JP2018065762A - Ursolic acid-containing liposome dispersion liquid - Google Patents
Ursolic acid-containing liposome dispersion liquid Download PDFInfo
- Publication number
- JP2018065762A JP2018065762A JP2016205015A JP2016205015A JP2018065762A JP 2018065762 A JP2018065762 A JP 2018065762A JP 2016205015 A JP2016205015 A JP 2016205015A JP 2016205015 A JP2016205015 A JP 2016205015A JP 2018065762 A JP2018065762 A JP 2018065762A
- Authority
- JP
- Japan
- Prior art keywords
- liposome dispersion
- dispersion liquid
- ursolic acid
- sorbitan
- phospholipid
- 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
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 47
- 239000006185 dispersion Substances 0.000 title claims abstract description 43
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 title claims abstract description 26
- 229940096998 ursolic acid Drugs 0.000 title claims abstract description 26
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000007788 liquid Substances 0.000 title claims abstract description 20
- -1 sorbitan fatty acid ester Chemical class 0.000 claims abstract description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 22
- 239000000194 fatty acid Substances 0.000 claims abstract description 22
- 229930195729 fatty acid Natural products 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 18
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- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 13
- 150000003432 sterols Chemical class 0.000 claims abstract description 12
- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 7
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 18
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 9
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 9
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 8
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 8
- 239000002537 cosmetic Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000008347 soybean phospholipid Substances 0.000 claims description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 3
- FGUZFFWTBWJBIL-XWVZOOPGSA-N [(1r)-1-[(2s,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] 16-methylheptadecanoate Chemical group CC(C)CCCCCCCCCCCCCCC(=O)O[C@H](CO)[C@H]1OC[C@H](O)[C@H]1O FGUZFFWTBWJBIL-XWVZOOPGSA-N 0.000 claims description 3
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- RUHCWQAFCGVQJX-RVWHZBQESA-N (3s,8s,9s,10r,13r,14s,17r)-3-hydroxy-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-1-one Chemical compound C1C=C2C[C@H](O)CC(=O)[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 RUHCWQAFCGVQJX-RVWHZBQESA-N 0.000 claims description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 claims description 2
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 4
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- 229910052740 iodine Inorganic materials 0.000 description 4
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- 238000000926 separation method Methods 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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Landscapes
- Cosmetics (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、安定なウルソール酸含有リポソーム分散液及び該リポソーム分散液を配合した外用剤組成物に関する。 The present invention relates to a stable ursolic acid-containing liposome dispersion and an external preparation composition containing the liposome dispersion.
ウルソール酸は、ローズマリー、セージ、デュボイシアなどの植物に、ごくわずかに含まれる成分で、抗炎症作用、美白作用、抗酸化作用、酵素コラゲナーゼの働きを抑制したり、コラーゲン線維の産生を増強する効果があることが知られる。 Ursolic acid is a very small component in plants such as rosemary, sage, and dubosia. It suppresses the action of anti-inflammatory, whitening, antioxidant, and enzyme collagenase, and enhances the production of collagen fibers. It is known to be effective.
しかしながら、ウルソール酸は、水にも油にも溶けにくいという性質から、ウルソール酸を配合した化粧品が製品化される例は少ない。 However, since ursolic acid is hardly soluble in water and oil, there are few examples in which cosmetics containing ursolic acid are commercialized.
ウルソール酸を化粧品に適応するための可溶化技術としては、特開2006−36716号(特許文献1)や特開2013-116880号(特許文献2)が知られている。
特許文献1は、ウルソール酸を油滴に含有させたものを用いた乳化形態をとるものであり、特許文献2は、水性分散物における油相(分散相)を構成する分散粒子に関するギジ技術であり、いずれも本発明のようなリポソーム技術とは相違する。
JP-A-2006-36716 (Patent Document 1) and JP-A-2013-116880 (Patent Document 2) are known as solubilization techniques for applying ursolic acid to cosmetics.
Patent Document 1 takes an emulsified form using an oil droplet containing ursolic acid, and Patent Document 2 is a gigi technique related to dispersed particles constituting an oil phase (dispersed phase) in an aqueous dispersion. Yes, both are different from the liposome technology of the present invention.
本発明の目的は、ウルソール酸を内包する新規なリポソーム分散液を提供し、ウルソール酸を含有した安定な外用剤組成物の製造に役立てることを目的とする。 An object of the present invention is to provide a novel liposome dispersion encapsulating ursolic acid and to be useful for the production of a stable external preparation composition containing ursolic acid.
即ち、本発明は、以下のとおりである。
1)以下の成分(A)〜(E)を含有するリポソーム分散液。
(A)ウルソール酸又はその塩
(B)リン脂質
(C)ポリオキシアルキレンステロールエーテル
(D)ソルビタン脂肪酸エステル及びモノグリセリン脂肪酸エステルからなる群より選ばれる1種又は2種以上の非イオン界面活性剤
(E)多価アルコール
2)(B)リン脂質が、大豆リン脂質又は水素添加大豆リン脂質である1)記載のリポソーム分散液。
3)(C)ポリオキシアルキレンステロールエーテルが、ポリオキシアルキレンコレステロールエーテル又はポリオキシアルキレンフィトステロールエーテルであり、HLBが10以上のものである1)又は2)に記載のリポソーム分散液。
4)(D)非イオン界面活性剤が、ソルビタンイソステアリン酸エステル又はソルビタンオレイン酸エステルである1)〜3)のいずれかに記載のリポソーム分散液。
5)(D)非イオン界面活性剤が、モノグリセリンイソステアリン酸エステル又はモノグリセリンオレイン酸エステルである1)〜3)のいずれかに記載のリポソーム分散液。
6)(E)多価アルコールが、1,3ブチレングリコール及び/又はジプロピレングリコールである1)〜5)のいずれかに記載のリポソーム分散液。
7)1)〜6)のいずれかに記載のリポソーム分散液を配合した外用剤組成物。
8)化粧料である7)記載の外用剤組成物。
That is, the present invention is as follows.
1) Liposome dispersion containing the following components (A) to (E).
(A) Ursolic acid or salt thereof (B) Phospholipid (C) Polyoxyalkylene sterol ether (D) One or more nonionic surfactants selected from the group consisting of sorbitan fatty acid esters and monoglycerin fatty acid esters (E) Polyhydric alcohol 2) (B) The liposome dispersion liquid according to 1), wherein the phospholipid is soybean phospholipid or hydrogenated soybean phospholipid.
3) The liposome dispersion liquid according to 1) or 2), wherein (C) polyoxyalkylene sterol ether is polyoxyalkylene cholesterol ether or polyoxyalkylene phytosterol ether, and HLB is 10 or more.
4) (D) The liposome dispersion liquid according to any one of 1) to 3), wherein the nonionic surfactant is sorbitan isostearate or sorbitan oleate.
5) The liposome dispersion liquid according to any one of 1) to 3), wherein (D) the nonionic surfactant is monoglycerin isostearate or monoglycerin oleate.
6) The liposome dispersion liquid according to any one of 1) to 5), wherein (E) the polyhydric alcohol is 1,3 butylene glycol and / or dipropylene glycol.
7) An external preparation composition containing the liposome dispersion liquid according to any one of 1) to 6).
8) The external preparation composition according to 7), which is a cosmetic.
本発明により、ウルソール酸を含有するリポソーム分散液を提供が可能となり、経時安定性に優れたウルソール酸含有外用剤組成物の提供が可能となった。 According to the present invention, it is possible to provide a liposome dispersion containing ursolic acid, and it is possible to provide a ursolic acid-containing external preparation composition excellent in stability over time.
本発明のリポソーム分散液は、(A)ウルソール酸、(B)リン脂質、(C)ポリオキシアルキレンステロールエーテル、及び(D)ソルビタン脂肪酸エステル又はモノグリセリン脂肪酸エステル、(E)多価アルコールを含有することを特徴とする。 The liposome dispersion of the present invention contains (A) ursolic acid, (B) phospholipid, (C) polyoxyalkylene sterol ether, and (D) sorbitan fatty acid ester or monoglycerin fatty acid ester, (E) polyhydric alcohol. It is characterized by doing.
(1)ウルソール酸
本発明においてウルソール酸とは、環状トリテルペン系成分であり、セージ、ローズマリー、りんご、バジル、ビルベリー、クランベリー、エルダーフラワー、ペパーミント、ラベンダー、オレガノ、タイム、サンザシ、プルーンなどから公知の方法を用いて抽出することができ、ナトリウムなどの塩として配合することもできる。
ウルソール酸は市販品を購入し、利用することが可能であり、このような市販品としては、ウルソール酸 90%、セージ葉エキスを10%含む「URSOLIC EXTRACT 90%CG」(サビンサジャパン製)等が例示できる。
ウルソール酸又はその塩の含有量は、本発明のリポソーム分散液中0.001〜4(W/W)%であることが好ましく、より好ましくは0.005〜3(W/W)%である。
(1) Ursolic acid In the present invention, ursolic acid is a cyclic triterpene component, and is known from sage, rosemary, apple, basil, bilberry, cranberry, elderflower, peppermint, lavender, oregano, thyme, hawthorn, prune, etc. This method can be used for extraction and can be formulated as a salt such as sodium.
Ursolic acid is commercially available and can be used. Examples of such commercially available products include “URSOLIC EXTRACT 90% CG” (manufactured by Sabinsa Japan) containing 90% ursolic acid and 10% sage leaf extract. Can be illustrated.
The content of ursolic acid or a salt thereof is preferably 0.001 to 4 (W / W)%, more preferably 0.005 to 3 (W / W)% in the liposome dispersion of the present invention. .
(2)リン脂質
本発明のリポソーム分散液は、リン脂質を必須成分として含有する。
リン脂質は、化粧料、医薬部外品、医薬品等に使用されるものであれば特に限定される物ではなく、天然リン脂質、水素添加リン脂質等のリン脂質誘導体、合成リン脂質等を含めた概念のものである。
(2) Phospholipid The liposome dispersion liquid of the present invention contains phospholipid as an essential component.
Phospholipids are not particularly limited as long as they are used in cosmetics, quasi drugs, pharmaceuticals, etc., including natural phospholipids, phospholipid derivatives such as hydrogenated phospholipids, synthetic phospholipids, etc. Concept.
リン脂質としては、例えば、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、大豆レシチン、卵黄レシチン等の天然リン脂質、天然リン脂質中の不飽和炭素鎖を水素により飽和とした水素添加大豆リン脂質、水素添加卵黄リン脂質等の水素添加リン脂質、ジオレイルホスファチジルコリン等の合成リン脂質等が挙げられる。 Examples of phospholipids include natural phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, and egg yolk lecithin, and hydrogenation in which unsaturated carbon chains in natural phospholipids are saturated with hydrogen. Examples thereof include hydrogenated phospholipids such as soybean phospholipid and hydrogenated egg yolk phospholipid, and synthetic phospholipids such as dioleyl phosphatidylcholine.
リン脂質は、その1種を単独で使用しても、2種以上を組み合わせて使用してもよい。
本発明においては、大豆レシチン、卵黄レシチン等のリン脂質、水素添加大豆リン脂質、水素添加卵黄リン脂質等の水素添加リン脂質、合成リン脂質を用いることが好ましく、水素添加リン脂質がさらに好ましく、水素添加することにより高度不飽和結合がなくなり酸化に対する安定性は向上する。
また、これにより、リポソームの酸化安定性や温度安定性が向上する。
水素添加リン脂質のヨウ素価は10以下が酸化安定性を保つためにも好ましい。
One phospholipid may be used alone, or two or more phospholipids may be used in combination.
In the present invention, it is preferable to use phospholipids such as soybean lecithin and egg yolk lecithin, hydrogenated phospholipids such as hydrogenated soybean phospholipid and hydrogenated egg yolk phospholipid, and synthetic phospholipids, more preferably hydrogenated phospholipids, Hydrogenation eliminates highly unsaturated bonds and improves the stability against oxidation.
This also improves the oxidative stability and temperature stability of the liposomes.
The iodine value of the hydrogenated phospholipid is preferably 10 or less in order to maintain oxidation stability.
リン脂質は、市販品を購入し、利用することが可能である。
このような市販品としては、例えば、「レシノールS−10EX」(PC含有量95質量%以上、ヨウ素価10以下)、「レシノールS−10E」(PC含有量75〜85質量%、ヨウ素価10以下)、「レシノールS−10M」(PC含有量55〜65質量%、ヨウ素価10以下)等の水素添加大豆リン脂質(以上、いずれも日光ケミカルズ株式会社製)等が例示できる。
リン脂質の含有量は、本発明のリポソーム分散液中1〜15(W/W)%であることが好ましく、より好ましくは2〜7(W/W)%である。
Phospholipids can be purchased from commercial products.
Examples of such commercially available products include “Resinol S-10EX” (PC content 95% by mass or more and iodine value 10 or less), “Resinol S-10E” (PC content 75 to 85% by mass, iodine value 10). The following can be exemplified: hydrogenated soybean phospholipids such as “Resinol S-10M” (PC content of 55 to 65 mass%, iodine value of 10 or less).
The content of phospholipid is preferably 1 to 15 (W / W)%, more preferably 2 to 7 (W / W)% in the liposome dispersion of the present invention.
(3)ポリオキシアルキレンステロールエーテル
発明のリポソーム分散液は、ポリオキシアルキレンステロールエーテルを必須成分として含有する。ポリオキシアルキレンの付加モル数が10〜40であるポリオキシアルキレンステロールエーテルは、フィトステロール骨格又はコレステロール骨格等のステロール骨格に、ポリオキシアルキレンの付加モル数が10〜40付加したものであるが、平均付加モル数は、好ましくは15〜30、より好ましくは20〜30である。
(3) Polyoxyalkylene sterol ether The liposome dispersion of the invention contains polyoxyalkylene sterol ether as an essential component. The polyoxyalkylene sterol ether having a polyoxyalkylene addition mole number of 10 to 40 is obtained by adding a polyoxyalkylene addition mole number of 10 to 40 to a sterol skeleton such as a phytosterol skeleton or a cholesterol skeleton. The number of added moles is preferably 15 to 30, more preferably 20 to 30.
ステロールに付加させるポリオキシアルキレンとしては、例えば、ポリオキシエチレン、ポリオキシプロピレン、ポリオキシエチレン・ポリオキシプロピレン等の「アルキレン」の炭素数が2〜5(好適には2〜3)であるポリオキシアルキレンが挙げられる。好ましくは、ポリオキシエチレンである。
ステロール骨格部分の構造としては、コレステロール、コレスタノール、ラノステロール、セレブロステロール、デヒドロコレステロール、コプロスタノール等の動物系ステロール骨格;β−シトステロール、スチグマステロール、カンペステロール及びエルゴステロール、フコステロール、スピナステロール及びブラシカステロール等の植物系ステロール骨格;ミコステロール及びチモステロール等の微生物系ステロール骨格;これらを水素付加又は水付加した誘導体が挙げられる。好ましくは、フィトステロール、コレステロールである。
Examples of the polyoxyalkylene to be added to the sterol include polyoxyethylene, polyoxypropylene, polyoxyethylene / polyoxypropylene, and the like in which “alkylene” has 2 to 5 carbon atoms (preferably 2 to 3). Examples include oxyalkylene. Preferably, it is polyoxyethylene.
Examples of the structure of the sterol skeleton part include animal sterol skeletons such as cholesterol, cholestanol, lanosterol, cerebrosterol, dehydrocholesterol, and coprostanol; β-sitosterol, stigmasterol, campesterol and ergosterol, fucostosterol, spinasterol, and Examples thereof include plant sterol skeletons such as brush casterol; microbial sterol skeletons such as mycostolol and timosterol; and derivatives obtained by hydrogenation or water addition thereof. Preferable are phytosterol and cholesterol.
動物系ステロール骨格を有するものは動物から主として得られる。例えば、魚油(例えばいわし油)から得られたコレステロール;羊毛脂から得られ、コレステロールやラノステロールを主成分とするラノリンアルコール;これらの水素付加物等が挙げられる。
また、植物系ステロール骨格を有するものは植物から主として得られる。フィトステロールとは、一般的に、β−シトステロール、スチグマステロール、カンペステロール、フコステロール、スピナステロール、ブラシカステロール及びエルゴステロール等から選ばれる1種又は2種以上のものをいい、特に2種以上の混合物をいう。
これらポリオキシアルキレンステロールエーテルは単独で又は2種以上組み合わせて用いることができる。
Those having an animal sterol skeleton are mainly obtained from animals. For example, cholesterol obtained from fish oil (for example, sardine oil); lanolin alcohol obtained from wool fat and mainly composed of cholesterol and lanosterol; and hydrogenated products thereof.
Those having a plant sterol skeleton are mainly obtained from plants. Phytosterol generally means one or more selected from β-sitosterol, stigmasterol, campesterol, fucostosterol, spinasterol, brassicasterol, ergosterol, and the like, and in particular, two or more types Refers to a mixture.
These polyoxyalkylene sterol ethers can be used alone or in combination of two or more.
より具体的には、POE(10)コレステリルエーテル、POE(15)コレステリルエーテル、POE(20)コレステリルエーテル、POE(24)コレステリルエーテル及びPOE(30)コレステリルエーテル等のポリオキシエチレンコレステリルエーテル類;POE(20)コレスタノール、POE(25)コレスタノール及びPOE(30)コレスタノール等のポリオキシエチレンコレスタノール類;POE(5)フィトステロール、POE(10)フィトステロール、POE(20)フィトステロール、POE(25)フィトステロール及びPOE(30)フィトステロール等のポリオキシエチレンフィトステロール類;POE(20)フィトスタノール、POE(25)フィトスタノール及びPOE(30)フィトスタノール等のポリオキシエチレンフィトスタノール類等が挙げられる。 More specifically, polyoxyethylene cholesteryl ethers such as POE (10) cholesteryl ether, POE (15) cholesteryl ether, POE (20) cholesteryl ether, POE (24) cholesteryl ether and POE (30) cholesteryl ether; POE (20) Polyoxyethylene cholestanols such as cholestanol, POE (25) cholestanol and POE (30) cholestanol; POE (5) phytosterol, POE (10) phytosterol, POE (20) phytosterol, POE (25) Polyoxyethylene phytosterols such as phytosterol and POE (30) phytosterol; POE (20) phytostanol, POE (25) phytostanol and POE (30) phytostanol Polyoxyethylene phytostanols, etc. and the like.
市販品としては、EMALEX CS−10(日本エマルジョン社製)、EMALEX CS−20(日本エマルジョン社製)、EMALEX CS−30(日本エマルジョン社製)、NIKKOL BPS−10(日本サーファクタント工業社製)、NIKKOL BPS−20(日本サーファクタント工業社製)、NIKKOL BPS−30(日本サーファクタント工業社製)等が挙げられる。 Commercially available products include EMALEX CS-10 (manufactured by Nippon Emulsion), EMALEX CS-20 (manufactured by Nippon Emulsion), EMALEX CS-30 (manufactured by Nippon Emulsion), NIKKOL BPS-10 (manufactured by Nippon Surfactant Kogyo), NIKKOL BPS-20 (manufactured by Nippon Surfactant Kogyo Co., Ltd.), NIKKOL BPS-30 (manufactured by Nippon Surfactant Kogyo Co., Ltd.) and the like.
なお、前記具体例における括弧内の数値は、エチレンオキサイドの平均付加モル数を示す。以下も同様である。
これらのなかでも、ポリオキシエチレンコレステリルエーテル類及びポリオキシエチレンフィトステロール類が、浸透性及び安定性の点から好ましい。更に、POE(10〜30)コレステロール及びPOE(10〜30)フィトステロールが好ましい。より、POE(20〜30)コレステロール及びPOE(20〜30)フィトステロールが好ましい。
これらポリオキシアルキレンステロールエーテルは1種を単独で使用しても、2種以上を組み合わせて使用してもよい。ポリオキシステロールエーテルの含有量は、特に限定されないが、本発明のリポソーム分散液中0.01〜10(W/W)%が好ましく、より好ましくは0.1重量%〜5重量%である、
In addition, the numerical value in the parenthesis in the specific example indicates the average added mole number of ethylene oxide. The same applies to the following.
Among these, polyoxyethylene cholesteryl ethers and polyoxyethylene phytosterols are preferable from the viewpoints of permeability and stability. Furthermore, POE (10-30) cholesterol and POE (10-30) phytosterol are preferred. More preferred are POE (20-30) cholesterol and POE (20-30) phytosterol.
These polyoxyalkylene sterol ethers may be used alone or in combination of two or more. The content of polyoxysterol ether is not particularly limited, but is preferably 0.01 to 10 (W / W)%, more preferably 0.1 to 5% by weight in the liposome dispersion of the present invention.
(4)ソルビタン脂肪酸エステル
本発明においてソルビタン脂肪酸エステルとは、ソルビタンと脂肪酸とのエステルであり、より好ましくはソルビタンと液状脂肪酸とのエステルである。
(4) Sorbitan fatty acid ester In this invention, sorbitan fatty acid ester is ester of sorbitan and a fatty acid, More preferably, it is ester of sorbitan and a liquid fatty acid.
例えば、オレイン酸ソルビタン、ステアリン酸ソルビタン、パルミチン酸ソルビタン、ラウリン酸ソルビタン、ヤシ脂肪酸ソルビタン、イソステアリン酸ソルビタン、モノオレイン酸ソルビタン、モノイソステアリン酸ソルビタン、セスキオレイン酸ソルビタン、セスキイソステアリン酸ソルビタン、ジイソステアリン酸ソルビタン、トリオレイン酸ソルビタン、トリイソステアリン酸ソルビタンが挙げられる。 For example, sorbitan oleate, sorbitan stearate, sorbitan palmitate, sorbitan laurate, coconut fatty acid sorbitan, sorbitan isostearate, sorbitan monooleate, sorbitan monoisostearate, sorbitan sesquioleate, sorbitan sesquiisostearate, sorbitan diisostearate, And sorbitan trioleate and sorbitan triisostearate.
(5)モノグリセリン脂肪酸エステル
本発明においてモノグリセリン脂肪酸エステルとは、モノグリセリンと脂肪酸とを反応させて得られるエステルであり、モノ、ジ、トリエステルの3種類がある。
(5) Monoglycerin fatty acid ester In the present invention, the monoglycerin fatty acid ester is an ester obtained by reacting monoglycerin and a fatty acid, and there are three types of mono-, di- and triesters.
例えば、カプリル酸グリセリル、カプリン酸グリセリル、ラウリン酸グリセリル、ミリスチン酸グリセリル、パルミチン酸グリセリル、ステアリン酸グリセリル、イソステアリン酸グリセリルが挙げられる。
なお、ソルビタン脂肪酸エステル及びモノグリセリン脂肪酸エステルの含有量の合計は、本発明のリポソーム分散液中0.01〜7(W/W)%が好ましく、より好ましくは0.05〜4(W/W)%である、
Examples include glyceryl caprylate, glyceryl caprate, glyceryl laurate, glyceryl myristate, glyceryl palmitate, glyceryl stearate, and glyceryl isostearate.
The total content of sorbitan fatty acid ester and monoglycerin fatty acid ester is preferably 0.01 to 7 (W / W)%, more preferably 0.05 to 4 (W / W) in the liposome dispersion of the present invention. )%
(6)多価アルコール
本発明の多価アルコールは、1分子中にヒドロキシル基を2個以上持つアルコールを意味し、例えば、プロピレングリコール、1,3−ブチレングリコール、ジプロピレングリコール、1,2−ペンタンジオール、グリセリン、ジグリセリン、ソルビトールが挙げられる。好ましくはジプロピレングリコール、1,3−ブチレングリコールであり、ジプロピレングリコールと1,3−ブチレングリコールを組み合わせ用いることがさらに好ましい。
多価アルコールの含有量は、本発明のリポソーム分散液中1.5〜50(W/W)%が好ましく、より好ましくは10〜30(W/W)%である。
(6) Polyhydric alcohol The polyhydric alcohol of the present invention means an alcohol having two or more hydroxyl groups in one molecule. For example, propylene glycol, 1,3-butylene glycol, dipropylene glycol, 1,2- Examples include pentanediol, glycerin, diglycerin, and sorbitol. Dipropylene glycol and 1,3-butylene glycol are preferred, and a combination of dipropylene glycol and 1,3-butylene glycol is more preferred.
The content of the polyhydric alcohol is preferably 1.5 to 50 (W / W)%, more preferably 10 to 30 (W / W)% in the liposome dispersion of the present invention.
(7)リポソーム
本発明のリポソームは、皮膚への浸透及びメラノサイトへのデリバリー等を考慮すると小さい粒径のものが好ましく、平均粒径が250nm以下のリポソームが好ましく、さらに好ましくは50〜200nmであり、特に好ましくは90〜160nmである。
粒径の測定は濃厚系粒径アナライザーFPAR−1000(大塚電子株式会社製)を用いて測定される。
粒径の下限は、製造される範囲で特に限定されないが、安定性の点から50nmが好ましい。
(7) Liposomes The liposome of the present invention preferably has a small particle size in consideration of penetration into the skin, delivery to melanocytes, etc., and preferably has an average particle size of 250 nm or less, more preferably 50 to 200 nm. Particularly preferably, the thickness is 90 to 160 nm.
The particle size is measured using a concentrated particle size analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.).
Although the minimum of a particle size is not specifically limited in the range manufactured, 50 nm is preferable from a stability point.
(リポソーム分散液の調製例)
次に、リポソーム分散液の調製例を挙げる。
表1に掲げた各々の成分を用いて以下の方法でリポソーム分散液を製造した。
表1は使用した各成分の割合を(W/W)%(精製水を加えリポソーム分散液を100gとしたときの各成分のグラム数)で示している。
(Preparation example of liposome dispersion)
Next, an example of preparing a liposome dispersion is given.
Using each of the components listed in Table 1, a liposome dispersion was produced by the following method.
Table 1 shows the ratio of each component used in (W / W)% (grams of each component when purified water is added and the liposome dispersion is 100 g).
(調製法)
(I)リン脂質をポリオキシアルキレンステロールエーテルと多価アルコール(例えば、1,3ブチレングリコール)を溶解した水に加温して分散溶解する。
(II)ウルソール酸をソルビタン脂肪酸エステル(又はモノグリセリン脂肪酸エステル)、と多価アルコール(例えば、ジプロピレングリコール)に溶解する。
(III) (II)を(I)に加えてホモミキサーでプレ混合をする。
(IV) (III)の混合物を高圧ホモミキサーで混合(圧力:150Mpas、10パス)し、リポソーム分散液を得る。
(Preparation method)
(I) The phospholipid is heated and dispersed in water in which polyoxyalkylene sterol ether and a polyhydric alcohol (for example, 1,3 butylene glycol) are dissolved.
(II) Ursolic acid is dissolved in sorbitan fatty acid ester (or monoglycerin fatty acid ester) and polyhydric alcohol (for example, dipropylene glycol).
(III) (II) is added to (I) and premixed with a homomixer.
(IV) The mixture of (III) is mixed with a high-pressure homomixer (pressure: 150 Mpas, 10 passes) to obtain a liposome dispersion.
(8)外用剤組成物
本発明の外用剤組成物には、上記リポソーム分散液に加え、通常化粧品、医薬部外品、医薬品等の皮膚外用剤に用いられる他の成分を本発明の効果を損なわない範囲で適宜配合することができる。
前記任意配合成分としては、成分中に含まれる物質が複数の成分に該当する場合がある記載であり、また前記と一部重なる記載も含まれるが、例えば、油分、保湿剤、多価アルコール、増粘剤、水溶性高分子、皮膜形成剤、非水溶性高分子、油ゲル化剤、高分子エマルジョン、粉末、顔料、染料、レーキ、低級アルコール、糖類、紫外線吸収剤、アミノ酸類、ビタミン類、美白剤、皮膚賦活剤、血行促進剤、抗脂漏剤、抗炎症剤(消炎剤)等の薬剤、植物抽出物、有機酸、有機アミン、金属イオン封鎖剤、pH調整剤、酸化防止剤、抗菌剤(防腐殺菌剤)、収斂剤、清涼剤、香料、水等を挙げることができる。
他に加えてもよい配合成分としては、油相成分、水溶性高分子、界面活性剤、有機及び無機顔料、有機粉体、紫外線吸収剤、防腐剤、殺菌剤、酸化防止剤、植物抽出物、pH調整剤、アルコール、色素、香料、血行促進剤、冷感剤、制汗剤、精製水等があげられる。
(8) External preparation composition In addition to the above-mentioned liposome dispersion liquid, the external preparation composition of the present invention has the effects of the present invention in addition to other components that are usually used in external preparations for skin such as cosmetics, quasi drugs, and pharmaceuticals. It can mix | blend suitably in the range which is not impaired.
The optional compounding component is a description in which a substance contained in the component may correspond to a plurality of components, and also includes a description partially overlapping with the above, for example, oil, humectant, polyhydric alcohol, Thickener, water-soluble polymer, film-forming agent, water-insoluble polymer, oil gelling agent, polymer emulsion, powder, pigment, dye, lake, lower alcohol, saccharide, UV absorber, amino acids, vitamins , Whitening agent, skin activator, blood circulation promoter, antiseborrheic agent, anti-inflammatory agent (anti-inflammatory agent), plant extract, organic acid, organic amine, sequestering agent, pH adjuster, antioxidant , Antibacterial agents (preservative antiseptics), astringents, refreshing agents, fragrances, water and the like.
Other ingredients that may be added include oil phase ingredients, water-soluble polymers, surfactants, organic and inorganic pigments, organic powders, UV absorbers, preservatives, bactericides, antioxidants, plant extracts , PH adjusters, alcohols, pigments, fragrances, blood circulation promoters, cooling agents, antiperspirants, purified water, and the like.
本発明の外用剤組成物の形態としては、特に限定されないが、例えば、乳液、クリーム、化粧水、パック等が挙げられる。
また、剤型としては、特に限定されないが、液状、ゲル状、ペースト状、クリーム状、ジェル状、分散液状等が挙げられる。
Although it does not specifically limit as a form of the external preparation composition of this invention, For example, emulsion, cream, lotion, a pack, etc. are mentioned.
The dosage form is not particularly limited, and examples thereof include liquid, gel, paste, cream, gel, and dispersion liquid.
以下、本発明を実施例により詳細に説明するが、これら実施例は本発明を限定するものではない。
以下の組成にてウルソール酸含有リポソーム分散液を調製し、平均粒子径、外観・透明度、経時安定性について評価した。
なお、平均粒子径、外観透明度、経時安定性は以下のように評価を行った。
(1)平均粒子径
調製直後の試験品の平均粒子径について評価した。
◎:平均粒子径が100nm以下
○:平均粒子径が200nm以下
△:平均粒子径が250nm以下
×:分布が大きく測定不可
(2)外観・透明度
◎:透明度度高い
○:透明感あり
△:濁っている
×:分離
(3)経時安定性(目視判断)
調製後40℃で保存し、外観の変化を観察し評価を行った。
◎ : 調製後40℃保存1ヶ月以上変化なし
○ : 調製後40℃保存1ヶ月でややにごりは認められるが、透明性は維持される
△ : 調製後40℃保存1週間で分離
× : 調製後40℃保存1日で分離
(4)総合評価
◎: 非常に良い
○: 良い
△: 悪い
×: 非常に悪い
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, these Examples do not limit this invention.
Ursolic acid-containing liposome dispersions were prepared with the following composition, and the average particle size, appearance / transparency, and stability over time were evaluated.
In addition, the average particle diameter, appearance transparency, and temporal stability were evaluated as follows.
(1) Average particle diameter The average particle diameter of the test product immediately after preparation was evaluated.
◎: Average particle size is 100 nm or less ○: Average particle size is 200 nm or less Δ: Average particle size is 250 nm or less ×: Distribution is large and cannot be measured (2) Appearance / Transparency ◎: High transparency ○: Transparency △: Cloudy ×: Separation (3) Stability over time (visual judgment)
After preparation, it was stored at 40 ° C., and changes in appearance were observed and evaluated.
◎: No change for more than 1 month after preparation at 40 ° C ○: Transparency is maintained after storage at 40 ° C for 1 month after preparation, but transparency is maintained Δ: Separation after 1 week at 40 ° C after preparation ×: After preparation Separated at 40 ° C. for 1 day (4) Overall evaluation ◎: Very good ○: Good △: Bad ×: Very bad
BPS-30 :NIKKOL BPS-30(日本サーファクタント工業社製)
BPS-20 :NIKKOL BPS-20(日本サーファクタント工業社製)
BPS-30: NIKKOL BPS-30 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-20: NIKKOL BPS-20 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-30 :NIKKOL BPS-30(日本サーファクタント工業社製)
BPS-20 :NIKKOL BPS-20(日本サーファクタント工業社製)
BPS-30: NIKKOL BPS-30 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-20: NIKKOL BPS-20 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-30 :NIKKOL BPS-30(日本サーファクタント工業社製)
BPS-20 :NIKKOL BPS-20(日本サーファクタント工業社製)
BPS-30: NIKKOL BPS-30 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-20: NIKKOL BPS-20 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-30 :NIKKOL BPS-30(日本サーファクタント工業社製)
BPS-20 :NIKKOL BPS-20(日本サーファクタント工業社製)
実施例1〜20のリポソーム分散液は、外観・透明度は透明感がある、あるいは透明度が高く、リポソームの平均粒子径はいずれも200nm以下であった。また、40℃で1月保存後も透明性が維持されていた。
BPS-30: NIKKOL BPS-30 (Nippon Surfactant Kogyo Co., Ltd.)
BPS-20: NIKKOL BPS-20 (Nippon Surfactant Kogyo Co., Ltd.)
The liposome dispersions of Examples 1 to 20 had a transparent appearance or transparency, or had a high transparency, and the average particle diameter of the liposomes was 200 nm or less. In addition, transparency was maintained after storage at 40 ° C in January.
一方、ポリオキシアルキレンステロールエーテル(C成分)を含有していない比較例3,5は、調製後から分離しており、多価アルコール(E成分)を含有していない比較例2、4は調製直後から濁りが生じており、40℃保存により1日で分離が生じた。ソルビタン脂肪酸エステルもモノグリセリン脂肪酸エステル(D成分)も含有していない比較例1は、外観・透明度は透明感があり、リポソームの平均粒子径は200nm以下と優れた性状を示したが、40℃で1月保存したところ分離が認められた。 On the other hand, Comparative Examples 3 and 5 which do not contain polyoxyalkylene sterol ether (C component) are separated after preparation, and Comparative Examples 2 and 4 which do not contain polyhydric alcohol (E component) are prepared. Immediately after that, turbidity occurred, and separation occurred in one day by storage at 40 ° C. Comparative Example 1 containing neither sorbitan fatty acid ester nor monoglycerin fatty acid ester (component D) had a transparent appearance and transparency, and the liposome had an average particle size of 200 nm or less, but showed excellent properties. When stored for 1 month, separation was observed.
実施例21
美容液 (W/W)%
キサンタンガム 0.4
ヒドロキシエチルセルロース 0.1
カルボキシビニルポリマー 0.1
1,3−ブチレングリコール 5.0
水酸化カリウム(1%水溶液) 2.5
実施例2のリポソーム分散液 5.0
防腐剤 適量
精製水 全量100
Example 21
Essence (W / W)%
Xanthan gum 0.4
Hydroxyethyl cellulose 0.1
Carboxyvinyl polymer 0.1
1,3-butylene glycol 5.0
Potassium hydroxide (1% aqueous solution) 2.5
Liposome dispersion of Example 2 5.0
Preservative Suitable amount Purified water Total 100
実施例22
化粧水 (W/W)%
グリセリン 5.0
1,3−ブチレングリコール 3.0
クエン酸 0.1
クエン酸ナトリウム 0.3
PCA−Na 0.5
実施例3のリポソーム分散液 5.0
防腐剤 適量
精製水 全量100
〈調製方法〉 精製水に全成分を添加し均一になるまで攪拌する。
Example 22
Lotion (W / W)%
Glycerin 5.0
1,3-butylene glycol 3.0
Citric acid 0.1
Sodium citrate 0.3
PCA-Na 0.5
Liposome dispersion of Example 3 5.0
Preservative Suitable amount Purified water Total 100
<Preparation method> Add all ingredients to purified water and stir until uniform.
実施例22
クリーム (W/W)%
(A)
POE(40)モノステアリン酸 2.0
自己乳化型モノステアリン酸グリセリル 5.0
ステアリン酸 2.0
セタノール 2.0
スクワラン 12.0
マカデミアナッツ油 4.0
メチルポリシロキサン(300cSt) 0.2
防腐剤 適量
(B)
1,3−ブチレングリコール 7.0
精製水 全量100
(C) 実施例5のリポソーム分散液 5.0
〈調製方法〉A、Bともに80°Cで加温溶解し,BをAに撹拌しながら徐々に加え乳化する。撹拌しながら冷却し、40°Cで(C)を加えて撹拌をして30〜35℃で攪拌を止め、放置する。
Example 22
Cream (W / W)%
(A)
POE (40) monostearic acid 2.0
Self-emulsifying glyceryl monostearate 5.0
Stearic acid 2.0
Cetanol 2.0
Squalane 12.0
Macadamia nut oil 4.0
Methyl polysiloxane (300 cSt) 0.2
Preservative appropriate amount (B)
1,3-butylene glycol 7.0
Purified water total 100
(C) Liposome dispersion of Example 5 5.0
<Preparation method> Both A and B are dissolved by heating at 80 ° C, and B is gradually added to A while stirring to emulsify. Cool with stirring, add (C) at 40 ° C., stir, stop stirring at 30-35 ° C., and leave to stand.
本発明のウルソール酸含有リポソーム分散液は、経時安定性に優れ、ウルソール酸含有外用剤組成物の原料として有用である。 The ursolic acid-containing liposome dispersion of the present invention has excellent temporal stability and is useful as a raw material for ursolic acid-containing external preparation compositions.
Claims (8)
(A)ウルソール酸又はその塩
(B)リン脂質
(C)ポリオキシアルキレンステロールエーテル
(D)ソルビタン脂肪酸エステル及びモノグリセリン脂肪酸エステルからなる群より選ばれる1種又は2種以上の非イオン界面活性剤
(E)多価アルコール Liposome dispersion containing the following components (A) to (E).
(A) Ursolic acid or salt thereof (B) Phospholipid (C) Polyoxyalkylene sterol ether (D) One or more nonionic surfactants selected from the group consisting of sorbitan fatty acid esters and monoglycerin fatty acid esters (E) Polyhydric alcohol
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