JP3658114B2 - Topical skin preparation - Google Patents

Description

製法：(1)〜(6)の油相成分を混合，加熱して均一に溶解し、７０℃に保つ。一方、(7)〜(11)の水相成分を混合，加熱して均一とし、７０℃とする。この水相成分に前記油相成分を攪拌しながら徐々に添加して乳化し、冷却する。
【００１５】
［実施例３］ 皮膚用ゲル剤
(1)ジプロピレングリコール １０．０（重量％）
(2)カルボキシビニルポリマー ０．５
(3)水酸化カリウム ０．１
(4)パラオキシ安息香酸メチル ０．１
(5)精製水 ８９．２
(6)サポシンＤ ０．１
製法：(5)に(2)を均一に溶解させた後、(1)に(4)を溶解させて添加し、次いで(3)を加えて増粘させ、(6)を添加，溶解する。
【００１６】

製法：(1)〜(7)の油相成分を混合，溶解して７５℃に加熱する。一方、(8)〜(11)の水相成分を混合，溶解して７５℃に加熱する。次いで、上記水相成分に油相成分を添加して予備乳化した後、ホモミキサーにて均一に乳化し、冷却する。
【００１７】
［実施例５］ 水中油型乳剤性軟膏
(1)白色ワセリン ２５．０（重量％）
(2)ステアリルアルコール ２５．０
(3)グリセリン １２．０
(4)ラウリル硫酸ナトリウム ０．５
(5)サポシンＤ ２．０
(6)パラオキシ安息香酸メチル ０．１
(7)精製水 ３５．４
製法：(1)〜(4)の油相成分を混合，加熱して均一に溶解し、７５℃に保つ。一方、(5)〜(7)の水相成分を混合，加熱して均一とし、７５℃とする。この水相成分に前記油相成分を攪拌しながら徐々に添加して乳化し、冷却する。
【００１８】
［実施例６］ 皮膚用リポソーム液
（リポソーム）
(1)ホスファチジルコリン ２０．０（重量％）
(2)水素添加大豆レシチン ２０．０
(3)サポシンＤ ５．０
(4)精製水 ５５．０
製法：(1)〜(3)を５０℃にて(4)に分散させ、超音波処理してリポソームを形成させた後、遠心分離によりリポソームを回収する。
（リポソーム液）
上記リポソームを１０．０重量％となるように、１０．０重量％エタノール水溶液に分散させる。
【００１９】
［実施例７］ 化粧水
(1)エタノール １０．００（重量％）
(2)1,3-ブチレングリコール ３．５０
(3)サポシンＤ ０．０２
(4)パラオキシ安息香酸メチル ０．１０
(5)香料 ０．１０
(6)精製水 ８６．２８
製法：(1)〜(5)を順次(6)に添加，混合し、均一とする。
【００２０】
［実施例８］ 油中水型エモリエントクリーム
(1)流動パラフィン ３０．００（重量％）
(2)マイクロクリスタリンワックス ２．００
(3)ワセリン ５．００
(4)ジグリセリルオレイン酸エステル ５．００
(5)L-グルタミン酸ナトリウム １．６０
(6)L-セリン ０．４０
(7)プロピレングリコール ３．００
(8)サポシンＤ ０．０３
(9)パラオキシ安息香酸メチル ０．１０
(10)精製水 ５２．７２
(11)香料 ０．１５
製法：(5)，(6)を(10)の一部に溶解して５０℃とし、５０℃に加熱した(4)に攪拌しながら徐々に添加する。これをあらかじめ混合し７０℃に加熱溶解した(1)〜(3)に均一に分散して油相とする。一方、(7)〜(9)を(10)の残部に溶解して７０℃に加熱し、水相とする。この水相を前記油相に攪拌しながら徐々に添加し、ホモミキサーにて乳化する。冷却後４０℃にて(11)を添加，混合する。
【００２１】
［実施例９］ 美容液
(1)エタノール １０．００（重量％）
(2)プロピレングリコール ４．００
(3)ポリエチレングリコール1500 ２．００
(4)ポリオキシエチレン(25E.O.)オレイルエーテル ０．２０
(5)クインスシード ０．２０
(6)サポシンＤ ０．０４
(7)パラオキシ安息香酸メチル ０．１０
(8)香料 ０．１０
(9)精製水 ８３．３６
製法：(9)に(5)を添加し均一として十分増粘させた後、(1)〜(4)，(7)，(8)を混合，溶解して添加し、次いで(6)を添加，溶解する。
【００２２】
［実施例１０］ パック剤
(1)ビーガム ５．００（重量％）
(2)スクワラン ２．００
(3)グリセリン ５．００
(4)酸化亜鉛 １０．００
(5)カオリン １０．００
(6)エタノール ５．００
(7)パラオキシ安息香酸メチル ０．１０
(8)香料 ０．１０
(9)サポシンＤ ０．０５
(10)精製水 ６２．７５
製法：(10)に(3)，(9)を加え、(1)を添加して膨潤後、(4)，(5)を添加し、次いで(7)，(8)を(6)に溶解して添加，混合し、ペースト状とする。
【００２３】

製法：(1)〜(8)の油相成分を混合，加熱し、７０℃とする。一方、(9)〜(11)の水相成分を混合，加熱溶解して７０℃とし、これを前記油相成分に攪拌しながら添加して予備乳化を行った後、ホモミキサーにて均一に乳化し、冷却した後、４０℃にて(12)を添加，混合する。
【００２４】
まず、本発明に係る実施例１〜実施例１１について、２５℃で３カ月間静置して状態を観察し、製剤安定性を評価した。この際、表１に示す比較例２〜比較例１１についても同時に評価した。評価結果は、状態の変化を認めない場合を○、着色，異臭，エマルションの分離や凝集等の変化が若干認められた場合を△、かかる変化が顕著に認められた場合を×として表した。
【表１】

【００２５】
次に、本発明に係る実施例１〜実施例１１について４８時間の閉塞貼付試験と、使用時の不快感及び刺激感の評価を行った。この際、表２に示す比較例２’〜比較例１１’についても同時に評価した。閉塞貼付試験は成人男性パネラー３０名を１群とし、表３に示す判定基準に従って皮膚刺激指数を求め、３０名の平均値を算出した。使用時の不快感及び刺激感については、２０〜５０才代の男女パネラー２０名を１群とし、実施例及び比較例をブラインドにて皮膚に塗布した後、３０秒〜１分の間に感じる刺すような痛み，ヒリヒリ感，チクチク感といった刺激感や不快感について、表４に示す基準に従って評価させ、各パネラーの評価点の平均値を算出した。以上の結果は表５及び表６に示した。
【表２】

【表３】

【表４】

【００２６】
【表５】

表５より明らかなように、本発明の実施例はいずれも良好な製剤安定性を示す。これに対し、乳化型の皮膚外用剤においてサポシンＤを含有しない比較例２〜比較例１１においては、十分な製剤安定性が得られていなかった。
【００２７】
【表６】

表６において、本発明の実施例にはいずれも特に皮膚刺激性は認められておらず、使用時の刺激感，不快感についても、微妙に感じられる程度であった。これに対し、乳化型の皮膚外用剤においてサポシンＤを含有せず、界面活性剤を増量した比較例２’〜比較例１１’については、若干の皮膚刺激が認められ、また使用時の刺激感及び不快感も強くなっていた。
【００２８】
続いて、実施例１〜実施例６について肌荒れ症状の改善効果を評価した。その際、各実施例においてサポシンＤを精製水に代替したものをそれぞれ比較例１〜比較例６として、同時に評価した。評価は、乾燥や炎症等による顕著な肌荒れ症状を有する女性パネラー２０名を１群とし、各群に実施例及び比較例のそれぞれを１日２回ずつ１カ月間連続使用させ、１カ月後の皮膚の状態を観察し、使用開始前と比較して行った。皮膚の肌荒れ症状は表７に示す判定基準に従って点数化し、２０名の平均値を算出し、表８に示した。
【表７】

【００２９】
【表８】

表８より、本発明の実施例使用群では、いずれにおいても顕著な肌荒れ症状の改善が認められている。特に、サポシンＤ含量の高い実施例４，実施例５、及びリポソームの形態とした実施例６については、非常に高い肌荒れ改善効果が見られた。これに対し、サポシンＤを含まない比較例使用群では、いずれにおいても有意な改善は認められておらず、比較例１使用群では若干の悪化が見られた。
【００３０】
次いで、実施例７〜実施例１１について使用試験を行い、保湿性及び使用後の皮膚の状態について官能評価させた。この際、各実施例においてサポシンＤを精製水に代替したものをそれぞれ比較例７〜比較例１１とし、同時に試験した。使用試験は２０〜５０才代の女性パネラー２０名を１群とし、各群に実施例及び比較例をそれぞれブラインドにて１カ月間使用させて行った。官能評価は、保湿性については「とてもしっとりする；５点」，「ややしっとりする；４点」，「どちらともいえない；３点」，「ややしっとり感に欠ける；２点」，「しっとり感に欠ける；１点」、皮膚の状態については「良好；５点」，「やや良好；４点」，「普通；３点」，「やや悪い；２点」，「悪い；１点」として点数化し、２０名の平均値を求めた。結果は表９に示した。
【００３１】
【表９】

表９において、本発明の実施例使用群では、保湿性及び皮膚の状態の両評価項目について、いずれも各比較例使用群に比べて有意に高い評価を得ており、各実施例は、保湿性，皮膚の状態ともに高く評価されていた。
【００３２】
【発明の効果】
以上詳述したように、本発明により、安定性が高く、安全性が良好で皮膚に対する刺激性及び感作性が低く、さらに使用の際不快感を生じることがほとんどなく、しかも皮膚に良好な保湿性を与え、皮膚の炎症等による肌荒れ症状の改善に有効な皮膚外用剤を得ることができた。本発明に係る皮膚外用剤の有するかかる効果は、有効成分として含有させたサポシンＤの生体ホメオスタシス機能正常化或いは補助作用によるところが大きいものと考えられる。従って、本発明に係る皮膚外用剤により、皮膚の生理機能の維持系が補助或いは活性化され、酸化的ストレスをはじめとする種々の要因による傷害から皮膚を保護することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an external preparation for skin that can maintain the physiological function of skin in a normal state, can protect skin cells from injury caused by oxidative stress, and has high stability and safety. More specifically, the present invention relates to an external preparation for skin containing saposin D in an external preparation base.
[0002]
[Prior art]
Conventionally, many skin preparations and skin preparations have been used to improve the symptoms of skin dryness, abnormal keratinization, inflammation, etc. to keep the skin healthy and beautiful and to protect the skin from aging and various lesions. Cosmetics have been developed. In these, moisturizers and emollients that improve skin conditions, cell activators that enhance skin cell activity, antioxidants that can prevent cell damage due to oxidative stress, and the like have been incorporated.
[0003]
As the humectant and emollient, the blending of mucopolysaccharides such as hyaluronate and chondroitin sulfate, sphingolipids, and ceramide has been studied recently. In addition to vitamins, hormones, etc., cell activators include cell growth factors such as epidermal cell growth factor and fibroblast growth factor, substances having a fibroblast proliferation action such as α-hydroxy acid, and animals and plants. The use of extracts and the like is being studied. As antioxidants, in addition to classic tocopherols, use of superoxide dismutase and various active oxygen scavenging substances has been attempted.
[0004]
However, skin is also a living tissue, and is controlled through a complex pathway including a variety of signal transduction substances, receptor proteins, enzymes, and the like. Therefore, for example, even if a substance having a fibroblast growth promoting action is added, the action is transient, and conversely, negative feedback by the living body is often received.
[0005]
[Problems to be solved by the invention]
Therefore, in the present invention, focusing on the homeostasis function of the living body, the development of an external skin preparation capable of maintaining the normal physiological function of the skin was studied. That is, an object of the present invention is to provide an external preparation for skin that can assist and activate the maintenance system of skin physiological functions.
[0006]
[Means for Solving the Problems]
In the present invention, the above-mentioned problem has been solved by including saposin D in a skin external preparation base. Saposin D is a low molecular weight protein having a peptide chain consisting of 83 amino acids and an oligomannose sugar chain, and has an action of activating sphingomyelinase and ceramidase.
[0007]
[Action]
Saposin D is a peptide having a sugar chain and exhibits heat resistance and amphiphilicity. Therefore, it is suitable for blending into an emulsified external preparation base that requires a heating process, and also has the ability to solubilize fats and oils contained in the external preparation base. It is also possible to improve the emulsion stability and dispersion stability of the oil-soluble substance and to improve the stability of the preparation. Moreover, since it has amphipathic properties, it is easy to form vesicles such as phospholipids and liposomes, and the percutaneous absorbability can be enhanced.
[0008]
When the skin external preparation according to the present invention is applied to the skin, sphingomyelinase and ceramidase are specifically activated by the action of saposin D, and the production of ceramide and then sphingosine from sphingomyelin is promoted. The ceramide and sphingosine thus produced improve the ability to regulate various cell functions, including promoting and controlling the proliferation of epithelial cells and fibroblasts. In addition, the ability of ceramide to inhibit the production of hydrogen peroxide and superoxide anion can be expected to suppress the production of lipid peroxides on the skin, and can protect the skin from injury caused by oxidative stress.
[0009]
In addition, due to the physical characteristics resulting from the peptide chain and sugar chain constituting saposin D, it is possible to obtain good moisturizing and emollient properties when a skin external preparation containing the same is applied to the skin.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Saposin D exhibits a sphingomyelinase and ceramidase activating action at a concentration of about 1 μM. In the present invention, it is contained in an amount of about 0.005 to 5.0% by weight in consideration of the effect of external preparation base and other additive components, transdermal absorbability, and bioavailability.
[0011]
Moreover, the skin external preparation which concerns on this invention can be provided with dosage forms, such as a lotion agent, an emulsion, a gel agent, cream, and ointment. In addition, it can also be provided as a skin cosmetic such as lotion, milky lotion, cream, cosmetic liquid, massage agent, and pack agent. External preparation base contains commonly used oils, waxes, hydrocarbons, fatty acids, lower alcohols, higher alcohols, polyhydric alcohols, esters, surfactants, water-soluble polymer compounds, etc. Can be made. Furthermore, other skin cell activators, anti-inflammatory agents, reactive oxygen species scavengers, whitening agents, moisturizers, UV absorbers, antiseptic / antifungal agents, fragrances, and the like can also be included.
[0012]
【Example】
Further, the present invention will be described in detail by examples.
[0013]
[Example 1] Skin lotion
(1) Ethanol 5.00 (wt%)
(2) Hydroxyethyl cellulose 1.00
(3) Saposin D 0.05
(4) Purified water 93.95
Manufacturing method: (1) to (3) are sequentially added to (4) and dissolved uniformly.
[0014]

Production method: The oil phase components (1) to (6) are mixed, heated and uniformly dissolved, and kept at 70 ° C. On the other hand, the aqueous phase components (7) to (11) are mixed and heated to be uniform, and set to 70 ° C. The oil phase component is gradually added to the aqueous phase component with stirring, emulsified, and cooled.
[0015]
[Example 3] Gel for skin
(1) Dipropylene glycol 10.0 (wt%)
(2) Carboxyvinyl polymer 0.5
(3) Potassium hydroxide 0.1
(4) Methyl paraoxybenzoate 0.1
(5) Purified water 89.2
(6) Saposin D 0.1
Manufacturing method: (2) is uniformly dissolved in (5), then (4) is dissolved and added to (1), then (3) is added to increase the viscosity, and (6) is added and dissolved .
[0016]

Production method: The oil phase components (1) to (7) are mixed, dissolved, and heated to 75 ° C. On the other hand, the water phase components (8) to (11) are mixed and dissolved and heated to 75 ° C. Subsequently, after adding an oil phase component to the said water phase component and pre-emulsifying, it emulsifies uniformly with a homomixer and it cools.
[0017]
Example 5 Oil-in-water emulsion ointment
(1) White petrolatum 25.0 (wt%)
(2) Stearyl alcohol 25.0
(3) Glycerin 12.0
(4) Sodium lauryl sulfate 0.5
(5) Saposin D 2.0
(6) Methyl paraoxybenzoate 0.1
(7) Purified water 35.4
Production method: The oil phase components (1) to (4) are mixed, heated and uniformly dissolved, and kept at 75 ° C. On the other hand, the aqueous phase components (5) to (7) are mixed and heated to be uniform, and set to 75 ° C. The oil phase component is gradually added to the aqueous phase component with stirring, emulsified, and cooled.
[0018]
[Example 6] Liposome liquid for skin (liposome)
(1) Phosphatidylcholine 20.0 (wt%)
(2) Hydrogenated soybean lecithin 20.0
(3) Saposin D 5.0
(4) Purified water 55.0
Production method: (1) to (3) are dispersed in (4) at 50 ° C. and sonicated to form liposomes, which are then collected by centrifugation.
(Liposome solution)
The liposome is dispersed in a 10.0% by weight ethanol aqueous solution so as to be 10.0% by weight.
[0019]
[Example 7] Lotion
(1) Ethanol 10.00 (wt%)
(2) 1,3-butylene glycol 3.50
(3) Saposin D 0.02
(4) Methyl paraoxybenzoate 0.10
(5) Fragrance 0.10
(6) Purified water 86.28
Manufacturing method: Add (1) to (5) to (6) sequentially and mix to make uniform.
[0020]
[Example 8] Water-in-oil emollient cream
(1) Liquid paraffin 30.00 (wt%)
(2) Microcrystalline wax 2.00
(3) Vaseline 5.00
(4) Diglyceryl oleate 5.00
(5) Sodium L-glutamate 1.60
(6) L-serine 0.40
(7) Propylene glycol 3.00
(8) Saposin D 0.03
(9) Methyl paraoxybenzoate 0.10
(10) Purified water 52.72
(11) Fragrance 0.15
Production method: Dissolve (5) and (6) in a part of (10) to 50 ° C, and gradually add to (4) heated to 50 ° C with stirring. This is mixed in advance and uniformly dispersed in (1) to (3) which is heated and dissolved at 70 ° C. to obtain an oil phase. On the other hand, (7) to (9) are dissolved in the remainder of (10) and heated to 70 ° C. to obtain an aqueous phase. The aqueous phase is gradually added to the oil phase with stirring and emulsified with a homomixer. After cooling, add and mix (11) at 40 ° C.
[0021]
[Example 9] Cosmetic liquid
(1) Ethanol 10.00 (wt%)
(2) Propylene glycol 4.00
(3) Polyethylene glycol 1500 2.00
(4) Polyoxyethylene (25E.O.) oleyl ether 0.20
(5) Quinn Seed 0.20
(6) Saposin D 0.04
(7) Methyl paraoxybenzoate 0.10
(8) Fragrance 0.10
(9) Purified water 83.36
Manufacturing method: (5) is added to (9) and thickened sufficiently to be uniform, then (1) to (4), (7), (8) are mixed and dissolved, and then (6) is added. Add and dissolve.
[0022]
[Example 10] Packing agent
(1) Veegum 5.00 (wt%)
(2) Squalane 2.00
(3) Glycerin 5.00
(4) Zinc oxide 10.00
(5) Kaolin 10.00
(6) Ethanol 5.00
(7) Methyl paraoxybenzoate 0.10
(8) Fragrance 0.10
(9) Saposin D 0.05
(10) Purified water 62.75
Manufacturing method: Add (3) and (9) to (10), add (1) and swell, then add (4) and (5), then add (7) and (8) to (6) Dissolve, add and mix to make paste.
[0023]

Production method: The oil phase components (1) to (8) are mixed and heated to 70 ° C. On the other hand, the aqueous phase components (9) to (11) are mixed, dissolved by heating to 70 ° C., and this is added to the oil phase component with stirring and pre-emulsified. After emulsifying and cooling, (12) is added and mixed at 40 ° C.
[0024]
First, about Example 1-Example 11 which concerns on this invention, it left still at 25 degreeC for 3 months, the state was observed, and formulation stability was evaluated. At this time, Comparative Examples 2 to 11 shown in Table 1 were also evaluated at the same time. The evaluation results are represented by ◯ when no change in the state is observed, Δ when a slight change such as coloring, off-flavor, emulsion separation or agglomeration is observed, and x when such a change is remarkably recognized.
[Table 1]

[0025]
Next, a 48-hour occlusion sticking test and evaluations of discomfort and irritation during use were performed for Examples 1 to 11 according to the present invention. At this time, Comparative Examples 2 ′ to 11 ′ shown in Table 2 were also evaluated at the same time. In the occlusion patch test, 30 adult male panelists were taken as one group, the skin irritation index was determined according to the criteria shown in Table 3, and the average value of 30 persons was calculated. About the feeling of discomfort and irritation at the time of use, 20 male and female panelists in their 20s to 50s make a group, and after Examples and Comparative Examples are blindly applied to the skin, they feel for 30 seconds to 1 minute. Stimulation and discomfort such as stinging pain, tingling, and tingling sensation were evaluated according to the criteria shown in Table 4, and the average value of the evaluation points of each panel was calculated. The above results are shown in Tables 5 and 6.
[Table 2]

[Table 3]

[Table 4]

[0026]
[Table 5]

As is clear from Table 5, all the examples of the present invention show good formulation stability. On the other hand, in Comparative Example 2 to Comparative Example 11 which does not contain saposin D in the emulsified skin external preparation, sufficient formulation stability was not obtained.
[0027]
[Table 6]

In Table 6, no skin irritation was observed in any of the examples of the present invention, and the feeling of irritation and discomfort at the time of use was only slightly felt. On the other hand, in Comparative Example 2 ′ to Comparative Example 11 ′ that did not contain saposin D and increased the amount of surfactant in the emulsified external skin preparation, some skin irritation was observed, and irritation during use And discomfort increased.
[0028]
Subsequently, Examples 1 to 6 were evaluated for the effect of improving rough skin symptoms. At that time, in each example, saposin D replaced with purified water was evaluated as Comparative Examples 1 to 6 at the same time. The evaluation is made up of 20 female panelists who have marked skin roughness due to dryness, inflammation, etc., and each group of Examples and Comparative Examples is used twice a day for 1 month. The skin condition was observed and compared with that before the start of use. The rough skin symptoms were scored according to the criteria shown in Table 7, and the average value of 20 people was calculated and shown in Table 8.
[Table 7]

[0029]
[Table 8]

From Table 8, the improvement of the remarkable rough skin symptom is recognized in any example use group of this invention. In particular, in Examples 4 and 5 having a high saposin D content and Example 6 in the form of liposomes, a very high roughening effect was observed. On the other hand, no significant improvement was observed in any of the comparative example use groups not containing saposin D, and some deterioration was observed in the comparative example 1 use group.
[0030]
Next, a use test was performed on Example 7 to Example 11, and sensory evaluation was performed on moisture retention and skin condition after use. At this time, in each of the Examples, Saposin D was replaced with purified water, and Comparative Examples 7 to 11 were respectively tested. In the use test, 20 female panelists in their 20s to 50s were made into one group, and each of the examples and comparative examples was used blindly for one month. The sensory evaluation was “Very moist; 5 points”, “Slightly moist; 4 points”, “Neither can be said; 3 points”, “Slightly moist feeling; 2 points”, “Moist feeling” 1 point, and skin condition is “good; 5 points”, “slightly good; 4 points”, “normal; 3 points”, “slightly bad; 2 points”, “bad”, 1 point The average value of 20 people was calculated | required. The results are shown in Table 9.
[0031]
[Table 9]

In Table 9, in the example use group of the present invention, both evaluation items of the moisturizing property and the skin condition were significantly higher than those in each comparative example use group. Both sex and skin condition were highly evaluated.
[0032]
【The invention's effect】
As described in detail above, the present invention provides high stability, good safety, low irritation and sensitization to the skin, and almost no discomfort during use, and good for the skin. It was possible to obtain an external preparation for skin that gave moisturizing properties and was effective in improving rough skin symptoms caused by skin inflammation and the like. Such an effect of the external preparation for skin according to the present invention is considered to be largely due to normalization of the homeostatic function of saposin D contained as an active ingredient or an auxiliary action. Therefore, the external preparation for skin according to the present invention assists or activates the maintenance system of the physiological function of the skin, and can protect the skin from injury caused by various factors including oxidative stress.

Claims (2)

A skin external preparation containing saposin D. The skin external preparation according to claim 1, wherein the skin external preparation is a skin cosmetic.