CN109330980A - 姜黄素增溶物 - Google Patents

姜黄素增溶物 Download PDF

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CN109330980A
CN109330980A CN201811453446.4A CN201811453446A CN109330980A CN 109330980 A CN109330980 A CN 109330980A CN 201811453446 A CN201811453446 A CN 201811453446A CN 109330980 A CN109330980 A CN 109330980A
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达留什·贝赫纳姆
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Abstract

本发明涉及一种由姜黄素和至少一种乳化剂所组成的增溶物，其中姜黄素的成分小于或等于10重量％，优选小于或等于7.5重量％,特别优选为6重量％，乳化剂具有在13至18之间的范围内的HLB值，该乳化剂特别是聚山梨酯80或聚山梨酯20或聚山梨酯20与聚山梨酯80的混合物，其中加载有姜黄素的胶束的平均直径在5nm至40nm之间，优选在6nm至20nm之间，特别优选在7nm至10nm之间。

Description

姜黄素增溶物
技术领域
本发明涉及一种姜黄素增溶物。
背景技术
姜黄素是一种姜黄属提取物并且上百年以来作为调料、食用色素(E100)，但也作为传统医学中的药物以及在近十年来通过大量研究结果的发表而在现代医学中在免疫、成骨、血管生成、细胞生成和神经再生和致癌方面作为有效成分广泛地为人所熟知。
姜黄素在大量的最终产品(营养补充品)中，例如在胶囊或液体的混合饮料中，以单纯形态(粉末)或结合辅料而提供，所结合的辅料例如是油、甘油、乙醇、磷脂或卵磷脂、环糊精、阿拉伯胶、明胶、果胶、食用脂肪酸或皂草苷的糖酯。然而，在此的问题在于，这些配方并不是透明的，没有得出水质的、清澈溶液并且具有极低的吸收率，即，生物利用度。
为了提高生物利用度，已知除了姜黄素以外还利用其它用于提供载体系统(例如像是乳剂或脂质体)的成分。姜黄素在乳剂中溶解于亲脂相中并且以滴状而在含水环境中得以稳定，而在脂质体中姜黄素则能够保持在磷脂层中。因此，生物利用度虽然可升高最多至50％,不过，像是脂质体的这类配方机械上非常不稳定并且不能抵抗胃内的环境。
发明内容
在现代医学中,姜黄素因其特别与神经再生(尤其是阿尔茨海默病)以及致癌物质(癌)之间的联系而受到了特别的关注。为了能够预防这些主要与年龄相关的、同时具有在国民经济方面威胁性程度的常见病，本发明的目的在于，通过一种相应适合的配方，对姜黄素的吸收率，即生物利用度，进行优化。另外，本发明的目的还在于，实现姜黄素在相应的最终产品中，例如在食品和营养补充品中稳定、平均的精细分布。
本发明提供了一种胶态的姜黄素配方，在以此为基础的临床研究的范围内，与纯的姜黄素相比，可以确定了至少高出230倍的生物利用度。本发明提供了一种由姜黄素和至少一种具有在13至18之间的范围内的HLB值的乳化剂所组成的增溶物，其中姜黄素的成分小于或等于10重量％，优选小于或等于7.5重量％,特别优选6重量％，乳化剂特别是聚山梨酯80或聚山梨酯20或聚山梨酯20与聚山梨酯80的混合物，其中加载有姜黄素的胶束的平均直径在5nm至40nm之间，优选在6nm至20nm之间，特别优选在7nm至10nm之间。
因此，在不会使胶束爆裂以及在用水稀释时使姜黄素作为沉积物析出的条件下，能够以有利的方式实现具有姜黄素的胶束的高负载。
根据本发明的透明并且完全水溶稳定的姜黄素配方，在没有上述辅料的前提下，例如在明胶软胶囊及明胶硬胶囊、不含明胶的胶囊(硬和/或软)和在饮料或基于水的液态的最终产品中，无关于pH值地具有稳定的透明度和此外明显优化的生物利用度。从相关产业方面而言，为了作为胶囊填充以及作为透明的姜黄素饮料的创新产品，急迫地寻求具有姜黄素配方的这样的透明度和水溶能力以及这样特别高的生物利用度的产品。根据发明者的了解，目前还不存在满足了这些需求的姜黄素配方。
在根据本发明的增溶物中的胶束的特别小的体积促成了清澈并持久透明的产品。较窄的颗粒尺寸分布也为此起到了作用，因为胶束的直径分布仅为从大约4nm到30nm。
根据动态光散射原理，以180°的反向散射装置利用波长为780nm的激光来测量胶束的颗粒尺寸分布。通过小的颗粒尺寸，以有利的方式，实现了特别对于肉眼观感而言清澈的液体的形成。增溶物的清澈度也特别通过其极低的浊度而得以体现。
为此，应用以下工作假设:增溶物或其它一种姜黄素配方的含水稀释物越是清澈，那么其增溶效果就越好。增溶效果越好，那么生物利用度就越好。
根据本发明的增溶物的特征还在于，在口服了以增溶物形式的500mg姜黄素一个小时后，在人体血浆中测得的姜黄色素总浓度为大约500ng姜黄色素/mL血浆±100ng姜黄色素/mL血浆。与此相比，在口服了以粉末形式的纯姜黄素一个小时后，仅达到大约1.3ng姜黄色素/mL血浆。
这个值是基于在年龄在19至29岁之间的24个健康人中实施的临床研究而得出的，这些人单次口服了500mg剂量的纯姜黄素或以根据本发明的增溶物的形式的姜黄素。在服用姜黄素后的24个小时之内的不同时间点，获取了血液样本。为了最小化同时消化的食物所造成的可能影响，对测试人群提供了统一标准化的膳食。在服用了以单纯形式的姜黄素一个小时后，测量到小于1nmol/L血浆，在服用8小时后为2.4nmol/L以及在服用24小时后为2.4nmol/L。与此相比，在根据本发明的增溶物中的姜黄素的情况下，在服用了一个小时后，测得1.964nmol/L血浆，服用8个小时后已经为307.1nmol/L并且在服用了24小时后为67.7nmol/L。就此使用了具有66.5重量％的姜黄素的增溶物(作为商品而标明为申请者的“6％NovaSOL curcumin”)。因此显示出,与单纯的姜黄素相比，通过作为根据本发明增溶物的配方，血浆中的姜黄素浓度增加了36至2800倍。
经24个小时的时间段，在血浆中的姜黄素总浓度曲线下方的面积(area underthe total curcumin plasma concentration-time curve AUC)在服用单纯姜黄素的情况下为42.6nmol h/L，而在服用根据本发明的增溶物的情况下为9821.4nmol h/L。总的来说，根据本发明的姜黄素增溶物在经24小时的血浆AUC处于大约9500至大约10000nmol h/L的范围。
由此，66.5％的姜黄素增溶物的生物利用度明显优于单纯形态的姜黄素的生物利用度。通过24小时的血浆AUC观察，通过根据本发明的增溶物的配方生物利用度升高了大约230倍。
这个生物利用度在增溶物的极低的浊度中就可以看出，该浊度可以理解为对于生物利用度而言的一种特征值。通过根据ISO 7027标准规范，在增溶物以1：1000的比例在水中稀释的条件下，利用红外线的散射测量，测得根据本发明的增溶物的浊度小于30FNU,优选小于20FNU，并且特别优选处于0.5FNU至2FNU的范围内。
根据本发明的增溶物在21℃且pH7的条件下存放24小时以后，同样地在37℃且pH1.1的条件下存放1小时后，还是保持这个低的浊度，也就是说，一方面是在室温的存放条件下在含水稀释液中的情况下，另一方面是在通过胃部的情况下。因此，根据发明者的现有理解，在根据本发明的增溶物中的姜黄素在经过胃部以后还是以稳定的、非常小的胶束的形式存在，并且可以因此特别好地被后来的消化道吸收。
为了浊度的试验性测定,利用标准悬浮物来将浊度测量仪校准。因此，不是以测量到的光线强度的形式而是以校准的悬浮物的浓度的形式来进行显示。在任意悬浮物的测量中，因此显示值的意思是相应液体像所示浓度的标准悬浮物一样导致了同样的光散射。国际规定的浊度标准是福尔马肼(Formazin)。标识“FNU”属于最常用的单位，它的意思是福尔马肼散射浊度单位(“Formazine Nephelometric Units”)。这例如是在水处理当中用于根据ISO 7072标准的规定在90°的情况下测量而使用到的单位。通过根据ISO 7027标准的规定，在增溶物以1：1000的比例在水中稀释的情况下，利用红外线的散射光测量，测得根据本发明的增溶物的浊度小于30FNU，优选小于20FNU，并且特别优选处在0.5FNU至2FNU之间。
根据不同的应用情况，根据本发明，增溶物可以包含最多到5重量％的水和/或12重量％至20重量％的甘油。
以有利的方式已证实，根据本发明的增溶物能够为了口服而以简单的形式在胶囊中提供，因为该增溶物不会腐蚀胶囊。因此，本发明也提供以增溶物填充的胶囊，其中该胶囊能够以明胶硬胶囊或明胶软胶囊的形式，或者以不含明胶的软胶囊或不含明胶的硬胶囊的形式来构造。
一种其它的给药方式是，含有根据本发明的增溶物的液体，其中该液体可以为食物、饮料、化妆制品(特别是例如乳霜、乳液或软膏)或者药剂产品。该液体可以特别含有该增溶物的含水稀释液。在液体中的根据本发明的增溶物的适用性与其粘度无关，同样，该增溶物既可以加入亲水介质中又可以加入亲脂介质中。
附图说明
图1中示出了不同姜黄素配方的样本的照片。
具体实施方式
下面，对根据本发明的增溶物的实施例进行描述。
颗粒大小的测量借助于ParticleMetrix NANOTRAC反散射颗粒分析仪(Rueckstreu-Teilchenanalysator)来实施。测量原理以在180°外差后向散射装置(Heterodyn-Rueckstreuanordnung)中的动态光散射(DLS)为基础。在这个几何形状中将一部分激光混入到散射光中。像是傅里叶光谱仪(Fourier-Spektrometer)中的所有波长的叠加一样，这在信噪比方面具有同样正面的影响。样本的颜色对于测量的质量没有影响。在1000倍的含水稀释中实施测量。为此通过搅拌将增溶物溶解在水中。该增溶物可以完全清澈地溶解在水中。该溶液是稳定且透明的。
实施例1:具有聚山梨酯80的姜黄素增溶物
为了制造增溶物而只使用了930g的聚山梨酯80以及70g的95％的姜黄素粉末。在这70g中含有95％的姜黄素，即，66.5g。
作为聚山梨酯80能够使用商用标准的制剂，例如像是TEGO SMO20V、InCoPa或Crillet 4/Tween 80-LQ-(SG)、Croda或Lamesorb SMO 80、Cognis。作为95％的姜黄素粉末同样地能够使用商用标准的制剂，例如Oleoresin Turmeric 95％(curcumin powder)、Jupiter Leys或Curcumin BCM-95-SG、Eurochem或Curcumin BCM-95-CG、Eurochem或Curcuma Oleoresin 95％、Henry Lamotte。
将聚山梨酯80加热到大约48℃至大约52℃。在搅拌下将姜黄素粉末缓慢加入到聚山梨酯80中。在将姜黄素粉末加入的过程中继续加热到大约87℃至大约91℃。将产生的增溶物冷却到大约60℃以下，随后就已准备好用于灌装。
增溶物是橙黄色至红色的、非常深色的、和色彩浓郁或者透明的。
以减少聚山梨酯80的份额为代价，能够将姜黄素份额提高至大约10重量％。
实施例2:具有聚山梨酯20的姜黄素增溶物
为了制造增溶物而只使用了894g的聚山梨酯20以及106g的95％的姜黄素粉末。在这106g中含有95％的姜黄素，即，100.7g。
作为聚山梨酯20能够使用商用标准的制剂，例如像是TEGO SML 20V、InCoPa或Tween 20、Crillet 1-LQ-(SG)、Croda或Lamesorb SML 20、Cognis。作为95％的姜黄素粉末同样地能够使用商用标准的制剂，例如Oleoresin Turmeric 95％(curcumin powder)、Jupiter Leys或Curcumin BCM-95-SG、Eurochem或Curcumin BCM-95-CG、Eurochem或Curcuma Oleoresin 95％、Henry Lamotte。
将聚山梨酯20加热到大约63℃至大约67℃。在搅拌下将姜黄素粉末缓慢加入到聚山梨酯20中。在将姜黄素粉末加入的过程中继续加热到大约83℃至大约87℃。将产生的增溶物缓慢冷却到大约45℃以下，随后就已准备好用于灌装。
增溶物是橙黄色至红色、非常深色和颜色浓郁或者透明的。
在以聚山梨酯20的份额为代价的条件下能够改变姜黄素的份额。
在附加的图1中，示出了不同姜黄素配方的样本的照片。在图片的左侧示出了在加入水中后、在21℃的温度、在中性条件下(pH7)存放24小时后的样本。在图片的右侧示出了在加入水中后、在37℃温度、以像是胃中(pH 1.1)一样的条件、在物理条件下存放1小时后的样本。对初始制剂中加入了同量的水，从而使在所示出的样本中的姜黄素浓度为11.4g/L。
对以下的配方进行详细地对比。
样本A:
姜黄素提取物，单纯形态，粉末，95％姜黄素(BCM 95)。在1升水中加入12g的粉末。
样本B:
17.5％的姜黄素微粒，粉末，Raps。在1升水中加入65.1g的粉末。
样本C:
13％的姜黄素制剂，粉末，Wacker Chemie。在1升水中加入87.7g
的粉末。
样本D:
按照实施例1的根据本发明的姜黄素增溶物。在1升的水中加入200g的液态增溶物。
在室温且中性条件下以及在37℃且酸性条件下都能够看出样本A、B和C既有沉淀物形成又有相分离，而样本D则是清澈且均相的。此外根据本发明的增溶物在-20℃至100℃的总温度区间内没有显示出相分离以及沉淀物形成。此外，样本D既在室温且中性条件下又在37℃且酸性条件下显示变红，由此，以黑白照片，该样本显得比变橙黄的样本A、B和C要明显更深色。
对于专业人员明显的是，本发明并不局限于以上所述的实施例，而是能够以多种方式而变化。特别是这些单个实施例的特征也可以相互组合或相互替换。

Claims (21)

1.一种增溶物，所述增溶物由姜黄素和至少一种乳化剂组成，
其中所述姜黄素具有6-10重量％的份额，所述至少一种乳化剂具有在13至18之间的范围内的HLB值，所述乳化剂是聚山梨酯80或聚山梨酯20或聚山梨酯20与聚山梨酯80的混合物，其中，加载有所述姜黄素的胶束的平均直径在5nm至40nm之间，
其特征在于，
根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在37℃且pH1.1的条件下存放1小时后，所述增溶物的浊度小于30FNU。
2.根据权利要求1所述的增溶物，其特征在于，所述姜黄素具有小于或等于7.5重量％的份额。
3.根据权利要求1所述的增溶物，其特征在于，所述姜黄素具有6重量％的份额。
4.根据权利要求1所述的增溶物，其特征在于，加载有所述姜黄素的胶束的平均直径在6nm至20nm之间。
5.根据权利要求1所述的增溶物，其特征在于，加载有所述姜黄素的胶束的平均直径在7nm至10nm之间。
6.根据权利要求1所述的增溶物，其特征在于，所述胶束的直径分布的范围从大约4nm达到大约30nm。
7.根据上述权利要求中的任意一项所述的增溶物，其特征在于，在口服了以根据上述权利要求中的任意一项所述的增溶物的形式的500mg姜黄素一个小时后，在人体血浆中测得的姜黄色素总浓度为大约500ng姜黄色素/mL血浆±100ng姜黄色素/mL血浆。
8.根据权利要求1所述的增溶物，其特征在于，作为血浆中姜黄色素总浓度的曲线下方的面积(area under the total curcumin plasma concentration-time curve AUC)，经24个小时的时间段而在人体血浆中测得的姜黄色素总浓度在大约9500nmol h/L至大约10000nmol h/L的范围内。
9.根据权利要求1所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，所述增溶物的浊度小于30FNU。
10.根据权利要求9所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，所述增溶物的浊度小于20FNU。
11.根据权利要求9所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，所述增溶物的浊度处于0.5FNU至2FNU之间的范围内。
12.根据权利要求1所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在21℃且pH7的条件下存放24小时以后，所述增溶物的浊度小于30FNU。
13.根据权利要求12所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在21℃且pH7的条件下存放24小时以后，所述增溶物的浊度小于20FNU。
14.根据权利要求12所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在21℃且pH7的条件下存放24小时以后，所述增溶物的浊度处于0.5FNU至2FNU之间的范围内。
15.根据权利要求1所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在37℃且pH1.1的条件下存放1小时后，所述增溶物的浊度小于20FNU。
16.根据权利要求1所述的增溶物，其特征在于，根据ISO 7027标准的规定，在所述增溶物以1：1000的比例在水中稀释的情况下，通过利用红外线的散射光测量而测得，在37℃且pH1.1的条件下存放1小时后，所述增溶物的浊度处于0.5FNU至2FNU之间的范围内。
17.根据权利要求1所述的增溶物，其特征在于，所述增溶物含有最多5重量％的水。
18.根据权利要求1所述的增溶物，其特征在于所述增溶物包含12重量％至20重量％的甘油。
19.以根据上述权利要求中的任意一项所述的增溶物来填充的胶囊，其特征在于，所述胶囊构造为明胶软胶囊或明胶硬胶囊，或者构造为不含明胶的软胶囊或不含明胶的硬胶囊。
20.含有根据权利要求1至18中的任意一项所述的增溶物的液体，其特征在于，从包括了食品、饮料、化妆品以及制药产品的组别中选择所述液体。
21.根据权利要求20所述的液体，其特征在于，所述液体包含了所述增溶物的含水稀释液。
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