CN1165653A - 类胡萝卜素和维生素的稳定含水增溶物 - Google Patents
类胡萝卜素和维生素的稳定含水增溶物 Download PDFInfo
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- CN1165653A CN1165653A CN97109610A CN97109610A CN1165653A CN 1165653 A CN1165653 A CN 1165653A CN 97109610 A CN97109610 A CN 97109610A CN 97109610 A CN97109610 A CN 97109610A CN 1165653 A CN1165653 A CN 1165653A
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Abstract
适用于非肠道给药的类胡萝卡素和维生素的稳定含水增溶物，其中类胡萝卜素和不溶于水的维生素在非离子乳化剂作用下呈胶粒溶液形式，其胶粒小于100nm，以增溶物的量为基准，其中增溶物含有至少一种浓度为0.1至10重量百分比的类胡萝卜素，浓度为0.1至20重量百分比的不溶于水的亲脂性维生素或维生素衍生物，以及浓度为1至40重量百分比的非离子乳化剂，其条件为亲脂性维生素含量至少与类胡萝卜素含量相等。
Description
本发明涉及借助于非离子乳化剂制备的适用于非肠道给药的类胡萝卜素和维生素的稳定含水增溶物。
类胡萝卜素、维生素和微量元素在营养生理学中具有非常重要的作用。人和动物体摄取不足会导致出现类胡萝卜素、维生素和微量元素缺乏的症状。患某些疾病的病人不能口服食物或药物，需要非肠道营养法。在这些情况下，也必需用这种方式提供上述物质。而且，还存在下列情况：甚至是通过口腔营养的患者也极度缺乏类胡萝卜素、维生素和微量元素，因此需要迅速恢复到其所需生理浓度。在这种情况下，非肠道给药也是必需的。再者，对多种疾病如动脉粥样硬化、必肌梗塞、中风、斑变性、灰内障、帕金森氏病和癌症的预防作用，被认为是由于使用了一些超过生理水平的类胡萝卜素、维生素和微量元素引起的。因为氧化剂和自由基导致细胞改变，所以这种物质中的氧化剂、清除自由基成分被认为是产生这些作用的原因。而且，这些人体必需的化合物被认为可以加强免疫系统，因而用维生素E后T淋巴细胞，特别是辅助性T细胞增加。
在这点上，β-胡萝卜素和其它类胡萝卜素、生育酚或生育酚衍生物、抗坏血酸或抗坏血酸衍生物以及硒化合物尤为重要。这些物质或其中的一些物质的组合，通常被称作抗氧化剂组合。
目前，适用于非肠道给药、允许以大于或等于生理水平的给药量使用上述类胡萝卜素和维生素的制剂尚得不到。
EP0055817和DE4031094A1公开了β-胡萝卜素增溶物，此增溶物含有一种HLB为12至16的非离子表面活性剂作为增溶剂。
WO9406310A1描述了一种HLB为10至18的乳化剂和β-胡萝卜素的增溶物的制备方法，意欲将此增溶物用于食品工业着色。为稳定β-胡萝卜素，可以以一种常规方法向此试剂中加入少量的抗氧化剂。
本发明的目的之一是提供含有β-胡萝卜素和维生素的增溶物，它对于沉淀作用是稳定的，适用于非肠道给药。一般认为，以至少与β-胡萝卜素相同的量或大于β-胡萝卜素的量加入其它亲油组分，将干扰增溶的β-胡萝卜素的胶粒结构，使本身不溶于水的β-胡萝卜素沉淀。预计较大量的维生素(通常以盐形式)的存在也有相似的干扰作用。
我们已发现，通过类胡萝卜素和维生素或维生素衍生物的适于非肠道给药的含水增溶物达到了此目的。增溶物中类胡萝卜素和不溶于水的维生素借助于非离子乳化剂，以胶粒溶液的形式存在，此胶粒小于100nm，在长时间内保持物理上和化学上的绝对稳定。以增溶物的量为基准，其中增溶物含有至少一种浓度为0.1至10重量百分比的类胡萝卜素，浓度为0.1至20重量百分比的不溶于水的亲脂性维生素或维生素衍生物，以及浓度为1至40重量百分比的非离子乳化剂。另外，必须满足的条件是：亲脂性维生素的量不少于类胡萝卜素的量。
我们还发现，由于类胡萝卜素、亲脂性维生素特别是生育酚或生育酚酯、以及非离子表面活性剂之间存在意想不到的相互作用，混合物中非离子表面活性剂的量小于使用单个活性物质增溶所相应的总量。这使得制剂易于被人局部或全身耐受。令人惊奇的是，在制剂中类胡萝卜素和亲脂性维生素的组合，降低了类胡萝卜素受温度的影响，因而抑制了分解。与不加亲脂性维生素相比，增溶发生得更快。
据估计，良好稳定作用的令人惊奇的结果是由于形成了复合胶粒，胶粒中可能存在分子水平上的相互作用。
通常，增溶物中胶粒的平均颗粒大小为5至100nm。这些颗粒的大小远远小于注射乳剂1μm的最小要求。
适宜的非离子乳化剂是常规的生理上可耐受的化合物，尤其是那些HLB为10至20的化合物。特别应该提及的是带有20至60个氧乙烯单元的聚氧乙烯甘油三蓖麻酸酯，带有10至40个氧乙烯单元的聚氧乙烯12-羟基硬脂酸酯，带有10至40个氧乙烯单元的聚氧乙烯脱水山梨醇脂肪酸酯，以及具有下式的聚氧乙烯/聚氧丙烯嵌段共聚物，其中a和c为10至130，优选约80，b为15至70，优选约30。
特别适宜的类胡萝卜素为β-胡萝卜素，还有蕃茄红素，虾青素，芜青黄质(canthaxanthin)，柠檬黄质，玉米黄质，阿朴叶黄素和/或阿朴叶黄素酯。特别适宜的亲脂性维生素是生育酚，生育酚乙酸酯，生育酚琥珀酸酯，视黄醛，视黄醇，视黄醇酯，视黄酸，维生素D3和/或维生素D2。
以增溶物为基准，优选类胡萝卜素的量为0.4至6重量百分比，亲脂性维生素为0.4至10重量百分比，乳化剂为5至25重量百分比。
以安瓿、预装注射器、灌输液、滴液或糖浆形式存在时，当然也可以用一种生理可接受的载体进一步稀释此增溶物。
水相中还可以含有其它亲水性维生素如维生素C或B族维生素。矿物质和微量元素如硒化合物可有可无。
最后，此增溶物中可含有其它药物活性物质如N-乙酰基半胱氨酸。
优选的抗氧化剂组合包括β-胡萝卜素、生育酚或生育酚酯和抗坏血酸。硒化合物和N-乙酰基半胱氨酸可有可无。
制备本发明的制剂通常是通过将类胡萝卜素、亲脂性维生素和乳化剂在高于120℃的温度下短暂加热形成一种溶液，然后立即将其与亲水性原料在水或缓冲溶液中的的溶液混合进行冷却，也可以将其与水或缓冲溶液混合，然后加入亲水性维生素。另可以进行的方法包括在120℃以上将类胡萝卜素与乳化剂一起短暂加热，并且将此溶液与一种用已知方法单独制备的在水或缓冲液中的亲脂性维生素的增溶物混合。
优选EP0055817的方法分批进行制备。特别优选EP0479066的方法连续进行制备。这两个专利的方法和其中所述的条件在此并入本文。
如果此增溶物用于非肠道给药，冷却后，通过过滤，例如通过孔径为0.22μm的过滤器过滤，将此增溶物消毒，然后装入安瓿、预装注射器、管瓶或灌输瓶中。对于口腔给药，可以省去过滤消毒，而且可将此增溶物装入滴瓶或糖浆瓶中。在这种情况下，在增溶物的制备过程中或在其后，加入增甜剂和调味剂，对改善其味道是有益的。
实施例实施例1
将23.0g聚氧乙烯(带15个氧乙烯单元的12一羟基硬脂酸酯(SolutolHS15)、5.0g生育酚乙酸酯和0.5g丁基化羟基甲苯引入一个通有氮气的烧瓶中并加热至180℃。然后，在搅拌的同时，将6.0gβ-胡萝卜素溶解，停止加热，将一种60.5g注射用水中含有4.9g抗坏血酸钠和0.1g抗坏血酸的约20℃的溶液加入此热混合物中，同时进行湍动混合。由此获得一种透明、深红色、低粘度增溶物，将其通过孔径为0.45μm的过滤器过滤并装入带有橡皮塞的管瓶中。
β-胡萝卜素含量 5.8％
生育酚乙酸酯含量 5.1％
抗坏血酸含量 4.2％
胶粒大小 32nm
pH值 5.8
此制剂在室温和30°贮存6个月后，仍完全透明而且含量没有变化。实施例2
在一个通有氮气的烧瓶中，将23.0g SolutolHs15和5.0g生育酚加热至180℃。然后，在搅拌的同时，溶解4.0gβ-胡萝卜素，停止加热，将一种在63.0g注射用水中含有4.9g抗坏血酸钠和0.1g抗坏血酸的20℃的溶液加入此热混合物中。由此获得一种透明的、深红色、低粘度增溶物，将此增溶物通过孔径为0.45μm的过滤器过滤，并装入带有橡皮塞的管瓶中。
此制剂在室温和30℃下贮存6个月后，仍完全透明，而且含量没有变化。
β-胡萝卜素含量 3.9％
生育酚乙酸酯含量 5.2％
抗坏血酸含量 4.3％
胶粒大小 27nm
pH值 6.0实施例3
在一个通有氮气的烧瓶中，将23.0g SolutolRHS15，10.0g生育酚乙酸酯和0.5g生育酚加热至180℃。然后，在搅拌的同时，溶解6.0gβ-胡萝卜素，停止加热，并且将20℃的一种在54.0g注射用水中含5.5g抗坏血酸钠和0.1g抗坏血酸的溶液加入此热混合物中。冷却至室温后，将此透明、深红色的增溶物通过孔径为0.45μm的过滤器过滤，并且装入安瓿中。
β-胡萝卜素含量 5.7％
生育酚乙酸酯含量 10.4％
抗坏血酸含量 5.1％
胶粒大小 42nm
pH值 6.0实施例4连续制备
将40gβ-胡萝卜素在250g SolutolHS15、50g生育酚乙酸酯和10g丁基化羟基甲苯中的悬浮液在70℃下加入加热的转化炉中。借助物样通过量为2L/h的高压泵，将此悬浮液送入浸在一个油浴中的加热旋管内。其内径为2mm，长度为6m，传热油为温度170℃，停留时间设定为34秒。此时间足以溶解β-胡萝卜素。在加热旋管中经过所述的停留时间后，此β-胡萝卜素溶液进入一个T形混合室，在此处以180 °的角度与来自物料通过量为4.7L/h的高压泵的含有6.8％抗坏血酸钠、0.2％抗坏血酸和0.01％乙基汞硫代水杨酸钠的水溶液进行湍动混合。在25巴的压力下，通过压力控制阀排放产物。由此获得一种抗氧化剂的黑红色胶束溶液。
通过孔径为0.45μm的过滤器过滤此增溶物，并在氮气下将其装入带有橡皮塞的管瓶中。
β-胡萝卜素含量 3.3％
生育酚乙酸酯含量 4.3％
抗坏血酸含量 4.3％
胶粒大小 28nm
pH值 5.9实施例5
将13.0g SolutolHS15和0.5g生育酚加入通有氮气的烧瓶中，并且加热至180℃。然后，在搅拌的同时，将4.0gβ-胡萝卜素溶解，停止加热，并将82.5g单独制备的生育酚乙酸酯/抗坏血酸增溶物加入此热混合液中。
将5.0g生育酚乙酸酯与10.0g SolutolHS15混合，并加热至65℃，以制备此生育酚乙酸酯/抗坏血酸增溶物。在剧烈搅拌的同时，将在62.5g软化水中含4.9g抗坏血酸钠和0.1g抗坏血酸的溶液慢慢加入此混合液中。
冷却至室温后，将此透明、深红色抗氧化剂增溶物通过孔径为0.45μm的过滤器过滤，并将其装入带有橡皮塞的管瓶中。
β-胡萝卜素含量 3.9％
生育酚乙酸酯含量 5.2％
抗坏血酸含量 4.3％
胶粒大小 29nm
pH值 6.1实施例6
在80℃下平衡的转化炉中将20.0g生育酚乙酸酯和0.5g生育酚与200g SolutolHS15混合。然后在通入氮气的同时，将10.0gβ-胡萝卜素均匀悬浮。凭借物料通过量为2L/h的高压泵将此悬浮液送入浸入油浴中的加热旋管中。此加热浴温度是170℃，在加热旋管中的停留时间大约为34秒。离开加热旋管后，将此透明红色溶液收集于通有氮气的烧瓶中。然后将单独制备的溶液缓慢搅拌入此溶液中，单独制备的溶液为406.0g 0.1摩尔浓度的氢氧化钠溶液和1164.0g注射用水的混合液中含100.0g抗坏血酸钠、40.0g烟酰胺、15.0g盐酸吡哆素、10.0g二水核黄素-5-磷酸钠、10.0g盐酸硫胺素和25.0g右泛酰醇。将此制剂冷却至室温，并通过孔径为0.45μm的过滤器过滤。
β-胡萝卜素含量 0.48％
生育酚乙酸酯含量 1.05％
抗坏血酸钠含量 4.9％
二水核黄素-5-磷酸钠含量 0.50％
盐酸硫胺素含量 0.46％
烟酰胺含量 2.10％
盐酸吡哆素含量 0.74％
胶粒大小 19nm
pH值 5.5实施例7(对比实验)
用上述实施例4中连续制备的方法进行如下实验：制剂A：β-胡萝卜素 6％
SolutolHS15 23％
注射用水加至 100％制剂B：β-胡萝卜素 6％
生育酚 1.2％
SolutolHS15 23％
注射用水加至 100％制剂C：β-胡萝卜素 6％
生育酚乙酸酯 10％
SolutolHS15 23％
注射用水加至 100％
每个实验中的油浴温度为170℃。结果：制剂A：缺乏稳定性的混浊增溶物制剂B：缺乏稳定性的混浊增溶物制剂C：透明、稳定的增溶物。
仅在加入相当大量的脂溶性维生素的情况下，才可能制备稳定的增溶物，尤其是当β-胡萝卜素的浓度较高时。实施例8
在一个通有氮气的烧瓶中，将23.0g SolutolHS15和5g生育酚加热至180℃。然后在搅拌的同时，将4.0gβ-胡萝卜素溶解，停止加热，将一种在62.4g注射用水中含有5.5g抗坏血酸钠和0.1g抗坏血酸的20℃的溶液加入此热的混合物中。冷却至室温后，将此透明、深红色增溶物通过孔径为0.45μm的过滤器过滤，并将其装入管瓶中。
β-胡萝卜素含量 3.8％
生育酚含量 5.0％
抗坏血酸含量 5.2％
胶粒大小 27nm
pH值 6.0实施例9
在60℃下将一种400g SolutolHS15中的16g虾青素和32g生育酚乙酸酯的悬浮液引入，类似于实施例4中所述的连续制备方法。以2.2L/h的物料通过量，将此悬浮液通过内径为2mm、长度为12m的加热旋管，此旋管浸于210℃左右的油浴中。62秒的停留时间足以将虾青素溶解于乳化剂中。然后将1.5g/L抗坏血酸和37g/L抗坏血酸钠的水溶液以5.4L/h的物料通过量送入用于湍动混合的混合室中。在30巴的压力下，将产物通过压力控制阀排出。获得一种黑红色胶束虾青素溶液，并通过孔径为0.22μm过滤器将其过滤。
虾青素含量 0.8％
生育酚乙酸酯含量 2.0％
抗坏血酸钠+抗坏血酸含量 2.7％
胶粒大小 30mm
pH值 5.9
Claims (8)
1、一种适用于非肠道给药的类胡萝卜素和维生素或维生素衍生物的稳定 含水增溶物，其中类胡萝卜素和不溶于水的维生素借助于非离子乳化剂呈胶粒溶液形式，其胶粒小于100nm，以增溶物的量为基准，其中增溶物含有至少一种浓度为0.1至10重量百分比的类胡萝卜素，浓度为0.1至20重量百分比的不溶于水的亲脂性维生素或维生素衍生物，以及浓度为1至40重量百分比的非离子乳化剂，其条件为亲脂性维生素含量至少与类胡萝卜素含量相等。
2、如权利要求1所述的稳定增溶物，其中类胡萝卜素的含量为0.4至6重量百分比，亲脂性维生素的含量为0.4至10重量百分比，非离子乳化剂的含量为5至25重量百分比。
3、如权利要求1所述的稳定增溶剂，含有类胡萝卜素、亲脂性维生素和亲水性维生素，矿物质可有可无。
4、如权利要求1所述的增溶物，含有类胡萝卜素、生育酚或生育酚酯，以及抗坏血酸，硒化合物和N-乙酰基半胱氨酸可有可无。
5、如权利要求1所述的增溶物，其中的类胡萝卜素包括β-胡萝卜素，蕃茄红素，虾青素，芫青黄质，柠檬黄质，玉米黄质，阿朴叶黄素和/或阿朴叶黄素酯；亲脂性维生素包括生育酚，生育酚乙酸酯，生育酚琥珀酸酯，视黄醛，视黄醇，视黄醇酯，视黄酸，维生素D3和/或维生素D2；非离子增溶剂选自HLB为10至20的聚氧乙烯甘油三蓖麻酸酯、聚氧乙烯的12-羟基硬脂酸酯、聚氧乙烯脱水山梨醇脂肪酸酯以及聚氧乙烯/聚氧丙烯嵌段共聚物。
6、如权利要求1所述的增溶物，它可直接使用或用生理上可接受的载体稀释后，以安瓿、预装注射器、灌输液、滴液或糖浆的形式使用。
7、制备如权利要求1所述的增溶物的方法，它包括，将类胡萝卜素与亲脂性维生素或维生素衍生物和非离子乳化剂在120℃以上短暂加热直至形成一种溶液，并立即将其与水或亲水性组分的水溶液湍动混合，然后冷却此混合物。
8、制备如权利要求1中所述的增溶物的方法，它包括，仅将类胡萝卜素与非离子乳化剂在120℃以上短暂加热，直至形成一种溶液，并立即将其与一种单独制备的亲脂性维生素的增溶物湍动混合，然后冷却此混合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19609477A DE19609477A1 (de) | 1996-03-11 | 1996-03-11 | Stabile wäßrige Solubilisate von Carotinoiden und Vitamine |
| DE19609477.1 | 1996-03-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1165653A true CN1165653A (zh) | 1997-11-26 |
| CN1096264C CN1096264C (zh) | 2002-12-18 |
Family
ID=7787924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97109610A Expired - Fee Related CN1096264C (zh) | 1996-03-11 | 1997-03-11 | 类胡萝卜素和维生素的稳定含水增溶物 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5891907A (zh) |
| EP (1) | EP0800825A1 (zh) |
| JP (1) | JPH09249554A (zh) |
| CN (1) | CN1096264C (zh) |
| AU (1) | AU1620497A (zh) |
| CA (1) | CA2199415A1 (zh) |
| DE (1) | DE19609477A1 (zh) |
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| CN111991301A (zh) * | 2020-09-21 | 2020-11-27 | 四川梅奥由享生物科技有限公司 | 具有抗炎美白修复保湿多重功效的乳液 |
| CN114081069A (zh) * | 2021-11-11 | 2022-02-25 | 光明乳业股份有限公司 | 一种含虾青素的乳制品及其制备方法 |
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-
1996
- 1996-03-11 DE DE19609477A patent/DE19609477A1/de not_active Ceased
-
1997
- 1997-03-04 EP EP97103484A patent/EP0800825A1/de not_active Withdrawn
- 1997-03-06 CA CA002199415A patent/CA2199415A1/en not_active Abandoned
- 1997-03-06 JP JP9050801A patent/JPH09249554A/ja active Pending
- 1997-03-07 AU AU16204/97A patent/AU1620497A/en not_active Abandoned
- 1997-03-10 US US08/813,978 patent/US5891907A/en not_active Expired - Fee Related
- 1997-03-11 CN CN97109610A patent/CN1096264C/zh not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101623235B (zh) * | 2008-07-07 | 2013-05-22 | 株式会社芳珂 | 干燥脂质体制剂 |
| CN111568858A (zh) * | 2020-04-30 | 2020-08-25 | 佛山科学技术学院 | 一种虾青素水溶液的制备方法 |
| CN111991301A (zh) * | 2020-09-21 | 2020-11-27 | 四川梅奥由享生物科技有限公司 | 具有抗炎美白修复保湿多重功效的乳液 |
| CN114081069A (zh) * | 2021-11-11 | 2022-02-25 | 光明乳业股份有限公司 | 一种含虾青素的乳制品及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US5891907A (en) | 1999-04-06 |
| AU1620497A (en) | 1997-09-18 |
| CA2199415A1 (en) | 1997-09-11 |
| JPH09249554A (ja) | 1997-09-22 |
| CN1096264C (zh) | 2002-12-18 |
| DE19609477A1 (de) | 1997-09-18 |
| EP0800825A1 (de) | 1997-10-15 |
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