JP2008088133A - Vesicle composition and skin care preparation comprising the same - Google Patents
Vesicle composition and skin care preparation comprising the same Download PDFInfo
- Publication number
- JP2008088133A JP2008088133A JP2006273357A JP2006273357A JP2008088133A JP 2008088133 A JP2008088133 A JP 2008088133A JP 2006273357 A JP2006273357 A JP 2006273357A JP 2006273357 A JP2006273357 A JP 2006273357A JP 2008088133 A JP2008088133 A JP 2008088133A
- Authority
- JP
- Japan
- Prior art keywords
- vesicle composition
- phospholipid
- derivative
- vesicle
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
本発明は、所定のリン脂質誘導体を含有するベシクル組成物、及びそれを用いた皮膚外用剤に関する。 The present invention relates to a vesicle composition containing a predetermined phospholipid derivative and a skin external preparation using the same.
従来、化粧料等の皮膚外用剤中に、非水溶性の有効成分を配合する方法として、水系担体に、ベシクル粒子として分散させる方法が広く利用されている。その一例として、セラミドと、リン脂質と、所定のカチオン性界面活性剤とを含有する外用組成物;及びセラミドと、ステロール乃至はその配糖体と、所定のカチオン性界面活性剤と、リン脂質とを含有する外用組成物が提案されている(例えば、特許文献1及び2)。また、角質層の皮膚バリア回復を高める活性物質に対する水ベースの伝達システムであって、水、脂肪酸、コレステロール、セラミド/リン脂質部分を含む伝達システムが提案されている(例えば、特許文献3)。この様に、従来、リン脂質は、ベシクル分散系の調製に広く用いられている。 Conventionally, a method of dispersing vesicle particles in an aqueous carrier has been widely used as a method of blending a water-insoluble active ingredient into a skin external preparation such as cosmetics. As an example, an external composition containing ceramide, phospholipid, and a predetermined cationic surfactant; and ceramide, sterol or a glycoside thereof, a predetermined cationic surfactant, and a phospholipid The composition for external use containing these is proposed (for example, patent document 1 and 2). In addition, a water-based transmission system for an active substance that enhances skin barrier recovery of the stratum corneum has been proposed (for example, Patent Document 3) including water, fatty acid, cholesterol, and a ceramide / phospholipid moiety. Thus, conventionally, phospholipids have been widely used for the preparation of vesicle dispersions.
ところで、リン脂質は、一般的に、グリセリン骨格のC−1、2位に脂肪酸がエステル結合している。従来ベシクル分散系の調製に用いられているリン脂質では、このエステル結合が経時によって切断されてしまい、その結果、脂肪酸が遊離することがしばしばある。遊離した脂肪酸は、系のpHを低下させ、ベシクルの分散安定性を低下させる。また、遊離した脂肪酸は、皮膚外用剤の黄色化及び臭気を生じさせ、皮膚外用剤の品質の低下の原因になる。かかる状況下、脂肪酸の遊離等による劣化がなく、経時安定性に優れたベシクル組成物の提供が望まれている。 By the way, phospholipids generally have a fatty acid ester-bonded at positions C-1 and 2 of the glycerin skeleton. In phospholipids conventionally used for the preparation of vesicle dispersions, this ester bond is cleaved over time, and as a result, fatty acids are often released. The liberated fatty acids lower the pH of the system and reduce the dispersion stability of the vesicles. Moreover, the liberated fatty acid causes yellowing and odor of the external preparation for skin and causes deterioration of the quality of the external preparation for skin. Under such circumstances, it is desired to provide a vesicle composition that is not deteriorated due to liberation of fatty acids and has excellent temporal stability.
一方、有効成分の中には、皮膚吸収性が低い物質もあり、かかる有効成分を安定的に配合するのみならず、皮膚に適用した際には、皮膚に効率よく吸収させることができる技術も望まれている。例えば、有効成分を所定の光分解性リン脂質を成分とする光破砕性リポソームに内包させることにより、有効成分の皮膚吸収性を改善させた皮膚化粧料が提案されている(例えば、特許文献4)。
本発明は前記諸問題に鑑みなされてものであって、pHの変動、変色及び異臭がなく、経時安定性に優れているとともに、皮膚浸透性にも優れたベシクル組成物及び皮膚外用剤を提供することを課題とする。 The present invention has been made in view of the above problems, and provides a vesicle composition and an external preparation for skin that are free from pH fluctuations, discoloration, and offensive odor, have excellent temporal stability, and are excellent in skin permeability. The task is to do.
前記課題を解決するため、本発明のベシクル組成物は、2位アシル基が不飽和脂肪酸の残基であるリン脂質誘導体の少なくとも1種と、スフィンゴシン誘導体の少なくとも1種とを含有することを特徴とする。
本発明の態様として、前記スフィンゴシン誘導体が、セラミドであることを特徴とする前記ベシクル組成物;前記不飽和脂肪酸の残基が、オレイン酸の残基であることを特徴とする前記ベシクル組成物;前記リン脂質誘導体と前記スフィンゴシン誘導体とを、重量比で1:0.001〜1:0.5含有することを特徴とする前記ベシクル組成物;前記リン脂質誘導体が、大豆由来のリン脂質を原料とするリン脂質誘導体であることを特徴とする前記ベシクル組成物;コレステロール及び/又はフィトステロールをさらに含有する前記ベシクル組成物;及び前記リン脂質誘導体が、天然水素添加リン脂を原料とし、且つ下記一般式(1)で表されるリン脂質誘導体であることを特徴とする前記ベシクル組成物;が提供される。
In order to solve the above problems, the vesicle composition of the present invention contains at least one phospholipid derivative in which the 2-position acyl group is a residue of an unsaturated fatty acid and at least one sphingosine derivative. And
As an aspect of the present invention, the vesicle composition wherein the sphingosine derivative is ceramide; the vesicle composition wherein the unsaturated fatty acid residue is an oleic acid residue; The vesicle composition containing the phospholipid derivative and the sphingosine derivative in a weight ratio of 1: 0.001 to 1: 0.5; the phospholipid derivative is made from soybean-derived phospholipid as a raw material The vesicle composition characterized by being a phospholipid derivative; the vesicle composition further containing cholesterol and / or phytosterol; and the phospholipid derivative using natural hydrogenated phospholipid as a raw material, and The vesicle composition characterized by being a phospholipid derivative represented by the formula (1) is provided.
また、別の観点から前記ベシクル組成物を含有することを特徴とする皮膚外用剤;及びスフィンゴシン誘導体を2位アシル基が不飽和脂肪酸の残基であるリン脂質誘導体のリポソームに内包させることを含むスフィンゴシン誘導体の皮膚浸透性を向上させる方法;が提供される。 Further, the preparation for external application to the skin containing the vesicle composition from another viewpoint; and including a sphingosine derivative in a liposome of a phospholipid derivative in which the 2-position acyl group is a residue of an unsaturated fatty acid. There is provided a method of improving the skin permeability of sphingosine derivatives.
本発明によれば、pHの変動、変色及び異臭がなく、経時安定性に優れているとともに、皮膚浸透性にも優れたベシクル組成物及び皮膚外用剤を提供することができる。 According to the present invention, it is possible to provide a vesicle composition and an external preparation for skin that are free from fluctuations in pH, discoloration, and unpleasant odor, have excellent temporal stability, and are excellent in skin permeability.
以下、本発明について詳細に説明する。本明細書において「〜」とはその前後に記載される数値を下限値及び上限値として含む意味で使用される。
本発明のベシクル組成物は、2位アシル基が不飽和脂肪酸の残基であるリン脂質誘導体の少なくとも1種を含有する。前記リン脂質誘導体は、スフィンゴシン誘導体のベシクルの安定化に寄与するとともに、スフィンゴシン誘導体を皮膚へ浸透させ易くする作用を有する。さらに、前記リン脂質誘導体は、脂肪酸の遊離がない又は少ないので、経時安定性に優れたベシクル組成物の調製が可能となる。
Hereinafter, the present invention will be described in detail. In the present specification, “to” is used to mean that the numerical values described before and after it are included as a lower limit value and an upper limit value.
The vesicle composition of the present invention contains at least one phospholipid derivative in which the 2-position acyl group is a residue of an unsaturated fatty acid. The phospholipid derivative contributes to stabilization of the vesicle of the sphingosine derivative and has an effect of facilitating the penetration of the sphingosine derivative into the skin. Furthermore, since the phospholipid derivative has no or little liberation of fatty acid, it becomes possible to prepare a vesicle composition having excellent stability over time.
前記リン脂質誘導体は、2位アシル基として不飽和脂肪酸の残基を有する。前記不飽和脂肪酸としては、炭素数14〜22の不飽和脂肪酸が好ましく、炭素数18〜22の不飽和脂肪酸がより好ましく、オレイン酸、ガドレイン酸及びエルカ酸等の炭素数18〜22のモノ(不飽和結合が一つ)不飽和脂肪酸がさらに好ましい。中でも、オレイン酸が特に好ましい。また、前記リン脂質誘導体の1位については特に制限はないが、飽和脂肪酸の残基であるのが好ましい。該飽和脂肪酸としては、ミリスチン酸及びステアリン酸等の炭素数14〜18の飽和脂肪酸が好ましい。 The phospholipid derivative has an unsaturated fatty acid residue as the 2-position acyl group. As the unsaturated fatty acid, an unsaturated fatty acid having 14 to 22 carbon atoms is preferable, an unsaturated fatty acid having 18 to 22 carbon atoms is more preferable, and mono (18 to 22 carbon atoms such as oleic acid, gadoleic acid and erucic acid ( One unsaturated bond) and more preferably an unsaturated fatty acid. Of these, oleic acid is particularly preferable. Further, the position 1 of the phospholipid derivative is not particularly limited, but is preferably a saturated fatty acid residue. The saturated fatty acid is preferably a saturated fatty acid having 14 to 18 carbon atoms such as myristic acid and stearic acid.
本発明に用いる前記リン脂質誘導体の原料は、安定性の観点から、天然由来のリン脂質であるのが好ましく、天然由来であり且つ水素添加によって不飽和脂肪酸を実質的に有しない天然水素添加リン脂質であるのがより好ましい。このような水素添加天然リン脂質原料としては、植物又は黄卵由来のリン脂質がより好ましく、水素添加大豆リン脂質がさらに好ましい。また、ベシクルの分散安定性の観点から、リン脂質原料中のホスファチジルコリン含有量は、85重量%であるのが好ましく、90重量%であるのがより好ましい。 The raw material of the phospholipid derivative used in the present invention is preferably a naturally-derived phospholipid from the viewpoint of stability, and is naturally-derived phospholipid that is naturally-derived and does not substantially contain unsaturated fatty acids by hydrogenation. More preferably, it is a lipid. As such a hydrogenated natural phospholipid raw material, a phospholipid derived from a plant or yolk is more preferable, and hydrogenated soybean phospholipid is more preferable. From the viewpoint of vesicle dispersion stability, the phosphatidylcholine content in the phospholipid raw material is preferably 85% by weight, more preferably 90% by weight.
本発明に用いる前記リン脂質誘導体の好ましい例には、下記一般式(1)で表されるリン脂質誘導体が含まれる。 Preferable examples of the phospholipid derivative used in the present invention include a phospholipid derivative represented by the following general formula (1).
式中、R1COは、炭素数14〜18の脂肪酸(好ましくは飽和脂肪酸)の残基であり、R2COは、炭素数18〜22の分子内に二重結合を一つ有する不飽和脂肪酸の残基である。なお、用いる原料の純度によっては、R1COには不飽和脂肪酸の残基が混在する場合があるが、その場合には不飽和脂肪酸の割合は0.1モル%以下であるのが好ましい。また、同様に用いる原料の純度によっては、R2COには2個以上の不飽和基を持つ炭素数14〜22の不飽和脂肪酸の残基が混在するが、かかる場合は、2個以上の不飽和基を持つポリ不飽和脂肪酸の割合が0.1モル%以下で、且つ分子内に二重結合を一つ有する不飽和脂肪酸の割合が90モル%以上であるのが好ましい。混在する割合が上記範囲であると、脂肪酸の遊離がない又は少ないリン脂質誘導体となる。
上記一般式(1)で表されるリン脂質誘導体は、天然水素添加リン脂質を原料とし製造されたものであるのが、安全性等の観点で好ましい。
In the formula, R 1 CO is a residue of a fatty acid having 14 to 18 carbon atoms (preferably a saturated fatty acid), and R 2 CO is unsaturated having one double bond in the molecule having 18 to 22 carbon atoms. Fatty acid residue. Depending on the purity of the raw material used, unsaturated fatty acid residues may be mixed in R 1 CO. In that case, the unsaturated fatty acid ratio is preferably 0.1 mol% or less. Similarly, depending on the purity of the raw material used, R 2 CO may contain residues of unsaturated fatty acids having 14 to 22 carbon atoms having two or more unsaturated groups. The ratio of polyunsaturated fatty acid having an unsaturated group is preferably 0.1 mol% or less, and the ratio of unsaturated fatty acid having one double bond in the molecule is preferably 90 mol% or more. When the mixing ratio is in the above range, the phospholipid derivative is free or free of fatty acids.
The phospholipid derivative represented by the general formula (1) is preferably produced from natural hydrogenated phospholipid as a raw material from the viewpoint of safety and the like.
前記リン脂質誘導体の合成例としては以下の例が挙げられる。
まず、天然水素添加リン脂質(特に好ましくは水素添加大豆リン脂質)を原料に用い、2位を塩化カルシウム共存下、ホスホリパーゼA2で加水分解し、リゾリン脂質を得る。次に、このリゾリン脂質の2位を、炭素数18〜22の脂肪酸(2個以上の不飽和基を持つ不飽和脂肪酸が0.1モル%以下であり、分子内に二重結合を一つ有する不飽和脂肪酸が90モル%以上である)でアシル化する。アシル化の方法としては、特に限定されず、通常のアシル化法を用いればよい。アシル化によって、2位アシル基が不飽和脂肪酸の残基であるリン脂質誘導体が得られる。
Examples of the synthesis of the phospholipid derivative include the following examples.
First, natural hydrogenated phospholipid (particularly preferably hydrogenated soybean phospholipid) is used as a raw material, and the 2nd position is hydrolyzed with phospholipase A 2 in the presence of calcium chloride to obtain lysophospholipid. Next, the position 2 of this lysophospholipid is a fatty acid having 18 to 22 carbon atoms (the unsaturated fatty acid having two or more unsaturated groups is 0.1 mol% or less, and one double bond is present in the molecule). The unsaturated fatty acid is 90 mol% or more). The acylation method is not particularly limited, and a normal acylation method may be used. Acylation provides a phospholipid derivative in which the 2-position acyl group is a residue of an unsaturated fatty acid.
前記リン脂質誘導体の相転移温度は、低いのが好ましい。37℃以下であるのが好ましく、25℃以下であるのがより好ましく、0℃以下であるのがさらに好ましい。相転移温度が前記範囲であると、より安定なベシクル組成物を調製できるとともに、経時安定性がより改善される。 The phase transition temperature of the phospholipid derivative is preferably low. It is preferably 37 ° C. or lower, more preferably 25 ° C. or lower, and even more preferably 0 ° C. or lower. When the phase transition temperature is within the above range, a more stable vesicle composition can be prepared, and stability over time is further improved.
本発明のベシクル組成物は、スフィンゴシン誘導体の少なくとも1種を含有する。スフィンゴシン誘導体の例には、N−アシルスフィンゴシン、N−ヒドロキシアシルフィトスフィンゴシン、及びN−アシルフィトスフィンゴシンが含まれる。中でもセラミドが好ましい。セラミドには、タイプ1〜タイプ7の7タイプが存することが知られており、それらのいずれも利用できる。中でも、N−ステアロイルフィトスフィンゴシン等のN−アシルフィトスフィンゴシンが好ましい。また、下記一般式(2)又は(3)で表される化合物も好ましい。 The vesicle composition of the present invention contains at least one sphingosine derivative. Examples of sphingosine derivatives include N-acyl sphingosine, N-hydroxyacyl phytosphingosine, and N-acyl phytosphingosine. Of these, ceramide is preferred. It is known that there are seven types of ceramide, Type 1 to Type 7, and any of them can be used. Among these, N-acyl phytosphingosine such as N-stearoyl phytosphingosine is preferable. Moreover, the compound represented by the following general formula (2) or (3) is also preferable.
前記式(2)中、R1及びR2は、各々1個以上の水酸基が置換することのある炭素数6〜28の直鎖もしくは分岐鎖の飽和又は不飽和の炭化水素基を表す。
前記式(3Z)中、aは12〜20、bは20〜40、dは7〜49、及びeは10〜98の整数を表し、R3は、各々1個以上の水酸基が置換することのある炭素数6〜28の直鎖もしくは分岐鎖の飽和又は不飽和の炭化水素基を表す。
Formula (2), R 1 and R 2 represents a straight-chain or branched-chain saturated or unsaturated hydrocarbon group having a carbon number of 6 to 28 which may each one or more hydroxyl groups are substituted.
In the formula (3Z), a represents an integer of 12 to 20, b represents 20 to 40, d represents an integer of 7 to 49, and e represents an integer of 10 to 98, and each R 3 is substituted with one or more hydroxyl groups. A linear or branched saturated or unsaturated hydrocarbon group having 6 to 28 carbon atoms.
また、本発明では、スフィンゴシン誘導体として、市販品を用いてもよい。 Moreover, in this invention, you may use a commercial item as a sphingosine derivative.
本発明のベシクル組成物は、前記リン脂質誘導体の1種のみを含有していてもよいし、2種以上を含有していてもよい。また、前記スフィンゴシン誘導体についても、1種のみを含有していてもよいし、2種以上を含有していてもよい。本発明のベシクル組成物における前記リン脂質誘導体と前記スフィンゴシン誘導体との重量比は、1:0.001〜1:0.5であるのが好ましく、1:0.01〜1:0.3であるのがより好ましい。重量比が前記範囲であると、より安定性の高いベシクル組成物となる。 The vesicle composition of the present invention may contain only one kind of the phospholipid derivative, or may contain two or more kinds. Moreover, also about the said sphingosine derivative | guide_body, only 1 type may be contained and 2 or more types may be contained. The weight ratio of the phospholipid derivative to the sphingosine derivative in the vesicle composition of the present invention is preferably 1: 0.001 to 1: 0.5, and preferably 1: 0.01 to 1: 0.3. More preferably. When the weight ratio is in the above range, a more stable vesicle composition is obtained.
本発明のベシクル組成物は、分散安定性等に寄与する添加剤をさらに含有していてもよい。中でもコレステロール及びフィトステロールを添加すると、より安定なベシクル組成物となるので好ましい。コレステロール又はフィトステロールを含有した態様では、前記リン脂質誘導体とコレステロール又はフィトステロールとの質量比は、1:0.001〜1:0.7であるのが好ましく、1:0.02〜1:0.4であるのがより好ましい。また、前記スフィンゴシン誘導体とコレステロール又はフィトステロールとの質量比は、1:10〜1:0.001であるのが好ましく、1:5〜1:0.01であるのがより好ましい。 The vesicle composition of the present invention may further contain an additive that contributes to dispersion stability and the like. Among these, addition of cholesterol and phytosterol is preferable because a more stable vesicle composition is obtained. In the aspect containing cholesterol or phytosterol, the mass ratio of the phospholipid derivative to cholesterol or phytosterol is preferably 1: 0.001-1: 0.7, and 1: 0.02-1: 0. 4 is more preferable. The mass ratio of the sphingosine derivative to cholesterol or phytosterol is preferably 1:10 to 1: 0.001, and more preferably 1: 5 to 1: 0.01.
また、本発明のベシクル組成物は、本発明の効果を阻害しない範囲で、ベシクル粒子中に内包される成分として、スフィンゴシン誘導体とともに、他の生理活性物質、例えば、酵素、ペプチド、ホルモン、細胞増殖因子、プラセンタエキス、ATP、サイクリックATP、インターフェロン、ビタミンA類、トコフェロール、カロチン、ローヤルゼリー、菌代謝物、プロスタグランディン及びビタミンD、などが配合されていてもよい。さらに、スフィンゴシン誘導体とともに、他の有効成分、例えば、アスタキサンチン、及びその誘導体等の有効成分を配合してもよい。 In addition, the vesicle composition of the present invention, as long as it does not inhibit the effects of the present invention, as a component encapsulated in vesicle particles, together with sphingosine derivatives, other physiologically active substances such as enzymes, peptides, hormones, cell growth Factors, placenta extract, ATP, cyclic ATP, interferon, vitamins A, tocopherol, carotene, royal jelly, fungal metabolites, prostaglandins and vitamin D may be blended. Furthermore, you may mix | blend another active ingredient, for example, active ingredients, such as an astaxanthin and its derivative, with a sphingosine derivative.
本発明のベシクル組成物の分散媒については特に制限はなく、精製水のみであっても、精製水と親水性有機溶媒との混合溶媒であってもよい。また、本発明のベシクル組成物には、pH調整剤、界面活性剤、水溶性高分子等の添加剤を種々添加してもよい。 The dispersion medium of the vesicle composition of the present invention is not particularly limited, and may be purified water alone or a mixed solvent of purified water and a hydrophilic organic solvent. Moreover, you may add various additives, such as a pH adjuster, surfactant, and water-soluble polymer, to the vesicle composition of this invention.
本発明のベシクル組成物の調製方法については特に制限されず、一般的な方法により調製することができる。例えば、ボルテクスイング法(A.D.Bangham、J.Mol.Biol.,13,238(1965))、ソニケーション法(C.Huang,Biochem.,8,344(1969))、プレベシクル法(H.Trauble,Neurosci.Res.Prog.Bull.,9,273(1971))、エタノール注入法(S.Batzri,Biochem.Biophys.Acta.,298,1015(1973))、フレンチプレス押出法(Y.Barenholz,FEBS Lett.,99,210(1979))、コール酸除去法(Y.Kagawa,J.Biol.Chem.,246,5477(1971))、トリトンX−100バッチ法(W.J.Gerritsen,Eur.J.Biochem.,85,255(1978))、Ca2+融合法(D.Papahadojopoulos,Biochem.Biophys.Acta.,394,483(1975))、エーテル注入法(D.Deazer,Biochem.Biophys.Acta.,443,629(1976))、アニーリング法(R.Lawaczeck,Biochem.Biophys.Acta.,443,313(1976))、凍結融解融合法(M.Kasahara,J.Biol.Chem.,252,7384(1977))、W/O/Wエマルジョン法(S.Matsumoto,J.Colloid InterfaceSci.,62,149(1977))、逆相蒸発法(F.Szoka,Proc.Natl.Acad.Sci.USA,75,4194(1978))、多価アルコール法(特開昭60−7932号)等により調製することができる。 The method for preparing the vesicle composition of the present invention is not particularly limited, and can be prepared by a general method. For example, the vortex swing method (AD Bangham, J. Mol. Biol., 13, 238 (1965)), sonication method (C. Huang, Biochem., 8, 344 (1969)), prevesicle method (H Trauble, Neurosci.Res.Prog.Bull., 9, 273 (1971)), ethanol injection method (S. Batzri, Biochem. Biophys. Acta., 298, 1015 (1973)), French press extrusion method (Y. Barenholz, FEBS Lett., 99, 210 (1979)), cholic acid removal method (Y. Kagawa, J. Biol. Chem., 246, 5477 (1971)), Triton X-100 batch method (W. J. Gerritsen). , Eur.J.Bioc hem., 85, 255 (1978)), Ca2 + fusion method (D. Papahadojopoulos, Biochem. Biophys. Acta., 394, 483 (1975)), ether injection method (D. Dezer, Biochem. Biophys. Acta., 443). 629 (1976)), annealing method (R. Lawaczeck, Biochem. Biophys. Acta., 443, 313 (1976)), freeze-thaw fusion method (M. Kasahara, J. Biol. Chem., 252, 7384 (1977). )), W / O / W emulsion method (S. Matsumoto, J. Colloid Interface Sci., 62, 149 (1977)), reverse phase evaporation method (F. Szoka, Proc. Natl. Acad. S). i.USA, 75,4194 (1978)), can be prepared by polyhydric alcohols method (JP 60-7932) and the like.
本発明のベシクル組成物は、種々の用途に用いることができる。皮膚浸透性が高いことから、皮膚外用剤中に配合するのが好ましい。皮膚外用剤に対する本発明のベシクル組成物の含有量は特に限定されないが、好ましくは、1.0〜90質量%(以下、単に「%」という)であり、より好ましくは3.0〜50%である。皮膚外用剤における前記リン脂質誘導体の最終的濃度が、5%以下であるのが好ましく、0.01〜3%であるのがより好ましい。 The vesicle composition of the present invention can be used for various applications. Since skin permeability is high, it is preferable to mix in a skin external preparation. The content of the vesicle composition of the present invention relative to the external preparation for skin is not particularly limited, but is preferably 1.0 to 90% by mass (hereinafter simply referred to as “%”), more preferably 3.0 to 50%. It is. The final concentration of the phospholipid derivative in the external preparation for skin is preferably 5% or less, more preferably 0.01 to 3%.
本発明の皮膚外用剤の形態は、特に限定されず、例えば、乳液、クリーム、化粧水、美容液、パック、洗浄料、メーキャップ化粧料のいずれの皮膚外用剤であってもよい。また、剤型についても特に限定されず、分散液、軟膏、液剤、エアゾール、貼付剤、パップ剤、リニメント剤等のいずれの化粧料であっても外用医薬品等であってもよい。 The form of the external preparation for skin of the present invention is not particularly limited, and may be any external preparation for skin such as emulsion, cream, lotion, cosmetic liquid, pack, cleansing agent, and makeup cosmetic. Also, the dosage form is not particularly limited, and it may be any cosmetic such as a dispersion, ointment, liquid, aerosol, patch, poultice, liniment, or external medicine.
又、本発明の皮膚外用剤は、前記ベシクル組成物以外に、化粧料や医薬部外品、外用医薬品等に通常使用される各種の成分、即ち、水、アルコール、油剤、界面活性剤、増粘剤、粉体、キレート剤、pH調整剤、保湿剤、美白剤、抗炎症剤、細胞賦活剤等の各種薬効剤、動植物・微生物由来の抽出物、香料等を、本発明の効果を損なわない範囲で適宜加えることができる。 In addition to the vesicle composition, the external preparation for skin of the present invention includes various components usually used in cosmetics, quasi-drugs, external medicines, that is, water, alcohols, oils, surfactants, Viscous agents, powders, chelating agents, pH adjusters, moisturizers, whitening agents, anti-inflammatory agents, cell activators, and other medicinal agents, extracts derived from animals, plants and microorganisms, fragrances, etc. It can be added as long as it is not.
以下に実施例を挙げて本発明をさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されることはない。
[リン脂質誘導体1の調製]
水素添加大豆リン脂質ホスファチジルコリン(ホスファチジルコリン純度:90%品、C16:0=17.7モル%、C18:0=81.9モル%)120gを、クロロホルム1800ミリリットルに溶解し、塩酸100ミリモルトリス(ヒドロキシメチル)アミノメタン緩衝液(pH=8.0)880ミリリットル、100ミリモル塩化カルシウム水溶液1320ミリリットル、及びホスホリパーゼA22400単位を加え、40℃で24時間反応し、2位のアシル基を加水分解した。反応後、反応液に蒸留水を加え、2層に分離した後、下層をフラスコに分取し、エバポレータで溶媒留去し、さらにヘキサンを加えて冷却した後、ろ過して析出物64.3gを得た。これにクロロホルム及びメタノールを加え、溶解し、イオン交換樹脂(アンバーライトIRC−50、ロームアンドハース社製)を充填したカラムに通液し、その後濃縮した。アセトンに溶解して、静置後、ろ過して析出物60.3gを得た。この析出物は、1−アシル−2−リゾホスファチジルコリン(1位アシルC16:0=24.6mol%、C18:0=75.4mol%)であった。
The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to the following examples.
[Preparation of Phospholipid Derivative 1]
120 g of hydrogenated soybean phospholipid phosphatidylcholine (phosphatidylcholine purity: 90% product, C16: 0 = 17.7 mol%, C18: 0 = 81.9 mol%) was dissolved in 1800 ml of chloroform, and 100 mmol of hydrochloric acid Tris (hydroxyl) Methyl) aminomethane buffer (pH = 8.0) 880 ml, 100 mmol calcium chloride aqueous solution 1320 ml, and phospholipase A 2 2400 units were added and reacted at 40 ° C. for 24 hours to hydrolyze the 2-position acyl group. . After the reaction, distilled water was added to the reaction solution, and after separating into two layers, the lower layer was separated into a flask, the solvent was distilled off with an evaporator, and further cooled with hexane, followed by filtration and 64.3 g of a precipitate. Got. Chloroform and methanol were added and dissolved therein, and the solution was passed through a column filled with an ion exchange resin (Amberlite IRC-50, manufactured by Rohm and Haas), and then concentrated. It melt | dissolved in acetone, and after leaving still, it filtered and 60.3g of deposits were obtained. This precipitate was 1-acyl-2-lysophosphatidylcholine (1-position acyl C16: 0 = 24.6 mol%, C18: 0 = 75.4 mol%).
上記得られた析出物に、オレイン酸無水物溶液、ジメチルアミノピリジンを加え、40℃で24時間反応させた。得られた反応液をエバポレータで溶媒留去し、酢酸エチル及び蒸留水を加え、2層に分離させた。下層を分取し、クロロホルムを加え、2層に分離し、下層を分取した。得られた下層にクロロホルムを加えて希釈し、イオン交換樹脂(アンバーライトIRC−50、ロームアンドハース社製)を充填したカラムに通液し、その後濃縮した。アセトンに溶解して、ろ過して静置後、1−アシル−2−オレオイル−3−ホスファチジルコリンを50.1g得た。これをリン脂質誘導体1として用いた。得られたリン脂質誘導体1は、R1COが、水素添加飽和大豆リン脂質由来の脂肪酸の残基(パルミチン酸およびステアリン酸が主構成脂肪酸、双方の合計が100mol%)であり、R2COがオレイン酸の残基(99.2mol%)である前記一般式(1)で表される化合物であった。 To the precipitate obtained above, an oleic anhydride solution and dimethylaminopyridine were added and reacted at 40 ° C. for 24 hours. The obtained reaction solution was evaporated using an evaporator, and ethyl acetate and distilled water were added to separate the solution into two layers. The lower layer was fractionated, chloroform was added, and it separated into two layers, and the lower layer was fractionated. Chloroform was added to the resulting lower layer for dilution, and the solution was passed through a column filled with an ion exchange resin (Amberlite IRC-50, manufactured by Rohm and Haas), and then concentrated. After dissolving in acetone, filtering and allowing to stand, 50.1 g of 1-acyl-2-oleoyl-3-phosphatidylcholine was obtained. This was used as phospholipid derivative 1. In the obtained phospholipid derivative 1, R 1 CO is a residue of a fatty acid derived from hydrogenated saturated soybean phospholipid (palmitic acid and stearic acid are main constituent fatty acids, the total of both being 100 mol%), and R 2 CO Is a compound represented by the above general formula (1), which is a residue (99.2 mol%) of oleic acid.
[リン脂質誘導体1の安定性評価]
上記調製したリン脂質誘導体1、卵黄レシチン、及び大豆レシチンをそれぞれ用いて、下記表1に示す組成のリポソーム含有水分散液(分散液1〜3)をそれぞれ調製し、40℃で1ヶ月保存して、pH変化、臭いの変化及び色の変化を評価した。
(調製方法)
A:成分1〜3のいずれかを成分6の一部で水和した後、成分6の残部に分散する。
B:Aをマイクロフルイダイザーにて処理する。
C:Bに成分4及び5を添加し、リポソーム含有水分散液(試料1〜3)を得る。
(評価)
pH変化量:調製直後及び上記条件で保存後に、各試料のpHをpHメータで測定し、算出した。
臭いの変化:◎ ほとんど変化なし
× 明らかに変化を感じる
色の変化: ◎ ほとんど変化なし
× 目視で明らかに変化がわかる
[Stability evaluation of phospholipid derivative 1]
Using the prepared phospholipid derivative 1, egg yolk lecithin and soybean lecithin, liposome-containing aqueous dispersions (dispersions 1 to 3) having the compositions shown in Table 1 below are prepared and stored at 40 ° C. for 1 month. The change in pH, change in odor, and change in color were evaluated.
(Preparation method)
A: One of the components 1 to 3 is hydrated with a part of the component 6, and then dispersed in the remainder of the component 6.
B: A is processed with a microfluidizer.
C: Components 4 and 5 are added to B to obtain liposome-containing aqueous dispersions (samples 1 to 3).
(Evaluation)
pH change amount: Immediately after preparation and after storage under the above conditions, the pH of each sample was measured with a pH meter and calculated.
Odor change: ◎ Almost no change
× Clearly feel the change Color change: ◎ Almost no change
× Clearly visible change
(組成と評価結果) (Composition and evaluation results)
上記表1に示す結果から、リン脂質誘導体1を用いて調製した分散液1は、卵黄レシチン及び大豆レシチンをそれぞれ用いて調製した分散液2及び3と比較して、pHの変化量が小さく、臭い及び色の変化もなかった。これは、リン脂質誘導体1が安定で、保存中に脂肪酸の遊離が生じないことによるものと考えられる。 From the results shown in Table 1 above, the dispersion 1 prepared using the phospholipid derivative 1 has a smaller pH change compared to the dispersions 2 and 3 prepared using egg yolk lecithin and soybean lecithin, respectively. There was no change in odor and color. This is considered to be because the phospholipid derivative 1 is stable and no liberation of fatty acid occurs during storage.
[ベシクル組成物の皮膚浸透性評価]
下記表に示す成分(1)〜(9)を80℃に加熱混合し、均一に分散した後、マイクロフルイダイザーにて処理し、蛍光物質(C−12 NBD Ceramide、Cayman Chemical社製)で標識したベシクル組成物、試料4(実施例)、試料5及び6(ともに比較例)をそれぞれ調製した。
[Evaluation of skin permeability of vesicle composition]
Components (1) to (9) shown in the following table are heated and mixed at 80 ° C. and uniformly dispersed, then treated with a microfluidizer, and labeled with a fluorescent material (C-12 NBD Ceramide, manufactured by Cayman Chemical). The prepared vesicle composition, Sample 4 (Example), Samples 5 and 6 (both Comparative Examples) were prepared.
東洋紡社製3次元皮膚モデル(TESTSKIN LSE)を、フランツ型拡散セルにセットし、蛍光物質(C−12 NBD Ceramide、Cayman Chemical社製)で標識した、上記試料4〜6をそれぞれ一定時間塗布した。その後、3次元皮膚モデルを取り出し、凍結した後、薄層切片とし、共焦点レーザー顕微鏡(FV−1000、オリンパス社製)で撮影を行った。蛍光物質の角層への浸透度合いを、下記の式より算出した。
浸透度合い (%)=蛍光物質が浸透した厚さ/角層全体の厚さ×100
算出された浸透度合いは、試料4は56%、試料5は28%及び、試料6は20%であった。即ち、本発明の実施例である試料4が、比較例である試料5及び6と比較して、皮膚浸透性が非常に高いことがわかった。
Toyobo Co., Ltd. 3D skin model (TESTSKIN LSE) was set in a Franz diffusion cell and labeled with a fluorescent substance (C-12 NBD Ceramide, manufactured by Cayman Chemical Co.) for each of the above samples 4 to 6 for a certain period of time. . Thereafter, the three-dimensional skin model was taken out and frozen, and then taken as a thin-layer slice, and photographed with a confocal laser microscope (FV-1000, manufactured by Olympus Corporation). The degree of penetration of the fluorescent material into the stratum corneum was calculated from the following formula.
Penetration degree (%) = Thickness penetrated by fluorescent substance / total thickness of stratum corneum × 100
The calculated degrees of penetration were 56% for sample 4, 28% for sample 5, and 20% for sample 6. That is, it was found that Sample 4 which is an example of the present invention has very high skin permeability compared to Samples 5 and 6 which are comparative examples.
[ベシクル組成物の安定性評価]
下記表に示す組成のベシクル組成物試料をそれぞれ調製した。
(調製方法)
下記表3に示す成分(1)〜(9)を80℃に加熱混合し、均一に分散した後、マイクロフルイダイザーにて処理した。そこに、(10)〜(13)を添加混合し、ベシクル組成物の試料7〜15をそれぞれ調製した。
(評価方法)
調製した各試料を顕微鏡にて観察し、セラミドの結晶析出の有無を確認した。また、各試料についてベシクルがその形態を保っているか否かについて、電子顕微鏡で観察し、ベシクルの形態保持性を評価した。
さらに、各試料を40℃の恒温槽に4週間放置し、セラミドの結晶析出の有無、及びベシクルの形態保持性を評価した。
[評価]
◎:セラミドの結晶析出もなく、ベシクルの形態についても全く変化は認められない。
○:セラミドの結晶析出もほとんどなく、またベシクルの形態についてもほとんど変化は認められない。
△:セラミドの結晶析出及び/又はベシクルの形態について、やや変化が認められる。
×:セラミドの結晶析出及び/又はベシクルの形態について明らかに変化が認められる。
[Stability evaluation of vesicle composition]
Vesicle composition samples having the compositions shown in the following table were prepared.
(Preparation method)
Components (1) to (9) shown in Table 3 below were heated and mixed at 80 ° C. and dispersed uniformly, and then processed with a microfluidizer. Thereto, (10) to (13) were added and mixed to prepare vesicle composition samples 7 to 15, respectively.
(Evaluation methods)
Each of the prepared samples was observed with a microscope to confirm the presence or absence of ceramide crystal precipitation. Moreover, it was observed with an electron microscope whether each vesicle maintained the form about each sample, and the shape retention property of the vesicle was evaluated.
Further, each sample was left in a constant temperature bath at 40 ° C. for 4 weeks to evaluate the presence or absence of ceramide crystal precipitation and the vesicle shape retention.
[Evaluation]
A: There is no ceramide crystal precipitation, and no change is observed in the form of vesicles.
○: There is almost no crystal precipitation of ceramide, and there is almost no change in the form of vesicles.
Δ: Slight changes are observed in the ceramide crystal precipitation and / or vesicle morphology.
X: A clear change is observed in the ceramide crystal precipitation and / or vesicle morphology.
(組成と評価結果) (Composition and evaluation results)
上記表3の結果から明らかなように、本発明の実施例である試料7〜12のベシクル組成物は、セラミドの分散性及び分散安定性の双方に優れたものであった。これらの試料は、上記条件で放置した後も、その良好な分散性及び分散安定性を維持したが、中でも、コレステロール又はフィトステロールをリン脂質に対して1:0.25〜1:0.02含有する試料7、10、11、12は、経時安定性に特に優れていた。試料7〜12は、リン脂質誘導体1の代わりに水素大豆リン脂質又は卵黄レシチンを用いた比較例用の試料13〜15と比較して、いずれの項目の評価結果も優れていた。
なお、試料13及び15は、コレステロールとの併用により、調製時の分散性及び分散安定性はある程度改善があるものの、上記条件で放置した後には、セラミドの結晶析出及びベシクル粒子の変形又は破壊が観察され、実施例の試料と比較して、経時安定性は格段に劣っていた。
As is clear from the results in Table 3 above, the vesicle compositions of Samples 7 to 12, which are examples of the present invention, were excellent in both dispersibility and dispersion stability of ceramide. These samples maintained their good dispersibility and dispersion stability even after being left under the above conditions. Among them, cholesterol or phytosterol was contained in the range of 1: 0.25 to 1: 0.02 with respect to the phospholipid. Samples 7, 10, 11, and 12 to be performed were particularly excellent in stability over time. Samples 7 to 12 were superior in evaluation results for all items as compared to Comparative Samples 13 to 15 using hydrogen soybean phospholipid or egg yolk lecithin instead of phospholipid derivative 1.
Samples 13 and 15 have some improvement in dispersibility and dispersion stability at the time of preparation due to the combined use with cholesterol. However, after standing under the above conditions, ceramide crystal precipitation and deformation or destruction of vesicle particles occur. Observed, the stability over time was significantly inferior compared to the samples of the examples.
[ベシクル組成物の調製]
下記の成分(1)〜(6)を80℃に加熱混合し、均一に分散した後、マイクロフルイダイザーにて処理してベシクル組成物1を調製した。
(成分) (%)
(1) リン脂質誘導体1 10.0
(2) コレステロール 2.5
(3) セラミドII 2.5
(4) グリセリン 10.0
(5) 1,3−ブチレングリコール 10.0
(6) 精製水 残量
[Preparation of vesicle composition]
The following components (1) to (6) were heated and mixed at 80 ° C. and dispersed uniformly, and then treated with a microfluidizer to prepare a vesicle composition 1.
(Ingredient) (%)
(1) Phospholipid derivative 1 10.0
(2) Cholesterol 2.5
(3) Ceramide II 2.5
(4) Glycerin 10.0
(5) 1,3-butylene glycol 10.0
(6) Purified water remaining
[化粧水の調製]
下記の成分(1)〜(6)を混合して攪拌し、化粧水1を調製した。
(成分) (%)
(1) ベシクル組成物1 40.0
(2) 1,3−ブチレングリコール 15.0
(3) グリセリン 5.0
(4) キサンタンガム 0.1
(5) 防腐剤 適量
(6) 精製水 残量
得られた化粧水は、皮膚浸透性に優れ、肌に保湿及びエモリエント感に与え、且つ安定性も良好な化粧水であった。
[Preparation of lotion]
The following components (1) to (6) were mixed and stirred to prepare skin lotion 1.
(Ingredient) (%)
(1) Vesicle composition 1 40.0
(2) 1,3-butylene glycol 15.0
(3) Glycerin 5.0
(4) Xanthan gum 0.1
(5) Preservative Appropriate amount (6) Purified water Remaining amount The obtained lotion was a skin lotion that was excellent in skin permeability, moisturized and emollient on the skin, and had good stability.
[軟膏の調製]
A.下記成分(1)〜(5)を加熱溶解し、75℃に保つ。
B.下記成分(7)及び(8)を加熱混合し、75℃に保つ。
C.AをBに徐々に加える。
D.Cを冷却しながら下記成分(6)を加え、軟膏を調製した。
(成分) (%)
(1) ステアリン酸 18.0
(2) セタノール 4.0
(3) ポリオキシエチレン付加コレステロール*1 0.5
(4) トリエタノールアミン 1.0
(5) グリセリン 5.0
(6) ベシクル組成物1 30.0
(7)防腐剤 適量
(8)精製水 残量
*1 日光ケミカルズ社製
得られた軟骨は、皮膚浸透性に優れ、肌荒れ改善効果に有効な軟膏であった。
[Preparation of ointment]
A. The following components (1) to (5) are dissolved by heating and maintained at 75 ° C.
B. The following components (7) and (8) are heated and mixed and maintained at 75 ° C.
C. Gradually add A to B.
D. While cooling C, the following component (6) was added to prepare an ointment.
(Ingredient) (%)
(1) Stearic acid 18.0
(2) Cetanol 4.0
(3) Polyoxyethylene-added cholesterol * 1 0.5
(4) Triethanolamine 1.0
(5) Glycerin 5.0
(6) Vesicle composition 1 30.0
(7) Preservative Appropriate amount (8) Purified water Residual amount * 1 Nikko Chemicals Co., Ltd. The obtained cartilage was an ointment that was excellent in skin permeability and effective in improving rough skin.
[パックの調製]
A.成分(1)、(2)、(6)及び(9)を混合し、70℃に加熱し、撹拌する。
B.成分(3)、(4)及び(5)を加熱し、混合する。
C.上記Bを先のAに加え、混合した後、冷却して(7)及び(8)を均一に分散してパックを得た。
(成分) (%)
(1) ポリビニルアルコール 20.0
(2) エタノール 20.0
(3) グリセリン 5.0
(4) フィトステロール*1 0.2
(5) カオリン 6.0
(6) 防腐剤 適量
(7) 香料 適量
(8) ベシクル組成物1 10.0
(9)精製水 残量
*1 エーザイ社製
得えられたパックは、肌に潤いを付与するパックであった。
[Preparation of pack]
A. Ingredients (1), (2), (6) and (9) are mixed, heated to 70 ° C. and stirred.
B. Ingredients (3), (4) and (5) are heated and mixed.
C. The above B was added to the previous A, mixed and then cooled to uniformly disperse (7) and (8) to obtain a pack.
(Ingredient) (%)
(1) Polyvinyl alcohol 20.0
(2) Ethanol 20.0
(3) Glycerin 5.0
(4) Phytosterol * 1 0.2
(5) Kaolin 6.0
(6) Preservative appropriate amount (7) perfume appropriate amount (8) vesicle composition 1 10.0
(9) Purified water remaining amount * 1 Eisai Co., Ltd. The obtained pack was a pack that moisturizes the skin.
[洗浄料の調製]
A.下記成分(8)、(9)、(10)及び(11)を混合し、70℃に加熱する。
B.下記成分(1)〜(6)を混合し、70℃に加熱する。
C.上記Bを先のAに加え、しばらく70℃に保ち、反応が終了後、50℃まで冷却し、成分(7)、(12)を加え、冷却して洗浄料を得た。
(成分) (%)
(1) ステアリン酸 10.0
(2) パルミチン酸 8.0
(3) ミリスチン酸 12.0
(4) ラウリン酸 4.0
(5) オレイルアルコール 1.5
(6) 精製ラノリン 1.0
(7) 香料 適量
(8)防腐剤 適量
(9)グリセリン 18.0
(10)水酸化カリウム 6.0
(11)精製水 残量
(12) ベシクル組成物1 15.0
*1 旭化成社製
*2 日光ケミカルズ社製
得られた洗顔料は、洗浄後の肌に潤いを付与し、肌のかさつきを防止する洗浄料であった。
[Preparation of cleaning material]
A. The following components (8), (9), (10) and (11) are mixed and heated to 70 ° C.
B. The following components (1) to (6) are mixed and heated to 70 ° C.
C. The above B was added to the previous A and kept at 70 ° C. for a while. After the reaction was completed, the mixture was cooled to 50 ° C., components (7) and (12) were added and cooled to obtain a cleaning material.
(Ingredient) (%)
(1) Stearic acid 10.0
(2) Palmitic acid 8.0
(3) Myristic acid 12.0
(4) Lauric acid 4.0
(5) Oleyl alcohol 1.5
(6) Purified lanolin 1.0
(7) Perfume appropriate amount (8) preservative appropriate amount (9) glycerin 18.0
(10) Potassium hydroxide 6.0
(11) Purified water remaining amount (12) Vesicle composition 1 15.0
* 1 Asahi Kasei Co., Ltd. * 2 Nikko Chemicals Co., Ltd. The facial cleanser obtained was a cleansing agent that moisturizes the skin after washing and prevents skin roughness.
Claims (8)
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010229066A (en) * | 2009-03-26 | 2010-10-14 | Kose Corp | Detergent composition |
JP2014208626A (en) * | 2013-03-27 | 2014-11-06 | 株式会社コーセー | Liposome composition |
JP2015113326A (en) * | 2013-12-13 | 2015-06-22 | 株式会社コーセー | Surface treated powder supporting ceramide-containing composition |
WO2018123004A1 (en) * | 2016-12-28 | 2018-07-05 | 小林製薬株式会社 | Topical composition for suppressing melanogenesis |
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JPH11130651A (en) * | 1997-10-24 | 1999-05-18 | Kose Corp | Lipid dispersion composition and cosmetic containing the same |
JP2000281688A (en) * | 1999-03-29 | 2000-10-10 | Nof Corp | Production of mixed acid-type 1,2-diacyl-3- glycerophospholipid |
JP2006193464A (en) * | 2005-01-13 | 2006-07-27 | Pola Chem Ind Inc | Composition for external use |
JP2006199633A (en) * | 2005-01-21 | 2006-08-03 | Pola Chem Ind Inc | Composition for external use |
JP2006265104A (en) * | 2005-03-22 | 2006-10-05 | Nof Corp | Phospholipid derivative for external preparation for skin, external preparation for skin, liposome and fat emulsion |
-
2006
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH11130651A (en) * | 1997-10-24 | 1999-05-18 | Kose Corp | Lipid dispersion composition and cosmetic containing the same |
JP2000281688A (en) * | 1999-03-29 | 2000-10-10 | Nof Corp | Production of mixed acid-type 1,2-diacyl-3- glycerophospholipid |
JP2006193464A (en) * | 2005-01-13 | 2006-07-27 | Pola Chem Ind Inc | Composition for external use |
JP2006199633A (en) * | 2005-01-21 | 2006-08-03 | Pola Chem Ind Inc | Composition for external use |
JP2006265104A (en) * | 2005-03-22 | 2006-10-05 | Nof Corp | Phospholipid derivative for external preparation for skin, external preparation for skin, liposome and fat emulsion |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010229066A (en) * | 2009-03-26 | 2010-10-14 | Kose Corp | Detergent composition |
JP2014208626A (en) * | 2013-03-27 | 2014-11-06 | 株式会社コーセー | Liposome composition |
JP2015113326A (en) * | 2013-12-13 | 2015-06-22 | 株式会社コーセー | Surface treated powder supporting ceramide-containing composition |
WO2018123004A1 (en) * | 2016-12-28 | 2018-07-05 | 小林製薬株式会社 | Topical composition for suppressing melanogenesis |
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