JP4304352B2 - Transdermal absorption control agent containing sophorolipid and method for producing the same - Google Patents
Transdermal absorption control agent containing sophorolipid and method for producing the same Download PDFInfo
- Publication number
- JP4304352B2 JP4304352B2 JP2007229294A JP2007229294A JP4304352B2 JP 4304352 B2 JP4304352 B2 JP 4304352B2 JP 2007229294 A JP2007229294 A JP 2007229294A JP 2007229294 A JP2007229294 A JP 2007229294A JP 4304352 B2 JP4304352 B2 JP 4304352B2
- Authority
- JP
- Japan
- Prior art keywords
- sophorolipid
- agent
- control agent
- molecular assembly
- absorption control
- 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.)
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Landscapes
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、ベシクルなどを用いた経皮吸収促進剤に関し、特にバイオサーファクタントの一種であるソホロリピッドを用いることで、強度の外力を必要とすることなく熱力学的に安定なベシクル又はミセル等の分子集合体を形成して得られる経皮吸収制御剤及びその製造方法に関する。 The present invention relates to a percutaneous absorption enhancer using vesicles and the like, and in particular, by using sophorolipid which is a kind of biosurfactant, molecules such as vesicles or micelles which are thermodynamically stable without requiring strong external force. The present invention relates to a percutaneous absorption control agent obtained by forming an aggregate and a method for producing the same.
リン脂質などの両親媒性物質を水に懸濁させると、このリン脂質が会合して二分子膜を形成し、水相を閉じこめたベシクルを形成することが以前より知られている。このベシクルは、リポソームとも呼ばれ、生体膜のモデルや、薬物担体として脚光を集めた。 It has long been known that when an amphiphilic substance such as a phospholipid is suspended in water, the phospholipid associates to form a bilayer and form a vesicle that confines the aqueous phase. These vesicles, also called liposomes, have attracted attention as models of biological membranes and drug carriers.
その後、ベシクル形成能を有する様々な両親媒性物質を見出す努力が行われ、2本の長鎖アルキル基を有する界面活性剤、例えば臭化ジドデシルジメチルアンモニウム(DDAB:didodecyldimethylammonium bromide)等が見出されており、ベシクルは内部に油溶解性と水溶性の双方の有効成分を保持できる基材として、化粧品や医薬品分野において活用されつつある。 Thereafter, efforts were made to find various amphiphiles having the ability to form vesicles, and surfactants having two long-chain alkyl groups, for example, didodecyldimethylammonium bromide (DDAB) were found. Thus, vesicles are being used in the cosmetics and pharmaceutical fields as a base material that can hold both oil-soluble and water-soluble active ingredients.
しかし、一般にベシクルは水溶液の状態では熱力学的に不安定であり、ベシクル粒子同士の凝集や融合、膜成分の結晶化による沈澱の生成、粒子径の増大などがおこり、効力の低下や外観変化による商品価値の損失が生じやすかった。 In general, however, vesicles are thermodynamically unstable in the state of an aqueous solution, causing aggregation and fusion of vesicle particles, formation of precipitates due to crystallization of membrane components, increase in particle size, etc., resulting in reduced efficacy and changes in appearance. Loss of merchandise value was likely to occur.
一方で、近年、アニオン系の界面活性剤、例えばオクチル硫酸ナトリウム(SOS:sodium octyl sulfate)とカチオン系の界面活性剤、例えばセチルトリメチルアンモニウムブロマイド(CTAB:cetyltrimethylammonium bromide)の混合により、強度の機械的外力を付与することなく、熱力学的に安定なベシクルを形成することが報告されている(K.Tsuchiya,H.Nakanishi,H.Sakai,M.Abe,Langmuir,20,2117-2122(2004))。 On the other hand, in recent years, mixing of an anionic surfactant such as sodium octyl sulfate (SOS) and a cationic surfactant such as cetyltrimethylammonium bromide (CTAB) has resulted in a strong mechanical strength. It has been reported that thermodynamically stable vesicles can be formed without applying external force (K. Tsuchiya, H. Nakanishi, H. Sakai, M. Abe, Langmuir, 20, 2117-2122 (2004)). ).
この熱力学的に安定なベシクルは、ベシクル粒子同士の凝集や融合、膜成分の結晶化による沈澱の生成、粒子径の増大などが生じず、長期間分散安定であるため、実用上も極めて大きな利点を有している。 This thermodynamically stable vesicle does not cause aggregation or fusion of vesicle particles, formation of precipitates due to crystallization of membrane components, increase in particle diameter, and the like. Has advantages.
ところが、カチオン系の界面活性剤は毒性を示すため、皮膚に塗布する経皮吸収促進剤の成分としては適していない。また、界面活性剤の成分が増える程、調整に手間がかかり、実用性が低下するという問題があった。
しかしながら、従来提供されているベシクル形成能を有する界面活性剤は、その多くが多成分系であり、一部ポリエチレングリコールとリン脂質の混合系も報告されているものの(例えば特許文献1参照)、アニオン系界面活性剤とカチオン性界面活性剤を混合するものがほとんどであった。
このため、毒性の面からもカチオン性を有さない、特に単一の成分で熱力学的に安定なベシクルを形成し得る物質を提供することが、ベシクルの利用範囲を拡充する上で必要不可欠な状況であった。
However, cationic surfactants are toxic and are not suitable as components for transdermal absorption enhancers applied to the skin. In addition, there is a problem that as the amount of the surfactant component increases, the adjustment takes time and the practicality decreases.
However, many of the surfactants having vesicle-forming ability that have been provided in the past are multi-component systems, and some mixed systems of polyethylene glycol and phospholipid have been reported (for example, see Patent Document 1). Most of them mixed an anionic surfactant and a cationic surfactant.
For this reason, it is indispensable to expand the range of use of vesicles by providing substances that are not cationic in terms of toxicity and that can form thermodynamically stable vesicles with a single component. It was a serious situation.
また、皮膚を薬効成分の作用部位とする場合は、薬剤のターゲット部位である皮膚において薬剤濃度を高めるような経皮外用剤を用いることが好ましい。
このような要望を実現するため、経皮外用剤に、界面活性剤が形成する通常のベシクル(例えば、特許文献2参照)や、リン脂質が形成するリポソーム(例えば、特許文献3参照)、油分などの低分子の経皮吸収促進剤を配合したり、あるいは剤型を工夫するなどの方法が提案されている。
In addition, when the skin is used as the site of action of the medicinal component, it is preferable to use a transdermal external preparation that increases the drug concentration in the skin that is the drug target site.
In order to realize such a demand, a normal vesicle formed by a surfactant (for example, refer to Patent Document 2), a liposome formed by a phospholipid (for example, refer to Patent Document 3), an oil component, and the like as a transdermal external preparation There have been proposed methods of blending a low-molecular transdermal absorption enhancer such as, or devising a dosage form.
しかしながら、通常の合成界面活性剤を含む経皮外用剤は、上述した通り、毒性が懸念されるという問題がある。
また、これらの従来の経皮外用剤では、未だ十分な皮膚浸透効果が得られない場合が多く、さらなる改善が求められていた。
However, as described above, a transdermal external preparation containing a normal synthetic surfactant has a problem of concern about toxicity.
Further, these conventional transdermal external preparations still often do not provide a sufficient skin penetration effect, and further improvements have been demanded.
このような状況において、数多く存在する界面活性剤の中でも、微生物によって量産されるバイオサーファクタントと呼ばれるものが近年大きく注目されている。
バイオサーファクタントは、生分解性が高く、低毒性で環境にも優しいことが知られている。このため、化粧品工業、食品工業、医薬品工業、化学工業、環境分野等にこれらのバイオサーファクタントを幅広く適用することは、持続可能社会の実現と高機能製品の提供という、両面を兼ね備えており極めて有意義である。
Under such circumstances, among so many existing surfactants, what is called biosurfactant mass-produced by microorganisms has attracted much attention in recent years.
Biosurfactants are known to have high biodegradability, low toxicity, and environmental friendliness. For this reason, the broad application of these biosurfactants in the cosmetics, food, pharmaceutical, chemical, and environmental fields has both the realization of a sustainable society and the provision of high-performance products, which is extremely meaningful. It is.
そこで、本発明者らは、鋭意検討した結果、バイオサーファクタントの一種であり、同一分子内に二つの親水基を持つ界面活性剤であるソホロリピッドが、単成分において水中で熱力学的に安定なベシクル又はミセル等の分子集合体を形成することを発見し、さらにその分子集合体に有効成分を含ませることに成功し、本発明を完成させた。 Therefore, as a result of intensive studies, the present inventors have found that sophorolipid, which is a kind of biosurfactant and has two hydrophilic groups in the same molecule, is a vesicle that is thermodynamically stable in water as a single component. Alternatively, the inventors have found that a molecular assembly such as a micelle is formed, and succeeded in including an active ingredient in the molecular assembly, thereby completing the present invention.
なお、ソホロリピッドに関連する技術として、本出願人は、特許文献4に記載の羅漢果抽出物及びソホロリピッドを含有する皮膚外用組成物を提案している。
しかしながら、この特許文献4に記載の発明は、羅漢果の線維芽細胞賦活作用、コラーゲン合成促進作用、紫外線保護効果を増強し、肌荒れ改善効果を発揮させるために、羅漢果抽出物及びソホロリピッドを含有する皮膚外用組成物を提供するものである。
また、特許文献4においては、単成分において水中で熱力学的に安定なベシクル又はミセル等の分子集合体を形成させることや、ソホロリピッドを経皮吸収制御剤の成分として使用することについては、考慮されていない。
In addition, as a technique related to sophorolipid, the present applicant has proposed an external composition for skin containing Rahan fruit extract and sophorolipid described in Patent Document 4.
However, the invention described in Patent Document 4 is a skin containing Rakan fruit extract and sophorolipid in order to enhance the fibroblast activation action, collagen synthesis promoting action, ultraviolet ray protection effect of Rahan fruit and to exhibit the effect of improving rough skin. An external composition is provided.
Further, in Patent Document 4, consideration is given to forming a molecular assembly such as a vesicle or micelle that is thermodynamically stable in water as a single component, or using sophorolipid as a component of a transdermal absorption control agent. It has not been.
本発明は、単成分で生分解性に優れ毒性もない界面活性剤からなり、かつ強度の機械的外力を付与することなく容易に調製可能で熱力学的に安定なベシクル又は巨大ミセルの分子集合体からなる経皮吸収制御剤及びその製造方法を提供することを目的とする。
また、皮膚への刺激がなく、角質細胞間脂質のラメラ液晶構造に溶解させることができ、ラメラ液晶形成を促進して肌荒れ改善効果を有すると同時に有効成分を効率よく皮膚に取り入れることができる経皮吸収制御剤及びその製造方法を提供することを目的とする。
The present invention comprises a single-component, biodegradable, non-toxic surfactant, and a molecular assembly of thermodynamically stable vesicles or giant micelles that can be easily prepared without imparting strong mechanical external force An object is to provide a transdermal absorption control agent comprising a body and a method for producing the same.
In addition, there is no irritation to the skin, it can be dissolved in the lamellar liquid crystal structure of keratin intercellular lipids, and it can promote the formation of lamellar liquid crystals and has an effect of improving rough skin, while at the same time being able to efficiently incorporate active ingredients into the skin. It is an object of the present invention to provide a skin absorption controlling agent and a method for producing the same.
上記目的を達成するため、本発明の経皮吸収制御剤は、ソホロリピッドを含むベシクルの分子集合体からなるものとしてある。
ソホロリピッドは、バイオサーファクタントの一種であり、単成分で生分解性に優れ、毒性のない界面活性剤である。
In order to achieve the above object, the percutaneous absorption control agent of the present invention comprises a molecular assembly of vesicles containing sophorolipid .
Sophorolipid is a kind of biosurfactant, a single component, excellent biodegradability and non-toxic surfactant.
また、ソホロリピッドは、強度の機械的外力を付与することなく、熱力学的に安定なベシクル又は巨大ミセルの分子集合体を形成することができる。
このため、経皮吸収制御剤をこのようなソホロリピッドを含む分子集合体からなるものにすることで、強度の機械的外力を付与することなく容易に調製可能で長期間にわたり安定なものにすることが可能である。
In addition, the sophorolipid can form a molecular assembly of thermodynamically stable vesicles or giant micelles without applying a strong mechanical external force.
For this reason, the percutaneous absorption control agent is made of a molecular assembly containing such a sophorolipid, so that it can be easily prepared without giving mechanical external force and is stable over a long period of time. Is possible.
また、このようなベシクル又は巨大ミセルの分子集合体の直径としては、40〜200nmとすることが好ましい。
分子集合体をこのようなものとすれば、これを含む経皮吸収制御剤を皮膚に塗布したときに、好適に角質細胞間の間隙に入り込み、細胞間脂質からなるラメラ液晶に溶解させることができる。
The diameter of the molecular assembly of such vesicles or giant micelles is preferably 40 to 200 nm.
If the molecular assembly is like this, when a percutaneous absorption control agent containing the molecular assembly is applied to the skin, it can suitably enter the space between the corneocytes and dissolve in the lamellar liquid crystal composed of intercellular lipids. it can.
また、分子集合体を、少なくとも抗酸化剤、抗菌剤、抗炎症剤、血行促進剤、美白剤、肌荒れ防止剤、老化防止剤、発毛促進剤、保湿剤、ホルモン剤、色素、配糖体、タンパク質、脂質、又はビタミン類のいずれかの有効成分を含めたものとすることが好ましい。
経皮吸収制御剤をこのようにすれば、皮膚に塗布することで、分子集合体が角質細胞間の間隙に入り込み、細胞間脂質からなるラメラ液晶に融解して、分子集合体の含有成分をラメラ液晶内に拡散させることができる。
このため、本発明における分子集合体に有効成分を含有させることで、その有効成分の経皮吸収を顕著に促進させることが可能となる。
In addition, at least antioxidants , antibacterial agents, anti-inflammatory agents, blood circulation promoters, whitening agents, skin roughening agents, anti-aging agents, hair growth promoters, moisturizers, hormone agents, pigments, glycosides It is preferable to contain any active ingredient of protein, lipid, or vitamins.
When the transdermal absorption control agent is applied to the skin in this way, the molecular assembly enters the interstices between the corneocytes and melts into the lamellar liquid crystal composed of intercellular lipids. It can be diffused into the lamellar liquid crystal.
For this reason, it becomes possible to accelerate | stimulate the percutaneous absorption of the active ingredient notably by containing an active ingredient in the molecular assembly in this invention.
また、ソホロリピッドは、次の式(1)で表されるラクトン型ソホロリピッド、式(2)で表される酸型ソホロリピッド、又は式(3)で表される酸型ソホロリピッド塩とすることが好ましい。 The sophorolipid is preferably a lactone type sophorolipid represented by the following formula (1), an acid type sophorolipid represented by the following formula (2), or an acid type sophorolipid salt represented by the following formula (3).
本発明におけるソホロリピッドをこれらのようなものにすれば、強度の機械的外力を付与することなく、長期間にわたり安定なベシクルや巨大ミセルを容易に形成させることができる。 If the sophorolipid in the present invention is as described above, stable vesicles and giant micelles can be easily formed over a long period of time without applying a strong mechanical external force.
また、本発明の経皮吸収制御剤の製造方法は、微生物を用いてソホロリピッドを生産し、このソホロリピッドに水を加えて濃度が0.3mg/mL〜8000mg/mLになるように調整して、ソホロリピッドを含むベシクルの分子集合体を形成させる方法としてある。
ソホロリピッドの濃度をこのような範囲にすれば、熱力学的に安定なベシクルの分子集合体を形成させることができる。
In addition, the method for producing a percutaneous absorption control agent of the present invention produces sophorolipid using microorganisms, and adjusts the sophorolipid to have a concentration of 0.3 mg / mL to 8000 mg / mL by adding water , This is a method for forming a molecular assembly of vesicles containing sophorolipid .
If the concentration of sophorolipid in this range, it is possible to form molecular aggregates of a thermodynamically stable vesicles.
また、本発明の経皮吸収制御剤の製造方法は、上記のようにソホロリピッドの濃度を調整した後、次いで少なくとも抗酸化剤、抗菌剤、抗炎症剤、血行促進剤、美白剤、肌荒れ防止剤、老化防止剤、発毛促進剤、保湿剤、ホルモン剤、色素、配糖体、タンパク質、脂質、又はビタミン類のいずれかの有効成分を混合する方法としてある。 Further, the method for producing a transdermal absorption control agent of the present invention comprises adjusting the concentration of sophorolipid as described above, and then at least an antioxidant , an antibacterial agent, an anti-inflammatory agent, a blood circulation promoter, a whitening agent, and a rough skin prevention agent , An anti-aging agent, hair growth promoter, moisturizer, hormone agent, pigment, glycoside, protein, lipid, or vitamin.
このように有効成分を混合することで、ソホロリピッドを含む分子集合体に有効成分を含有させることができ、その経皮吸収を促進することが可能となる。
また、有効成分として脂質や油分等を配合し、その配合量を調整することで、分子集合体の粘性を調整することもできる。
このため、皮膚内における有効成分の放出を制御することが可能である。
By mixing the active ingredient in this way, the active ingredient can be contained in the molecular assembly containing sophorolipid, and the percutaneous absorption thereof can be promoted.
Moreover, the viscosity of a molecular assembly can also be adjusted by mix | blending lipid, oil, etc. as an active ingredient, and adjusting the compounding quantity.
For this reason, it is possible to control the release of the active ingredient in the skin.
また、本発明の経皮吸収制御剤の製造方法は、ソホロリピッドを含む水溶液のpHを4.5〜11.5に調整する方法としてある。
pHをこのような範囲にすることで、分子集合体の大きさを適切な範囲に調節することが可能となる。
Moreover, the manufacturing method of the transdermal absorption control agent of this invention is as a method of adjusting pH of the aqueous solution containing sophorolipid to 4.5-11.5.
By setting the pH within such a range, the size of the molecular assembly can be adjusted to an appropriate range.
本発明によれば、単成分で生分解性に優れ毒性もない界面活性剤からなり、かつ強度の機械的外力を付与することなく容易に調製可能で熱力学的に安定なベシクル又は巨大ミセル等の分子集合体からなる経皮吸収制御剤を提供することが可能となる。
また、皮膚への刺激がなく、角質細胞間脂質のラメラ液晶構造に溶解させることができ、ラメラ液晶形成を促進して肌荒れ改善効果を有すると同時に有効成分を効率よく皮膚に取り入れることができる経皮吸収制御剤を提供することが可能となる。
According to the present invention, a single component, a biodegradable and non-toxic surfactant, a thermodynamically stable vesicle or giant micelle that can be easily prepared without imparting a strong mechanical external force, etc. It is possible to provide a percutaneous absorption control agent comprising the molecular assembly.
In addition, there is no irritation to the skin, it can be dissolved in the lamellar liquid crystal structure of keratin intercellular lipids, and it can promote the formation of lamellar liquid crystals and has an effect of improving rough skin, while at the same time being able to efficiently incorporate active ingredients into the skin. It is possible to provide a skin absorption controlling agent.
以下、本発明の実施形態を具体的に説明する。
[ソホロリピッド]
本発明で用いるバイオサーファクタントの一種であるソホロリピッド(以下、SLと称する場合がある。)は、キャンディダ属に属する微生物、例えばCandida bombicola、C.apicola、C.petrophilum、C.bogoriensisなどの酵母を培養することにより、その培地中に生産物として得ることができる。
Hereinafter, embodiments of the present invention will be specifically described.
[Sophoro lipid]
Sophorolipid (hereinafter sometimes referred to as SL), which is a kind of biosurfactant used in the present invention, is a microorganism belonging to the genus Candida, such as Candida bombicola, C.I. apicola, C.I. petrophilum, C.I. By culturing yeast such as bogoriensis, it can be obtained as a product in the medium.
ソホロリピッドは、ソホロース又はヒドロキシル基が一部アセチル化したソホロースと、ヒドロキシル脂肪酸とからなる糖脂質である。なお、ソホロースとはβ1→2結合した2分子のブドウ糖からなる糖であり、ヒドロキシル脂肪酸はヒドロキシル基を有する脂肪酸である。
ソホロリピッドは、以下の式(4)に示す通り、分子内のソホロースが結合したラクトン型と、ヒドロキシル脂肪酸のカルボキシル基が遊離した酸型とに大別され、ラクトン型ソホロリピッド、酸型ソホロリピッド、酸型ソホロリピッド塩が存在する。
Sophorolipid is a glycolipid composed of sophorose or sophorose partially hydroxylated with hydroxyl groups and hydroxyl fatty acid. Sophorose is a sugar composed of two molecules of glucose linked by β1 → 2, and hydroxyl fatty acid is a fatty acid having a hydroxyl group.
As shown in the following formula (4), the sophorolipid is roughly classified into a lactone type in which sophorose in the molecule is bonded and an acid type in which the carboxyl group of hydroxyl fatty acid is liberated, and the lactone type sophorolipid, acid type sophorolipid, acid type Sophorolipid salt is present.
式(4)において、R1およびR2は、それぞれ独立して水素(−H)又はアセチル基(−COCH3)であり、nは一般に11〜20の数であり、kは0以上2n未満の偶数であり、飽和脂肪族炭化水素鎖または二重結合を少なくとも1個有する不飽和脂肪族炭化水素鎖を構成している。Xはアルカリ金属イオン、アンモニウムイオン、アルカノールアミンイオンなどである。)
これらのソホロリピッドの分子長は、約1.8nmである。
In Formula (4), R 1 and R 2 are each independently hydrogen (—H) or an acetyl group (—COCH 3 ), n is generally a number from 11 to 20, and k is from 0 to less than 2n And an unsaturated aliphatic hydrocarbon chain having at least one saturated aliphatic hydrocarbon chain or double bond. X is an alkali metal ion, an ammonium ion, an alkanolamine ion, or the like. )
The molecular length of these sophorolipids is about 1.8 nm.
[ベシクル]
次に、本発明におけるベシクルについて説明する。
一般に、ベシクルは水溶液の状態では熱力学的に不安定であり、ベシクル粒子同士の凝集や融合、膜成分の結晶化による沈澱の生成、粒子径の増大などがおこる。
これに対して、長期間これらの現象が生じず、分散安定であるものを、熱力学的に安定なベシクルという。
[Vesicles]
Next, the vesicle in the present invention will be described.
In general, vesicles are thermodynamically unstable in the state of an aqueous solution, and vesicle particles aggregate and fuse with each other, precipitates are generated by crystallization of film components, and particle diameter increases.
On the other hand, those that do not cause these phenomena for a long time and are stable in dispersion are called thermodynamically stable vesicles.
ベシクルでは、二分子膜層が形成されるが、このときベシクルの球状分子集合体の曲率半径がベシクルを生じるような大きさになるように、ベシクルの構成成分の親水基及び炭化水素鎖が構成されている。
すなわち、炭化水素鎖が親水基と比較して小さすぎる場合は、曲率半径がベシクルを生じるにはあまりに大きくなり、通常のミセルが生成されることになる。また、炭化水素鎖が、親水基と比較して大きすぎる場合も、曲率半径が小さくなりすぎて、ベシクルは生じない。
In the vesicle, a bilayer layer is formed. At this time, the hydrophilic group and hydrocarbon chain of the vesicle are constituted so that the radius of curvature of the spherical molecular aggregate of the vesicle is large enough to generate the vesicle. Has been.
That is, if the hydrocarbon chain is too small compared to the hydrophilic group, the radius of curvature will be too large to produce vesicles and normal micelles will be generated. Also, when the hydrocarbon chain is too large compared to the hydrophilic group, the radius of curvature becomes too small and no vesicles are produced.
したがって、熱力学的に安定なベシクルを形成させるためには、親水基と炭化水素鎖の適度なバランスが必要不可欠となる。
このバランスを制御するため、近年、アニオン系の界面活性剤(例えばSOS)とカチオン系の界面活性剤(例えばCTAB)を混合することで、強度の機械的外力を付与することなく、熱力学的に安定なベシクルが形成されることが報告されている。
しかしながら、このようなカチオン系の界面活性剤を含むベシクルには毒性があるため、経皮外用剤に好適なものとは言えない。
Therefore, in order to form a thermodynamically stable vesicle, an appropriate balance between the hydrophilic group and the hydrocarbon chain is indispensable.
In order to control this balance, an anionic surfactant (for example, SOS) and a cationic surfactant (for example, CTAB) are mixed in recent years without applying a strong mechanical external force. It has been reported that stable vesicles are formed.
However, since vesicles containing such cationic surfactants are toxic, they cannot be said to be suitable for transdermal external preparations.
本発明は、ソホロリピッドが熱力学的に安定なベシクル又は巨大ミセルの形成に適した親水基および炭化水素鎖のバランスを有しているという新たな知見にもとづいて、このソホロリピッドを、経皮吸収制御剤を構成するためのベシクル又は巨大ミセルの成分として用いることによりなし得たものである。 The present invention is based on the new finding that sophorolipid has a balance of hydrophilic groups and hydrocarbon chains suitable for the formation of thermodynamically stable vesicles or giant micelles. It can be achieved by using it as a component of vesicles or giant micelles for constituting the agent.
図1は、このような本発明におけるソホロリピッドを含む球状分子集合体を示す模式図である。図1において、酸型ソホロリピッド塩(SL−Na)が、CACを超える濃度の場合に自発的に会合して、球状分子集合体を形成することが示されている。ソホロリピッド分子は双頭型(親水基−疎水基−親水基)の分子であり、糖/糖間の糖/カルボキシル基間の相互作用(水素結合)を考慮すると、一般的な二分子膜構造のベシクルとは異なり、同図に示すような一分子膜構造の球状分子集合体を形成すると考えられる。 FIG. 1 is a schematic diagram showing a spherical molecular assembly including the sophorolipid in the present invention. FIG. 1 shows that acid-type sophorolipid salt (SL-Na) spontaneously associates at a concentration exceeding CAC to form a spherical molecular assembly. The sophorolipid molecule is a double-headed molecule (hydrophilic group-hydrophobic group-hydrophilic group), and considering the interaction between sugar / sugar sugar / carboxyl group (hydrogen bond), a general vesicle of bilayer structure Unlike this, it is thought that a spherical molecular assembly having a monomolecular film structure as shown in the figure is formed.
なお、ソホロリピッドにより形成される球状分子集合体がベシクルであるか、あるいは巨大ミセルであるかを明確に区別することは困難であるが、内部に水相が存在している球状分子集合体についてはベシクルと捉えることができる。ただし、ソホロリピッドにより形成される球状分子集合体を含む水溶液の熱力学的性質はミセルに非常に似ているという特徴がある。 Although it is difficult to clearly distinguish whether a spherical molecular aggregate formed by sophorolipid is a vesicle or a giant micelle, for a spherical molecular aggregate in which an aqueous phase exists It can be regarded as a vesicle. However, the thermodynamic properties of aqueous solutions containing spherical molecular aggregates formed by sophorolipid are very similar to micelles.
また、後述するように、この球状分子集合体には有効成分を含有させることが可能である。図1では、球状分子集合体に羅漢果配糖体を含有させた、酸型SL−羅漢果エキス混合分子集合体が示されている。同図に示すように、羅漢果エキスは、球状分子集合体にその膜成分として含有されるとともに、球状分子集合体の内水相にも含有されている。 Further, as will be described later, this spherical molecular assembly can contain an active ingredient. FIG. 1 shows an acid-type SL-rahan fruit extract mixed molecular aggregate in which a spherical molecular aggregate contains rahan glycoside. As shown in the figure, the rahan fruit extract is contained as a membrane component in the spherical molecular assembly and also in the inner aqueous phase of the spherical molecular assembly.
[経皮吸収制御剤の製造方法]
次に、ソホロリピッドを含む球状分子集合体と、その球状分子集合体からなる経皮吸収制御剤の製造方法について説明する。
(1)ソホロリピッドの生産
まず、キャンディダ属の酵母(Candida bombicola、C.apicola、C.petrophilum、C.bogoriensis等)を培養して、ソホロリピッドを生産させる。
[Method for producing transdermal absorption control agent]
Next, a spherical molecular assembly containing sophorolipid and a method for producing a transdermal absorption control agent comprising the spherical molecular assembly will be described.
(1) Production of Sophorolipid First, Candida yeast (Candida bombicola, C. apicola, C. petrophyllum, C. bogoriensis, etc.) is cultured to produce sophorolipid.
このときの培養条件は特に限定されないが、例えば、次のような条件とすることが好ましい。
まず、培養液の初発pHは、4.0〜5.5の範囲内で調整することが好ましい。一方、培養中のpH調節は行わなくても適切に培養することが可能である。
また、培養に適した温度範囲は20〜35℃であり、28〜30℃の場合に最も良く培養できる。
さらに、培養にあたって、通気攪拌することが望ましい。その通気攪拌速度としては、5L〜5KL容量の培養の場合で、通気量0.1〜2.0vvm、攪拌速度100rpm〜600rpmとすることが好ましい。
The culture conditions at this time are not particularly limited, but for example, the following conditions are preferable.
First, the initial pH of the culture solution is preferably adjusted within the range of 4.0 to 5.5. On the other hand, it is possible to appropriately culture without adjusting the pH during the culture.
Moreover, the temperature range suitable for culture | cultivation is 20-35 degreeC, and it can culture | cultivate best in the case of 28-30 degreeC.
Furthermore, it is desirable to aerate and agitate during culture. As the aeration stirring speed, it is preferable that the aeration volume is 0.1 to 2.0 vvm and the stirring speed is 100 rpm to 600 rpm in the case of culture of 5 L to 5 KL capacity.
培養液組成としては、炭素源として油脂及び糖類を用いることが好ましい。油脂全体の濃度は、50〜200g/Lの範囲とすることが好ましく、100〜150g/Lの範囲とすることがより好ましい。糖類は、グルコースなどの単糖類又はスクロースなどの二糖類を用いることが好ましい。また、その培養初発濃度としては、30〜150g/Lの範囲とすることが好ましく、90〜120g/Lの範囲とすることがより好ましい。窒素源としては、特に限定されないが、例えば2〜5g/Lの酵母エキス、0.5〜2g/Lの尿素等を用いることができる。さらに、生育に必要な各種有機物及びリン酸塩・マグネシウム塩等の無機塩類を適当量添加しても良い。 As a culture solution composition, it is preferable to use fats and oils and saccharides as a carbon source. The concentration of the entire fat is preferably 50 to 200 g / L, and more preferably 100 to 150 g / L. As the saccharide, it is preferable to use a monosaccharide such as glucose or a disaccharide such as sucrose. The initial culture concentration is preferably in the range of 30 to 150 g / L, more preferably in the range of 90 to 120 g / L. Although it does not specifically limit as a nitrogen source, For example, 2-5 g / L yeast extract, 0.5-2 g / L urea, etc. can be used. Further, various organic substances necessary for growth and inorganic salts such as phosphates and magnesium salts may be added in appropriate amounts.
培養時間は特に限定されないが、例えば6〜9日間くらいとすることができる。
ソホロリピッドは、このようにキャンディダ属の酵母を培養して得られた培養液中に複数分子種の混合物として蓄積される。通常、ラクトン型を50%以上含んでいる。
The culture time is not particularly limited, but can be, for example, about 6 to 9 days.
Sophorolipid is accumulated as a mixture of a plurality of molecular species in the culture solution obtained by culturing yeast of the genus Candida in this way. Usually, it contains 50% or more of lactone type.
(2)ソホロリピッドの抽出・精製
次に、上記のようにして得られた培養液からソホロリピッドを抽出して精製する。その抽出・精製方法としては、特に限定されないが、例えば、次のようにすることができる。
まず、培養液から、遠心分離、デカンテーション、酢酸エチル抽出などの方法でソホロリピッドを含む成分を分離後、さらにヘキサンで洗浄することで、茶褐色、粘性のある液体として、ソホロリピッド濃度約50%の含水物が得られる。なお、酸型ソホロリピッド塩(SL−Na)の調製法は、特に限定されないが、アルカリ還流による調製法を用いることができる。
(2) Extraction and purification of sophorolipid Next, the sophorolipid is extracted from the culture solution obtained as described above and purified. The extraction / purification method is not particularly limited. For example, it can be performed as follows.
First, components containing sophorolipid are separated from the culture solution by methods such as centrifugation, decantation, and ethyl acetate extraction, and then washed with hexane to obtain a brownish, viscous liquid with a sophorolipid concentration of about 50%. Things are obtained. In addition, although the preparation method of acid type sophorolipid salt (SL-Na) is not specifically limited, the preparation method by alkali reflux can be used.
(3)球状分子集合体の製造
次に、得られたソホロリピッドを水に添加して懸濁し、水溶液内においてベシクル又は巨大ミセルと呼ばれる球状分子集合体を製造する。
このとき、ソホロリピッドの濃度範囲としては、0.3mg/mL〜8000mg/mLとすることが好ましく、0.3mg/mL〜1000mg/mLにすることがより好ましい。
ソホロリピッドの濃度範囲をこのようにすれば、熱力学的に安定なベシクル又は巨大ミセルを形成させることができる。
(3) Production of Spherical Molecular Aggregate Next, the obtained sophorolipid is added and suspended in water to produce a spherical molecular aggregate called vesicle or giant micelle in an aqueous solution.
At this time, the concentration range of sophorolipid is preferably 0.3 mg / mL to 8000 mg / mL, and more preferably 0.3 mg / mL to 1000 mg / mL.
When the concentration range of the sophorolipid is set in this way, thermodynamically stable vesicles or giant micelles can be formed.
また、ソホロリピッドを水に添加した後に行う懸濁においては、強度の機械的外力を付与する必要はなく、試験管を2、3回振る程度の攪拌により、ベシクル又は巨大ミセルを形成させることができる。
このように、ソホロリピッドを用いることによって、高速回転分散処理、超音波分散処理、高圧ホモジナイザー分散処理などを行うことなく、ベシクル又は巨大ミセルを形成させることができる。
In addition, in suspension performed after adding sophorolipid to water, it is not necessary to apply a strong mechanical external force, and vesicles or giant micelles can be formed by stirring the test tube a few times. .
Thus, by using sophorolipid, vesicles or giant micelles can be formed without performing high-speed rotational dispersion processing, ultrasonic dispersion processing, high-pressure homogenizer dispersion processing, or the like.
さらに、本発明によれば、ソホロリピッドを用いることによって、複数の界面活性剤やコサーファクタントを用いることなく、容易に均一かつ微細なベシクル又は巨大ミセル等の分子集合体を得ることが可能になっている。
このようにして得られたベシクル又は巨大ミセルの粒子径は100nm程度であり、少なくとも一年以上は安定である。
Furthermore, according to the present invention, by using sophorolipid, it becomes possible to easily obtain a molecular assembly such as uniform and fine vesicles or giant micelles without using a plurality of surfactants and cosurfactants. Yes.
The vesicles or giant micelles thus obtained have a particle size of about 100 nm and are stable for at least one year.
なお、通常の界面活性剤の場合は、濃度の増加とともに、表面に吸着していき、飽和に達する濃度である臨界ミセル濃度(CMC)をむかえると、ミセルと呼ばれる、分子長の二倍程度の分子集合体を形成する。
これに対し、ソホロリピッドは、分子長が約1.8nmであるが、表面が飽和に達する濃度になると、粒子径が約100nmにも及ぶ球状分子集合体を形成した。この球状分子集合体は、電子顕微鏡観察の結果から、ソホロリピッドにより形成されたベシクル又は巨大ミセルであることが判明した。
In the case of a normal surfactant, as the concentration is increased, it is adsorbed on the surface, and when the critical micelle concentration (CMC), which is a concentration reaching saturation, is changed, it is called micelle, which is about twice the molecular length. Form a molecular assembly.
On the other hand, the sophorolipid has a molecular length of about 1.8 nm, but when the surface reached a saturation concentration, it formed a spherical molecular aggregate having a particle diameter of about 100 nm. This spherical molecular assembly was found to be vesicles or giant micelles formed by sophorolipid from the results of electron microscope observation.
(4)混合分子集合体の製造
次に、ソホロリピッドを含む水溶液に、必要に応じて、以下に示す有効成分を配合し、ソホロリピッド−有効成分混合分子集合体を製造する。なお、有効成分を配合しない場合は、この工程は行わない。
また、有効成分の配合量としては、特に限定されないが、安定なベシクル又は巨大ミセルを形成させる観点から、ソホロリピッドの重量に対して1重量%〜100重量%とすることが好ましい。有効成分は、球状分子集合体の膜中及び球状分子集合体の内水相に取り込まれ、安定化される。
(4) Manufacture of mixed molecular assembly Next, the active ingredient shown below is mix | blended with the aqueous solution containing sophorolipid as needed, and a sophorolipid-active ingredient mixed molecular assembly is manufactured. In addition, this process is not performed when an active ingredient is not mix | blended.
The amount of the active ingredient is not particularly limited, but is preferably 1% by weight to 100% by weight with respect to the weight of the sophorolipid from the viewpoint of forming stable vesicles or giant micelles. The active ingredient is incorporated into the membrane of the spherical molecular assembly and the inner aqueous phase of the spherical molecular assembly and stabilized.
後述するように、本発明のソホロリピッドを含む球状分子集合体からなる経皮吸収制御剤は、角質層の細胞間脂質(ラメラ液晶)に溶解して混合液晶を形成し、球状分子集合体における含有物を角質層内に放出する。これによって、本発明の経皮吸収制御剤は、ソホロリピッドや有効成分の経皮吸収を促進する。
また、有効成分として脂質や油分等を配合し、その配合量を調整することにより、ソホロリピッドを含むベシクル膜の粘性を調整することができ、含有物の放出をコントロールすることもできる。
As will be described later, the transdermal absorption control agent comprising the spherical molecular assembly containing the sophorolipid of the present invention dissolves in the intercellular lipid (lamellar liquid crystal) in the stratum corneum to form a mixed liquid crystal, and is contained in the spherical molecular assembly. Release objects into the stratum corneum. Thereby, the percutaneous absorption control agent of the present invention promotes percutaneous absorption of sophorolipid and active ingredients.
Moreover, the viscosity of the vesicle membrane containing sophorolipid can be adjusted by blending lipids, oils, and the like as active ingredients, and adjusting the blending amount, and the release of inclusions can also be controlled.
本発明の経皮吸収制御剤に配合する有効成分としては、例えば、配糖体、抗酸化剤、抗菌剤、抗炎症剤、血行促進剤、美白剤、肌荒れ防止剤、老化防止剤、発毛促進剤、保湿剤、ホルモン剤、色素、タンパク質、脂質、ビタミン類等とすることが好ましい。
また、配糖体としては、羅漢果配糖体、ステビオサイド、グリチルリチンなどの甘味配糖体、スウェルチアマリン、セコイリドイド、ベルリンなどの苦味配糖体、サポニン、カルデノライドとブファジエノライドなどのステロイド配糖体、ヒアルロン酸などのアミノ酸配糖体、プエラリンなどのイソフラボン配糖体、アスタキサンチンなどのカロテノイドを挙げることができる。
なお、羅漢果、羅漢果配糖体を配合する場合、これらの濃度範囲としては、特に限定されるものではないが、ソホロリピッドの重量に対して当量未満とすることが好ましい。
Examples of the active ingredient to be blended in the percutaneous absorption control agent of the present invention include, for example, glycosides, antioxidants, antibacterial agents, anti-inflammatory agents, blood circulation promoters, whitening agents, skin roughening agents, antiaging agents, hair growth Accelerators, moisturizers, hormone agents, pigments, proteins, lipids, vitamins and the like are preferable.
Glycosides include sweet glycosides such as Rahan fruit glycoside, stevioside and glycyrrhizin, bitter glycosides such as swell thiamarin, sequoidoid, and Berlin, and steroids such as saponin, cardenolide and bufadienolide. Examples include saccharides, amino acid glycosides such as hyaluronic acid, isoflavone glycosides such as puerarin, and carotenoids such as astaxanthin.
In addition, when blending Rahan fruit and Rahan fruit glycoside, the concentration range is not particularly limited, but it is preferably less than the equivalent with respect to the weight of Sophorolipid.
また、本発明の経皮吸収制御剤に配合する有効成分として、例えば、マカデミアナッツ油、アボガド油、トウモロコシ油、オリーブ油、ナタネ油、ゴマ油、ヒマシ油、サフラワー油、綿実油、ホホバ油、ヤシ油、パーム油、液状ラノリン、硬化ヤシ油、硬化油、モクロウ、硬化ヒマシ油、ミツロウ、キャンデリラロウ、カルナウバロウ、イボタロウ、ラノリン、還元ラノリン、硬質ラノリン、ホホバロウ等のオイル、ワックス類、流動パラフィン、スクワラン、プリスタン、オゾケライト、パラフィン、セレシン、ワセリン、マイクロクリスタリンワックス等の炭化水素類、オレイン酸、イソステアリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ベヘン酸、ウンデシレン酸等の高級脂肪酸類、セチルアルコール、ステアリルアルコール、イソステアリルアルコール、ベヘニルアルコール、オクチルドデカノール、ミリスチルアルコール、セトステアリルアルコール等の高級アルコール等、イソオクタン酸セチル、ミリスチン酸イソプロピル、イソステアリン酸ヘキシルデシル、アジピン酸ジイソプロピル、セバチン酸ジ−2−エチルヘキシル、乳酸セチル、リンゴ酸ジイソステアリル、ジ−2−エチルヘキサン酸エチレングリコール、ジカプリン酸ネオペンチルグリコール、ジ−2−ヘプチルウンデカン酸グリセリン、トリ−2−エチルヘキサン酸グリセリン、トリ−2−エチルヘキサン酸トリメチロールプロパン、トリイソステアリン酸トリメチロールプロパン、テトラ−2−エチルヘキサン酸ペンタンエリトリット等の合成エステル油類、ジメチルポリシロキサン、メチルフェニルポリシロキサン、ジフェニルポリシロキサン等の鎖状ポリシロキサン、オクタメチルシクロテトラシロキサン、デカメチルシクロペンタシロキサン、ドデカメチルシクロヘキサンシロキサン等の環状ポリシロキサン、アミノ変性ポリシロキサン、ポリエーテル変性ポリシロキサン、アルキル変性ポリシロキサン、フッ素変性ポリシロキサン等の変性ポリシロキサン等のシリコーン油等の油剤類、脂肪酸セッケン(ラウリン酸ナトリウム、パルミチン酸ナトリウム等)、ラウリル硫酸カリウム、アルキル硫酸トリエタノールアミンエーテル等のアニオン界面活性剤類、塩化ステアリルトリメチルアンモニウム、塩化ベンザルコニウム、ラウリルアミンオキサイド等の必須成分に分類されないカチオン界面活性剤類、イミダゾリン系両性界面活性剤(2−ココイル−2−イミダゾリニウムヒドロキサイド−1−カルボキシエチロキシ2ナトリウム塩等)、ベタイン系界面活性剤(アルキルベタイン、アミドベタイン、スルホベタイン等)、アシルメチルタウリン等の両性界面活性剤類、ソルビタン脂肪酸エステル類(ソルビタンモノステアレート、セスキオレイン酸ソルビタン等)、グリセリン脂肪酸類(モノステアリン酸グリセリン等)、プロピレングリコール脂肪酸エステル類(モノステアリン酸プロピレングリコール等)、硬化ヒマシ油誘導体、グリセリンアルキルエーテル、POEソルビタン脂肪酸エステル類(POEソルビタンモノオレエート、モノステアリン酸ポリオキエチレンソルビタン等)、POEソルビット脂肪酸エステル類(POE−ソルビットモノラウレート等)、POEグリセリン脂肪酸エステル類(POE−グリセリンモノイソステアレート等)、POE脂肪酸エステル類(ポリエチレングリコールモノオレート、POEジステアレート等)、POEアルキルエーテル類(POE2−オクチルドデシルエーテル等)、POEアルキルフェニルエーテル類(POEノニルフェニルエーテル等)、プルロニック型類、POE・POPアルキルエーテル類(POE・POP2−デシルテトラデシルエーテル等)、テトロニック類、POEマシ油・硬化ヒマシ油誘導体(POEヒマシ油、POE硬化ヒマシ油等)、ショ糖脂肪酸エステル、アルキルグルコシド等の非イオン界面活性剤類、ポリエチレングリコール、グリセリン、1,3−ブチレングリコール、エリスリトール、ソルビトール、キシリトール、マルチトール、プロピレングリコール、ジプロピレングリコール、ジグリセリン、イソプレングリコール、1,2−ペンタンジオール、2,4−ヘキシレングリコール、1,2−ヘキサンジオール、1,2−オクタンジオール等の多価アルコール類、ピロリドンカルボン酸ナトリウム、乳酸、乳酸ナトリウム等の保湿成分類、グアガム、クインスシード、カラギーナン、ガラクタン、アラビアガム、ペクチン、マンナン、デンプン、キサンタンガム、カードラン、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロース、メチルヒドロキシプロピルセルロース、コンドロイチン硫酸、デルマタン硫酸、グリコーゲン、ヘパラン硫酸、ヒアルロン酸、ヒアルロン酸ナトリウム、トラガントガム、ケラタン硫酸、コンドロイチン、ムコイチン硫酸、ヒドロキシエチルグアガム、カルボキシメチルグアガム、デキストラン、ケラト硫酸, ローカストビーンガム,サクシノグルカン,カロニン酸,キチン,キトサン、カルボキシメチルキチン、寒天、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、ポリアクリル酸ナトリウム、ポリエチレングリコール、ベントナイト等の増粘剤、表面を処理されていても良い、マイカ、タルク、カオリン、合成雲母、炭酸カルシウム、炭酸マグネシウム、無水ケイ酸(シリカ)、酸化アルミニウム、硫酸バリウム等の粉体類、表面を処理されていても良い、ベンガラ、黄酸化鉄、黒酸化鉄、酸化コバルト、群青、紺青、酸化チタン、酸化亜鉛の無機顔料類、表面を処理されていても良い、雲母チタン、魚燐箔、オキシ塩化ビスマス等のパール剤類、レーキ化されていても良い赤色202号、赤色228号、赤色226号、黄色4号、青色404号、黄色5号、赤色505号、赤色230号、赤色223号、橙色201号、赤色213号、黄色204号、黄色203号、青色1号、緑色201号、紫色201号、赤色204号等の有機色素類、ポリエチレン末、ポリメタクリル酸メチル、ナイロン粉末、オルガノポリシロキサンエラストマー等の有機粉体類、パラアミノ安息香酸系紫外線吸収剤、アントラニル酸系紫外線吸収剤、サリチル酸系紫外線吸収剤、桂皮酸系紫外線吸収剤、ベンゾフェノン系紫外線吸収剤、糖系紫外線吸収剤、2−(2’−ヒドロキシ−5’−t−オクチルフェニル)ベンゾトリアゾール、4−メトキシ−4’−t−ブチルジベンゾイルメタン等の紫外線吸収剤類、エタノール、イソプロパノール等の低級アルコール類、ビタミンA又はその誘導体、ビタミンB6塩酸塩,ビタミンB6トリパルミテート,ビタミンB6ジオクタノエート,ビタミンB2又はその誘導体,ビタミンB12,ビタミンB15又はその誘導体等のビタミンB類、α−トコフェロール,β−トコフェロール,γ−トコフェロール,ビタミンEアセテート等のビタミンE類、ビタミンD類、ビタミンH、パントテン酸、パンテチン、ピロロキノリンキノン等のビタミン類などが好ましい。植物由来のタンパク質、例えば小麦タンパク質及び大豆タンパク質、大豆イソフラボン;動物由来のタンパク質、例えばケラチン、ケラチン加水分解物及びスルホン系のケラチン、ラクトフェリン、コラーゲン、エラスチン及びこれらの誘導体並びにその塩類等のタンパク質などが好ましい。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、ホスファチジン酸、ホスファチジルグリセロール、ホスファチジルイノシトール、カルジオリピン、卵黄レシチン、水添卵黄レシチン、大豆レシチン、水添大豆レシチン等のグリセロリン脂質類、スフィンゴエミリン、セラミドホスホリルエタノールアミン、セラミドホスホリルグリセロールから選ばれるスフィンゴリン脂質類、プラスマローゲン類、及び/又はこれらからなる群より選ばれる1種類、糖脂質が、ジガラクトシルジグリセリド、ガラクトシルジグリセリド硫酸エステル等のグリセロ脂質類、ガラクトシルセラミド、ガラクトシルセラミド硫酸エステル、ラクトシルセラミド、ガングリオシドG7、ガングリオシドG6、ガングリオシドG4等のスフィンゴ糖脂質類、及び/又はこれらの混合物、モノグリセリド、ジグリセリド、トリグリセリド、スフリンゴ脂質、テルペン、ステロイド、プロスタグランジン等の脂質などを用いることも好ましい。 In addition, as an active ingredient to be blended in the transdermal absorption control agent of the present invention, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, Oils such as palm oil, liquid lanolin, hydrogenated coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibota wax, lanolin, reduced lanolin, hard lanolin, jojoba wax, waxes, liquid paraffin, squalane, Hydrocarbons such as pristane, ozokerite, paraffin, ceresin, petrolatum, microcrystalline wax, higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, cetyl alcohol , Steer Alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, higher alcohol such as cetostearyl alcohol, cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, Cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, tri-2-ethylhexanoic acid Synthetic ester oils such as trimethylolpropane, trimethylolpropane triisostearate, pentane erythritol tetra-2-ethylhexanoate, dimethylpolysiloxane Chain polysiloxane such as xane, methylphenyl polysiloxane, diphenyl polysiloxane, cyclic polysiloxane such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane, amino-modified polysiloxane, polyether-modified polysiloxane, Oil agents such as silicone oil such as alkyl-modified polysiloxane and fluorine-modified polysiloxane such as modified polysiloxane, fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, alkyl sulfate triethanolamine ether, etc. Activating agents, cationic surfactants not classified as essential components such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide, imi Dazoline-based amphoteric surfactants (such as 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt), betaine-based surfactants (such as alkyl betaines, amide betaines, sulfobetaines), acylmethyl taurines Amphoteric surfactants such as, sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan sesquioleate), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), Hardened castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-Sol) POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.) , POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE pear oil / hardened castor oil derivative (POE) Castor oil, POE hydrogenated castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside, polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sol Tall, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-hexanediol, 1,2-octanediol, etc. Moisturizing ingredients such as polyhydric alcohols, sodium pyrrolidone carboxylate, lactic acid, sodium lactate, guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose , Methyl hydroxypropyl cellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, Keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratosulfate, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl Thickener such as polymer, sodium polyacrylate, polyethylene glycol, bentonite, surface may be treated, mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide , Powders such as barium sulfate, surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide inorganic pigments, surface treated Pearl particles such as titanium mica, fish phosphorus foil, bismuth oxychloride, red 202, red 228, red 226, yellow 4, blue 404, yellow 5 may be raked Organic pigments such as red 505, red 230, red 223, orange 201, red 213, yellow 204, yellow 203, blue 1, green 201, purple 201, red 204, Organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer, paraaminobenzoic acid UV absorber, anthranilic acid UV absorber, salicylic acid UV absorber, cinnamic acid UV absorber, Benzophenone UV absorber, sugar UV absorber, 2- (2′-hydroxy-5′-t-octylphenyl) benzotriazole, 4 UV absorbers such as methoxy-4'-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol, vitamin A or derivatives thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 Or a derivative thereof, vitamin B such as vitamin B12, vitamin B15 or a derivative thereof, vitamin E such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin D, vitamin H, pantothenic acid, pantethine Vitamins such as pyrroloquinoline quinone are preferred. Proteins derived from plants such as wheat protein and soybean protein, soybean isoflavones; proteins derived from animals such as keratin, keratin hydrolyzate and sulfone keratin, lactoferrin, collagen, elastin and their derivatives, and salts thereof preferable. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, cardiolipin, egg yolk lecithin, hydrogenated egg yolk lecithin, soybean lecithin, glycerophospholipids such as hydrogenated soybean lecithin, sphingoemilin, ceramide phosphorylethanolamine, ceramide Sphingophospholipids selected from phosphorylglycerol, plasmalogens, and / or one kind selected from the group consisting of these, glycerolipids such as digalactosyl diglyceride and galactosyl diglyceride sulfate, galactosylceramide, galactosylceramide Sulfate ester, lactosylceramide, ganglioside G7, ganglioside G6, ganglioside G4 Glycosphingolipids such, and / or mixtures thereof, monoglycerides, diglycerides, triglycerides, Sufuringo lipids, terpenes, steroids, it is also preferable to use such lipids such prostaglandins.
(5)経皮吸収制御剤の製造
次に、以上の工程により製造されたソホロリピッドを含む球状分子集合体を含む水溶液を用いて、経皮吸収制御剤を製造する。
このとき、経皮吸収制御剤の剤型としては、例えば、ローション類、乳液類、クリーム類、パック類、ゲル等とすることができる。
そして、この経皮吸収制御剤を化粧品や皮膚外用剤などの医薬品の成分として使用することができる。また、食品の添加剤として使用することも可能である。
(5) Manufacture of transdermal absorption control agent Next, a transdermal absorption control agent is manufactured using the aqueous solution containing the spherical molecular assembly containing the sophorolipid manufactured by the above process.
At this time, the dosage form of the transdermal absorption control agent can be, for example, lotions, emulsions, creams, packs, gels, and the like.
And this transdermal absorption control agent can be used as a component of pharmaceuticals, such as cosmetics and a skin external preparation. It can also be used as a food additive.
このとき、ソホロリピッドの配合量としては、化粧品や皮膚外用剤の全成分組成物において、0.01%〜20.0重量%とすることが好ましく、0.1〜10.0重量%とすることがより好ましい。ソホロリピッドの配合量をこのような範囲にすれば、ソホロリピッドを経皮吸収促進剤などの経皮吸収コントロール剤として好適に利用することが可能である。
なお、本発明の経皮吸収制御剤に、さらに保湿剤、防腐剤、界面活性剤、増粘剤、油剤、溶剤、香料、pH調整剤等を本発明の目的を達成する範囲内で適宜配合してもよい。
At this time, the blending amount of sophorolipid is preferably 0.01% to 20.0% by weight and preferably 0.1 to 10.0% by weight in the total composition of cosmetics and skin external preparations. Is more preferable. When the blending amount of sophorolipid is within such a range, sophorolipid can be suitably used as a transdermal absorption control agent such as a transdermal absorption enhancer.
In addition, a moisturizer, preservative, surfactant, thickener, oil agent, solvent, fragrance, pH adjuster, and the like are appropriately added to the transdermal absorption control agent of the present invention within the scope of achieving the object of the present invention. May be.
[ラメラ液晶形成促進作用]
次に、ソホロリピッドのラメラ液晶形成促進作用について説明する。
皮膚の角質層におけるバリア機能は、細胞間脂質により構成されるラメラ液晶が大きく関与している。例えば、乾燥して傷んだ肌においては、ラメラ液晶の構造が崩壊して、ラメラ液晶が減少していることが実証されている。
[Acceleration of lamellar liquid crystal formation]
Next, the lamellar liquid crystal formation promoting action of sophorolipid will be described.
A lamellar liquid crystal composed of intercellular lipids is largely involved in the barrier function in the stratum corneum of skin. For example, in dry and damaged skin, it has been demonstrated that the structure of the lamellar liquid crystal collapses and the lamellar liquid crystal decreases.
したがって、角質層におけるラメラ構造を再生することができれば、角質層の水分保持能を回復して、皮膚にうるおいを与え、肌荒れを解消することができるものと考えられる。
また、経皮吸収においては、有効成分及び有効成分と相互作用する経皮吸収促進剤が、細胞間脂質のラメラ構造に入り込むことは重要である。
本発明の経皮吸収制御剤は、ソホロリピッドを含む球状分子集合体が角質細胞間脂質のラメラ液晶形成促進作用を有し、肌荒れ改善効果を有することが判明している。
また、本発明の経皮吸収制御剤は、ラメラ液晶形成促進に寄与していることから、ラメラ液晶に溶解して混合液晶を形成することが証明され、有効成分を角質細胞間に拡散させることが可能となっている。
Therefore, if the lamellar structure in the stratum corneum can be regenerated, it is considered that the moisture retention ability of the stratum corneum can be recovered, moisture is given to the skin, and rough skin can be eliminated.
In transdermal absorption, it is important that the active ingredient and the transdermal absorption enhancer that interacts with the active ingredient enter into the lamellar structure of the intercellular lipid.
In the percutaneous absorption control agent of the present invention, it has been found that a spherical molecular assembly containing sophorolipid has an action of promoting the formation of lamellar liquid crystal of keratin intercellular lipid and has an effect of improving skin roughness.
Further, since the transdermal absorption control agent of the present invention contributes to the promotion of lamellar liquid crystal formation, it is proved that it dissolves in lamellar liquid crystal to form a mixed liquid crystal and diffuses active ingredients between keratinocytes. Is possible.
図2は、このような本発明のソホロリピッドを含む球状分子集合体からなる経皮吸収促進剤の皮膚浸透のようすを示す模式図である。
図2において、羅漢果配糖体を有効成分として含む混合球状分子集合体が示されており、これが角質細胞間の間隙に入り込んで、ラメラ液晶に溶解して混合液晶を形成するようすが示されている。また、有効成分である羅漢果配糖体が、角質層内において拡散するようすが示されている。
FIG. 2 is a schematic diagram showing the skin permeation of a transdermal absorption enhancer comprising a spherical molecular assembly containing the sophorolipid of the present invention.
FIG. 2 shows a mixed spherical molecular aggregate containing Rahan fruit glycoside as an active ingredient, which enters into the gaps between the corneocytes and dissolves in lamellar liquid crystals to form mixed liquid crystals. Yes. In addition, it is shown that Rahan fruit glycoside, which is an active ingredient, diffuses in the stratum corneum.
以上説明したように、本発明の経皮吸収制御剤は、ソホロリピッドを用いることにより、従来技術のように複数の界面活性剤や強度の機械的外力を必要とすることなく、ベシクル又は巨大ミセルの分子集合体を形成することができる。
このため、経皮吸収制御剤の製造プロセスを簡略化することができ、大幅な製造コストの削減を期待することが可能である。
As described above, the percutaneous absorption control agent of the present invention uses a sophorolipid, which does not require a plurality of surfactants or a strong mechanical external force as in the prior art, and does not require vesicles or giant micelles. A molecular assembly can be formed.
For this reason, the manufacturing process of a transdermal absorption control agent can be simplified, and it can be expected that the manufacturing cost is greatly reduced.
また、ソホロリピッドは生分解性に優れるのみならず、毒性がなく、酵母により各種の再生可能資源から生産することができる。このため、ソホロリピッドを用いることは、従来の複数の界面活性剤などを用いる場合に比べ、地球環境保全の観点からも好ましい。
さらに、本発明におけるソホロリピッドを含むベシクル等は、熱力学的に安定であるため、長期間分散安定であり、かつ100nm程度の微細な粒子径を有するため、ベシクルに内包させた化粧品成分や医薬品成分、さらに食品成分の吸収促進などを期待することもできる。
In addition, sophorolipid is not only excellent in biodegradability but also has no toxicity, and can be produced from various renewable resources by yeast. For this reason, the use of sophorolipid is preferable from the viewpoint of global environmental conservation as compared with the case of using a plurality of conventional surfactants.
Furthermore, since vesicles containing sophorolipid in the present invention are thermodynamically stable, have a long-term dispersion stability, and have a fine particle size of about 100 nm, cosmetic ingredients and pharmaceutical ingredients encapsulated in vesicles Furthermore, it can be expected to promote absorption of food components.
また、ソホロリピッド、又はそのベシクルや巨大ミセルなどの分子集合体は、角質細胞間の間隙に入り込んで、細胞間脂質のラメラ液晶に溶解することができ、ラメラ液晶形成を促進して肌荒れ改善効果を有する。
さらに、分子集合体に含まれた有効成分を、効率よく皮膚に取り入れることができる。また、有効成分として脂質や油分等を配合することで、分子集合体の粘性を調整でき、その分子集合体の内容物の放出をコントロールすることも可能である。
In addition, sophorolipid, or molecular aggregates such as vesicles and giant micelles, can enter the gaps between the corneocytes and dissolve in the lamellar liquid crystals of intercellular lipids, promoting the formation of lamellar liquid crystals and improving skin roughness. Have.
Furthermore, the active ingredient contained in the molecular assembly can be efficiently taken into the skin. Further, by blending lipid, oil, and the like as active ingredients, the viscosity of the molecular assembly can be adjusted, and the release of the contents of the molecular assembly can be controlled.
以下、本発明の実施例について説明するが、本発明はこれらに限定されるものではない。
(実施例1)臨界会合体形成濃度の算出
まず、本発明で用いるソホロリピッドの臨界会合体形成濃度(CAC)及びその際の表面張力値(γCAC)を求めるため、ペンダントドロップ法による表面張力測定を行った。
ソホロリピッドとしては、上述した「(1)ソホロリピッドの生産」に記載した工程により生産した、酸型ソホロリピッド(SL−H)と酸型ソホロリピッド塩(SL−Na)を用いた。
Examples of the present invention will be described below, but the present invention is not limited thereto.
(Example 1) Calculation of critical aggregate formation concentration First, in order to obtain the critical aggregate formation concentration (CAC) and the surface tension value (γCAC) of the sophorolipid used in the present invention, surface tension measurement by pendant drop method was performed. went.
As the sophorolipid, acid-type sophorolipid (SL-H) and acid-type sophorolipid salt (SL-Na) produced by the process described in "(1) Production of sophorolipid" were used.
表面張力の測定は、協和界面科学社製のdrop masterDM500を用いて行った。結果を図3に示す。
図3に示されるように、酸型ソホロリピッド(SL−H)のCAC及びγCACの値は、それぞれ0.30mg/mL、35.3mN/mであった。また、酸型ソホロリピッド塩(SL−Na)のCAC及びγCACの値は、それぞれ0.84mg/mL、32.4mN/mであった。
The surface tension was measured using a drop master DM500 manufactured by Kyowa Interface Science. The results are shown in FIG.
As shown in FIG. 3, the CAC and γCAC values of acid-type sophorolipid (SL-H) were 0.30 mg / mL and 35.3 mN / m, respectively. The CAC and γCAC values of the acid-type sophorolipid salt (SL-Na) were 0.84 mg / mL and 32.4 mN / m, respectively.
この結果から、酸型ソホロリピッド塩(SL−Na)については、1mg/mL以上の濃度の水溶液とすれば、十分に会合体が形成されることがわかる。
そこで、以下の実施例及び試験例においては、1mg/mLの酸型ソホロリピッド塩(SL−Na)及び1%酸型ソホロリピッド塩(SL−Na)を使用した。
From this result, it can be seen that, when the acid-type sophorolipid salt (SL-Na) is an aqueous solution having a concentration of 1 mg / mL or more, an aggregate is sufficiently formed.
Therefore, in the following Examples and Test Examples, 1 mg / mL acid type sophorolipid salt (SL-Na) and 1% acid type sophorolipid salt (SL-Na) were used.
(実施例2)球状分子集合体の電子顕微鏡(TEM)観察
次に、実施例1で用いた酸型ソホロリピッド塩(SL−Na)10mgと、水10mLとを、500mLトールビーカーに加えて、ソホロリピッドの濃度を1mg/mLとし、トールビーカーを手で2、3回軽く震盪することにより攪拌した。
そして、この水溶液中に形成された球状分子集合体を、電子顕微鏡(TEM)で観察した。この電子顕微鏡としては、日本電子社製のJEM−1010を用いた。結果を図4に示す。
Example 2 Observation of Spherical Molecular Assembly by Electron Microscope (TEM) Next, 10 mg of acid type sophorolipid salt (SL-Na) used in Example 1 and 10 mL of water were added to a 500 mL tall beaker, sophorolipid. The concentration was adjusted to 1 mg / mL, and the tall beaker was agitated by shaking a few times by hand.
And the spherical molecular assembly formed in this aqueous solution was observed with the electron microscope (TEM). As this electron microscope, JEM-1010 manufactured by JEOL Ltd. was used. The results are shown in FIG.
図4に示される通り、形成された球状分子集合体は、通常のミセルではなく、粒子径100nm程度のベシクル様構造を呈していた。また、この実施例2で用いた酸型ソホロリピッド塩(SL−Na)水溶液は、少なくとも一年以上安定であった。
したがって、得られたベシクル様構造が、熱力学的に安定であることが明らかになった。
このようなソホロリピッドを含む粒子径100nm程度のベシクル様構造は、新規の球状分子集合体である。
As shown in FIG. 4, the formed spherical molecular assembly was not a normal micelle, but had a vesicle-like structure with a particle diameter of about 100 nm. Moreover, the acid type sophorolipid salt (SL-Na) aqueous solution used in Example 2 was stable for at least one year.
Therefore, it was revealed that the obtained vesicle-like structure was thermodynamically stable.
Such a vesicle-like structure having a particle diameter of about 100 nm containing sophorolipid is a novel spherical molecular assembly.
(実施例3)球状分子集合体への有効成分の配合、及び粒子径の測定
次に、実施例2において製造された、酸型ソホロリピッド塩(SL−Na)からなる球状分子集合体に、有効成分として羅漢果配糖体を配合した。また、球状分子集合体の粒子径を測定した。
(Example 3) Compounding of active ingredient into spherical molecular assembly and measurement of particle diameter Next, it is effective for the spherical molecular assembly made of acid-type sophorolipid salt (SL-Na) produced in Example 2. Rakan fruit glycoside was blended as an ingredient. Moreover, the particle diameter of the spherical molecular aggregate was measured.
このとき、羅漢果配糖体の配合割合として、酸型ソホロリピッド塩(SL−Na)水溶液に対し、羅漢果配糖体を0.02重量%、0.1重量%配合して得られた混合分子集合体のサンプルをそれぞれ作成した。
そして、これらのサンプルと、羅漢果配糖体を配合していないサンプルについて、動的光散乱法(DLS)を用いて、分子集合体の粒子径を測定した。この動的光散乱法には、大塚電子社製DLS−7000を用いた。結果を図5に示す。
At this time, the mixed molecular assembly obtained by blending 0.02% by weight and 0.1% by weight of Luohan Glycoside with respect to the aqueous solution of acid sophorolipid (SL-Na) as a blending ratio of Luohan Glycoside Each body sample was made.
And the particle diameter of the molecular assembly was measured about these samples and the sample which is not mix | blending the Rakan fruit glycoside using the dynamic light scattering method (DLS). For this dynamic light scattering method, DLS-7000 manufactured by Otsuka Electronics Co., Ltd. was used. The results are shown in FIG.
通常、界面活性剤が形成するミセルの粒子径は分子長の2倍程度の大きさになることが知られている。
しかしながら、図5に示される通り、酸型ソホロリピッド塩(1mg/mL)を含み、羅漢果配糖体を配合していない分子集合体の粒子径は、96.2nmであり、酸型ソホロリピッド塩の分子長約1.8nmに比較して大きな粒子径のベシクル様構造が形成されることが判明した。この結果は、実施例2において説明した電子顕微鏡(TEM)による観察結果とも良く一致していた。
Usually, it is known that the particle size of the micelle formed by the surfactant is about twice the molecular length.
However, as shown in FIG. 5, the particle size of the molecular assembly containing acid-type sophorolipid salt (1 mg / mL) and not blended with Luohan Glycoside is 96.2 nm. It has been found that a vesicle-like structure having a large particle diameter is formed as compared with a length of about 1.8 nm. This result was in good agreement with the observation result by the electron microscope (TEM) described in Example 2.
さらに、図5に示される通り、羅漢果配糖体の配合量に依存して、分子集合体の粒子径が増大することも明らかになった。
以上の結果から、希薄溶液において、酸型ソホロリピッド塩(SL−Na)の分子集合体に羅漢果配糖体を配合可能であることが明らかになった。
Furthermore, as shown in FIG. 5, it was also clarified that the particle diameter of the molecular assembly increases depending on the blending amount of Rahan fruit glycoside.
From the above results, it was revealed that Rahan fruit glycoside can be blended with the molecular aggregate of acid-type sophorolipid salt (SL-Na) in a dilute solution.
(実施例4)球状分子集合体へのpHの影響
次に、酸型ソホロリピッド塩(SL−Na)からなる分子集合体(1mg/mL)へのpHの影響について、動的光散乱法(DLS)及び電子顕微鏡(TEM)観察により検討した。
すなわち、動的光散乱法(DLS)により、種々のpHにおける酸型ソホロリピッド塩(SL−Na)からなる分子集合体の粒子径を測定し、分子集合体形成に対するpHの影響を調査した。なお、pHの調整は、実施例2において作成した酸型ソホロリピッド塩(SL−Na)からなる球状分子集合体を含む水溶液に、pH調整剤を添加することにより行った。結果を図6に示す。
また、電子顕微鏡(TEM)を用いて、酸型ソホロリピッド塩(SL−Na)が形成する分子集合体を撮影した。結果を図7に示す。
Example 4 Effect of pH on Spherical Molecular Assembly Next, the dynamic light scattering method (DLS) is described with respect to the effect of pH on a molecular assembly (1 mg / mL) composed of acid-type sophorolipid salt (SL-Na). ) And electron microscope (TEM) observation.
That is, the particle diameter of a molecular assembly composed of acid-type sophorolipid salts (SL-Na) at various pH values was measured by dynamic light scattering (DLS), and the influence of pH on the molecular assembly formation was investigated. In addition, pH adjustment was performed by adding a pH adjuster to the aqueous solution containing the spherical molecular assembly which consists of the acid type sophorolipid salt (SL-Na) created in Example 2. The results are shown in FIG.
In addition, a molecular assembly formed by the acid-type sophorolipid salt (SL-Na) was photographed using an electron microscope (TEM). The results are shown in FIG.
図6に示される通り、pHの上昇に伴って、球状分子集合体の粒子径が増大することが明らかになった。
また、図7に示される通り、いずれのpHにおいてもベシクル様の分子集合体が確認された。
さらに、特にpH4.5の場合に、球状分子集合体の粒子径が小さくなることが判明した。このような粒子径が小さい球状分子集合体からなる経皮吸収制御剤によれば、経皮吸収促進効果がより向上することが期待される。
As shown in FIG. 6, it was revealed that the particle diameter of the spherical molecular assembly increases with increasing pH.
Further, as shown in FIG. 7, vesicle-like molecular aggregates were confirmed at any pH.
Furthermore, it was found that the particle diameter of the spherical molecular aggregate becomes small particularly at pH 4.5. According to such a transdermal absorption control agent comprising a spherical molecular aggregate having a small particle size, it is expected that the percutaneous absorption promotion effect is further improved.
以上のことから、経皮吸収制御剤を製造するにあたっては、ソホロリピッドを含む水溶液のpHを4.5〜11.5に調整すれば、適切に球状分子集合体が形成されることがわかる。
弱酸性を含むこのようなpHの範囲でベシクル様の分子集合体を形成できることは、これを含む経皮吸収制御剤を製造するにあたり、実用上大変有効である。
From the above, when producing a transdermal absorption controlling agent, it can be seen that if the pH of the aqueous solution containing sophorolipid is adjusted to 4.5 to 11.5, a spherical molecular assembly is appropriately formed.
The ability to form a vesicle-like molecular assembly in such a pH range including weak acidity is very effective in practical use in producing a transdermal absorption control agent containing the same.
(実施例5)ラメラ液晶の形成
次に、人工的な角質細胞間脂質に、ソホロリピッドを含む球状分子集合体からなる経皮吸収制御剤等を添加し、ラメラ液晶の形成状況を、偏光板を用いて顕微鏡写真撮影により評価した(桜井 哲人、フレグランス ジャーナル、33(10)、57(2005))。
(Example 5) Formation of lamellar liquid crystal Next, a percutaneous absorption control agent comprising a spherical molecular assembly containing sophorolipid is added to artificial interstitial lipids, and the formation state of lamellar liquid crystal is changed to a polarizing plate. And evaluated by microphotographing (Tetsuhito Sakurai, Fragrance Journal, 33 (10), 57 (2005)).
人工的な角質細胞間脂質は、次のように作成した。まず、セラミドII、コレステロール、ステアリン酸、硫酸コレステロール、水を、12:8:8:2:70の割合で混合し、80℃で約1時間加熱して脂質成分を融解させ、10℃で10分間超音波処理を行った。さらに、再度80℃で約1時間融解混合を行った後、10℃で10分間超音波処理を行った。これにより、人工角質細胞間脂質を得た。 Artificial keratinocyte lipids were prepared as follows. First, ceramide II, cholesterol, stearic acid, cholesterol sulfate, and water are mixed at a ratio of 12: 8: 8: 2: 70, and heated at 80 ° C. for about 1 hour to melt the lipid component, and 10 at 10 ° C. Sonicate for minutes. Further, after melting and mixing again at 80 ° C. for about 1 hour, ultrasonic treatment was performed at 10 ° C. for 10 minutes. Thereby, artificial keratinocyte lipid was obtained.
また、人工角層細胞間脂質の作成にあたり、その組成中の水を、それぞれ1%酸型ソホロリピッド塩(SL−Na)、1%酸型ソホロリピッド塩(SL−Na)+1%羅漢果配糖体、1%レシチンに置き換えて、上記と同様の操作を行い、これらの組成を含む人工角層細胞間脂質を得た。
そして、以上の人工角質細胞間脂質について、ラメラ液晶の形成状況の撮影を行った。結果を図8に示す。
Further, in the preparation of the artificial stratum corneum intercellular lipid, the water in the composition was converted into 1% acid sophorolipid salt (SL-Na), 1% acid sophorolipid salt (SL-Na) + 1% Rahan Glycoside, By replacing with 1% lecithin, the same operation as described above was performed to obtain artificial stratum corneum intercellular lipids containing these compositions.
And about the above artificial keratinocyte lipid, the formation condition of the lamellar liquid crystal was image | photographed. The results are shown in FIG.
図8に示される通り、「(a)人工角質細胞間脂質のみ」に比較して、「(b)1%酸型ソホロリピッド塩(SL−Na)」及び「(c)1%酸型ソホロリピッド塩(SL−Na)+1%羅漢果配糖体」を添加した場合に、ラメラ液晶の形成が顕著に増加している。また、その効果は、「(d)1%レシチン」を添加した場合よりも大きくなっている。
このことから、ソホロリピッドを含む球状分子集合体により、ラメラ液晶の形成が大きく促進されることがわかった。
As shown in FIG. 8, “(b) 1% acid type sophorolipid salt (SL-Na)” and “(c) 1% acid type sophorolipid salt” are compared with “(a) artificial corneocyte lipid only”. When "(SL-Na) + 1% Rahan fruit glycoside" is added, the formation of lamellar liquid crystal is remarkably increased. In addition, the effect is greater than when “(d) 1% lecithin” is added.
From this, it was found that the formation of lamellar liquid crystal was greatly promoted by the spherical molecular aggregate containing sophorolipid.
また、ソホロリピッドと羅漢果配糖体を含む球状分子集合体を人工角質細胞間脂質に添加した場合にも、ラメラ液晶の形成が顕著に増加している。
このことから、相互作用している羅漢果配糖体はソホロリピッドと一緒にラメラ液晶に入り込み、角質層内に拡散すると考えられる。
In addition, the formation of lamellar liquid crystals is also significantly increased when spherical molecular aggregates containing sophorolipid and Rahan fruit glycoside are added to the lipids between artificial keratinocytes.
From this, it is considered that the interacting Rakan fruit glycoside enters the lamellar liquid crystal together with the sophorolipid and diffuses into the stratum corneum.
(試験例1)経皮透過試験
ソホロリピッドを含む球状分子集合体の皮膚浸透効果を調べるため、人工皮膚を用いて、ソホロリピッドの経皮透過試験を行った。人工皮膚としては、3次元培養皮膚モデルLSE−high(東洋紡製)を用いた。
この人工皮膚の表面に、1%酸型ソホロリピッド塩(SL−Na)からなる球状分子集合体を適用して、一定時間後に透過したソホロリピッドを高速液体クロマトグラフィー(HPLC)で定量した。結果を図9に示す。
(Test Example 1) Percutaneous Permeation Test In order to examine the skin permeation effect of a spherical molecular assembly containing sophorolipid, a percutaneous permeation test of sophorolipid was performed using artificial skin. As the artificial skin, a three-dimensional cultured skin model LSE-high (manufactured by Toyobo) was used.
A spherical molecular assembly composed of 1% acid type sophorolipid salt (SL-Na) was applied to the surface of the artificial skin, and the sophorolipid permeated after a predetermined time was quantified by high performance liquid chromatography (HPLC). The results are shown in FIG.
図9に示される通り、ソホロリピッドの経皮透過率は、時間依存的に顕著に増加した。このことから、ソホロリピッドを含む球状分子集合体は、優れた皮膚浸透効果を有することがわかる。 As shown in FIG. 9, the transdermal permeability of sophorolipid increased remarkably in a time-dependent manner. From this, it can be seen that the spherical molecular assembly containing sophorolipid has an excellent skin penetration effect.
(試験例2)ソホロリピッドによる羅漢果配糖体の経皮吸収促進試験
ソホロリピッドを含む球状分子集合体による有効成分の経皮吸収促進効果を調べるため、人工皮膚を用いて、ソホロリピッドによる羅漢果配糖体の経皮吸収促進試験を行った。人工皮膚としては、試験例1と同様に、3次元培養皮膚モデルLSE−high(東洋紡製)を用いた。
この人工皮膚の表面に、0.1%羅漢果配糖体と、0.1%羅漢果配糖体及び1%酸型ソホロリピッド塩(SL−Na)からなる混合分子集合体とをそれぞれ適用して、2時間後に羅漢果配糖体の主成分であるモグロサイドVをHPLCで定量した。結果を図10に示す。
To investigate the percutaneous absorption promoting effect of the active ingredient according to Test Example 2 sophorolipid spherical molecular assembly comprising a percutaneous absorption enhancer test sophorolipid of Luo Han Guo glycosides by using an artificial skin, the Luo Han Guo glycosides by sophorolipid A transdermal absorption promotion test was conducted. As the artificial skin, a three-dimensional cultured skin model LSE-high (manufactured by Toyobo) was used as in Test Example 1.
On the surface of this artificial skin, 0.1% Rahan Fruit Glycoside, and a mixed molecular assembly composed of 0.1% Rahan Fruit Glycoside and 1% acid type sophorolipid salt (SL-Na), respectively, Two hours later, Mogroside V, which is the main component of Luohan Glycoside, was quantified by HPLC. The results are shown in FIG.
図10に示される通り、0.1%羅漢果配糖体については、適用2時間後でもモグロサイドVがほぼ100%残存しているのに対し、0.1%羅漢果配糖体に1%酸型ソホロリピッド塩(SL−Na)を添加したものについては、適用2時間後のモグロサイドVの残存率は88%に減少している。 As shown in FIG. 10, in the case of 0.1% Luohan Glycoside, almost 100% of Mogroside V remains even after 2 hours of application, whereas 1% acid form in 0.1% Luogan Glycoside. In the case where the sophorolipid salt (SL-Na) was added, the residual ratio of mogroside V after 2 hours of application was reduced to 88%.
すなわち、1%酸型ソホロリピッド塩(SL−Na)を添加することにより、羅漢果配糖体の経皮吸収率が顕著に増加している。
このことから、ソホロリピッドが羅漢果配糖体の経皮吸収促進剤として機能することがわかった。
That is, by adding 1% acid type sophorolipid salt (SL-Na), the percutaneous absorption rate of Rahan fruit glycoside is remarkably increased.
From this, it was found that sophorolipid functions as a percutaneous absorption enhancer for Rahan fruit glycoside.
(試験例3)保湿試験
ソホロリピッドを皮膚外用剤に含有させた場合の、水分保持能の変化を調べるため、図11に示すように、ソホロリピッドを含まない組成物1と、ソホロリピッドを0.1%配合した組成物2を準備した。
そして、6名の被験者の皮膚に組成物1、組成物2をそれぞれ0.02g塗布し、4時間前後の水分量の変化をCorneometerCM825(Courage+Khazaka社製)で測定してその平均値を算出した。結果を図12に示す。
(Test Example 3) Moisturizing test In order to examine the change in water retention capacity when sophorolipid was added to the external preparation for skin, as shown in FIG. 11, composition 1 containing no sophorolipid and 0.1% of sophorolipid were used. A blended composition 2 was prepared.
Then, 0.02 g of the composition 1 and the composition 2 were applied to the skins of 6 subjects, and the change in the amount of water around 4 hours was measured with Corneometer CM825 (manufactured by Curage + Khazaka) to calculate the average value. The results are shown in FIG.
図12に示す通り、皮膚の水分保持能は、ソホロリピッドを0.1%配合した組成物2を塗布した場合の方が、ソホロリピッドを含まない組成物1を塗布した場合よりも増加した。
ソホロリピッドがヒアルロン酸や羅漢果配糖体などの保湿成分の経皮吸収を促進した結果、保湿効果が増加したと考えられる。
As shown in FIG. 12, the water retention capacity of the skin, who when applied to a 0.1% compounded composition 2 sophorolipid is increased than when applying the composition 1 containing no sophorolipid.
It is thought that the moisturizing effect increased as a result of sophorolipid promoting the percutaneous absorption of moisturizing ingredients such as hyaluronic acid and Rahan fruit glycoside.
本発明のソホロリピッドを含む球状分子集合体からなる経皮吸収制御剤は、化粧品や医薬品、食品などの添加剤として、好適に使用することが可能である。 The transdermal absorption control agent comprising a spherical molecular assembly containing the sophorolipid of the present invention can be suitably used as an additive for cosmetics, pharmaceuticals, foods and the like.
Claims (10)
前記分子集合体が角質細胞間の間隙に入り込み、細胞間脂質からなるラメラ液晶に融解して、前記分子集合体の含有成分を前記ラメラ液晶内に拡散することを特徴とする経皮吸収制御剤。 When the transdermal absorption controlling agent according to any one of claims 1 to 3 is applied to the skin,
The percutaneous absorption control agent characterized in that the molecular assembly enters a space between keratinocytes, melts into a lamellar liquid crystal composed of intercellular lipids, and diffuses the components of the molecular assembly into the lamellar liquid crystal. .
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JP5906194B2 (en) * | 2011-01-13 | 2016-04-20 | 株式会社カネカ | Skin preparation |
EP2821495B1 (en) | 2012-03-02 | 2016-10-05 | Saraya Co., Ltd. | High-purity acid-form sophorolipid (sl) containing composition and process for preparing same |
CN105593370B (en) | 2013-08-09 | 2021-07-06 | 莎罗雅株式会社 | Sophorolipid compound and composition comprising the same |
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US10307466B2 (en) | 2014-03-10 | 2019-06-04 | Saraya Co., Ltd. | Composition comprising sophorolipid, physiologically active substance and oil or fat, and method for producing the same |
JP6157524B2 (en) * | 2015-03-04 | 2017-07-05 | サラヤ株式会社 | Low toxicity sophorolipid-containing composition and use thereof |
JP2016160264A (en) * | 2016-01-04 | 2016-09-05 | サラヤ株式会社 | Low-toxicity sophorolipid-containing compositions and uses thereof |
KR101931299B1 (en) * | 2016-11-29 | 2018-12-20 | 바이오인터체인지주식회사 | Composition for preventing hair loss or stimulating hair growth comprising sophorolipid as effective component |
US11312928B2 (en) | 2017-03-07 | 2022-04-26 | Saraya Co., Ltd. | Detergent composition comprising an acidic sophorose lipid and fatty acid salt mixture |
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