CN1140405A - 亲脂载体制剂 - Google Patents
亲脂载体制剂 Download PDFInfo
- Publication number
- CN1140405A CN1140405A CN95191484A CN95191484A CN1140405A CN 1140405 A CN1140405 A CN 1140405A CN 95191484 A CN95191484 A CN 95191484A CN 95191484 A CN95191484 A CN 95191484A CN 1140405 A CN1140405 A CN 1140405A
- Authority
- CN
- China
- Prior art keywords
- lipoid
- galactolipid
- dgdg
- polarity
- oil
- Prior art date
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Abstract
本发明涉及具有连续类脂相的亲脂载体制剂，该制剂含有与非极性类脂以及任选的一种极性溶剂相组合的极性类脂物质，其中的极性类脂物质是半乳糖脂。本发明还涉及所述的亲脂载体制剂用作药物组合物以及营养品、化妆品和食品中活性物质的载体的应用并且涉及药物组合物。
Description
技术领域
本发明涉及具有连续类脂相的亲脂载体制剂，该制剂含有一种极性类脂物、一种非极性类脂和任选地一种极性溶剂。所述的载体制剂适用于作为在药物组合物以及在化妆品、食品和农业产品中活性物质的载体。
发明背景
在药物工业中一个普遍的问题是将药物引入到具有生物相容性并且人类可以耐受的亲脂载体中。其原因在于首先是要引入的活性成分的化学结构及其性能的多样性，其次是基于成分的合适载体，该成分使得该载体充分灵活地将具有上述多种结构变化的活性成分引入。
为了形成灵活的亲脂载体，需要采用极性类脂，出于生物相容性及安全考虑优选地为天然膜类脂，并且与非极性类脂，如植物油或甾醇酯组合目前仅仅可获得的膜类脂是磷脂物质，它们主要由豆类或蛋类卵磷脂形成或通过合成途径产生。磷脂可以是两性离子的，如磷脂酰胆碱和磷脂酰乙醇胺，也可以是带负电荷的，如磷脂酰肌醇或磷脂酰甘油。
亲脂载体可以是有机溶液，如微乳化液或反向微团溶液、反向囊泡或油包水乳液。
人造奶油和涂胶是含有高达75％重量水相的油包水型乳液。该水相分散在甘油三酯油，典型地为一种植物油，如菜籽油中。该水相通常含有增稠剂，如明胶以使该富水油连续型乳液稳定。该乳化剂典型地为磷脂，如大豆磷脂(豆卵磷脂)。这些乳化剂由磷脂，如两性离子型磷脂酰胆碱和磷脂酰乙醇胺和离子型磷脂酰肌醇的混合物组成。这些卵磷脂是工业规模制造稳定的食品乳液中最常用的天然类脂，这一点是普通常识。还有一点已知的是这类乳液存在与卵磷脂乳化剂有关的缺陷和问题。
现有技术
只有很少几个具有连续类脂相的亲脂制剂的例子被报导。
WO92/05771描述了由类脂颗粒形成的至少含有两种类脂成分的基质，其中一种是非极性的而另一种是两亲的和极性的。这种由颗粒形成的含有生物活性物质的基质在与含水系统相互作用时会自发形成单个的类脂颗粒。据说该两亲和极性类脂组分形成双层并且选自磷脂，如磷脂酰胆碱；该非极性类脂为甘油单、双或三酯。
含有卵磷脂，即磷脂酰胆碱的微乳化液凝胶已经由P.L.Luisi进行了描述并特征化，例如参见D.Capitani等人，Langmuir，1993，Vol.9，pp685-689。除了磷脂以外，这些凝胶还含有少量水和有机溶剂，如烷烃、脂肪酸酯和胺。也可以将它们称为有机凝胶。这些凝胶可以用作为透皮输送药物的基质。
在油中存在反向囊泡(正常囊泡的反结构)(reverse vesicles)首先由H.Kunieda报导，参见H.kunieda等人，Advanced Materials，1992，Vol.4，pp291-293。反向囊泡是片状液晶的分散液，它会使大量油膨胀，即该囊泡由反向双层结构组成。该反向双层通常由亲水和亲脂两亲物的混合物组成。
糖基甘油酯是一种已知是植物细胞膜成分的糖脂。基于半乳糖的两种是最常见的单半乳糖基二酰基甘油，MGDG，和双半乳糖基二酰基甘油，DGDG，它们占该类囊体膜干重的最多为40％。
植物糖脂具有与甘油相连的碳水化合物单元(主要是半乳糖)。在MGDG中，半乳糖环的1-位与甘油具有β连接，而在DGDG中，在糖之间具有α，1→6键。次要成分是植物硫脂，更准确的名称为硫6-脱氧葡糖二酰基甘油，SQDG，它含有与末端脱氧葡糖残基上碳6相连的硫酸根(而不是羟基)。绝大多数植物糖脂可以用下列通式来描述
式中R1和R2独立地为具有2-24个碳原子和0-6个双键的饱和或不饱和脂肪酸残基、被进一步酯化的羟酸(即酸酐)、或氢；该碳水化合物是单糖单元；n＝1-5；R3为羟基或硫酸根基团。
SE9400368-8描述了一种工业适用方法，用于由植物，优选地由谷类，通过提取和色谱分离法制备糖基甘油酯。
在研究糖基甘油酯与非极性类脂，如甘油单-、双-、和三酯，脂肪醇和酸，甾醇和甾醇酯(任选地与其它极性类脂，如磷脂和鞘脂组合、无水或与少量水组合)的相互作用过程中，我们出乎意外地发现使这种制剂适用于作为药物亲脂载体以及作为护肤制剂、营养品和食品配料的性能。
本发明的描述
本发明提供了基于半乳糖脂的类脂载体，该半乳糖脂是一种极性类脂物，它与非极性类脂组合在一起。半乳糖脂的极性首基是半乳糖单元，与磷脂相比，它们具有相当不同的理化性能。因此，该引入机理是基于极性首基即半乳糖单元的羟基和半乳糖酰基甘油和非极性组分的亲脂链与所引入的化合物之间的相互作用。
本发明涉及具有连续类脂相的亲脂载体制剂，该制剂含有非极性类脂并且与极性类脂物以及任选的一种极性溶剂组成，其特征在于该极性类脂物是由至少50％二半乳糖基二酰基甘油和其余为其它的极性类脂组成的半乳糖脂物质。
在优选的制剂中，该糖脂物由约70-80％二半乳糖基二酰基甘油和20％-30％其它的极性类脂组成。
在另一种优选的制剂中，该半乳糖脂物最多达100％的二半乳糖基二酰基甘油组成。
该二半乳糖基二酰基甘油可以用下列通式描述
式中R1和R2独立地为具有10-22个碳原子和0-4个双键的饱和或不饱和脂肪酸残基或氢；R3为羟基或硫酸根基团。
作为脂肪酸残基R1和R2的优选例子可以提及天然存在的脂肪酰基基团，如来自饱和棕榈酸(C15H31CO；16∶0)和硬脂酸(C17H35CO；18∶0)；来自单不饱和油酸(C17H33CO；18∶1)；和来自多不饱和亚油酸(C17H31CO；18∶2)和亚麻酸(C17H29CO；18∶3)的残基。这些脂肪酸残基还可以含有通过被其它的脂肪酸酯化的羟基与甘油部分相连的羟酸，因此称作为交内酯(estolides)。
其它的极性类脂(该半乳糖脂物的一部分)是不同的糖脂和膦脂，如MGDG和磷脂酰胆碱。该组合取决于用来制造半乳糖脂的原料和工艺。
半乳糖脂物质中的成份的特定比例不是本发明的关键，只要DGDG的含量至少为50％即可。但是，对于许多应用来说，通过DGDG(最重要的形成双层的组分)的高含量可以获得最大的好处。
半乳糖脂物质几乎可以从任何一种植物中提取。优选的植物材料是种子和谷物的芯，例如小麦、黑麦、燕麦、玉米、大米、小米和芝麻。燕麦片以及麦麸具有较高的类脂浓度，因此适用于该制备工艺中。
基于半乳糖或任何其它的单糖单元，如葡萄糖的合成二糖基二酰基甘油以及基于除了半乳糖以外的其它碳水化合物单元如葡萄糖的由任何来源分离出的天然糖基甘油脂可以用于本发明。
对于非极性类脂物质没有特别的限制，举例来说可以提及植物油、动物油、人造油、脂肪酸、天然的和合成的甘油酯、甾醇酯、脂肪醇等等。
通过采用半乳糖脂可以出乎人们意外地获得所有种类的亲脂有机溶液。所引入的活性物质可以是有机溶液的一部分或者以例如悬浮液的形式来稳定。
举例来说，可以通过将半乳糖脂与一种非极性类脂，如三酰基甘油混合而获得亲脂载体制剂。三酰基甘油可以选自棕榈油或具有类似的相当高的固体脂肪含量或熔融范围的天然油。优选的并且实用的三酰基甘油是棕榈油馏分，它们是通过将工业棕榈油分馏成三酰基甘油的特定混合物而获得的，它们以甘油的主要是棕榈酸、油酸和硬脂酸酯的组合为基础。
还可以通过将糖基甘油脂与液体甘油三酯油，如中链三酰基甘油(MCT)和大豆油混合而制得亲脂载体制剂。
此外，非极性类脂-半乳糖脂混合物可以获得较高的水或水溶液含量，它们可以导致形成反向囊泡(reverse vesicles)、反向微团(reversemicelles)和油包水乳液。
反向囊泡可以通过将半乳糖脂和一种更高极性的两亲物如溶血磷脂酰胆碱以4∶1的重量比的混合物加入到甘油三酯油、优选地为MCT油中而制得。两亲物的总浓度低于3％(重量)。然后加入少量的水或水溶液，其量低于总制剂的1％(重量)。超声处理后，可以获得反向囊泡的细分散液。
在较高的糖脂浓度但较低的水含量(总制剂的0.5％-2％重量)下，可以制得反向微团。反向微团(也称为微乳化液)由在油中的水聚集物组成。反向微团在热力学上是稳定的，聚集物的形状和结构可以导致粘性系统，“微乳化液凝胶”。
在较高的水含量(＞5％总制剂重量)下，可以形成油包水乳液。这些乳液是两相系统，由在油中的细分散的水滴组成。油包水乳液在热力学上是不稳定的，但是在动力学上它们是稳定的。
该水溶液可以由纯水、缓冲溶液、盐水、葡萄糖、半乳糖、丙二醇、聚乙二醇、甘油等的溶液组成。此外，可以采用增稠剂，如明胶、琼脂糖、角叉胶、甲基纤维素和乙基羟乙基纤维素。
本发明还涉及上述亲脂载体制剂作为药物、化妆品、食品或农业产品中活性物质的载体的应用。
本发明还涉及含有上述亲脂载体制剂并与生物活性物质组合的药物组合物。
本发明还涉及含有上述亲脂载体制剂的药物组合物，其中非极性类脂是MCT油、晚樱草油、棕榈油馏分或一种生物活性物质。
生物活性物质可以是亲脂药物，如抗癌药物、抗菌特别是抗真菌药物、免疫抑制剂，如环孢菌素、皮肤病药物，如止疼药和消炎药、止痒药、消毒剂、收敛剂、润肤剂和激素，影响精神的药物、麻醉药以及其它亲脂的并且存在可以通过采用半乳糖脂而解决的配制问题的药物。还有许多的类脂，如游离脂肪酸、单-、双-和三酰基甘油、磷脂、胆甾醇酯和许多其它种类的类脂，它们本身具有治疗作用，并且可以以亲脂载体的形式有效配制(以半乳糖脂为基)。在这种情况下生物活性物质是非极性类脂。
通过在40-70℃的温度范围下在敞开的水浴中熔化棕榈油馏分可以制得药物和化妆品制剂。在小瓶中将活性成份和糖基甘油脂称重。将熔化的棕榈油馏分转移到小瓶中，并且采用旋转速度大约为1000rpm的高剪切混合机、在40-70℃的温度范围内将该混合物分散2-4分钟。加入用来形成局部适用的制剂的水或水溶液，并且用搅棒小心地将制剂混合。
可以将该药物组合物配制成给动物，特别是哺乳动物(包括人)的经口、肠道、非肠道、直肠、阴道、局部、眼内、鼻内或耳部给药的制剂。
局部护肤制剂可以根据它们的使用方式而粗分成药物局部护肤制剂和化妆品制剂。
作为药物局部护肤制剂的例子可以提及含有一种或多种活性成分的各种油膏，油膏包括含有油基和含有水包油或油包水乳液基的药膏。
当作为化妆品制剂使用时，除了主要成分以外，可以按照需要混合常用作化妆品成分的那些物质，例如油性物质、紫外吸收剂、乙醇、螯合剂、pH调节剂、防腐剂、增稠剂、颜料、香料等及其组合。
作为化妆品。可以将各种形式的皮肤化妆品制剂配制成例如含有油包水或水包油形乳化化妆品、乳膏、化妆品乳液、花露水、油性化妆品、唇膏、粉底、皮肤清洁制剂、生发液、头发定型制剂、头发整理制剂、头发生长促进剂等。
油包水型乳液，如人造奶油和涂胶可以通过常规方法制备。
半乳糖脂物质
如下所说半乳糖脂物质可以由不同的谷类制得并且如在实施例中所说可以用于制造本发明的载体试剂和药物组合物。在本说明书中，除非另有说明，％是指重量百分比。溶剂组合物中溶剂的比例按体积份给出。
来自燕麦的半乳糖脂物质
将200公斤燕麦芯(Kungsornen AB，Sweden)磨碎并且在提取罐中在搅拌的同时用1000升95％乙醇在70℃下提取3小时。在仍然较热的同时将料浆离心并分离出固体颗粒。将液体馏分在60℃下蒸发，结果产生约10公斤淡棕色油。
将该油加到含有6.25公斤硅胶(Matrex Silica Si，粒度20-45毫米，孔径60埃，来自Amicon Corp.，USA)的不锈钢柱中。柱温度为50℃，然后用30升己烷∶异丙醇＝90∶10的混合物冲洗该柱，以除去全部非极性类脂。
然后用20升己烷∶异丙醇＝60∶40的混合物从柱中洗脱半乳糖脂物质，由此产生半乳糖基二酰基甘油馏分。将该馏分蒸发产生约700克DGDG，它是主要的类脂。然后将该半乳糖脂物质分散在水中并进行冻干，结果产生自由流动的粉末。
由半乳糖脂富集DGDG
将在前面获得的具有约70％DGDG含量的来自燕麦的50克半乳糖脂溶解在250毫升己烷∶异丙醇＝70∶30的混合物中，结果产生300毫升的总量。将所得到的溶液装在硅胶(110克)柱上并且用1升己烷∶异丙醇＝70∶30的混合物将弱极性组分洗脱。将富集的DGDG馏分用2升丙酮洗脱。将该丙酮馏分蒸发并冻干。总共产生17克几乎纯净的DGDG产物。
半乳糖脂的氢化
将在前面获得的来自燕麦的200克半乳糖脂混合物溶解在2升温热的异丙醇中。将15克披钯碳催化剂(Pd 15％，水分53％，Engelhard Romes.r.i.，Italy)放在压力反应器的底部(型号4552M，Parr InstrumentCo.，USA)，该反应器在搅拌轴上带有两个搅拌器。然后将溶液在氮气密封下移入该反应器中，以减小起火危险。将该反应容器密封并且首先用氢气加压三次以除去空气，然后用氢气(Plus 4.5，来自AGA Gas AB，Sweden)加压三次。然后将氢气压力保持在6巴，将搅拌器设定为600rpm，并且将该混合物加热到70℃。用14分钟使该反应混合物达到其温度设定点。该氢化过程进行6小时，此后将反应产物通过0.45微米过滤器过滤，以除去碳颗粒和钯。在旋转蒸发器上将溶剂蒸发，将残余的固体物质分散在1600毫升去离子水中并冻干。
过滤和冻干后的氢化半乳糖脂的产量为155克。通过气相色谱对氢化性能进行评价；在氢化产物中只有饱和脂肪酸可以测出。
来自麦麸的半乳糖脂
在烧杯中用4升95％乙醇在70℃下将1公斤麦麸粉(ABSkanebrannerier，Sweden)提取3小时。然后在400-500千帕的压力下将料浆过滤并将获得的滤饼用1升95％乙醇冲洗。将合并的乙醇溶液在最高60℃下蒸发，由此产生约60克的黄色油。
将该油加到含有45克硅胶(Matrex Silica Si，粒度20-45微米，孔径60埃，来自Amicon Corp.，USA)的不锈钢柱中。然后用700毫升己烷∶异丙醇＝90∶10的混合物冲洗该柱，以除去中性类脂。
为了除去MGDG和一些其它的极性类脂，用1000毫升己烷∶异丙醇＝70∶30的混合物冲洗该柱。用1000毫升纯丙酮将DGDG洗脱。蒸发以后，可以获得约4克几乎纯净的DGDG产物。
来自黑麦的半乳糖脂
将100克黑麦片(Kungsornen AB，Sweden)在工业己烷和异丙醇，90∶10，的混合物中搅拌60分钟。将该料浆过滤并蒸发，结果产生0.5克极性类脂。将溶解在10毫升己烷∶异丙醇＝70∶30的混合物中的残余物装在三根串联联接的Sep-pak二氧化硅叠加柱上(Millipore Corp.，USA)，用20毫升同样的溶剂混合物冲洗并且用15毫升丙酮进行洗脱。将洗脱物蒸发并冻干，得到47毫克半乳糖脂。
不同的半乳糖脂物质的化学和物理特性
类脂类别分析
利用填充经二醇改性的二氧化硅(LiChrosphere 100 DIOL，5微米，250mm×4mm内径；E.Merck，Germany)的柱，通过高效液相色谱，HPLC，进行类脂类别分析。将该柱密封在保持在75℃下的水浴中。分析系统由HPLC泵CM4000(LDC/Milton Roy，USA)和一个带有20微升注射环(Rheodyne Inc.，USA)的注射器(型号7125)组成。所用的蒸发性散光检测器为Sedex45(S.E.D.E.R.E.，France)，其上配有Sedex55雾化室，其流动管温度和空气进口压力分别为97℃和2.0巴。
在分析过程中，流动相的流速为1毫升/分钟。用保持25分钟线性的双组分溶剂梯度，从100％A开始，到100％B结束，其中A＝己烷∶异丙醇∶正丁醇∶四氢呋喃∶异辛烷∶水＝64∶20∶6∶4.5∶4.5∶1，B＝异丙醇∶正丁醇∶四氢呋喃∶异辛烷∶水＝75∶6∶4.5∶4.5∶10。所有的溶剂均含有乙酸铵，180毫克/升。
数据收集和处理是采用GynkoSoft Data系统，版本4.22(SoftonGmbH，Germmny)进行的。典型的用于分析的注射量为100微克。识别是基于与正规标准(Karlshamns LipidTeknik AB，Sweden)相比的保持时间。在该系统中没有发现挥发性化合物。定量分析是基于峰值面积计算。
利用Zetasizer 4测试仪(Malvern Instrument Ltd.，UK)测定稀半乳糖脂水分散液的ζ电势。
表1
不同半乳糖脂物质的特性
| o-GL | o-h-GL | o-DGDG | w-GL | w-DGDG | r-GL | ||
| DGDG含量，面积％ | 73 | 70 | 72 | 100 | 80 | 100 | 67 |
| z-电势，mV | -74 | -76 | -30 | -51 | -75 | -38 | -37 |
在表1以及下表2中，采用下列缩写
o-GL ＝来自燕麦的半乳糖脂
o-h-GL ＝来自燕麦的氢化半乳糖脂
o-DGDG ＝来自燕麦的富集半乳糖脂
w-GL ＝来自小麦的半乳糖脂
w-DGDG ＝来自小麦的富集半乳糖脂
r-GL ＝来自黑麦的半乳糖脂
脂肪酸分析
在将类脂转酯化成脂肪酸甲酯之后，采用气相色谱对脂肪酸的特性进行分析。在配有毛细管柱(30米×0.25毫米内径)(DB-WAX；J&WScientific，USA)、一个柱上注射器和一个火焰电离检测器的Varian 3500Capillary Gas Chromatograph上，通过毛细管柱气相色谱将这些物质分离并定量分析。用氦作为载带气体。利用Gynkosoft Data系统，版本4.22(Softron GmbH，Germany)进行积分。通过将一毫克类脂试样加入到2毫升碳酸二甲酯∶异辛烷＝1∶1中对其进行转酯化。然后将1毫升含有2.3克溶解在200毫升甲醇中的钠的溶液加入，并且将试管剧烈摇动30秒，并在室温下放置15分钟以确保反应完成。加入3毫升水并摇动试管，然后在2×g下离心。将0.5微升有机层在下列分离条件下注射到色谱上。将炉子的温度设定在130℃下开始(2分钟)，增加到150℃(30℃/分钟)和220℃(3.2℃/分钟)，保持10分钟。注射器的温度为130℃，检测器的温度为250℃。开始时，气体流速为2.7毫升/分钟。其结果以采用外部标准法的标准重量百分比表示。对于没有标准或没有达到可接受纯度的次要成分不采用校准因子。
表2
脂肪酸组合物的特性
| 脂肪酸组分，重量％ | o-GL | o-h-GL | o-DGDG | w-GL | w-DGDG | r-GL | |
| c 14∶0 | 1 | ||||||
| c 16∶0 | 20 | 21 | 21 | 16 | 15 | 13 | 12 |
| c 18∶0 | 1 | 1 | 74 | 2 | 1 | 1 | |
| c 18∶1 n-9 | 17 | 17 | 19 | 6 | 5 | 8 | |
| c 18∶1 n-7 | 1 | 1 | 1 | 1 | 1 | 1 | |
| c 18∶2 n-6 | 53 | 52 | 58 | 71 | 68 | 69 | |
| c 18∶3 n-3 | 2 | 2 | 3 | 3 | 3 | 5 | |
| 次要的＜1％和未识别的 | 6 | 6 | 5 | 1 | 3 | 8 | 5 |
二半乳糖基二酰基甘油的NMR光谱
在13C频率100.614MHz下，在Bruker AM-400核磁谱仪(BrukerAnalytische Messtechnik GmbH.，Germany)上记录一维质子-去偶自然丰度13C NMR光谱。脉冲角度为36°，脉冲保持时间为1.0秒，分辨率为1.526Hz/数据点。在操作过程中施加3Hz宽线。将试样(10-40毫克)在730微升DMSO-d6(Aldrich Chemical Comp.，Inc.，USA)和20微升D2O(AldrichChemical Comp.，Inc.，USA)的混合物中稀释并转移到NMR管(5毫米内径)中。
表3
来自小麦和燕麦的二半乳糖基二酰基甘油的13C化学位移(ppm)
| 信号 | w-DGDG | o-DGDG |
| 脂肪酸部分c(n)c(n-1)c(n-2)c，亚甲基c，烯丙基c，双烯丙基c，烯属c3c2c1 | 13.821.930.828.3-28.926.525.1127.6-129.624.333.3，33.5172.2，172.5 | 13.721.930.828.4-29.026.525.1127.6-129.524.333.3，33.5172.1，172.4 |
| 甘油部分sn-1sn-2sn-3 | 52.359.856.6 | 62.469.866.6 |
| 双半乳糖部分c1(内部)c1’(外部)其它 | 103.699.460.4，66.367.7，68.2，68.6，69.3，70.1，71.1， | 103.699.460.4，66.3，67.7，68.2，68.6，69.3，70.1，71.1， |
| 72.8，72.8 | 72.8，72.9 |
实施例1.亲脂载体(含有20％γ-亚麻酸(GLA)的富集晚樱草油)的制备
采用下列成分制备亲脂载体：
组分 ％
半乳糖脂物质 50.0
富集的晚樱草油，20％GLA 50.0
在以22000rpm的转速高剪切混合下，将半乳糖脂分散在油中3分钟。将油相在50℃下保持40分钟，由此可以获得澄清的高粘性的亲脂载体，该载体在冷却到室温时将保持清澈。
实施例2.含有5％环孢菌素A的亲脂载体(含有20％GLA的富集晚樱草油)的制备
采用下列成分制备含有药物活性化合物的亲脂载体：
组分 ％
半乳糖脂物质 19.0
富集的晚樱草油，20％GLA 75.9
环孢菌素A 5.1
在以22000rpm的转速高剪切混合下，将半乳糖脂分散在油中2分钟。将亲脂载体加热到50℃下并且变得清澈。然后将环孢菌素A加入到该清澈的油相中。将该环孢菌素/油混合物保持在50℃，偶尔摇晃，直到获得清澈的液体。
实施例3.含有抗坏血基-6-GLA的亲脂载体的制备
采用下列组分制备一种凝胶：
组分 ％
抗坏血基-6-GLA 6.25
半乳糖脂物质 40.72
MCT油 53.03
将抗坏血基-6-GLA，抗坏血酸的γ-亚麻酸脂(来自Callanish Ltd.，Scotland)分散在油中。向该分散液中加入半乳糖脂物质并且将该混合物加热到约50℃并对其进行高剪切混合。在冷却到室温以后，可以获得粘性、淡乳白稳定的分散液。
实施例4.不含水的戒酒硫(disulfiram)药剂的制备
采用下列组分制备含有戒酒硫(一种抗酒精物)的肠胃外药剂：
组分 ％
来自燕麦的半乳糖脂 20.0
戒酒硫 32.0
MCT油 48.0
采用在2000rpm下的超混均化器将这些组分混合15分钟并且在3000rpm下将其混合5分钟。
由此制得一种悬浮液，它含有较高含量的细分散戒酒硫颗粒，具有平滑和均匀的稠度。该悬浮液具有特别好的物理稳定性，在室温下贮存时看不到有沉淀物。该悬浮液的粘度相当低，可以通过带有细针头(1.0毫米内径)的注射器输送该药剂。
该药剂适用于滴注到人体的十二指肠内，在那儿它可以作为戒酒硫贮存，从而产生增强的酒精抑制作用。
实施例5.反向囊泡的制备
采用下列组分制备反向囊泡：
组合物A 组合物B组分 ％ ％来自燕麦的半乳糖脂 1.65 1.56来自大豆的溶血磷脂酰胆碱 0.40 -来自大豆的磷脂酰肌醇 - 0.38水 0.56 0.64MCT油 97.39 97.42
在将这些组分称重以后，在30-40℃下将该混合物在超声浴中声处理1小时。所得到的细分散液能够稳定1周以上。利用配有视频增强系统(Argus 10；Hamamatsu Photonics Co.，Japan)的差示介面相对比显微镜(X2F-NTF-21；Nikon，Japan)对大反向囊泡的存在情况进行评价。
在该实施例中的反向囊泡是基于类脂组分的，这些组分适用于药物和化妆品应用中。以前，反向囊泡可以通过采用磷脂或烃油中的合成表面活性剂而制备，后两种组分通常对于人类使用来说毒性太大。此外，本发明的反向囊泡比以前所说的基于合成表面活性剂和烃油的系统具有更好的稳定性。
反向囊泡分散液是可以引入生物活性物质，例如蛋白质药物，如干扰素，和肽激素，如降钙素或胰岛素的有机溶液的一个例子。通过反向囊泡将水溶性蛋白质药物或激素引入到甘油三酯油中可以使药物很容易地透过亲脂细胞膜传送。药物分子位于对药物具有稳定作用的反向囊泡的双层上。尤其是，该药物在口服时可以免于在肠中被降解。
实施例6.反向微团的制备
以下列方式可以制备高粘性的反向微团凝胶(有机凝胶，微乳化液凝胶)：
组分 ％
来自燕麦的半乳糖脂 17.9
MCT油 81.3
水 0.8
将半乳糖脂物质和MCT油一起混合以形成一种均匀分散液。将水在连续磁搅拌下滴加到该分散液中。几乎随即就产生了透明凝胶并且保持高粘度超过一个月。
实施例7.微乳化液的制备
采用下列组分制备微乳化液：
组分 ％
抗坏血基-6-GLA 7.49
半乳糖脂物质 17.66
MCT油 63.53
水 11.32
将抗坏血基-6-GLA分散在油中。将半乳糖脂物质加入到该分散液中。在高剪切混合下将经过膜过滤的温水加入到该油相中。由此得到一种透明的淡黄色低粘度液体。
实施例8.制备油包水乳液
采用下列组分制备油包水乳液：
组分 ％
来自燕麦的半乳糖脂 20.0
MCT油 49.9
1.0％角叉菜胶凝胶水溶液 30.1
将半乳糖脂与MCT油混合形成均匀的透明分散液。在高剪切混合下，将在60℃下熔融的角叉菜胶慢慢加入到该油相中。在冷却到室温以后，可以获得一种高粘度乳白油状连续的乳液。
Claims (17)
1.具有连续类脂相的亲脂载体制剂，该制剂含有与非极性类脂以及任选的一种极性溶剂相组合的极性类脂物质，其特征在于该极性类脂物质是半乳糖脂，该物质的组成至少50％为二半乳糖基二酰基甘油，其余为其它的极性类脂。
2.根据权利要求1的亲脂载体制剂，其中该半乳糖脂物质由约70-80％的二半乳糖基二酰基甘油和20-30％其它的极性类脂组成。
3.根据权利要求1或2的亲脂载体制剂，其中该半乳糖脂物质由最多为100％的二半乳糖基二酰基甘油组成。
4.根据权利要求1-3中任一权项的亲脂载体制剂，它由1-50％重量的半乳糖脂物质和占制剂总重量最多为100％的非极性类脂组成。
5.根据权利要求1-3中任一权项的亲脂载体制剂，它是反向囊泡的形式，它含有占制剂总重量：
-0.5-3.0％的半乳糖脂物质和任选的其它的两亲物；
-0.1-1.0％的水溶液；和
-最多为100％的非极性类脂。
6.根据权利要求1-3中任一权项的亲脂载体制剂，它是反向微团的形式，它含有占制剂总重量：
-1-50％的半乳糖脂物质；
-0.1-5.0％的水溶液；和
-最多为100％的非极性类脂。
7.根据权利要求1-3中任一权项的亲脂载体制剂，它是油包水乳液的形式，它含有占制剂总重量：
-1-30％的半乳糖脂物质；
-1-80％的水溶液；
-最多为100％非极性类脂。
8.权利要求1-7中任一权项所说的亲脂制剂作为药物、化妆品和食品中活性成分的载体的应用。
9.一种药物组合物，它含有权利要求1-7中任一权项的亲脂载体制剂和生物活性物质。
10.根据权利要求9的药物组合物，其中非极性类脂是三酰基甘油油，优选地为中链三酰基甘油(MCT)油、晚樱草油、棕榈油馏分或生物活性物质。
11.根据权利要求9或10的药物组合物，用于经口、肠道、肠胃外、直肠、阴道、局部、眼内、鼻内、或耳部给药。
12.由至少50％的二半乳糖基二酰基甘油、其余为其它的极性类脂组成的半乳糖脂物质作为用于制备具有连续类脂相的亲脂载体制剂的极性类脂的应用，其中所说的制剂含有非极性类脂和极性类脂物质。
13.权利要求12所说的半乳糖脂物质的用途，该半乳糖脂物质由约70-80％二半乳糖基二酰基甘油和20-30％其它的极性类脂组成。
14.权利要求11或12所说的半乳糖脂物质的用途，该半乳糖脂物质由最多达100％的二半乳糖基二酰基甘油组成。
15.由至少50％的二半乳糖基二酰基甘油、其余为其它的极性类脂，任选地与磷脂或其它的两亲物组合而成的半乳糖脂物质在制备反向囊泡中的用途。
16.权利要求15所说的半乳糖脂物质的用途，该半乳糖脂物质由约70-80％二半乳糖基二酰基甘油和20-30％其它的极性类脂组成。
17.权利要求15或16所说的半乳糖脂物质的用途，该半乳糖脂物质由最多达100％的二半乳糖基二酰基甘油组成。
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| SE9003100D0 (sv) * | 1990-09-28 | 1990-09-28 | Kabivitrum Ab | Lipid formulation system |
| JP2774429B2 (ja) * | 1992-03-17 | 1998-07-09 | 株式会社ディ・ディ・エス研究所 | 糖骨格を有する分枝鎖型誘導体 |
-
1995
- 1995-02-06 ES ES95909185T patent/ES2158084T3/es not_active Expired - Lifetime
- 1995-02-06 AU AU17235/95A patent/AU691250B2/en not_active Ceased
- 1995-02-06 HU HU9602142A patent/HU221432B/hu not_active IP Right Cessation
- 1995-02-06 KR KR1019960704239A patent/KR100220546B1/ko not_active IP Right Cessation
- 1995-02-06 AT AT95909185T patent/ATE201980T1/de not_active IP Right Cessation
- 1995-02-06 EP EP95909185A patent/EP0743851B1/en not_active Expired - Lifetime
- 1995-02-06 CN CN95191484A patent/CN1091591C/zh not_active Expired - Fee Related
- 1995-02-06 DK DK95909185T patent/DK0743851T3/da active
- 1995-02-06 NZ NZ279954A patent/NZ279954A/en unknown
- 1995-02-06 WO PCT/SE1995/000117 patent/WO1995020945A1/en active IP Right Grant
- 1995-02-06 US US08/676,137 patent/US5716639A/en not_active Expired - Lifetime
- 1995-02-06 JP JP52055795A patent/JP3203359B2/ja not_active Expired - Lifetime
- 1995-02-06 DE DE69521300T patent/DE69521300T2/de not_active Expired - Lifetime
- 1995-02-06 CA CA002182577A patent/CA2182577C/en not_active Expired - Fee Related
- 1995-02-06 PL PL95315780A patent/PL178394B1/pl not_active IP Right Cessation
- 1995-02-09 MY MYPI95000299A patent/MY112435A/en unknown
- 1995-02-13 TW TW084101256A patent/TW482685B/zh not_active IP Right Cessation
-
1996
- 1996-08-02 FI FI963066A patent/FI963066A/fi not_active IP Right Cessation
- 1996-08-02 NO NO19963242A patent/NO312495B1/no not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101787059A (zh) * | 2009-05-12 | 2010-07-28 | 沈阳药科大学 | 双半乳糖基二酰甘油酯的制备方法及其应用 |
| CN101787059B (zh) * | 2009-05-12 | 2014-10-15 | 沈阳药科大学 | 双半乳糖基二酰甘油酯的制备方法及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO312495B1 (no) | 2002-05-21 |
| JPH09508415A (ja) | 1997-08-26 |
| NO963242D0 (no) | 1996-08-02 |
| ES2158084T3 (es) | 2001-09-01 |
| HU9602142D0 (en) | 1996-09-30 |
| PL178394B1 (pl) | 2000-04-28 |
| HUT75470A (en) | 1997-05-28 |
| JP3203359B2 (ja) | 2001-08-27 |
| AU691250B2 (en) | 1998-05-14 |
| KR100220546B1 (ko) | 1999-09-15 |
| MY112435A (en) | 2001-06-30 |
| CN1091591C (zh) | 2002-10-02 |
| US5716639A (en) | 1998-02-10 |
| ATE201980T1 (de) | 2001-06-15 |
| WO1995020945A1 (en) | 1995-08-10 |
| FI963066A (fi) | 1996-09-30 |
| NZ279954A (en) | 1998-02-26 |
| EP0743851B1 (en) | 2001-06-13 |
| CA2182577A1 (en) | 1995-08-10 |
| EP0743851A1 (en) | 1996-11-27 |
| HU221432B (en) | 2002-10-28 |
| TW482685B (en) | 2002-04-11 |
| DE69521300D1 (de) | 2001-07-19 |
| FI963066A0 (fi) | 1996-08-02 |
| DE69521300T2 (de) | 2002-05-02 |
| PL315780A1 (en) | 1996-12-09 |
| DK0743851T3 (da) | 2001-09-03 |
| NO963242L (no) | 1996-08-02 |
| CA2182577C (en) | 2002-08-20 |
| AU1723595A (en) | 1995-08-21 |
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Owner name: LEEPERKERR GROUP CO.,LTD. Free format text: FORMER OWNER: KARLSHAMNS LIPIDTEKNIK AB Effective date: 20010719 |
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Effective date of registration: 20010719 Applicant after: Lipocore Holding AB Applicant before: Karlshamns Lipidteknik AB |
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