OWO型多相乳液的特性及应用

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1、OIWlO型多相乳液的特性及应用吉田克典(株)资生堂基础研究中心摘要：本文以制备稳定的油包水包油(owo)型多相乳液为目的进行研讨。OIWlO型乳液是通 过一次乳化得到细微的水包油(OW)初级乳液，再将它添加到另一油相进行再乳化的两步乳化法 而制备出来。通过调查种种影响OWO型乳液稳定性的因素，可了解在二级乳化中配合由阳离子变 性粘土矿物与非离子表面活性剂所形成的包合物，可极大的促进该乳液的稳定性。我们使用了典型 的不稳定型药剂视黄酵(维生素A)，考察了OPO型乳液中药剂稳定性的效果。将视黄醇分别配 合在OIW,WIO及OVIO型乳液中，观察其经时残存率，发现OWO型乳液中视黄醇的稳定性最好。

2、 此外，将对视黄醇的氧化分解有催化作用的物质，如过氧化物，金属离子等从体系中排除，或添加 亲水性，亲油性的抗氧化剂都可更进一步提高视黄醇的稳定性。因此可明确，作为视黄醇之类的油 溶性活性成分的稳定制剂，OWO型乳液是一个非常好的载体。Abstract：A stable formula for OWO母pe multiple emulsions was investigatedAn OWO emulsion was prepared by a double-step procedure in which all OW emulsion was prepared in the first step

3、， and then the OW emulsion was”reemulsified”in an oil phaseIt was revealed that the inclusion compound of cation-exchanged montmofillonite clay mineral and lipophilic nonionic surfactant was all essential fur the stable formula of OIWIO emulsionThe stability of all-trans retinol(vitamin A alcoh01) w

4、as studied in OW,WOand OWO emulsionsThe remaining percentage of retinol was the highest in OWO emulsionThe stability of refinol in the emulsion was improved both by removing catalytic compounds for oxidation such as peroxide and metal-ions and by adding hydrophilic and hydrophobic antioxidants We co

5、nclude that the OWO emulsion is a useful formula to stabilize refinul关键词：o，wo型乳液，粘土矿物，视黄醇，维生素A，稳定化KOWO emulsion，c岛mineral，rctinol，vitantin A，stabilization引言多相乳液具有一分散相中包含着另一分散相的复合构造，理论上此构造存 在无限制重复分散的可能，一般来说三层构造，即W0W或OWO，较为普遍。上述多相乳液的 生成条件，基础物性020一直被作为基础研究的对象进行广泛研究，同时，从应用的角度出发，研究范 围扩充到药品供应系统4”，活性成分的稳定化

6、6，液膜分离操作的基质7及食品的结构改善8等领域。 此外近年来人们普遍追求化妆品的高功效性及优越的使用感。为满足上述要求，包含各种乳化法在 内的新型制荆技术被陆续开发，我们期待多相乳液正是能满足功能性及使用感的新型基质。多相乳液的制备方法大体可分为一步法(Single Step)和两步法(Double Step)。 一步法正如其名，是通过一次乳化过程达成多项乳化。它的生产工艺摘单，但是也存在内外相的组 成必须是完全一样，配方被限定等方面的缺点。两步法的工艺是将制备好的乳液进行再乳化而成。 例如：通过一次乳化得到细微的OW乳化体后，再分散到另一油相中进行再乳化而得到OWO多相乳液。两步法可较自由

7、的控制内外油相的组成，其高收率，制备再现性好等优点使其更具实用性。 本文主要介绍使用有机变性粘土矿物的新型OWO多相乳液的制备方法及该乳化体可使不稳定活性成份视黄醇(维生素A)稳定化的报告。1实验21试剂All-warts retinol(150万单位，g)为库拉雷化学(株式会社)的产品，其他试剂为化妆品的通用原料。22 OWO型乳液的制备 OWO型多相乳液通过两步乳化9”制成。首先将流动自油(Lp)均质搅拌添加到配合有亲水性表面活性剂聚氧乙烯氢化蓖麻油(HCO)的保湿剂相中，之后，加入水制备成OW初级乳化体。将制 备好的OW初级乳化体均质搅拌添加到配合有阳离子变性粘土矿物(Cat-Clay)

8、及亲油性表面活性剂 聚氧乙烯二异硬脂酸(DIS)的油相中便可得到OWO型乳液。2-3视黄醇(维生素A(VAD的定量“ 检测仪器为HPLC色谱系统(Nanospace，资生堂)，二极管排列检测器(SPDM10AV岛津制作所)。色谱柱为逆相硅胶柱(Vydac 201 TPl04-C18，The Separation Group)。全部检测重复两次，求其平均值。2-4内包率(Encapsulation()的测定 OWO型乳液的内油相中vA含量比例(内包率)是根据姜氏法2计算，即用离心法(2000xg，60分钟)强制分离少量外油相，分别定量分析外油相及整个乳化体的VA含量，用以下公式计算内包率：VAT

9、-VaoEncapsulation()= 屿z100vA，：整个乳化体的VA含量 VAo：外油相中的VA含量2结果与考察3-1 OWO型乳液基质的稳定性 图1为亲水性表面活性剂HCO的配合量与一次乳化体OW粒子径，最终OAVO型乳液粘度三者间的关系示意图。如图所示，随着HcO配合浓度增加，OAV乳化体的粒子径减小，而OWO型乳液的粘度在HCO=1时达到最大值。因此，当亲水性表面活性剂的配合量不足(薹o5)，OW 乳化体的粒子过大时，在WO二次乳化中OW乳化体的粒子不能完全被包进内相，其结果导致该 乳化体在表观上呈现内相比低的WO乳液状态，而且会使整个OAVO型乳液粘度过低。另一方面， 当亲水性

10、表面活性剂的配合量过剩时(盖2)，体系平衡(HLB)失控，无法形成稳定的WO乳化体， 导致OWO型乳液生成率及粘度低下。誊錾里AoJ口ioc器j；uloJ。l。点凸图1图2显示了二次乳化(WO)中使用的阳离子变性粘土矿物(CatClay)与亲油性表面活性剂(DIS) 的量比对OWO型乳液稳定性的影响。CatClay与DIS两者间的量比关系对OWO型乳液的稳定 性起着重要作用，如果仅单独添加CatClay或DIS，即使较高浓度也无法制备出多相乳液。这与以 前山口等人研讨的WO粘土矿物乳化法的结果是一致的。根据山口“等人的报道，在阳离子变性粘 土矿物上包接HLB=8左右的亲油性表面活性剂，将此包接

11、化合物又投入油分中可生成稳定的油性 凝胶。当亲油性表面活性剂与粘土矿物的量比为O21时，油性凝胶的粘度达到最大值，此时可制各 出最稳定的WO乳液。一暴一eloI；oDIS() 图2图3通过光学显微镜观察到的配合2CatClay与O4DIS制备成的稳定OWO型乳液的照片。 根据观察可看到OWO型乳液的基本构造，即在约25tm的WO粒子中还包含着1am以下的OW 粒子，此构造经过50，一个月的经时保存被确认无变化。通常认为OWO型乳液的不稳定因素主要有以下3点：(a)内油相粒子的合一(b)水相粒子的合一(c)内油相与外油相的合一。多相乳液 中虽然存在两个界面，内油相，水相水相，外油相，为了制各相应

12、的乳化体需添加亲水性表面 活性物质，需添加相应的亲油性表面活性物质。如果上述两界面使用通常的表面活性剂，在水相 中会形成混和胶束，使制备好的各界面膜随着时间推移表面活性剂的构成发生转移，促进上述(a) (c)的不稳定因素最终导致相分离。而这次我们使用的CatClay将DIS包接在粘土层中形成包和物”。 这种包和物不会与亲水性表面活性剂形成混和胶束，并在水相外油相的界面形成固定膜，特别是它 可使外油相呈凝胶状，消除了(b)与(c)的不稳定途径，进一步保证OWO型乳液的稳定性。图33-2视黄醇的稳定化 根据上述研讨，制各了稳定且再现性好的OWO型乳液后，我们便尝试利用该乳化体使活性成份取得稳定性。

13、试剂为油溶性活性成份中的典范A11trails retinol。维生素A是对生物的成长，免疫系统及视觉均很重要的油溶性维生素。自从发现它可控制皮肤 角质化的功能后，维生素A在化妆品领域中的应用引人关注”。可是维生素A中的A11ttmls retinol 与其他衍生物诸如palmitate，acetate相比，拥有高度的生物活性的同时，还易被光，热及氧化分解，使其有效浓度降低，产生异味等。因此稳定的配合非常困难。表l显示了视黄醇配合在各类制剂下的配方及经过50。C，4周后的残存率。如图可知，如将视黄 醇单纯溶解在流动白油中，结果是完全分解无残留。另一方面，配合在乳液中时均有较高的残存率， 其顺序

14、为OWWOOWO。其中OAVO多相乳液中的残存率为最高，这意味着OWO乳液有可 能成为不稳定活性成份的稳定化基质。Retin01010101Water phase 1,3-Buthyleneglycol 一555Glycerin一555HCO一 1 1Carboxyvinylpolymer一 01一一MetlIylparaben一01O101Water toloot0100t0100Outer oil phase Liquid paraffin一一278276Cat-Clay 一一22DtS 一 一0404ReOnoI 一一01一Remaining percentage of retinot塾

15、婴曼!塑!塑!坠Q2：箜：Z2：为进一步提高稳定性，我们将使用的乳化剂对视黄醇的影响进行了调查。我们已知过氧化物及 过渡金属可促进诸如维生素A之类易被氧化物质的分解。图4展示了o，w初级乳化时使用的HCO 的过氧化物值(POV)与维生素A棕桐酸酯残存率之间的关系。将维生素A棕榈酸酯添加到POV值为1-11meqkg的HCO中，经乳化得到OW乳液，将该乳液放置50。C保存时，维生素A棕榈酸酯的残 存率与表面活性剂中的POV值呈递减关系，即POV值越高，维生素A棕榈酸酯的残存率越低。孚一博争v誊-薯奄藿POV(meqkg_I)图4同样，我们还对二级乳化中使用的CatClay与亲油性表面活性剂的影响

16、进行了调查。通常使用 的catclay有两种：一种源于含有氧化铁等不纯物的天然成份(NCatclay)：另一种为纯铝镁硅酸盐 的合成成份(sCmclay)。与CatClay形成包和物的亲油性表面活性剂也有两种：一种来自于含有双 键的不饱和型油酸(DIO)：另一种源自饱和型异硬脂酸(DIs)。上述几种原料的组合对视黄醇稳定性 的影响如图5所示。正如预想一样，视黄醇在SCatclay与DIs的配合中稳定性最高，即使50，4 周后的残存率仍保持62，另一方面，Ncat-clay与DIO的配合中视黄醇的分解最快，同等条件下 只剩14的残存率，其他sCatclay与DIO，Ncatclay与DIS的配合

17、居中间位置。由此可知，尽 可能排除过渡金属及过氧化物是维持不稳定活性成份维生素A的稳定性的重要因素。这意味着不仅 要使用高纯度的原材料，而且在进行初期的配方开发时就应仔细考虑各种原材料的组合。基巷善瓣童嚣鐾i|I星舢图5为考察乳化体系对视黄醇稳定性的影响，我们还对内油相比的变化进行了研讨。首先制各内油 相比为0105的O，w乳液，利用该乳液制备出OWO乳液，观察其对视黄醇稳定性的影响。结果如图6所示，在OW乳液中VA残存率与内油相比无依存关系，50。C，2周后的残存率为62；而另 一方面，在OWO乳液中，随着内油相比从O1增加到05，视黄醇的残存率也从62升至71。 为了进一步观察OWO乳液中

18、内油相比与视黄醇稳定性之间的关系，我们检测其经时条件下的内包 率变化。c)l宴攀辨lIIc蔷嚣m蕾图6内包率的检测结果如图7所示，乳液制备后伴随着内油相比的增加，内包率也呈上升趋势，同 一样品在50，2周后的内包率都呈下降趋势，其中内相比越低，下降趋势越明显。由图4及图5已知，2周后视黄醇的残存率与内包率之间有及其密切的关系，因此为使OWO乳液中不稳定药剂稳定化， 必须将药剂锁在内油相中。当内油相比越高时，经时的内包率变化越小，其理由如下：视黄醇浓度 一定的条件下，内油相比越低内油相中的视黄醇浓度越高。另一方面，由于化学势的差，无论内外 油相的视黄醇浓度都会达到平衡状态。因此，内外油相视黄醇浓

19、度的差越大，越加速视黄醇由内油 相转移到外油相中。结果，内油相比越低(即内油相中的视黄醇浓度高)的owo乳液，其经时的内 包率呈显著下降，视黄醇的稳定性也很低。而内相比高达05时，其内包率却相反，也大幅下降。 这是因为内相比过高时也会导致乳液本身的稳定性降低。富一尝2苜暑饕再巷毒我们进一步利用OWO乳液对提高视黄醇的稳定性进行了研讨。图8为亲水性及亲油性抗氧 化剂的组合与视黄醇经时残存率的关系图。由图可知当亲油性抗氧化剂丁基化羟基甲苯(BHT)与亲水 性抗氧化剂维生素C配合时，可提高视黄醇的稳定性。可是，当配合了金属螯合剂EDTA时，受到 OWO乳液体系自身的稳定性下降的影响，反而导致视黄醇的

20、稳定性恶化。虽然在BHT，维生素C 及EDTA的组合下，视黄醇的残存率最高，可由于上述的理由，EDTA经时会破坏若干乳化，因此， 我们期待寻找一种可替代EDTA的螯合剂，更进一步提高视黄醇的稳定性。水)Ioc删州孽鼍葛篁_罡O24e8Time(weeks)图8参考文献1 Matsumoto，S，Kang，W，W，上Dispemion SciTechn0110，455(1989)2姜又远，松本幸男 油化学38，165(1989)3Brodin，AF，Kavaliunas，DR。Frank，SGActa Pharnt Suec15，1(1978)4Nakhare。S。Vyas，SPZ Microe

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23、l water dispersible nanoparticles(SunZerseTM)ofencapsulated microfine Zinc Oxide by Octyl Triazone and OMCGao Chunfang，Wang Changguo and Evelyn GSuNanjing Zhongshi Chemical Co，Ltdand Sino Lion(uSA)，LidAbstract：SunZerseTM is a highly effective，broadspectrum nanodispersion of microfine Zinc Oxide， and

24、 microfine Zinc Oxide is encapsulated by organic UVB absorbers OT(Octyl Triazone)and OMCThe highpressure homogenization technique yields 100encapsulated stable nano dispersion of microfine Zinc OxideMicrofine Zinc Oxide particles are cores of nanoparticles in water dispersion，encapsulated by the mem

25、brane of organic sunscrecn agents and selected estersPhospholipid and emulsifiers(anionic suffactant， nonionic surfactantamphiphilic surfactant)line across each other to form a multiplexmembrane，and the encapsulated rnicrofine Zinc Oxide is surrounded by the multiplexmembrane，All of these three surf

26、actants inlay each other,and tightly link oil phase and water phaseWe found the stability of nano dispersion issatisfactoryOur data shows Sun-Zerse“would be：1)Boosting SPF synergistically and dramatically2)Broad spectrum,covering from 290nm-400nm3)Verymild4、Cost effectiveKeywords：Sunscreen，Zinc Oxid

27、e，SunZerseTM，Octyl Triazone，OMC1IntroductionIn recent years，formulators are challenged to develop sunscrcen products to meet the requirements of growing consumer demand for broadspectrum protection and high SPF value Formulators must address the following requirements technically in order to obtain

28、the expected benefits of the sunscreen formula forthe competitive market1)Broad-spectrum protection Avobenzone has been used to provide UvA protection，but this sun care ingredient is not stable in formulaMetal ionsformaldehyde donor preservatives must be avoided in the formulaStabilizers for avobenz

29、one need to be added into the formula in order to avoiddegradation of UV absorption by avobenzoneMicrofine zinc oxide is another choice for UVA protection but aggregation and agglomeration of microfine Zinc oxide and its whitening phenomenon must be addressed21High SPF value In order to achieve 11ig

30、h SPE a lnixture of high concentration of organic sunscreen ingredients has been formulated into the sunscI_eeAl products，but high irritation has been observedHigh concentration of inorganic sunscroen ingredients，esptitanium dioxide，has been used in suncare products，but photocatalysis effect of inor

31、ganic sunscreen ingredients and whitening phenomenonmust be avoidad31，Cost effectivenessHiCa concentration of sunscreen filters results in disadvantages of highcost of the formula Formulators must be well trained in sunscmen product formulation in order todecrease the R&D cost and shorten the produc

32、t development period211To achieve higll SPF and broadspectrum protection，inorganic and organic UV filters have been used in combination in SUBSCre2n formulasMicrofine zinc oxide has been used more frequently after 1997when it was approved by the US FDA as safe and effective UV filter for personal ca

33、re productsZincOxide is chemically and physiologically stable and offers broad spectrum UV protectionTo address the aforementioned issues，a novel water dispersible，broadspectrum sunscreen， SunZerseTM was evelopedSunZerseTM is a nanopaticle microfine zinc oxide encapsulated by Octyl triazone(OT)and O

34、ctyl Methoxycinnamate(OMC)It provides mild，safe and cost-effective sunscreenprotection2Methodology21 Microflne zinc oxide and Its particle sizeZinc oxide witIl different particle sizes distribution are commercially avallable on the marketit provides UV protection mainly by its absorptionscattering a

35、nd the effectiveness of protection is inversely related to its particle size as shown in Stamatakis et als studies that the absorption of ZnO increases as particle size decreases throtIghout the UV regionAnd it showed that smaller the particle size，the less UVLight transmitted and beRer UVA protecti

36、onAlthough it can protect UVA effectively,but its contributionto SPF is very limitedZinc oxide size distribution is another important parameter；its sharp Gaussian distribution is preferredIn this study,microfine ZnO with a specific average particle size distribution was chosen22 Surface Treatment221

37、 Surface treatment vehicleVarious ingredients carl treat Microfine ZnO to obtain different properties，like hydrophobic or hydrophilic propertiesIt has been shown that formula with both Octyl Triazune and microfine ZnO has synergistic effectat 4microfine ZnOincreasing Octyl Tfiazone from 1to 3can imp

38、rove SPF dramatically from 7 to 30Organic sunscreen filter Octyl Tfiazone was considered to be the surface treatment vehicle，while another organic sunscreen filter OMC，which is not only a UVB filter,but alsosolubilizer for Octyl Triazone，was considered as covehicle for the surface treatmentOther lip

39、ids or estersare also included in the vehicle as solvent or solubilizers222 Aqueous dispersion ProcessHigh-pressure homogenization(HPH)technology has been applied as a reliable and powerful tool for the preparation of solid lipid nanoparticles(SLN)，which has been used in pharmaceutical industry fory

40、earsI-IPH technology were applied herein to process surface treated Zno into aqueous dispersionThedetailed description ofthe process is omitted due to a patent application is pending for this technology3 Sunscreen formulationThree prototype formulas were tested in this studyThey Were：Creaml：Sunscree

41、nCream(wlo)【FormulaNo1101，containin915SunZerseCream 2：Sunscrcen Cream(wlo)Formula No1102，containing 40ZnO，30OT and OMC；Cream 3：Sunscreen Cream(wow)Formula No1103containing 15Sun-ZerseTM4Results mad珊scussion41 Contribution to SPF by adding SunZerseTMTwo sunscreen prototype formulas(No1101 and 1102)wh

42、ich contain the same concentration ofbothorganic sunscreen filets Oetyl Tfiazone，OMC and the inorganic sunscreen microfine ZnO，have beenevaluated by In vitro SPF analyzer rOptomatrics sPF 290s)111e results are shown in Fig1It call be seenfrom Fig1 that Formula No1101 with SunZersc“was superior to Fo

43、rmula No1102 which simply212contained three single sunscreens，in terms of contribution to formulation SPF valueFurthermore，more effective UVA protection has been observed from formula No1 101 with SunZers一Fig 1SPF Data of Sunscreen CreamWave Length(nm)42 Stab竹Three accelerated stability tests of For

44、mula 1101，eg，three freeze-thaw cycle(0。C to roomtemperature)，oven at 50 oc and centrifugationwere performedPhotostability tests on formula l 101 and1 102 were carried out by simply testing the SPF values at time 0 hour and 10 hours after direct sunlight exposure using Optomatrics SPF 290 analyzeg Th

45、e results are shown on Table lTable 1Sta蛐ity Data1bst CentrifugationSPFVmueSamples2000rmin 3000rmin Int*eeze-Thaw50。C0veuO10Cyclehour hoursFormula 1102Pass Pass Pass Pass 3530 f4 months)Forulula 1102Pass SeparatedPass Pass 3020 r3 mortths)It is clearly shown that Formula No1 101 containing SunZersel

46、”has better stability over FormulaNo1102 containing three sm#e sunscreensAnd it carl also been seen that photostability of the sunsceen formula can be greatly improved by using SunZerseTM compared to the three sin#e SUnSCreens simply added to the formula43 TransmissivityTransmissivity tests(6um coat

47、ing)were carried out with Spectmphotometer 721 on formula 1101 and1 102，results are shown on Fig 2It is clear from Fig2 that higher transmissivity was observed inFormulaNo1101 whichcontainedSunZerse“indicating reductionoreliminatioilofwhitening effect213Fig 2Transmissivity Data of Sunscreen Cream44

48、Formulation Technical DifficultyEarlier studies show that combination of Microfine ZnO and organic sunscreen filters call be used in wo emulsion systems to achieve stable and high SPF valueHowever,this type of formulation demandshighly skillful formulation techniques and it is not easy to achieve On

49、 the other hand，SunZersel”canbe used in more emulsion systems，such as wow,1to obtaln stable and effective sunscreen products It is easy to use，and no difficult techniques are required to achieve broad spectrum protection and high SPFvalue in suncare formulationSunZerseTM can be regards asDrop and Mi

50、x”sunscreen to dramaticallylower the technical difficulties for sun care formulators5ConelusionSunZerseis a novel water dispersible nanoparticle microfine ZnO encapsulated with organicsunscreens Octyl Tfiazone and OMCIt has many advantages as a suusGgeeo agent as follows：1Broadspectrum UV protection

51、covering botIl UVB and UVA；2High SPF value at the same concentration of each sunscreen active；3Mild product due to less organic sunscreen filters needed；4 Easy to use for sunscreen formulators；5Easier manufacturing preparation；6Cost effectiveReference1Masaru Kobayashi and Wiuiam Kalriess。Photocataly

52、fic Acnvitv of Titanium Dioxide and ZincOxideCosmeticsT0ilelaies、，011128386 June 19972Guerrero；Angel A，Sunscreen compositions，United States patent No5，486，3523Cook；Edward J，Apparatus for forming emulsions，United States patent No4，533,2544Jane Evison，Broad Spectrum Sun Protection：the Issues and Status，Comnaonwealth Institute，LondonUKMarch 111219975Mark AMitchnick。Zinc Oxide，An Old Friend to the Rescue，CosmeticsToiletries Vol_107， October 1992214