic group having a molecular weight of 1,000,000 or less, which may have m functional groups and further have other substituents. N (m ≧ n) Q bonded to X are substituents represented by the following general formula (2), which may be the same as or different from each other. Represents an integer of 2 to 20. m represents an integer satisfying m ≧ n.

In the general formula (2), Z is a bond derived from a functional group of X, R ¹ CO represents an acyl group derived from a saturated or unsaturated fatty acid having 2 to 20 carbon atoms, R ² represents hydrogen, or a lower alkyl group having 1 to 3 carbon atoms which may be substituted with a hydroxyl group or a carboxyl group, and Y represents a carboxyl group, a sulfonic acid group, a sulfate group, or a phosphate group. Or any of their salts. j and k are each independently 0, 1, or 2, and j and k are not 0 at the same time. )   The liposome according to claim 4, wherein the carbon number of X is 1 to 40.   The liposome according to any one of claims 1 to 5, wherein the content of the multi-chain polyhydrophilic group type compound is 0.001% by mass or more and 50% by mass or less.   The liposome according to any one of claims 1 to 6, comprising (C) a nonionic surfactant, wherein (C) / (A) is 0.1 to 50 in terms of mass ratio.   The liposome according to any one of claims 1 to 7, comprising (D) a liposome-forming aid, wherein (D) / (A) is 0.01 to 10 by mass ratio.   The said (D) liposome formation adjuvant is 1 or more types chosen from the group which consists of cholesterol, the fatty acid ester of this cholesterol, the alkyl ether of this cholesterol, and a fatty acid, The Claim 8 characterized by the above-mentioned. Liposome.   A liposome preparation comprising (E) a physiologically active substance in the liposome according to any one of claims 1 to 9. An external preparation comprising the liposome according to any one of claims 1 to 9 or the liposome preparation according to claim 10.