CN1350841A - 萜烯醇乙氧基化物作为增溶剂在美容或药物制剂或食品制剂浓缩物中的应用 - Google Patents
萜烯醇乙氧基化物作为增溶剂在美容或药物制剂或食品制剂浓缩物中的应用 Download PDFInfo
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- CN1350841A CN1350841A CN01137561A CN01137561A CN1350841A CN 1350841 A CN1350841 A CN 1350841A CN 01137561 A CN01137561 A CN 01137561A CN 01137561 A CN01137561 A CN 01137561A CN 1350841 A CN1350841 A CN 1350841A
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- Prior art keywords
- water
- ethoxylate
- solubilizing agent
- oxirane
- slightly soluble
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Abstract
具有10个碳原子的以3～10mol环氧乙烷乙氧基化的萜烯醇在美容或药物制剂或食品制剂浓缩物中作为微溶于水或微分散于水化合物的增溶剂的应用,其中用量以成品制剂或者以浓缩物为基准计为至少3%重量。
Description
技术领域
本发明涉及萜烯醇类与3～10mol环氧乙烷的乙氧基化物以至少3wt％的用量作为增溶剂，在美容或药物制剂或食品制剂浓缩物中的应用。
背景技术
由GB 2 297 557得知，诸如香叶醇之类的精油可通过烷氧基化而变得可溶于水，同时不显著损失其气味特性。该文所描述的烷氧基化物因而旨在随后用作香料，即，用量非常小，加入到文中并未说明的制剂中。
已知美容和药物制剂使用名目繁多的增溶剂，来源于范围广泛的化合物种类。
这是由于，在均相药物或美容制剂中，疏水物质的增溶已具有非常重要的实际意义。
增溶应理解为表面活性化合物所带来的溶解性的改善，它能将微溶于水或不溶于水的物质转变为澄清的，至多乳光的水溶液，且在此过程中不改变这些物质的化学结构。
所制备的加溶物的特征在于，该微溶于水或不溶于水的物质以在水溶液中形成的表面活性化合物的缔合分子中的溶解形式——“胶束”——存在。制成的溶液为稳定单相体系，视觉上呈透明到乳光状，不需要输入较大量能量便可制成。
通过将制剂变成透明的，增溶剂可改善，例如美容制剂的外观。另外，在药物制剂的情况下，药用物质的生物利用率，并因而其效力，通过增溶剂的使用均可增加。
主要用于药物药用物质和美容活性成份的增溶剂是下列产品：
-乙氧基化(氢化)蓖麻油(例如，Cremophor品级，BASF)；
-乙氧基化脱水山梨醇脂肪酸酯(例如，Tween品级，ICI)；
-乙氧基化羟基硬脂酸(例如，Solutol品级，BASF)。
虽然这些已知增溶剂已证明是成功的，但它们在增溶作用和使用性能，以及生理相容性等方面仍需进一步改进。
发明内容
本发明的目的是提出一种新型增溶剂，它兼具有非常好的增溶性能、改善的稳定性、良好生理相容性以及方便的液体形式剂量配药的特征。
我们发现这一目的是由一种C10-萜烯醇类与3～10mol环氧乙烷的反应产物实现的，它不仅本身容易溶解在水中，而且对微溶或微分散于水中的化合物具有高于平均水平的增溶作用，只要以成品制剂或制剂浓缩物为基准至少3wt％的用量使用它们。
微溶于水或微分散于水中的化合物，即，美容或药物活性成份或食品添加剂，一般应理解为水中溶解度小于5wt％，尤其是小于1wt％的化合物。微分散于水中的物质通常是这样的物质，它不溶于或实际不溶于水中、只能利用增溶剂转化为水或主要含水介质中的稳定分散体。
就药物制剂而言，术语“微溶于水的活性成份”在这里也意在涵盖符合DAB 9(德国药典)、仅稍溶于水的活性成份。这里，分级标准如下：仅稍溶(可溶于30～100份溶剂中)；微溶(可溶于100～1000份溶剂中)；实际不溶(可溶于10,000份以上的溶剂中)。
本发明使用的反应产物还可方便地以液体形式进行剂量配药，其耐水解能力大于惯用的酯，并且为生理上相容的。特别是，它们具有非常低的溶血活性。
本发明使用的化合物例如是橙花醇、芳樟醇、薄荷醇、萜品醇，特别是与3～10mol，优选5～7mol环氧乙烷起反应的香叶醇和香茅醇。
增溶剂的用量，以成品制剂或浓缩物为基准计介于3～90wt％，优选3～50wt％，尤其是3～30wt％。
通过与环氧乙烷起反应制备本发明使用的化合物的方法，按本身已知的方式实施，例如可参见N.Schnfeldt，GrenzflchenaktiveEthylenoxid-Addukte[界面活性环氧乙烷加成物]，科学出版社，斯图加特，第1版(1976)以及增补卷(1984)。
一般而言，醇与环氧乙烷的反应是在催化剂，优选氢氧化钠或氢氧化钾(以待乙氧基化的醇为基准计一般介于0.05～5wt％，优选0.1～0.5wt％)的存在下、惰性气氛中进行，直至达到所要求的乙氧基化度。催化剂可以水溶液形式加入。在实际计量加入环氧乙烷之前有利的是，该混合物在50～110℃，优选60～90℃、减压下进行脱水。伯醇的乙氧基化在90～150℃，优选120～140℃进行；仲醇的乙氧基化在120～170℃，优选140～160℃进行。
反应产物可任选地进行后处理。此类处理包括，尤其是催化剂通过加酸而中和，例如加入磷酸或离子交换剂，或者加入吸附剂如硅酸盐或铝氧化物类。后处理可在10～180℃的温度，优选30～100℃进行，并且在搅拌下持续0.5～12h。这些完成以后通常进行过滤步骤，任选地采用过滤助剂，例如硅藻土。后处理也可采用这些添加剂的组合。
硅酸盐优选是碱金属或碱土金属硅酸盐，尤其是硅酸镁或硅酸钙，或硅酸铝，还有漂白土。可举出的市售产品例如是Ambosol、Tonsil FF或Magnesol。
用途：
本发明提供用作药物和美容制剂的增溶剂的水溶性两亲化合物。它们具有增溶药物和美容领域中微溶活性成份的性能，增溶微溶食品增补剂，例如维生素和类胡萝卜素，也可用在谷物保护组合物中以增溶微溶活性成份，以及增溶兽医用含水体系中的活性成份。
化妆品用增溶剂
本发明使用的化合物可用作美容制剂中的增溶剂。它们尤其适合作为化妆油的增溶剂。它们还具有对脂肪和油类的优良增溶能力，例如对花生油、霍霍巴油、椰子油、杏仁油、橄榄油、棕榈油、蓖麻油、大豆油或小麦胚芽油，或者对精油类，如矮松油、熏衣草花油、迷迭香油、云杉针叶油、松针油、桉树油、薄荷油、鼠尾草油、香柠檬油、松节油、蜂花油、刺柏油、柠檬油、茴香油、小豆蔻油、樟脑油等以及这些油的混合物。
另外，本发明所用的化合物还可用作例如下列不溶或微溶于水的紫外吸收剂的增溶剂：2-羟基-4-甲氧基二苯酮(UvinulM40，BASF)、2，2’，4，4’-四羟基二苯酮(UvinulD 50)、2，2’-二羟基-4，4’-二甲氧基二苯酮(UvinulD49)、2，4-二羟基二苯酮(Uvinul400)2-氰基-3，3-二苯基丙烯酸2-乙基己基酯(UvinulN539)、2，4，6-三苯胺基-对-(羰基-2’-乙基己基-1’-氧基)-1，3，5-三嗪(UvinulT 150)、3-(4-甲氧基苄叉)樟脑(Eusolex6300，Merck)、N，N-二甲基-4-氨基苯甲酸2-乙基己基酯(Eusolex6007)、水杨酸3，3，5-三甲基环己基酯、4-异丙基二苯甲酰甲烷(Eusolex8020)、对甲氧基肉桂酸2-乙基己基酯以及对甲氧基肉桂酸2-异戊基酯，以及它们的混合物。
因此，本发明还提供一种美容制剂，它包含至少一种本发明所用的化合物作为增溶剂。优选的制剂除了增溶剂之外，还包含一种或多种微溶美容活性成份，例如上面提到的油类或紫外吸收剂。
这类制剂是基于水或水/醇的加溶物。化合物I被用作增溶剂，与微溶美容活性成份之间的比例介于0.2∶1～50∶1，优选0.5∶1～20∶1，尤其优选1∶1～15∶1，更尤其优选2∶1～12∶1。
另外，在该制剂中还可加入另一些助剂，例如非离子、阳离子或阴离子表面活性剂，如烷基聚苷、脂肪醇硫酸酯、脂肪醇磺酸酯、脂肪醇醚硫酸酯、脂肪醇醚磺酸酯、链烷磺酸盐、脂肪醇乙氧基化物、脂肪醇磷酸酯、烷基甜菜碱、脱水山梨醇酯、POE脱水山梨醇酯、糖脂肪酸酯、脂肪酸聚甘油酯、脂肪酸偏甘油酯、脂肪酸羧酸酯、脂肪醇磺基琥珀酸酯、脂肪酸肌氨酸酯、脂肪酸羟乙磺酸酯、脂肪酸牛磺酸酯柠檬酸酯、硅氧烷共聚物、脂肪酸聚乙二醇酯、脂肪酸酰胺、脂肪酸链烷醇酰胺、季铵化合物、烷基酚乙氧基化物、脂肪胺乙氧基化物，助溶剂，例如乙二醇、丙二醇、甘油等。
另一些可加入的成分是天然或合成化合物，例如，羊毛脂衍生物、胆甾醇衍生物、肉豆寇酸异丙基酯、棕榈酸异丙基酯、电解质、染料、防腐剂、酸(例如，乳酸、柠檬酸)。
这类制剂例如可用于沐浴制剂，如沐浴油、剃须后用品、洗脸制剂、漱口制剂、生发油、科隆水、化妆水等。
增溶方法描述：
在美容制剂用加溶物的制备中，本发明使用的化合物可以以100％浓度的物质形式，或者作为水溶液使用。
一般地，将增溶剂溶解在水中，并在每种情况下与要使用的微溶美容活性成份，例如与上面所描述的精油或香精油，一起剧烈混合，例如采用磁搅拌器。
然而，也可将要使用的微溶美容活性成份溶解在增溶剂的熔体中，然后在连续搅拌下加入去离子水。
药物用途增溶剂
本发明使用的化合物适合在任何类型药物制剂中作为增溶剂，其特征在于，制剂中包含一种或多种微溶于水或不溶于水的药用物质或维生素，以及类胡萝卜素。尤其是，它们是口服或肠胃外用的水溶液或加溶物，例如静脉、肌内或皮下或腹膜内用的注射液。
再有，本发明使用的化合物适合以口服给药形式使用，例如片剂、胶囊、粉末、溶液。这里，它们使得微溶药用物质以更高的生物利用率供使用。
在肠胃外用途并采用增溶剂的情况下，也可采用乳液，例如脂肪乳液。为此，本发明化合物同样也适合用来加工微溶药用物质。
上述类型的药物制剂可通过按传统方法和使用已知和新型活性成份来加工本发明化合物与药物活性成份。
本发明的应用另外还包括药物助剂和/或稀释剂。具体的助剂是助溶剂、稳定剂和防腐剂。
活性成份可选自任何适应症领域。这里可举出的例子是苯并二氮类、抗高血压药、维生素、细胞抑制剂，特别是紫杉酚，麻醉剂、安定药、抗抑郁药、抗生素、抗霉菌药、杀真菌剂、化学治疗药、泌尿科药、血小板凝聚抑制剂、磺胺类、解痉药、荷尔蒙、免疫球蛋白、血清、甲状腺治疗剂、精神病用药、治疗帕金森病及其他抗运动机能亢进的药剂、眼药、神经病制剂、钙代谢调节剂、肌肉松弛剂、麻醉品、抗血脂剂、肝治疗剂、冠心病药剂、强心剂、免疫治疗剂、调节肽及其抑制剂、安眠药、镇静剂、妇科药、痛风治疗剂、纤维蛋白溶解药剂、酶制剂和转运蛋白、酶抑制剂、催吐剂、循环促进剂、利尿剂、诊断剂、肾上腺皮质激素、胆碱能药剂、胆管治疗剂、止喘药、支气管病药物(broncholytics)、β-受体阻断剂、钙拮抗剂、ACE抑制剂、动脉硬化药、消炎剂、抗凝剂、抗低渗药、抗低血糖药剂、抗高渗药剂、抗纤维蛋白溶解药剂、抗癫痫药物、止吐药、解毒药、抗糖尿病药、抗心率不齐药、抗贫血、抗过敏、抗蠕虫药、止痛药、苏醒药、醛固酮拮抗药以及减肥药(slimming agents)。
为将本发明化合物作为增溶剂用于药物制剂中，例如可采取将活性成份分散或溶解在增溶剂中，任选地同时加热，然后将该溶液与水在搅拌下混合来实现。
另一种制备方案涉及将增溶剂溶解在水相中，任选地予以温和加热，随后将活性成份溶解在该增溶剂水溶液中。增溶剂与活性成份同时地溶解在水相中也同样是可行的。
因此，本发明还提供一种药物制剂，它包含至少一种本发明使用的化合物作为增溶剂。优选的制剂除了包含增溶剂之外还包含微溶于水或不溶于水的药物活性成份，例如选自上述适应症领域的。
在上述药物制剂当中，尤其优选那些可采取肠胃外给药的制剂。
本发明增溶剂在药物制剂的含量，依活性成份而定，介于3～90wt％，优选3～50wt％，尤其优选3～30wt％。
食品制剂的增溶剂
如同在美容和药物领域一样，本发明使用的化合物也适合作为食品行业中的增溶剂，以增溶微溶于水或不溶于水的营养物、增补剂或添加剂，例如脂溶性维生素或类胡萝卜素。可举出的例子是用类胡萝卜素着色的透明饮料。
因此，本发明还提供用于食品制剂的浓缩物(母料)，其中浓缩物包含至少一种本发明使用的化合物作为增溶剂，其用量至少3wt％。优选的浓缩物除了包含增溶剂之外，还包含微溶于水或不溶于水的维生素或类胡萝卜素。
实施例
乙氧基化物的制备
实施例1
香茅醇+8 EO
265.5g(1.70mol)香茅醇和0.53g氢氧化钾的混合物在75℃和减压下(＜10mbar)脱水1h。600g(13.6mol)环氧乙烷在140℃、搅拌下经3.5h时间计量加入到充氮而被惰性化的压热釜中。在此操作期间，表计压力最高达到7bar。环氧乙烷计量加入完毕之后，混合物在140℃再搅拌1h。混合物在70℃和小于10mbar的减压下再搅拌1h，以3.54g Ambosol(Hoechst)处理，在80℃下搅拌1h，最后压滤。收率：850g(98.2％)；羟基值＝109mg KOH/g。
实施例2
香茅醇+5.5 EO
330g(2.12mol)香茅醇和0.66g氢氧化钾的混合物在60～70℃和减压(≥1mbar)下脱水至残余水含量为0.04％。在充氮而被惰性化的压热釜中，471g(10.7mol)环氧乙烷在130℃、搅拌下经4h时间计量加入到312g(2.00mol)所述香茅醇混合物中。在此操作期间，表计压力最高达到7bar。环氧乙烷计量加入完毕时，混合物在130℃再搅拌1h。混合物在70℃和≥1mbar的减压下再搅拌1h，以4.40g Ambosol处理，在80℃下搅拌1h，最后压滤。收率：772g(98.6％)；羟基值＝142mg KOH/g。
实施例3
香叶醇+9 EO
277.6g(1.80mol)香茅醇和0.56g氢氧化钾的混合物在70℃和减压下(＜10mbar)脱水1h。717g(16.3mol)环氧乙烷在140℃、搅拌下经4.5h时间计量加入到充氮而被惰性化的压热釜中。在此操作期间，表计压力最高达到7bar。环氧乙烷计量加入完毕之后，混合物在140℃再搅拌1.5h。混合物在70℃和小于10mbar的减压下再搅拌1h，以3.31g Ambosol处理，在70℃下搅拌1h，最后压滤。收率：1005g(定量)；羟基值＝100mg KOH/g。
应用
实施例4
(吡罗昔康注射液)
2.5g吡罗昔康在搅拌下引入到200g具有9mol环氧乙烷的香茅醇乙氧基化物与2.0g苯甲醇的混合物中。随后，混合物加热到50℃，并继续搅拌至吡罗昔康完全溶解。795.4g注射用水随后慢慢加入到该澄清溶液中，然后混合物冷却至室温。
用0.22μm过滤介质过滤而灭菌之后，该澄清溶液在无菌条件下转移到10mL安瓿瓶中，最后将安瓿瓶密封。
实施例5
(维生素E乙酸酯饮用溶液)
25g维生素E乙酸酯在60℃搅拌下溶解在200g具有6mol环氧乙烷的香茅醇乙氧基化物中。随后，775g由200g山梨醇、1.0g天冬甜素和2.0g桔味香料于572.0g纯净水中单独制成的溶液，慢慢加入到上述溶液中。冷却至室温后，该维生素E乙酸酯饮用溶液转移到100mL带螺旋盖子的瓶中。
实施例6
(地西泮粒剂)
10.0g地西泮在50℃溶解在200.0g 6重量份具有7mol环氧乙烷的香叶醇乙氧基化物与4重量份乙醇的混合物中。在Ldige犁头混合器中，该溶液喷洒到由1000.0g乳糖酶、850.0g微晶纤维素(AvicelPH 102)和20.0g高度分散二氧化硅(AerosilOX 50)组成的粉末混合物上。随后，粒剂经过在托盘干燥室内、30℃下干燥，然后转移到2.0g香袋中。
实施例7
(硝苯地平胶囊)
40.0g硝苯地平在避光和搅拌、60℃条件下溶解在200.0g具有6mol环氧乙烷的香茅醇乙氧基化物、400.0g聚乙二醇6000和360.0g聚氧乙烯/聚氧丙烯嵌段聚合物(Lutrol，F 68)的混合物中。该溶液转移到尺寸为00号的硬明胶胶囊中，每个计量加入500mg。待胶囊内容物冷却以后，胶囊的上下两部分通过以30％浓度明胶溶液处理而严密地密封住。
实施例8～13(对比例8～10)
萜烯醇乙氧基化物，各自加热到65℃，然后加入到药用物质中。然后，以小份加入pH7.0磷酸盐缓冲液(USP XXIII；34.0g磷酸二氢钾和145.5mL 1N氢氧化钠溶液溶解在4000.0g去离子水中，并以去离子水注满至5.0L)，直至增溶剂浓度以最终溶液为基准计达到20wt％。混合物在室温下搅拌直至达到药用物质的饱和浓度。所获得的饱和浓度，以wt％计，记于下表中。
表
| 实施例 | 化合物 | 磺胺噻唑 | 17-β-雌二醇 | 克霉唑 |
| 8 | 仅有pH7.0磷酸盐缓冲剂 | 0.07 | 0.0 | 0.0 |
| 9 | 脱水山梨醇脂肪酸酯(Tween80) | 0.7 | 0.09 | 0.03 |
| 10 | 乙氧基化蓖麻油(CremophorEL) | 0.7 | 0.06 | 0.01 |
| 11 | 香茅醇乙氧基化物，带8 EO | 0.95 | 0.23 | 0.39 |
| 12 | 香茅醇乙氧基化物，带6 EO | 0.78 | 0.30 | - |
| 13 | 香茅醇乙氧基化物，带9 EO | - | 0.14 | - |
实施例14
(防晒组合物)
25g具有6 EO的香茅醇乙氧基化物加热到60℃，然后在搅拌下将2.5g UvinulT 150溶解到其中。随后，62.5g二次蒸馏水、5g甘油和5g 1，2-丙二醇的混合物加热到60℃，在搅拌下小心地滴加到其中。这样便生成一种澄清溶液，冷却至室温后，转移到适当容器中。
Claims (8)
1.具有10个碳原子的被3～10mol环氧乙烷乙氧基化的萜烯醇，在美容或药物制剂或食品制剂浓缩物中作为微溶于水或微分散于水的化合物的增溶剂的用途，其中用量以成品美容和药物制剂或者以食品制剂浓缩物为基准计为至少3wt％。
2.权利要求1的用途，其中C10-萜烯醇乙氧基化物是香茅醇与5～7mol环氧乙烷的反应产物。
3.权利要求1的用途，其中C10-萜烯醇乙氧基化物是香叶醇与5～7mol环氧乙烷的反应产物。
4.一种美容或药物制剂，它包含至少3wt％的以3～10mol环氧乙烷烷氧基化的C10-萜烯醇类，作为微溶于水或微分散于水的活性成份的增溶剂。
5.权利要求4的美容或药物制剂，它包含以成品制剂为基准计3～50wt％的以3～10mol环氧乙烷烷氧基化的C10-萜烯醇类，作为微溶于水或微分散于水的活性成份的增溶剂。
6.权利要求4的美容或药物制剂，其中C10-萜烯醇乙氧基化物是香茅醇与5～7mol环氧乙烷的反应产物。
7.权利要求4的美容或药物制剂，其中C10-萜烯醇乙氧基化物是香叶醇与5～7mol环氧乙烷的反应产物。
8.一种食品制剂浓缩物，它包含3～50wt％的以3～10mol环氧乙烷烷氧基化的C10-萜烯醇类，作为微溶于水或微分散于水的食品添加剂的增溶剂。
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|---|---|---|---|---|
| US2440093A (en) * | 1943-07-12 | 1948-04-20 | Ind Rayon Corp | Terpene derivatives and method of producing the same |
| US2549438A (en) * | 1949-09-28 | 1951-04-17 | Petrolite Corp | Process for breaking petroleum emulsions |
| US2748088A (en) * | 1951-12-18 | 1956-05-29 | Petrolite Corp | Process for inhibiting foam |
| DE3042558A1 (de) * | 1980-11-12 | 1982-06-24 | Basf Ag, 6700 Ludwigshafen | Verfahren zur herstellung von kaelteflexiblen, gegebenenfalls zellhaltigen polyurethanelastomeren |
| GB9501861D0 (en) * | 1995-01-31 | 1995-03-22 | Croda Int Plc | Solubilised essential oils |
-
2000
- 2000-10-27 DE DE10053512A patent/DE10053512A1/de not_active Withdrawn
-
2001
- 2001-10-06 EP EP01123921A patent/EP1203589A1/de not_active Withdrawn
- 2001-10-22 JP JP2001324103A patent/JP2002193837A/ja not_active Withdrawn
- 2001-10-22 CA CA002359401A patent/CA2359401A1/en not_active Abandoned
- 2001-10-24 US US09/983,310 patent/US20020076426A1/en not_active Abandoned
- 2001-10-25 BR BR0104826-0A patent/BR0104826A/pt not_active Application Discontinuation
- 2001-10-26 KR KR1020010066195A patent/KR20020033070A/ko not_active Application Discontinuation
- 2001-10-26 AU AU83646/01A patent/AU8364601A/en not_active Abandoned
- 2001-10-29 CN CN01137561A patent/CN1350841A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR20020033070A (ko) | 2002-05-04 |
| DE10053512A1 (de) | 2002-05-02 |
| JP2002193837A (ja) | 2002-07-10 |
| AU8364601A (en) | 2002-05-02 |
| US20020076426A1 (en) | 2002-06-20 |
| EP1203589A1 (de) | 2002-05-08 |
| BR0104826A (pt) | 2002-07-02 |
| CA2359401A1 (en) | 2002-04-27 |
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