CN101212964A - 异黄酮纳米颗粒及其用途 - Google Patents
异黄酮纳米颗粒及其用途 Download PDFInfo
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- CN101212964A CN101212964A CNA2006800237970A CN200680023797A CN101212964A CN 101212964 A CN101212964 A CN 101212964A CN A2006800237970 A CNA2006800237970 A CN A2006800237970A CN 200680023797 A CN200680023797 A CN 200680023797A CN 101212964 A CN101212964 A CN 101212964A
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- CN
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- Prior art keywords
- isoflavone
- particle size
- compositions
- genistein
- carrier
- Prior art date
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Abstract
本发明涉及异黄酮纳米颗粒组合物,所述组合物包含纳米颗粒形式的异黄酮,并优选包含载体。异黄酮纳米颗粒组合物特别适用于制备化妆品组合物、药物组合物、食品、食品添加剂和饲料添加剂。在包含异黄酮纳米颗粒组合物的组合物中,避免异黄酮重结晶为更大的颗粒。
Description
本发明涉及异黄酮纳米颗粒组合物,所述组合物包含纳米颗粒形式的异黄酮,并优选包含载体。异黄酮纳米颗粒组合物特别适用于制备化妆品组合物、药物组合物、食品、食品添加剂、动物食品和动物食品添加剂。在包含异黄酮纳米颗粒组合物的组合物中,避免异黄酮重结晶为更大的颗粒。所述异黄酮优选地是染料木黄酮。
异黄酮是属于类黄酮的植物染料,并衍生自异黄酮。以下的异黄酮特别重要:
5 | 7 | 3′ | 4′ | ||
1 | 异黄酮 | H | H | H | H |
2 | 黄豆苷原 | H | OH | H | OH |
3 | 染料木黄酮 | OH | OH | H | OH |
4 | 樱黄素(Prunetin) | OH | OCH3 | H | OH |
5 | 鹰嘴豆芽素A(Biochanin A) | OH | OH | H | OCH3 |
6 | 二羟四氢黄酮 | OH | OH | OH | OH |
7 | 紫檀酸 | OH | OCH3 | OH | OH |
8 | 红车轴草素(Pratensein) | OH | OH | OH | OCH3 |
最重要的异黄酮之一是染料木黄酮。
染料木黄酮是具有抗菌活性的公知药物和化妆品活性成分。染料木黄酮是钙调蛋白(calmodulin)拮抗剂,并且染料木黄酮的酶抑制活性特别重要,例如抑制酪氨酸激酶、多巴羧化酶(dopa-carboxylase)等。染料木黄酮也可用在杀虫剂中。染料木黄酮的化学名称是4′,5,7-三羟基异黄酮,该化合物可通过从天然产物(例如大豆产物(例如Biochem.Biophys.Res.Commun.179:661-667,1991))中纯化获得,而该化合物也可通过本领域已知的方法化学合成。可从许多供应商商购得到高纯度的染料木黄酮。染料木黄酮的结构如下:
大量出版物涉及染料木黄酮及其用途,其可以参考例如US-A5,824,702、WO 03/068218或US-A 5,948,814,此处仅提到了本领域大量专利和专利申请中的三个近期文献。
染料木黄酮例如根据WO 2004/009576中公开的方法通常以晶体粉末的形式生产。这类粉末形式具有非常差的流动性。粉末流动性差使得晶体粉末难以用于制造片剂和其他应用形式,所述片剂和其他应用形式要求粉末自由流动。尝试与其他异黄酮一起制作配制品时,具有相同的问题。
此外,例如在食品补充剂中难以包括合理高浓度的、提供异黄酮(或染料木黄酮)高生物利用度形式的异黄酮,特别是染料木黄酮。
这些问题特别阐述于WO 99/38509中,该文献建议通过将例如染料木黄酮与两亲性载体偶合形成胶束来解决这些问题,所述胶束具有小于约100nm的平均直径。该文献中公开的两亲性载体实质上是聚乙二醇化的脂肪酸甘油酯,上述脂肪酸甘油酯是例如得自完全氢化或部分氢化的多种植物油的那些。
然而,这类胶束难以获得,并且它们的应用领域相当有限,WO99/38509中仅公开了营养补充剂。
就局部应用形式而言,尽管大量文献描述了染料木黄酮及其应用,但是目前市售的含染料木黄酮的局部用组合物仅含有非常低浓度的染料木黄酮,例如0.01wt.-%或更少,或含有染料木黄酮的有机增溶剂或溶剂,例如乙醇。然而,如果可能的话,应当避免局部用组合物中有机溶剂(例如乙醇)的存在,因为一些有机溶剂(例如乙醇)能够引起皮肤刺激。
如果某种方法制备的局部用组合物仅基于水作为溶剂,并含有较高浓度的商购染料木黄酮,例如高于0.1wt.-%,特别是高于0.2wt.-%或0.5wt.-%或更高的染料木黄酮,则这种局部用组合物在储存中成为沙砾状(gritty)。将这样的沙砾状局部用组合物涂敷至皮肤会引起刺激,特别是如果该组合物为化妆品组合物时,消费者的接受程度很低。另外,在成为沙砾状的同时,水性局部用配制品中染料木黄酮的活性在储存中还会降低。
本领域公知水不溶性药物活性化合物的纳米悬浮液和制备这种纳米悬浮液的方法,其可以参考例如US-A 5,858,410和US-A 5,145,684。这些文献公开了许多可以以纳米悬浮液的形式提供的活性成分,但是它们未提到染料木黄酮。这两篇文献均主要涉及提高药物生物利用度的方法,它们未阐述局部用组合物和在局部用组合物中存在的问题。
另外,存在数篇关于药物纳米颗粒或微米尺寸级药物颗粒的综述文章,例如“Advanced Drug Delivery Reviews 47(2001)3-19”。该文献公开了下述内容:以纳米颗粒形式提供药物可提高药物的饱和溶解度和溶解速率。该文献主要涉及用于口服或肠胃外给药的水不溶性药物的生物利用度。未公开局部用配制品和局部用配制品中存在的问题。未公开染料木黄酮。
另一综述文章“Pharmaceutical Development and Technology,Vol.9,No.1,1-13页,2004”比较了用于生产微米尺寸级药物颗粒的不同方法以及它们的优缺点。根据该文献,生产小颗干燥颗粒仍然是一个挑战,并讨论了一些特别在通过粉碎较大的干燥颗粒而非通过缔合分子级的分散药物来制备小颗粒时出现的问题。尽管该文献一般性地涉及到经微粒化的药物可被用于静脉用、局部用、口用或眼用组合物,但是主要焦点在于对肺干粉施用和提高弱水溶性药物的生物利用度。除上述一般信息外,未提及局部用组合物,也未提及染料木黄酮。
考虑到异黄酮(特别是染料木黄酮)在局部用和口服组合物中,在固体和液体组合物中,在药物、化妆品和营养工业中的广泛应用,需要以下述形式提供异黄酮(特别是染料木黄酮),所述形式能够容易地被操作,并可以配制形成所有种类的应用形式,不仅在口服组合物中具有高浓度,在局部组合物中也具有高浓度。
因此,以满足上述需要的形式提供异黄酮(特别是染料木黄酮)是本发明的一个目的。
特别地,异黄酮(如染料木黄酮)应当以下述形式被提供,所述形式使得可以制备局部用水性组合物(特别是局部用水性化妆品组合物),所述组合物优选不含乙醇,优选也不含其他有机溶剂,而含有高于0.01wt.-%的高浓度异黄酮(特别是染料木黄酮),但是优选更高的浓度,例如0.3wt.-%或更高。所述组合物在储存中应当稳定至少三个月,优选至少六个月,更优选至少一年,并在该储存时间内不发展为沙砾状。
异黄酮(例如染料木黄酮)也应当以适用于食品和食品添加剂或饮料或健康食品(例如豆腐、酸乳、橙汁等)的形式提供,该形式必须提供高的生物利用度、可混合度(mixability)、含量均一性(contentuniformity)、物理稳定性等。
本发明基于如下预料不到的发现:如果通过某些方法将异黄酮可选与载体和水一起微粒化,获得纳米颗粒组合物(其中颗粒具有3μm或更小的D[4.3]平均颗粒尺寸),则异黄酮(特别是染料木黄酮)的组合物是稳定的,所述异黄酮组合物中的异黄酮不是胶束形式。这些组合物在本文命名为异黄酮或染料木黄酮纳米颗粒组合物。
因此,本发明提供异黄酮纳米颗粒组合物和用于生产所述异黄酮纳米颗粒组合物的合适方法。
异黄酮纳米颗粒组合物含有异黄酮纳米颗粒,可选含有载体,且通常在其制备后即刻含有水,但是水可以被去除。优选地,所述组合物基本上由如下组分组成:
(i)异黄酮纳米颗粒或
(ii)异黄酮纳米颗粒和水或
(iii)异黄酮纳米颗粒和载体或
(iv)异黄酮纳米颗粒和水和载体
“基本由……组成”是指除特定的成分外,组合物中存在不多于10%,优选不多于5%,更优选不多于2%的其他成分。
异黄酮不是WO 99/38509中公开的胶束形式,本发明的方法不会形成这种胶束,且根据本发明所使用的载体优选不是WO 99/38509中公开的两亲性载体,即饱和的或单不饱和的聚乙二醇化的脂肪酸甘油酯。
未预料到的是,根据本发明的异黄酮和可选载体和可选水的纳米颗粒的组合物可以以0.3wt.-%或更高的高浓度掺入局部用水性组合物(例如化妆品组合物)中,这些局部用组合物在储存时不成为沙砾状。这些局部用组合物中异黄酮的活性在储存中也不降低。
异黄酮纳米颗粒组合物优选地通过高压匀化方法制备,其中用高压匀化器处理异黄酮(其优选地是晶体)、可选载体和水的混合物。特别优选的是另一过程,其中用搅动球磨机(agitated bead mill)处理异黄酮(其优选地是晶体)、可选载体和水的混合物。可选对得到的悬浮液进行干燥过程。
由本发明提供的染料木黄酮、可选载体和可选水的纳米颗粒组合物在现有技术中从未被描述过。为了避免这些组合物与药物组合物、化妆品组合物、营养组合物和本发明也包括的其他组合物混淆,上文定义的异黄酮、可选载体和可选水的纳米颗粒组合物被称作异黄酮(或染料木黄酮)纳米颗粒组合物。
本发明还提供了含异黄酮组合物的化妆品组合物、药物组合物、食品、饮料、动物食品、食品添加剂、杀虫剂和其他基本已知的组合物。营养产品的实例为豆腐、酸乳、橙汁等。本发明不仅包括含有异黄酮纳米颗粒组合物的局部用组合物,还包括含有异黄酮纳米颗粒组合物的口服或肠胃外组合物。优选含有异黄酮纳米颗粒组合物的药物组合物和化妆品组合物,特别是水性局部用组合物,所述组合物优选不含乙醇。
本发明还提供用于生产上文定义的异黄酮纳米颗粒组合物的方法。在优选的方法中,用高压匀化器处理异黄酮(其优选地是晶体)、可选载体和水的混合物,可选对得到的悬浮液进行干燥工艺。在甚至更优选的方法中,用搅动球磨机处理异黄酮、可选载体和水,可选对得到的悬浮液进行干燥工艺。
本发明进一步对本发明最优选的异黄酮(染料木黄酮)进行描述。但是,进一步的描述对于本发明涵盖的其他异黄酮也是有效的。当然也可以使用多于一种异黄酮(例如染料木黄酮)和一种或更多种其他异黄酮的混合物。本文使用的术语“异黄酮”旨在包括所有这些可能性。
本发明的染料木黄酮纳米颗粒组合物含有染料木黄酮,优选含有载体。所述载体并不受特定限制,并通常被添加以便于配制更易于操作的喷雾干燥粉末。不含载体时,喷雾干燥粉末会非常精细,这导致低产量和高度扬尘(dusting)。在优选的实施方案中,载体也起到稳定剂作用,以使水性悬浮液中纳米颗粒的絮凝作用最小化,特别是当稳定剂是例如改性淀粉、纤维素衍生物、阿拉伯树胶和乳蛋白时。一般地,载体选自一种或多种碳水化合物,一种或多种蛋白质,或碳水化合物和蛋白质的混合物。优选的碳水化合物是改性淀粉、山梨糖醇、麦芽糖、麦芽糖糊精、阿拉伯树胶、果胶、藻酸盐、瓜尔胶、黄原胶、纤维素衍生物(诸如羧甲基纤维素和羟丙基甲基纤维素),及其混合物。最优选的是改性淀粉和包含改性淀粉的混合物,该改性淀粉优选是一种被疏水改性的淀粉,结果其能够作为表面活性剂。这类疏水改性淀粉的实例是辛烯基琥珀酸淀粉钠,其例如可从National Starch and Co.New Jersey,USA以商品名“Capsul”购买。
如果载体包含蛋白质,则所述蛋白质优选地选自明胶、乳蛋白、大豆蛋白及其混合物。另外,如果适当的话,可以使用上文定义的一种或多种碳水化合物与上文定义的一种或多种蛋白质的混合物。
可包含在本发明染料木黄酮纳米颗粒组合物中的优选载体是下述载体,所述载体还具有稳定染料木黄酮水性悬浮液的能力。这类载体通常含有疏水部分和亲水部分,例如疏水改性淀粉、纤维素衍生物(诸如羟丙基甲基纤维素)、阿拉伯树胶和乳蛋白。这些载体/稳定剂是本发明染料木黄酮纳米颗粒组合物的优选组分。
然而,应当理解,载体对染料木黄酮悬浮液还起到稳定作用对本发明而言并非必需。本发明的染料木黄酮纳米颗粒组合物优选地被用于局部用、药物或化妆品组合物中,所述组合物可能已经含有悬浮稳定剂(或单独的配制过程足以再次悬浮染料木黄酮纳米颗粒),因此在本发明染料木黄酮纳米颗粒组合物中,悬浮稳定剂的存在并非绝对必需的。然而,如果本发明的染料木黄酮纳米颗粒组合物已经含有载体,且所述载体也具有悬浮稳定的活性,则可以减少局部用化妆品或药物组合物中悬浮稳定剂的用量,其中,所述局部用化妆品或药物组合物采用本发明的染料木黄酮纳米颗粒组合物来制备。本发明的染料木黄酮纳米颗粒组合物通常被制备为含有染料木黄酮、载体和水的水性悬浮液。在优选的实施方式中,将所述水性悬浮液随后进行合适的干燥(例如喷雾干燥或冻干),以消除大部分或所有水,并得到颗粒状或粉末状的产物。根据本发明,两种组合物均被优选:含有染料木黄酮、水和可选载体的水性悬浮液,和含有染料木黄酮和可选载体的干燥组合物。因此,在优选的实施方案中,本发明的组合物由染料木黄酮、载体和可选水组成。应当理解,本文使用的术语载体包括上文定义的数种不同载体的混合物。
如果本发明的染料木黄酮纳米颗粒组合物是粉末组合物或颗粒状组合物,则它们优选包含至少1wt.-%的染料木黄酮,优选20wt.-%或更多,更优选50wt.-%的染料木黄酮或更多,且90wt.-%%的染料木黄酮或更多也是优选的。染料木黄酮纳米颗粒组合物的其余部分为可选载体,和取决于干燥过程,未从染料木黄酮纳米颗粒组合物中去除的残余水。因此优选地,染料木黄酮纳米颗粒组合物含有99wt.-%或更少的载体和残余水(如果适用的话),优选80wt.-%或更少,更优选50wt.-%或更少的载体和残余水(如果适用的话),且10wt.-%或更少的载体和残余水(如果适用的话)也是优选的。优选地,本发明的染料木黄酮纳米颗粒组合物含有至少1wt.-%的载体和残余水(如果适用的话),优选本发明的染料木黄酮纳米颗粒组合物含有5wt.-%或更多的载体和残余水(如果适用的话)。优选的颗粒状或粉末状染料木黄酮纳米颗粒组合物含有1wt.-%到99wt.-%、30wt.-%到95wt.-%、30wt.-%到95wt.-%、50wt.-%到95wt.-%、70wt.-%到95wt.-%、70wt.-%到90wt.-%、90wt.-%到99wt.-%、90wt.-%到95wt.-%数量的染料木黄酮,其余部分为载体和残余水(如果适用的话)。当然,不含有载体,仅含有染料木黄酮和残余水(如果适用的话)的组合物也是优选的。粉末形式的染料木黄酮纳米颗粒组合物可通过常规的喷雾干燥工艺或冻干工艺由下述的水性悬浮液制备。
如果本发明的染料木黄酮纳米颗粒组合物是含有染料木黄酮、可选载体和水的水性悬浮液的形式,则水的用量不被特别限制,但是通常这些水性组合物会含有0.5%或更多,优选3%或更多,优选5%或更多的染料木黄酮和可选载体,更优选10%或更多,更优选20%或更多,30%或更多,40%或更多或50%或更多的染料木黄酮和可选载体,其余部分为水,其中染料木黄酮和载体的相对量如上文定义。存在于水性悬浮液中的水最小量是形成悬浮液必需的量。本发明的水性悬浮液可直接得自生产工艺,在这种情况下悬浮液中固体颗粒的量取决于用于制备悬浮液的设备,由此悬浮液中水的量也取决于用于制备悬浮液的设备。如果应当提供较高的固体含量,可以根据需要优选在恒定的温度下,从水性悬浮液中去除水(例如通过蒸发)。通过高压匀化或通过搅动球磨(湿磨)染料木黄酮和可选载体而直接获得的水性悬浮液是优选的,且这类悬浮液通常含有40%或更多的水。含有50%或更多水,其余部分为以上所定义相对量的染料木黄酮和可选载体的水性悬浮液也是优选的。
还优选下述组合物,所述组合物含有10wt.-%到50wt.-%数量的染料木黄酮,且载体含量以染料木黄酮与载体比值在10∶1到1∶10,优选在10∶1到1∶1,或在1∶1到1∶5(例如约1∶2)范围内表示,组合物的其余部分为水,例如含有25%染料木黄酮、5%载体和70%水的组合物。还优选含有10%到30%染料木黄酮(优选15%到25%的染料木黄酮,特别是约20%的染料木黄酮),15%到40%的载体(优选20%到30%的载体,特别是约25%的载体),其余部分为水的组合物。
本发明染料木黄酮纳米颗粒组合物的一个重要特征在于,染料木黄酮的颗粒尺寸,该颗粒尺寸为3μm或更小,优选1μm或更小,例如约0.5μm。本发明染料木黄酮纳米颗粒组合物中染料木黄酮的平均颗粒尺寸优选的范围是0.05μm到3μm,更优选0.05μm到1μm,还更优选0.05μm到0.5μm。另外,0.3μm到1.0μm的颗粒尺寸是优选的。对于平均颗粒尺寸,具有0.1而非0.05下限的上述范围也是优选的。上述所有颗粒尺寸都是平均颗粒尺寸D[4,3],即体积平均直径或De Brouckere平均直径。优选地,根据D[3,2]的染料木黄酮颗粒的颗粒尺寸在0.05到0.5,优选0.1到0.2的范围内,其中D[3,2]是表面平均直径或Sauter平均直径。本说明书中涉及的所有颗粒尺寸的测量均使用Malvern Instruments Ltd.UK的“Matersizer 2000”通过激光衍射技术进行,上述颗粒尺寸D[4,3]和D[3,2]的更多信息可参见例如“Basic principles of particle size analytics”,Dr.AlanRawle,Malvern Instruments Limited,Engima Business Part,Grovewood Road,Malvern,Worcestershire,WR 141 XZ,UK和the“Manual of Malvern particlesize analyzer”。
申请人不希望受任何理论束缚,并且未知本发明含载体染料木黄酮纳米颗粒组合物中的颗粒是否含有染料木黄酮和载体的混合物(这是指染料木黄酮和载体存在于同一颗粒中),或染料木黄酮颗粒和载体颗粒是否独立地存在于染料木黄酮纳米颗粒组合物中。染料木黄酮纳米颗粒组合物含有仅由染料木黄酮组成的颗粒、含有由染料木黄酮和载体二者组成的颗粒,且含有仅由载体组成的颗粒也是可以的。所有这些可能性均包含在本发明中,如果本发明的染料木黄酮纳米颗粒组合物包括含有染料木黄酮和载体二者的颗粒,则上述颗粒尺寸涉及本身包括染料木黄酮和载体二者的颗粒。
如果没有其他说明,则在该申请中,部分和百分比按重量计,并基于组合物的重量。
本发明的染料木黄酮纳米颗粒组合物可用于现有技术中染料木黄酮已使用的所有目的,但是本发明的染料木黄酮纳米颗粒组合物特别用于药物组合物、化妆品组合物、食品、动物食品或食品添加剂,最优选食品添加剂和化妆品组合物。
含有本发明染料木黄酮纳米颗粒组合物的本发明组合物在下文中以其最广泛的含义被称作“一般组合物”。
优选地,本发明的一般组合物是局部用组合物,例如液体或固体水包油乳液、油包水乳液、复合型乳液、微乳液、PET-乳液、bickering乳液、水凝胶、醇凝胶、脂凝胶(lipogel)、单相或多相溶液、泡沫、软膏、糊、悬浮液、粉末、乳膏、清洁剂、肥皂和其他常见组合物,它们也可以通过笔、作为面膜或作为喷雾涂敷。
本发明的一般组合物也可含有常见的化妆品佐剂和添加剂,例如防腐剂/抗氧化剂、脂肪物质/油、水、有机溶剂、硅酮、增稠剂、软化剂、乳化剂、遮光剂、化妆品活性消泡剂、湿润剂、香料、表面活性剂、填充剂、螯合剂、阴离子、阳离子、非离子或两亲性聚合物或其混合物、推进剂、酸化或碱化剂、染料、着色剂、色素或纳米色素(例如适用于通过物理阻挡紫外辐射而提供光防护效应的那些),或通常配制形成化妆品的任何其他成分。
本发明的一般组合物也可含有一种或多种其它药物或化妆品活性成分,特别是甜没药萜醇、烷基二醇(诸如1,2-戊二醇、己二醇或1,2-辛二醇)、维生素、泛醇、植醇、植烷三醇、神经酰胺和假神经酰胺、氨基酸和生物活性肽、蛋白质水解产物、AHA酸、多不饱和脂肪酸、植物提取物、DNA或RNA及其片段产物或碳水化合物。
另外,本发明的一般组合物可含有UV-A和UV-B滤光剂。与本发明化合物组合时,优选的UV-B或广谱遮蔽剂(即在约290nm至340nm间具有最大吸收的物质)的实例是以下的有机和无机化合物:
-丙烯酸酯,例如2-氰基-3,3-二苯基丙烯酸2-乙基己基酯(氰双苯丙烯酸辛酯(octocrylene),PARSOL340)、2-氰基-3,3-二苯基丙烯酸乙酯等等;
-樟脑衍生物,例如4-甲基亚苄基樟脑(PARSOL5000)、3-亚苄基樟脑、甲基硫酸樟脑苯甲烷铵(camphor benzalkonium methosulfate)、聚丙烯酰胺基甲基亚苄基樟脑、磺基亚苄基樟脑、磺基甲基亚苄基樟脑、对苯二亚甲基二樟脑酰胺磺酸等等;
-肉桂酸酯衍生物,例如甲氧基肉桂酸辛酯(PARSOLMCX)、甲氧基肉桂酸乙氧基乙基酯、甲氧基肉桂酸二乙醇胺酯(PARSOLHydro)、甲氧基肉桂酸异戊酯等等,以及键合到硅氧烷上的肉桂酸衍生物;
-对氨基苯甲酸衍生物,例如对氨基苯甲酸、对二甲基氨基苯甲酸2-乙基己基酯、N-氧丙烯化的对氨基苯甲酸乙酯、对氨基苯甲酸甘油酯;
-二苯甲酮,例如二苯甲酮-3、二苯甲酮-4、2,2′,4,4′-四羟基-二苯甲酮、2,2′-二羟基-4,4′-二甲氧基二苯甲酮等等;
-亚苄基丙二酸酯,例如4-甲氧基亚苄基丙二酸二-(2-乙基己基)酯;
-2-(4-乙氧基-苯胺亚甲基)丙二酸酯,例如欧洲专利公开EP 0895 776中所述的2-(4-乙氧基-苯胺亚甲基)丙二酸二乙酯;
-如欧洲专利公开EP 0358584 B1、EP 0538431 B1和EP 0709080 A1中所述的含有苯丙二酸基的有机硅氧烷化合物,特别是Parsol SLX;
-甲酚曲唑三硅氧烷(Drometrizole trisiloxane(Mexoryl XL));
-色素,例如微粒化的TiO2等等。术语“微粒化的”是指从约5nm到约200nm,特别是从约15nm到约100nm的颗粒尺寸。TiO2颗粒也可用金属氧化物(例如氧化铝或氧化锆)或有机涂层(例如多元醇、甲基硅酮、硬脂酸铝、烷基甲硅烷)包覆。这类包衣为本领域熟知。
-咪唑衍生物,例如2-苯基苯并咪唑磺酸及其盐(PARSOLHS)。2-苯基苯并咪唑磺酸的盐为例如碱金属盐(如钠盐或钾盐)、铵盐、吗啉盐、伯、仲和叔胺盐(例如单乙醇胺盐、二乙醇胺盐)等等。
-水杨酸酯衍生物,例如水杨酸异丙基苄酯、水杨酸苄酯、水杨酸丁酯、水杨酸辛酯(NEO HELIOPAN OS)、水杨酸异辛酯或水杨酸高薄荷酯(homosalate,HELIOPAN)等等。
-三嗪衍生物,例如辛基三嗪酮(UVINUL T-150)、二辛基丁酰胺基三嗪酮(UVASORB HEB)、二乙氧基苯酚甲氧苯基三嗪(Tinosorb S)等等。
与本发明化合物组合时,优选的广谱的或UV A遮光剂(即在约320nm到400nm之间有最大吸收的物质)的实例是以下的有机和无机化合物:
-二苯甲酰甲烷衍生物,例如4-叔丁基-4′-甲氧基二苯甲酰甲烷(PARSOL1789)、二甲氧基二苯甲酰甲烷、异丙基二苯甲酰甲烷等等;
-苯并三唑衍生物,例如2,2′-亚甲基-二-(6-(2H-苯并三唑-2-基)-4-(1,1,3,3,-四甲基丁基)-苯酚)(TINOSORB M)等等;
-亚苯基-1,4-二-苯并咪唑磺酸或盐,例如2,2-(1,4-亚苯基)二-(1H-苯并咪唑-4,6-二磺酸)(Neoheliopan AP);
-经氨基取代的羟基二苯甲酮,例如如欧洲专利公开EP 1046391中所述的2-(4-二乙氨基-2-羟基-苯甲酰基)-苯甲酸己酯;
因为二苯甲酰甲烷衍生物具有有限的光稳定性,所以其可以适当地光稳定这些UV-A遮光剂。因此,术语“常规的UV-A遮光剂”也指被以下物质稳定的二苯甲酰甲烷衍生物,例如PARSOL1789:
-如欧洲专利公开EP-A 0514491和EP-A 0780119中描述的3,3-二苯基丙烯酸酯衍生物;
-如US专利No.5,605,680中描述的亚苄基樟脑衍生物;
-如欧洲专利公开EP-A 0358584、EP-A 0538431和EP-A 0709080中描述的含苯丙二酸酯基的有机硅氧烷,特别是Parsol SLX。
在DE-A 10327432中很好地综述了可添加到本发明组合物中的UV-A和UV-B滤光剂。该文献中公开的所有UV过滤化合物也可用作本发明组合物的组分,并通过引用包含在本文中。
本发明的一般组合物优选含有一种或多种抗氧化剂/防腐剂。根据本发明,可以使用通常配制形成化妆品的所有已知抗氧化剂。特别优选选自由以下物质组成的组的抗氧化剂:氨基酸(例如甘氨酸、组氨酸、酪氨酸、色氨酸)及其衍生物,咪唑(例如尿刊酸)和衍生物,肽(例如D,L-肌肽、D-肌肽、L-肌肽)和衍生物(例如鹅肌肽),类胡萝卜素,胡萝卜烯(例如α-胡萝卜烯、β-胡萝卜烯、番茄红素)和衍生物,氯原酸和衍生物,硫辛酸和衍生物(例如二氢硫辛酸),金硫代葡萄糖,丙基硫脲嘧啶和其他巯基(例如硫氧还蛋白、谷胱甘肽、半胱氨酸、胱氨酸、胱胺及其糖酯、N-乙酰酯、甲酯、乙酯、丙酯、戊酯、丁酯、月桂酯、棕榈酯、油酯、y-亚油酯、胆固醇酯和甘油酯)及其盐,硫代二丙酸二月桂酯,硫代二丙酸二硬脂酯,硫代二丙酸及其衍生物(酯、醚、肽、脂质、核苷酸、核苷及盐)以及非常低剂量(例如pmol/kg到mmol/kg)的亚砜胺(sulfoximine)化合物(例如,丁硫氨酸亚砜胺(buthioninsulfoximine)、高半胱氨酸亚砜胺、丁硫氨酸砜(buthioninsulfone)、五、六、七硫堇亚砜胺),其它的(金属)螯合剂(例如α-羟基脂肪酸、棕榈酸、肌醇六磷酸、乳铁蛋白),β-羟酸(例如柠檬酸、乳酸、苹果酸),腐殖酸(huminic acid),没食子酸,没食子提取物,胆红素,胆绿素,EDTA,EGTA及其衍生物,不饱和脂肪酸及其衍生物(例如γ-亚油酸、亚油酸、油酸),叶酸及其衍生物,泛醌和泛醌醇及其衍生物,维生素C和衍生物(例如棕榈酸抗坏血酸酯和四异棕榈酸抗坏血酸酯、抗坏血酸磷酸镁、抗坏血酸磷酸钠、抗坏血酸乙酸酯),生育酚和衍生物(例如维生素-E-乙酸酯),天然维生素E、维生素A和衍生物的混合物(维生素-A-棕榈酸酯和乙酸酯)以及苯甲酸松柏基酯(coniferylbenzoate),芸香亭酸和衍生物,α-糖基芸香苷,阿魏酸,亚糠基葡萄糖醇,肌肽,丁基羟基甲苯,丁基羟基苯甲醚,三羟基丁酰苯,脲及其衍生物,甘露糖和衍生物,锌和衍生物(例如ZnO、ZnSO4),硒和衍生物(例如硒代蛋氨酸),茋和衍生物(例如茋氧化物、反式茋氧化物)和所述活性成分的合适的衍生物(盐、酯、醚、糖、核苷酸、核苷、肽和脂质)。一种或多种防腐剂/抗氧化剂可以以占本发明组合物总重的约0.01wt.%到约10wt.%的量存在。优选地,一种或多种防腐剂/抗氧化剂以约0.1wt.%到约1wt.%的量存在。
典型地,局部用配制品还含有表面活性成分,如乳化剂、增溶剂等等。乳化剂使两种或更多种不可溶合的成分均匀地组合。另外,乳化剂起稳定组合物的作用。可用于本发明从而形成O/W、W/O、O/W/O或W/O/W乳液/微乳液的乳化剂包括失水山梨糖醇油酸酯、失水山梨糖醇倍半油酸酯、失水山梨糖醇异硬脂酸酯、失水山梨糖醇三油酸酯、聚甘油-3-二异硬脂酸酯、油酸/异硬脂酸的聚甘油酯、聚甘油-6-六蓖麻醇酸酯、聚甘油-4-油酸酯、聚甘油-4-油酸酯/PEG-8丙二醇椰油酸酯、油酰胺DEA、TEA肉豆蔻酸酯、TEA硬脂酸酯、硬脂酸镁、硬脂酸钠、月桂酸钾、蓖麻醇酸钾、椰油酸钠、牛油酸钠、海狸香酸钾(potassium castorate)、油酸钠及其混合物。其他合适的乳化剂为磷酸酯及其盐,例如磷酸十六烷基酯(AmphisolA)、二乙醇胺磷酸十六烷基酯(Amphisol)、十六烷基磷酸钾(AmphisolK)、油酸甘油酯磷酸钠、氢化植物甘油磷酸酯及其混合物。另外,一种或多种合成聚合物可以被用作乳化剂。例如,PVP二十碳烯共聚物、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、丙烯酸酯/steareth-20甲基丙烯酸酯共聚物、PEG-22/十二烷基二醇共聚物、PEG-45/十二烷基二醇共聚物及其混合物。优选的乳化剂是磷酸十六烷基酯(AmphisolA)、二乙醇胺磷酸十六烷基酯(Amphisol)、十六烷基磷酸钾(AmphisolK)、PVP二十碳烯共聚物、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、PEG-20失水山梨糖异硬脂酸酯、失水山梨糖异硬脂酸酯及其混合物。所述一种或多种乳化剂以占本发明组合物总重量约0.01wt.%到约20wt.%的总量存在。优选地,使用约0.1wt.%到约10wt.%的乳化剂。
局部用组合物的脂质相可有利地选自:
-矿物油和矿物蜡;
-油例如癸酸甘油三酯或辛酸甘油三酯,优选蓖麻油;
-油或蜡和其他天然或合成的油,在优选的实施方案中,为脂肪酸与醇(例如异丙醇、丙二醇、丙三醇)的酯或脂肪醇与羧酸或脂肪酸的酯;
-苯甲酸烷基酯;和/或
-硅油,例如二甲基聚硅氧烷、二乙基聚硅氧烷、二苯基聚硅氧烷、环甲基硅酮
及其混合物。
可以掺入本发明的乳液、微乳液、油凝胶、水分散体或脂分散体的油相中的示例性脂肪物质有利地选自具有3到30个碳原子饱和和/或不饱和的、线性或支化的烷基羧酸和/或具有3到30个碳原子的饱和和/或不饱和的、线性或支化醇的酯,以及芳香族羧酸与具有3到30个碳原子的饱和和/或不饱和的、线性或支化醇的酯。这种酯可有利地选自棕榈酸辛酯、椰油酸辛酯、异硬脂酸辛酯、辛基十二烷基肉豆蔻酸酯、异壬酸十六烷基酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、油酸异丙酯、硬脂酸正丁酯、月桂酸正己酯、油酸正癸酯、硬脂酸异辛酯、硬脂酸异壬酯、异壬酸异壬酯、棕榈酸2-乙基己基酯、月桂酸2-乙基己基酯、硬脂酸2-己基癸基酯、棕榈酸2-辛基十二烷基酯、庚酸硬脂基酯、油酸油基酯、芥酸油基酯、油酸瓢儿菜基酯、瓢儿菜酸瓢儿菜基酯、硬脂酸十三烷酯、十三烷基偏苯三酸酯,以及这些酯的合成、半合成或天然的混合物,例如霍霍巴油。
其他适于在本发明局部用组合物中使用的脂肪成分包括极性油,例如卵磷脂和脂肪酸甘油三酯,即具有8到24个碳原子(优选12到18个碳原子)的饱和和/或不饱和的、直链或支化的羧酸的甘油三酯,其中脂肪酸甘油三酯优选地选自合成、半合成或天然的油(例如椰油酸甘油酯、橄榄油、葵花子油、大豆油、花生油、油菜籽油、甜杏仁油、棕榈油、椰子油、蓖麻油、氢化蓖麻油、小麦油、葡萄籽油、澳洲坚果油和其它);非极性油,例如线性的和/或支化的烃和蜡,例如矿物油、凡士林(矿脂);石蜡、角鲨烷和角鲨烯、聚烯烃、氢化聚异丁烯和异十六烷,优选的聚烯烃为聚癸烯;二烷基醚,例如二辛醚;线性或环状的硅油,例如优选环甲基硅酮(八甲基环四硅氧烷);十六烷基二甲基硅氧烷、六甲基环三硅氧烷、聚二甲基硅氧烷、聚(甲基苯基硅氧烷)及其混合物。
其他可有利地掺入本发明局部用组合物中的脂肪成分为异二十烷;新戊二醇二庚酸酯;丙二醇-二辛酸酯/二癸酸酯;辛酸/癸酸/二甘油基琥珀酸酯;丁二醇辛酸酯/癸酸酯;C12-13-烷基乳酸酯;二-C12-13烷基酒石酸酯;三异硬脂精;二季戊四醇六辛酸酯/六癸酸酯;丙二醇单异硬脂酸酯;三辛精;二甲基异山梨糖醇酯。特别有益的是使用苯甲酸C12-15-烷基酯和异硬脂酸2-乙基己基酯的混合物,苯甲酸C12-15-烷基酯和异壬酸异十三烷基酯的混合物,以及苯甲酸C12-15-烷基酯、异硬脂酸2-乙基己基酯和异壬酸异十三烷基酯的混合物。
本发明组合物的油相也可含有天然的植物蜡或动物蜡,例如蜂蜡、中国蜡、熊蜂蜡和其他昆虫蜡,以及牛油树脂和可可脂。
可向本发明的局部用组合物中掺入湿润剂以保持皮肤水分或补水。通过提供防护层而阻止水分从皮肤蒸发的湿润剂称为柔润剂(emollient)。另外,柔润剂对皮肤表面提供软化或舒缓的效果,并通常被认为对局部使用是安全的。优选的柔润剂包括矿物油,羊毛脂,矿脂,癸酸/辛酸三甘油醛,胆固醇,硅酮(例如二甲基硅酮、环甲基硅酮),杏仁油,霍霍巴油,鳄梨油,蓖麻油,芝麻油,葵花子油,椰子油和葡萄籽油,可可脂,橄榄油,芦荟提取物,脂肪酸(例如油酸和硬脂酸),脂肪醇(例如鲸蜡醇和十六烷基醇ENJAY),己二酸二异丙基盐,羟基苯甲酸酯,C9-15-醇的苯甲酸酯,异壬酸异壬基酯,醚(例如聚氧化丙烯丁基醚和聚氧化丙烯十六烷基醚),和苯甲酸C12-15-烷基酯及其混合物。最优选的柔润剂是羟基苯甲酸酯、芦荟、苯甲酸C12-15-烷基酯及其混合物。柔润剂以占组合物总重量约1wt.%到约20wt.%的量存在。优选的柔润剂量为约2wt.%到约15wt.%,最优选约4wt.%到约10wt.%。
结合水从而将水留在皮肤表面的湿润剂称为致湿剂(humectant)。合适的致湿剂可以掺入本发明的局部用组合物中,例如丙三醇、聚丙二醇、1,2-戊二醇、聚乙二醇、乳酸、吡咯烷酮羧酸、脲、磷脂、胶原、弹性蛋白、神经酰胺、卵磷脂山梨糖醇、PEG-4及其混合物。其他合适的湿润剂为下类可水溶和/或可溶胀和/或水凝胶多糖类的聚合湿润剂,例如透明质酸、壳聚糖和/或富含岩藻糖的多糖,所述富含岩藻糖的多糖可例如得自SOLABIA S产的Fucogel1000(CAS-Nr.178463-23-5)。一种或多种致湿剂以约0.5wt.%到约8wt.%,优选约1wt.%到约5wt.%可选存在于本发明的组合物中。
优选的本发明局部用组合物的水相可含有常见的化妆品或药物添加剂,例如醇(特别是低级醇,优选乙醇和/或异丙醇),低级二醇或多元醇及其醚(优选丙二醇、甘油、乙二醇、乙二醇单乙基或单丁基醚、丙二醇单甲基或单乙基或单丁基醚、二乙二醇单甲基或单乙基醚)和类似产品,聚合物,稳泡剂,电解质和特别是一种或多种增稠剂。可用于本发明配制品中以便利于获得合适产品稠度的增稠剂包括卡波姆(carbomer)、二氧化硅、硅酸镁和/或硅酸铝、蜂蜡、硬脂酸、硬脂醇多糖及其衍生物(例如黄原胶)、羟丙纤维素、聚丙烯酰胺、丙烯酸酯交联共聚物,优选卡波姆,例如单独的980、981、1382、2984、5984型carbopole或其混合物。可包含在本发明组合物中以中和例如乳化剂或增泡剂/稳泡剂成分的合适中和剂包括,但不限于,碱金属氢氧化物,例如氢氧化钠和氢氧化钾;有机碱,例如二乙醇胺(DEA)、三乙醇胺(TEA)、氨甲基丙醇及其混合物;氨基酸,例如精氨酸和赖氨酸,和任何前述物质的任何组合。中和剂可以以约0.01wt.%到约8wt.%,优选1wt.%到约5wt.%的量存在于本发明的组合物中。
可能需要向本发明组合物中添加电解质以改变疏水乳化剂的行为。因此,本发明的乳液/微乳液可优选地含有一种或数种包含如下阴离子盐的电解质,例如氯离子、硫酸根、碳酸根、硼酸根和铝酸根,但不仅限于此。其他合适的电解质可以基于如下有机阴离子,所述有机阴离子例如,但不限于,乳酸根、乙酸根、苯甲酸根、丙酸根、酒石酸根和柠檬酸根。阳离子优选选择铵离子、烷基铵离子、碱金属离子或碱土金属离子、镁离子、铁离子或锌离子。特别优选的盐是氯化钾和氯化钠、硫酸镁、硫酸锌及其混合物。电解质可以以约0.01wt.%到约8wt.%的量存在于本发明的组合物中。
本发明的局部用组合物可优选地以乳液、增稠乳液、凝胶、乳霜、乳、软膏、粉末或固体管棒的形式提供,并可选包装为气溶胶,以摩丝、泡沫或喷雾的形式提供。根据本发明的组合物也可以是在溶剂或脂肪物质中的悬浮液或分散液的形式,或者是乳液或微乳液(特别是O/W或W/O型,O/W/O或W/O/W型)的形式,例如乳霜或乳、微泡分散液;是软膏、凝胶、固体管棒或气溶胶摩丝的形式。乳液也可含有阴离子的、非离子的、阳离子的或两亲性的表面活性剂。
特别优选的是化妆品和药物组合物,还要更优选的是化妆品组合物。
本申请中使用的术语“化妆品制剂”或“化妆品组合物”是指RmppLexikon Chemie,10th edition 1997,Georg Thieme Verlag Stuttgart,New York.中标题为″Kosmetika″所定义的化妆品组合物。
本发明的化妆品或药物组合物含有本发明的染料木黄酮纳米颗粒组合物,以及化妆品或药物可接受的赋形剂或稀释剂。如果没有另外的说明,下文提到的赋形剂、添加剂、稀释剂等既适用于药物组合物,也适用于化妆品组合物。
本发明的局部用化妆品和药物组合物优选地包含多于0.01%、优选0.1%或更多、更优选0.2%或更多的染料木黄酮纳米颗粒,和可选载体。然而,通过将染料木黄酮纳米颗粒组合物掺入局部用化妆品和药物组合物中达到的效应在药物和化妆品组合物中含有0.3%或更多染料木黄酮最为显著,因为在这种高浓度下,本发明的局部用药物组合物和化妆品组合物中的染料木黄酮纳米颗粒的颗粒尺寸在储存时增长特别小(有时甚至存在降低)。在这种高浓度下的效应比低于0.3%较低浓度的效应显著得多,这一点特别惊人和有利,因为它允许提供具有非常高浓度染料木黄酮的化妆品和药物组合物,而这种化妆品和药物组合物使用现有技术的染料木黄酮组合物不能获得。因此,本发明的化妆品和药物组合物包括含有染料木黄酮和可选载体的纳米颗粒,其中所述染料木黄酮的浓度优选地为0.3%或更多,更优选地为0.5%或更多。以下范围的染料木黄酮和可选载体的纳米颗粒也是优选的:0.3%到3%,0.3%到2%,0.3%到1%,和下限为0.4%或0.5%而非0.3%的上述范围。
关于局部用化妆品和药物组合物的种类,和局部用化妆品和药物制剂的制备方法以及其它合适的添加剂,可以参考相关文献,例如Novak G.A.Die kosmetischen Prparate-Band 2,Die kosmetischen Prparate-Rezeptur,Rohstoffe,wissenschaftliche Grundlagen(Verlag für Chem.Industrie H.Ziolkowski KG,Augsburg)。
还可以将本发明的染料木黄酮纳米颗粒组合物包括在口服化妆品和药物组合物中,例如以丸剂、片剂、可包含颗粒或小片的胶囊形式,作为液体、口服配制品或作为食品添加剂,这通常是本领域技术人员公知的。用于制备口服组合物的有用步骤和有用添加剂公开于例如标准文献Remington:The Science and Practice of Pharmacy,Lippincot,Williams &Wilking(Editors)2000中,其通过引用被并入本文。优选将本发明的组合物掺入食品中,特别是掺入动物食品中,更特别地掺入宠物食品中。本领域已知如何制备这类食品。
作为用于口服组合物(特别是用于片剂)的常见添加剂,可以使用常见的赋形剂,例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸氢二钠或磷酸氢二钾、磷酸钠或磷酸钾、甘氨酸;崩解剂,例如淀粉或海藻酸;粘接剂,例如聚乙烯基吡咯烷酮、蔗糖、明胶和阿拉伯胶;润滑剂,例如硬脂酸镁、月桂基硫酸钠或滑石。如果组合物被装进明胶胶囊中,用于制备颗粒的常见添加剂为乳糖或乳酸盐以及具有高分子量的聚乙二醇。其它添加剂和赋形剂以及用于其它口服配制品和用于食品添加剂的添加剂和赋形剂是技术人员已知的,其可参考相关文献,例如“Grundzüge derLebensmitteltechnik”,Horst Dieter Tscheuschner(Editor),2.Edition,Hamburg,Beers 1996。
组合物还可包含一种或多种其它的药物或化妆品活性成分,特别是预防或减少痤疮、皱纹、细纹、萎缩、炎症的成分,以及局部麻醉剂,人工着色剂和促进剂,抗微生物剂和抗真菌剂与遮光剂。
实例为肽(例如MatrixylTM[五肽衍生物])、甘油、脲、胍(例如氨基胍);维生素及其衍生物,例如抗坏血酸、维生素A(例如类视黄醇衍生物,如棕榈酸视黄基酯或丙酸视黄基酯)、维生素E(例如乙酸生育酚酯)、维生素B3(例如烟酰胺)和维生素B5(例如泛酰醇)等等及其混合物、蜡基合成肽(例如棕榈酸辛酯和三山嵛精和失水山梨聚糖异硬脂酸酯和棕榈酰寡聚肽)、祛痘药剂(间苯二酚、水杨酸等等);抗氧化剂(例如植物甾醇、硫辛酸);类黄酮(例如异黄酮、植物雌激素);皮肤舒缓和愈合剂(如芦荟提取物、尿囊素等等);螯合剂和多价螯合剂;和适用于美容目的的试剂,如精油、香料、皮肤感受剂(skin sensates)、遮光剂、芳香化合物(例如丁香油、薄荷醇、樟脑、桉树油和丁香酚)、去角质活性剂(desquamatory active)、祛痘活性剂、维生素B3化合物、抗氧化剂、肽、羟基酸、自由基捕集剂、螯合剂、金合欢醇、消炎剂、局部麻醉剂、着色活性剂、皮肤增亮剂(skin-lightening agent)、抗蜂窝组织试剂、类黄酮、抗微生物活性剂和抗真菌活性剂(特别是甜没药萜醇)、烷基二醇(如1,2-戊二醇、己二醇或1,2-辛二醇)、维生素、泛酰醇、植醇、植烷醇、神经酰胺和假神经酰胺、氨基酸和生物活性肽、蛋白质水解产物、AHA酸、多不饱和脂肪酸、植物提取物、DNA或RNA及其分裂产物或碳水化合物、生物素、共轭脂肪酸、肉碱、维生素E、A、C、B3、B6、B12、寡聚肽、肌肽、生物醌(biochinonen)、六氢番茄红素(phytofluen))、八氢番茄红素、叶酸、及其相应的衍生物。
本发明的口服化妆品和药物组合物中染料木黄酮的含量通常为约0.1%到90%,优选地约1%到80%。典型地,在药物组合物如片剂中,染料木黄酮可高达50%,但是优选其在1%-10%的范围内。进行应用,使得所需效应发生,并取决于患者和所需效应。常见的日剂量可以在约1mg/天到1g/天的范围内,例如约5mg/天到100mg/天。
本发明的化妆品和药物组合物也可以是可注射组合物的形式,特别是当组合物用于促进头发生长时。可注射化妆品和药物组合物的制备方法是技术人员已知的,其可参考相关文献,特别是上述的Remington。
根据本发明,含本发明染料木黄酮纳米颗粒组合物的营养产品也是优选的,例如酸乳酪、豆腐、果汁(如橙汁)等。染料木黄酮纳米颗粒的含量未特别限制,但是这些产品中染料木黄酮的含量通常为0.01%或更多,优选0.1%或更多,但是通常不高于10%或5%。本发明的口服药物和营养产品具有特别的优点:染料木黄酮具有高生物可利用度以及出乎意料的高物理稳定性(染料木黄酮颗粒不会生长成不可接受的尺寸)。
优选地,通过在高压匀化器中弄碎染料木黄酮晶体和可选载体获得本发明的染料木黄酮纳米颗粒组合物。更优选地,通过在搅动球磨机中研磨染料木黄酮(特别是染料木黄酮晶体)和可选载体获得本发明的染料木黄酮纳米颗粒组合物。弄碎和研磨通常采用水性悬浮液进行。
合适的匀化器为现有技术中已知的并可商购,例如其可以为B.E.E.International Ltd.Migdal Haemek,Israel的DeBEE 2000高压匀化器。匀化器优选在500bar到4000bar下的压力下操作,更优选地在500 bar到3000bar的压力下操作,最优选地在500bar到2000bar的压力下操作。优选地,如EP-A 1008380中所公开的,匀化器装有喷嘴系统。
优选地,染料木黄酮和载体在高压匀化器中循环经过1到200次,更优选5到100次,例如5到30次。所需的循环次数可由一些常规实验容易地确定。
在特别优选的实施方案中,首先将无载体的染料木黄酮在高压匀化器中匀化例如5到100次(如5到30次),然后加入载体溶液,并继续匀化例如1到50次(如1到10次)。需要时可提高循环数。
据称,在匀化中,染料木黄酮晶体主要通过高压工艺中产生的气穴现象和剪切作用被弄碎,被加工的水性纳米悬浮液可以具有高达50%或甚至更高的固体含量。水性纳米悬浮液可被原样用于制备本发明的药物或化妆品组合物,或该水性纳米悬浮液可以首先进行干燥步骤,以获得粉末或颗粒组合物,所述组合物基本上由染料木黄酮、可选载体和最终通过干燥步骤未去除的残余水组成。干燥可通过常用方法如喷雾干燥或冻干完成。
本发明的染料木黄酮纳米颗粒组合物最优选通过在搅动球磨机中通过湿磨工艺弄碎来获得。合适的湿磨机为现有技术已知并可商购,例如其可为NETZSCH-Feinmahltechnik GmbH,Sedanstraβe 70,95100 Selb,Germany的Netzsch LMZ 4湿磨机。优选地,染料木黄酮和可选载体循环通过搅动球磨机1-50次,更优选3-40次,更优选5-30次,最优选8-25次。
研磨介质基本上可由例如Al2O3、Si3N4、TiO2、WC(碳化钨)或ZrO2组成,或这些化合物的组合。最优选使用ZrO2类的研磨介质,例如用Y2O3稳定的ZrO2。
所加工的水性纳米悬浮液可以具有高达25%或甚至更高的固体含量。
在本发明优选的实施方案中,通过选择合适的干燥条件尽可能多地去除水,水含量低于例如10%。
本说明书中涉及的颗粒尺寸的所有测量均使用Malvern InstrumentsLtd.UK.的“Mastersizer 2000”通过激光衍射技术进行。
以下的实施例仅用于说明,而不旨在限制本发明的范围。
实施例1
通过将从National Starch and Chemical Company,New Jersey,US以产品名Capsul获得的具有8%水分含量的辛烯基琥珀酸淀粉钠(490g)溶解于80℃的去离子水(490g)中来制备辛烯基琥珀酸淀粉钠溶液(46%)。
将染料木黄酮粉末(20g)与辛烯基琥珀酸淀粉钠溶液(391.4g)和去离子水(390g)混合并通过装配有130微米喷嘴的高压匀化器DeBEE2000,B.E.E.International Ltd.Israel,其流水线中具有约200g水,匀化压力为1500bar。匀化时背压(back pressure)被设定为120bar。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20℃到30℃。固体含量为约20%的悬浮液循环经过匀化器42次,直到达到所需的颗粒尺寸。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,且以1.469的折射率为基础的计算结果在下文显示于表I中。
表I:染料木黄酮颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(42次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.1微米 | 0.07微米 |
D(v,0.5) | 41.9微米 | 0.17微米 |
D(v,0.9) | 91.0微米 | 3.65微米 |
平均颗粒尺寸D[4,3]: | 48.5微米 | 0.97微米 |
平均颗粒尺寸D[3,2]: | 23.1微米 | 0.15微米 |
用Niro喷雾干燥器(GEA Niro A/S,Denmark)采用4bar的喷嘴压力干燥经匀化的染料木黄酮悬浮液。入口温度为约200℃,出口温度为约80℃。喷干的粉末含有约9.4%的染料木黄酮,水分含量为约5.87%。通过将喷雾干燥的粉末再次悬浮于水中并由激光衍射技术测量来测定染料木黄酮的颗粒尺寸,结果显示在表II中。
表II:经喷雾干燥的染料木黄酮形式的颗粒尺寸测量
匀化(42次)且喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.16微米 |
D(v,0.9) | 2.86微米 |
平均颗粒尺寸D[4,3] | 0.83微米 |
平均颗粒尺寸D[3,2] | 0.14微米 |
实施例2
将染料木黄酮粉末(30g)与去离子水(370g)混合并通过高压匀化器(装配有130微米的喷嘴;DeBEE 2000,B.E.E.International,Israel),其流水线中具有约200g水,匀化压力为1500bar。匀化时背压被设定为120bar。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20℃到30℃。固体含量为约5%的悬浮液循环经过匀化器40次,直到达到所需的颗粒尺寸。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,且以1.469的折射率为基础的计算结果在下文显示于表III中。
表III:染料木黄酮的颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(40次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.1微米 | 0.07微米 |
D(v,0.5) | 41.9微米 | 0.16微米 |
D(v,0.9) | 91.0微米 | 2.42微米 |
平均颗粒尺寸D[4,3] | 48.5微米 | 0.76微米 |
平均颗粒尺寸D[3,2] | 23.1微米 | 0.14微米 |
通过将具有8%水分含量的辛烯基琥珀酸淀粉钠(490g)溶解于80℃的去离子水(490g)中来制备辛烯基琥珀酸淀粉钠溶液(46%)。在第40次结束时将一部分辛烯基琥珀酸淀粉钠溶液(65g)加入进料斗中经匀化的染料木黄酮悬浮液中,该过程未停止匀化过程,并将混合物(约9%的固体)通过高压匀化器两次。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮的颗粒尺寸,结果显示在下文表IV中。
表IV:染料木黄酮颗粒尺寸测量
匀化(42次)后染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.16微米 |
D(v,0.9) | 0.93微米 |
平均颗粒尺寸D[4,3] | 0.41微米 |
平均颗粒尺寸D[3,2] | 0.14微米 |
用Niro喷雾干燥器(GEA Niro A/S,Denmark)采用4bar的喷嘴压力干燥经匀化的染料木黄酮悬浮液。入口温度为约200℃,出口温度为约80℃。喷干的粉末含有约48.5%的染料木黄酮,水分含量为约3.24%。通过将喷雾干燥的粉末再次悬浮于水中并由激光衍射技术测量来测定染料木黄酮的颗粒尺寸。结果显示在表V中。
表V:经喷雾干燥的染料木黄酮形式的颗粒尺寸测量
匀化(42次)且喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.15微米 |
D(v,0.9) | 1.14微米 |
平均颗粒尺寸D[4,3] | 0.55微米 |
平均颗粒尺寸D[3,2] | 0.14微米 |
实施例3
将染料木黄酮粉末(36g)与去离子水(364g)混合并通过高压匀化器(装配有130微米的喷嘴;DeBEE 2000,B.E.E.International,Israel),其流水线中具有约200g水,匀化压力为1500bar。匀化时背压被设定为120bar。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20℃到30℃。固体含量为约6%的悬浮液循环经过匀化器40次,直到达到所需的颗粒尺寸。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表VI中。
表VI:染料木黄酮颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(40次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.1微米 | 0.07微米 |
D(v,0.5) | 41.9微米 | 0.16微米 |
D(v,0.9) | 91.0微米 | 2.00微米 |
平均颗粒尺寸D[4,3] | 48.5微米 | 0.76微米 |
平均颗粒尺寸D[3,2] | 23.1微米 | 0.14微米 |
通过将具有8%水分含量的辛烯基琥珀酸淀粉钠(490g)溶解于80℃的去离子水(490g)中来制备辛烯基琥珀酸淀粉钠溶液(46%)。在第40次结束时将一部分辛烯基琥珀酸淀粉钠溶液(19.5g)加入进料斗中经匀化的染料木黄酮悬浮液中,该过程未停止匀化过程,并将混合物(约7.3%的固体)通过高压匀化器两次。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮的颗粒尺寸,结果显示在下文表VII中。
表VII:染料木黄酮颗粒尺寸测量
匀化(42次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.16微米 |
D(v,0.9) | 0.91微米 |
平均颗粒尺寸D[4,3] | 0.40微米 |
平均颗粒尺寸D[3,2] | 0.14微米 |
用Niro喷雾干燥器(GEA Niro A/S,Denmark)采用4bar的喷嘴压力干燥经匀化的染料木黄酮悬浮液。入口温度为约200℃,出口温度为约80℃。喷干的粉末含有约78.2%的染料木黄酮,水分含量为约2.31%。通过将喷雾干燥的粉末再次悬浮于水中并由激光衍射技术测量来测定染料木黄酮的颗粒尺寸。结果显示在下文表VIII中。
表VIII:经喷雾干燥的染料木黄酮形式的颗粒尺寸测量
匀化(42次)且喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.16微米 |
D(v,0.9) | 0.97微米 |
平均颗粒尺寸D[4,3] | 0.43微米 |
平均颗粒尺寸D[2,3] | 0.14微米 |
实施例4
将染料木黄酮粉末(120g)与去离子水(280g)混合并通过高压匀化器(装配有180微米的喷嘴;DeBEE 2000,B.E.E.International,Israel),其流水线中具有约200g水,匀化压力为700bar。匀化时背压被设定为120bar。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20℃到30℃。固体含量为约20%的悬浮液循环经过匀化器20次,直到达到所需的颗粒尺寸。通过激光衍射技术(Mastersizer 2000,Malvern InstrumentsLtd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表IX中。
表IX:染料木黄酮颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(20次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.1微米 | 0.07微米 |
D(v,0.5) | 41.9微米 | 0.15微米 |
D(v,0.9) | 91.0微米 | 2.62微米 |
平均颗粒尺寸D[4,3] | 48.5微米 | 0.83微米 |
平均颗粒尺寸D[3,2] | 23.1微米 | 0.13微米 |
实施例5
将染料木黄酮粉末(36g)与去离子水(364g)混合并通过高压匀化器(装配有130微米的喷嘴;DeBEE 2000,B.E.E.International,Israel),其流水线中具有约200g水,匀化压力为1500bar。匀化时背压被设定为120bar。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20℃到30℃。固体含量为约6%的悬浮液循环经过匀化器40次,直到达到所需的颗粒尺寸。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表X中。
表X:染料木黄酮颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(20次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.8微米 | 0.07微米 |
D(v,0.5) | 41.4微米 | 0.16微米 |
D(v,0.9) | 90.2微米 | 0.92微米 |
平均颗粒尺寸D[4,3] | 48.5微米 | 0.42微米 |
平均颗粒尺寸D[2,3] | 23.1微米 | 0.14微米 |
通过将具有6.18%水分含量的麦芽糖糊精(25g)溶解于去离子水(27g)中来制备麦芽糖糊精溶液(45%;52g)。在第40次结束时将一部分麦芽糖糊精溶液(19.5g)加入进料斗中经匀化的染料木黄酮悬浮液中,该过程未停止匀化过程,并将混合物(约7.3%的固体)再通过高压匀化器两次。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮的颗粒尺寸,结果显示在下文表XI中。
表XI:喷雾干燥的染料木黄酮形式的颗粒尺寸测量
匀化(42次)和喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.16微米 |
D(v,0.9) | 0.93微米 |
平均颗粒尺寸D[4,3] | 0.41微米 |
平均颗粒尺寸D[3,2] | 0.14微米 |
用Niro喷雾干燥器(GEA Niro A/S,Denmark)采用4bar的喷嘴压力干燥经匀化的染料木黄酮悬浮液。入口温度为约200℃,出口温度为约80℃。喷干的粉末含有约78.2%的染料木黄酮。通过将喷雾干燥的粉末再次悬浮于水中并由激光衍射技术测量来测定染料木黄酮的颗粒尺寸。结果显示在下文表XII中。
表XII:喷雾干燥的染料木黄酮形式的颗粒尺寸测量
匀化(42次)且喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 0.07微米 |
D(v,0.5) | 0.15微米 |
D(v,0.9) | 0.93微米 |
平均颗粒尺寸D[4,3] | 0.41微米 |
平均颗粒尺寸D[3,2] | 0.13微米 |
实施例6
通过将具有8%水分含量的Capsul(2.8kg;National Starch andChemical Company,New Jersey,US)溶解于70℃的去离子水(5.7kg)中来制备辛烯基琥珀酸淀粉钠溶液(30%)。
将染料木黄酮粉末(3.0kg)与辛烯基琥珀酸淀粉钠溶液(8.5kg)和去离子水(9.0kg)混合并通过采用1150 Upm旋转、使用0.4mm ZrO2型研磨介质的搅动球磨机(Netzsch type LMZ 4;Netzsch GmbH&Co.HoldingKG,Selb,Germany),所述研磨介质由采用Y2O3稳定的ZrO2组成。经搅动球磨机后的染料木黄酮悬浮液用热交换器冷却至约40℃到45℃。固体含量为约27%的悬浮液循环经过搅动球磨机2小时(整个研磨过程11个循环)直到达到所需的颗粒尺寸。
通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表XIII中。
表XIII:染料木黄酮颗粒尺寸测量
匀化前的染料木黄酮颗粒尺寸 | 匀化(11次)后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.8微米 | 0.07微米 |
D(v,0.5) | 41.4微米 | 0.16微米 |
D(v,0.9) | 90.2微米 | 0.45微米 |
平均颗粒尺寸D[4,3]: | 48.5微米 | 0.23微米 |
经匀化的染料木黄酮悬浮液可以是用于目标应用领域的喷雾,或可以使用实施例2中所述的步骤干燥的喷雾。
实施例7
在Jet粉碎机中通过干磨过程粉碎染料木黄酮粉末(6kg)。合适的粉碎机为Hosokawa Alpine公司的Alpine 100 AFG,使用5.0bar的喷压和20.000 Upm的筛轮速度。该染料木黄酮在图7所示的“摆动”测试中用于比较。
通过将具有8%水分含量的辛烯基琥珀酸淀粉钠(6.0kg;NationalStarch and Chemical Company,New Jersey,US)溶于70℃去离子水(6.1kg)中制备辛烯基琥珀酸淀粉钠溶液(48%)。
将粉碎的染料木黄酮粉末(6.0kg)与辛烯基琥珀酸淀粉钠溶液(12.1kg)和去离子水(24kg)混合,在700bar的匀化压力下通过高压匀化器,所述高压匀化器装配有如EP 1008380 A2中所述的混合装置。经喷嘴后的染料木黄酮悬浮液用热交换器冷却至约20到30℃。将固体含量约20%的悬浮液循环经过匀化器12次,直到达到所需的颗粒尺寸(最终染料木黄酮)。如图8所阐述的,通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表XIV中。
表XIV:染料木黄酮颗粒尺寸测量
研磨和匀化前的染料木黄酮颗粒尺寸 | 研磨和匀化后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.8微米 | 0.07微米 |
D(v,0.5) | 41.4微米 | 0.18微米 |
D(v,0.9) | 90.2微米 | 1.38微米 |
平均颗粒尺寸D[4,3]: | 48.5微米 | 0.53微米 |
匀化后的染料木黄酮也在“摆动”测试中使用,结果显示在图8中。
用具有约40bar的喷嘴压力的多级喷雾干燥器(Multi Stage Spraydryer)喷雾干燥经匀化的分散液。入口温度为约160℃,出口温度为约80℃,内部流动床的入口空气温度为约50℃。通过激光衍射技术(Mastersizer 2000,Malvern Instruments Ltd.UK)测定染料木黄酮颗粒尺寸,并以1.469的折射率为基础的计算结果在下文显示于表XV中。
表XV:染料木黄酮颗粒尺寸测量
研磨和匀化前的染料木黄酮颗粒尺寸 | 研磨、匀化和喷雾干燥后的染料木黄酮颗粒尺寸 | |
D(v,0.1) | 17.8微米 | 0.08微米 |
D(v,0.5) | 41.4微米 | 0.19微米 |
D(v,0.9) | 90.2微米 | 1.84微米 |
平均颗粒尺寸D[4,3]: | 48.5微米 | 0.65微米 |
实施例8
不同染料木黄酮形式的O/W乳液
#1 | #2 | |
成分 | %(w/w) | %(w/w) |
肉豆蔻酸甘油酯 | 5.00 | 4.00 |
鲸蜡醇 | 2.00 | 2.00 |
Steareth-2 | 2.00 | 2.00 |
Steareth-21 | 2.00 | 2.00 |
肉豆蔻酸异丙酯 | 10.00 | 5.00 |
辛酸/癸酸甘油三酯 | 8.00 |
BHT | 0.05 | 0.05 |
二甲基硅酮 | - | 2.00 |
苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丁酯&对羟基苯甲酸丙酯&对羟基苯甲酸异丁酯 | 0.80 | 0.80 |
染料木黄酮纳米颗粒的水性悬浮液(含5.5%染料木黄酮,约0.4微米) | 5.00 | - |
染料木黄酮(晶体,约12微米) | - | 0.10 |
水 | Ad.100 | Ad.100 |
聚山梨酯20 | 1.00 | |
丙二醇 | 5.00 | 4.00 |
乙氧基二甘醇 | 8.00 | 10.00 |
聚丙烯酰胺&C13-14异链烷烃&Laureth-7 | 2.00 | 1.00 |
三乙醇胺(10%) | 0.33 | 0.29 |
EDETA二钠 | 0.10 | 0.10 |
在典型化妆品配制品中使用由纳米颗粒组成的染料木黄酮形式与常规结晶形式相比的优点由图1和图2阐述。在不同温度下储存含活性成分的化妆品配制品时,其在室温下应当至少在一年内是稳定的。稳定性观察中所监测的一个重要参数是显微镜下化妆品配制品的外观。含有难以溶解活性成分的化妆品配制品在储存时会经常(有时仅在少许天内)产生结晶。观察在5℃下储存的配制品时,该现象甚至更显著。如图2所示(其中图2显示在室温下储存6个月后对含有常规晶体染料木黄酮的配制品#2的显微镜检验)产生这样大结晶的配制品存在许多缺点,即活性成分对皮肤的生物可利用度降低了,且在涂敷到皮肤上时化妆品消费者存在感受到上述晶体的风险。如图1所示(其中该图1显示在室温下储存6个月后,对含有稳定染料木黄酮纳米颗粒的配制品#1的显微镜检验)含有稳定的染料木黄酮纳米颗粒的相同化妆品制剂,甚至在室温下储存6个月后仍然完全稳定。
实施例9
不同染料木黄酮形式的O/W乳液
#3 | #4 | |
成分 | %(w/w) | %(w/w) |
肉豆蔻酸甘油酯 | 4.00 | 4.00 |
鲸蜡醇 | 2.00 | 2.00 |
Steareth-2 | 2.00 | 2.00 |
Steareth-21 | 2.00 | 2.00 |
肉豆蔻酸异丙酯 | 5.00 | 5.00 |
辛酸/癸酸甘油三酯 | 8.00 | 8.00 |
BHT | 0.05 | 0.05 |
二甲基硅酮 | 2.00 | 2.00 |
苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丁酯&对羟基苯甲酸丙酯&对羟基苯甲酸异丁酯 | 0.80 | 0.80 |
染料木黄酮纳米颗粒的水性悬浮液(含5.5%染料木黄酮,约0.4微米) | 5.45 | - |
染料木黄酮(晶体,约12微米) | - | 0.30 |
水 | Ad.100 | Ad.100 |
丙二醇 | 4.00 | 4.00 |
聚丙烯酰胺&C13-14异链烷烃&Laureth-7 | 1.00 | 1.00 |
氢氧化钾(10%) | 0.15 | 0.15 |
EDETA二钠 | 0.10 | 0.10 |
为了进一步阐述用染料木黄酮纳米颗粒与常规晶体染料木黄酮相比获得的益处,使上述化妆品配制品(#3和#4)进行非常具有挑战性的稳定性测试:将配制品在每24小时从5℃变化至43℃的温度下储存3周。在显微镜下观察配制品的外观,并表示在图3中(其中图3显示在5℃/43℃(各个温度24小时循环)下储存19天后,对含有稳定的染料木黄酮纳米颗粒的配制品#3的显微镜检验),并表示在图4中(其中图4显示在5℃/43℃(各个温度24小时循环)下储存19天后,对含有常规晶体染料木黄酮的配制品#4的显微镜检验)。
如图3所阐述的,染料木黄酮纳米颗粒仍然非常精细地分散在化妆品制剂中,相反地,图4阐述了相同制剂中的常规晶体染料木黄酮已形成大结晶。
实施例10
为了在分散体系中促进结晶,使用下述测试,所述测试中,温度在自定义的范围内以自定义的次序改变。该测试称为“摆动”测试(改变温度的测试)。该测试的目的是在较高温度溶解小颗粒和在较低温度促进重结晶。但是这也是显示配制品是否稳定的重压型测试。以下的配制品被用于“摆动”测试:
Pos. | 成分 | 含量 |
o | 辛酸/癸酸甘油三酯 | 8.00% |
o | 肉豆蔻酸异丙酯 | 5.00% |
o | 肉豆蔻酸甘油酯 | 4.00% |
o | 鲸蜡醇 | 2.00% |
o | 二甲基硅酮 | 2.00% |
o | Steareth-2 | 2.00% |
o | Steareth-21 | 2.00% |
o | 苯氧乙醇&对羟基苯甲酸甲酯&对羟苯甲酸乙酯&对羟基苯甲酸丁酯 | 0.80% |
o | BHT | 0.05% |
w | 水dem. | ad 100% |
w | 丙二醇 | 4.00% |
w | Edeta BD | 0.10% |
t | 聚丙烯酰胺&C13-14异链烷烃&Laureth-7 | 1.00% |
g | 染料木黄酮 | 0.1%-1.0% |
b | 10%氢氧化钾溶液 | 0.15% |
制造说明:
将油相和水相(o+w)分别加热至70℃(±5℃),并添加到一起。在适度搅动下加入增稠剂(t)。借助于Ultra-Turrax T25匀化器将混合物在24′000 RPM匀化30秒。在适度搅拌(马蹄搅拌器,120RPM)下将乳液缓慢冷却至45℃±5℃。在该温度下通过添加碱(b)将pH值调节至pH 6.5-7.0。向仍然是流体的乳液中添加染料木黄酮(g),并借助于Ultra-Turrax T25匀化器通过在24′000 RPM下再次匀化30秒进行掺合。在适度搅拌(马蹄搅拌器,120RPM)下将配制品缓慢冷却至25℃±5℃。
标准稳定性评估:
作为标准稳定性测试,使用以下条件:将配好的化妆品样品储存于5℃±2℃、环境温度(例如20-25℃)和43℃±2℃,检查点为2周、6周、3个月、6个月和12个月后。3个月后少量样品显示晶体生长,这意味着不能作出形态长期稳定的陈述。
通过“摆动”测试对稳定性进行评估:
为了促进结晶,使用“摆动”测试并将最低和最高温度选择为5℃和43℃。每个温度保持24小时。该测试的持续时间首先设定为20天,这意味着样品经历冷却/加热过程(=1个过程)10次。
图5到7显示“摆动”测试的结果。含染料木黄酮的乳液如上所述使用以下所述的染料木黄酮纳米颗粒组合物来制备。使用以下的染料木黄酮样品和浓度,制备后即刻对乳液进行测量,并使样品进行“摆动”测试的十个过程后对乳液进行测量:
图5(a):0.3%浓度的实施例3的组合物
图5(b):0.5%浓度的实施例3的组合物
图5(c):1.0%浓度的实施例3的组合物
图6(a):0.3%浓度的实施例6的组合物
图6(b):0.5%浓度的实施例6的组合物
图6(c):1.0%浓度的实施例6的组合物
图7(a):0.3%浓度的在Jet磨中干磨之后的实施例7的组合物
图7(b):0.5%浓度的在Jet磨中干磨之后的实施例7的组合物
图7(c):1.0%浓度的在Jet磨中干磨之后的实施例7的组合物
图8(a):0.3%浓度的如实施例7中所述的实施例7最终产物的组合物
图8(a):0.5%浓度的如实施例7中所述的实施例7最终产物的组合物
图8(a):1.0%浓度的如实施例7中所述的实施例7最终产物的组合物
所有图中放大倍数是相同的,并在图5(a)中指出了距离为500μm。
可以看到,即使在“摆动”测试的严格条件下,本发明的局部用化妆品组合物也不显示任何颗粒尺寸增长,甚至在0.3%到1.0%非常高的浓度下。事实上,“摆动”测试对颗粒尺寸或颗粒分布没有影响。
与之相反,在图7(其中使用在研磨或匀化之前的染料木黄酮)中,“摆动”测试过程中颗粒尺寸显著改变。形成了巨大的晶体,十个过程后可观察到晶簇。
Claims (30)
1.异黄酮纳米颗粒组合物,所述组合物包含异黄酮、可选载体和可选水,其特征在于所述异黄酮具有小于3μm的平均颗粒尺寸D[4.3],且所述载体,如果存在的话,选自碳水化合物、蛋白质及其混合物,所述平均颗粒尺寸D[4.3]通过激光衍射技术测定。
2.如权利要求1所述的异黄酮纳米颗粒组合物,其中所述异黄酮为染料木黄酮。
3.如权利要求1或2所述的异黄酮纳米颗粒组合物,其特征在于所述异黄酮具有1微米或更小的平均颗粒尺寸D[4.3],所述平均颗粒尺寸D[4.3]通过激光衍射技术测定。
4.如权利要求3所述的异黄酮纳米颗粒组合物,其特征在于所述异黄酮具有0.5微米或更小的平均颗粒尺寸D[4.3],所述平均颗粒尺寸D[4.3]通过激光衍射技术测定。
5.如权利要求1到4中任一项所述的异黄酮纳米颗粒组合物,其特征在于所述异黄酮具有0.05微米或更大的平均颗粒尺寸D[4.3],所述平均颗粒尺寸D[4.3]通过激光衍射技术测定。
6.如权利要求1到5中任一项所述的异黄酮纳米颗粒组合物,其中所述异黄酮纳米颗粒组合物包含载体。
7.如权利要求6所述的异黄酮纳米颗粒组合物,其中所述载体选自碳水化合物、蛋白质及其混合物。
8.如权利要求7所述的异黄酮纳米颗粒组合物,其中所述碳水化合物选自改性淀粉、山梨糖醇、麦芽糖、麦芽糖糊精、阿拉伯树胶、果胶、藻酸盐、瓜尔胶、黄原胶、纤维素衍生物及其混合物。
9.如权利要求7所述的异黄酮纳米颗粒组合物,其中所述蛋白质选自明胶、乳蛋白、大豆蛋白及其混合物。
10.如权利要求1到9中任一项所述的异黄酮纳米颗粒组合物,其中所述组合物是粉末或颗粒状组合物。
11.如权利要求10所述的异黄酮纳米颗粒组合物,其中所述组合物包含至少1wt.-%的异黄酮。
12.如权利要求11所述的异黄酮纳米颗粒组合物,其中所述组合物包含至少20wt.-%的异黄酮。
13.如权利要求12所述的异黄酮纳米颗粒组合物,其中所述组合物包含至少70wt.-%的异黄酮。
14.如权利要求1到9中任一项所述的异黄酮纳米颗粒组合物,其中所述组合物为水性悬浮液。
15.如权利要求14所述的异黄酮纳米颗粒组合物,所述组合物包括10%到30%的异黄酮,15%到40%的载体,其余部分为水。
16.用于生产异黄酮纳米颗粒组合物的方法,所述组合物包含异黄酮、可选载体和可选水,其中所述异黄酮具有小于3μm的平均颗粒尺寸D[4.3],所述平均颗粒尺寸D[4.3]通过激光衍射技术测定,其特征在于用高压匀化器处理包含晶体异黄酮和水和可选载体的混合物,直到获得所需的颗粒尺寸,并可选对得到的悬浮液进行干燥工艺。
17.如权利要求16所述的方法,其中所述方法用于制造如权利要求1到15中任一项所定义的异黄酮纳米颗粒组合物。
18.如权利要求16或17所述的方法,其中所述干燥工艺为喷雾干燥或冻干。
19.如权利要求16到18中任一项所述的方法,其中将所述异黄酮在水中预匀化,然后将其与所述载体混合并匀化。
20.如权利要求16到19中任一项所述的方法,其中在存在载体时在500bar到4000bar的压力下对异黄酮进行高压匀化。
21.用于生产异黄酮纳米颗粒组合物的方法,所述组合物包含异黄酮、可选载体和可选水,其中所述异黄酮具有小于3μm的平均颗粒尺寸D[4.3],所述平均颗粒尺寸D[4.3]通过激光衍射技术测定,其特征在于在搅动球磨机中用湿磨法处理包含异黄酮、水和可选载体的混合物,直到获得所需的颗粒尺寸,并可选对得到的悬浮液进行干燥工艺。
22.如权利要求21所述的方法,其中所述方法用于生产如权利要求1到15中任一项所定义的异黄酮纳米颗粒组合物。
23.如权利要求21或22所述的方法,其中所述异黄酮和可选载体通过搅动球磨机循环1到50次。
24.如权利要求21到23中任一项所述的方法,其中在湿磨法中使用ZrO2型的研磨介质。
25.药物组合物,所述组合物包含如权利要求1到15中任一项所要求保护的异黄酮纳米颗粒组合物。
26.化妆品组合物,所述组合物包含如权利要求1到15中任一项所要求保护的异黄酮纳米颗粒组合物。
27.如权利要求25或26所述的药物或化妆品组合物,所述组合物含有浓度为0.05到50wt.-%.的异黄酮。
28.营养产品,所述产品包含如权利要求1到15中任一项所要求保护的异黄酮纳米颗粒组合物。
29.如权利要求28所述的营养产品,所述产品选自豆腐、酸乳和果汁。
30.如权利要求1到15中任一项定义的异黄酮纳米颗粒组合物用于制备化妆品组合物、药物组合物、食品、食品添加剂或饲料添加剂的用途。
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WO2007000193A9 (en) | 2007-12-13 |
BRPI0612848B8 (pt) | 2021-05-25 |
EP1904053B1 (en) | 2011-08-17 |
KR101242851B1 (ko) | 2013-03-12 |
KR20080020643A (ko) | 2008-03-05 |
BRPI0612848B1 (pt) | 2020-03-31 |
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JP5134535B2 (ja) | 2013-01-30 |
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