CN112912084B - 芸香苷组成物 - Google Patents

芸香苷组成物 Download PDF

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CN112912084B
CN112912084B CN202080005297.4A CN202080005297A CN112912084B CN 112912084 B CN112912084 B CN 112912084B CN 202080005297 A CN202080005297 A CN 202080005297A CN 112912084 B CN112912084 B CN 112912084B
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rutin
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vitamin
water
arginine
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来田浩明
山口直人
小野光则
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Alps Pharmaceutical Industry Co ltd
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Abstract

一种包含芸香苷、L‑精氨酸及一抗坏血酸的碱盐的水溶性组成物，其中该芸香苷、L‑精氨酸及该抗坏血酸的碱盐之间的摩尔比率为1:1.6‑3.0:0.1‑2.0。

Description

芸香苷组成物
技术领域
本发明为有关于芸香苷组成物。
背景技术
芸香苷为一种O-糖苷基类黄酮，其展现广泛的生物活性。
举例而言，其已显示可预防血液凝块的形成。预防血液凝块可以帮助降低发展危及生命状况的机会，诸如心肌梗塞、中风、肺栓塞及深层静脉血栓。参见Punithavathi etal.,Cardiovasc.Toxicol.,2010,10(3):181-189,Ortolani et al.,Transplant Proc.,1995,27(5):2877-2888),Morling et al.2013,Cochrane Database Syst.Rev.4:Apr 30,and Morling et al.,2018,Cochrane Database Syst Rev.11:Nov 8。
在另一例子中，芸香苷已被测试用于治疗慢性静脉功能不全(chronic venousinsufficiency,CVI)，CVI为一种由瓣膜功能异常所导致的常见疾病，其伴随或不伴随通常发生在下肢的阻塞。
然而，芸香苷因为不良吸收而具有低生物体可用率，限制其作为一治疗剂的潜力。已开发具有较高水溶性的经酶促修饰的芸香苷(enzymatically modified rutin,EMR)以改善芸香苷的生物体可用率，参见Toyo Sugar Refining Co.,Ltd HP(alfa G-rutin)。然而，EMR为一种具有至少3种生物活性芸香苷衍生物的混合物，参见Akiyama et al.,J.FoodHyg.Soc.Japan,1999,41:54-60。根据目前美国联邦药物管理局指南，在人体中使用此种活性组分的混合物作为一药物不切实际。
需要开发展现芸香苷的高口服吸收且具有经改善的水溶性但不具有上述缺点的组成物。
发明内容
为满足上述需求，提供一种水溶性组成物，其含有芸香苷、L-精氨酸及一抗坏血酸的碱盐。在该组成物中，该芸香苷、L-精氨酸及该抗坏血酸的碱盐之间的摩尔比率为1:1.6-3.0:0.1-2.0。
在以下描述中阐明本发明的细节。从该详细描述、该等图式及该等所附权利要求，本发明的其他特征、目的及优点将显而易见。
附图说明
以下描述参考该等随附图式，其中：
图1为一显示调配物1(芸香苷)及调配物2(芸香苷/精氨酸)至Caco-2细胞中的渗透比率(％)的条形图；
图2为一血浆中芸香苷浓度对时间的图；
图3为一血浆中芸香苷浓度对时间的图。
具体实施方式
较佳实施例的详细说明。
如上所述，揭露一种水溶性组成物，其含有L-精氨酸、芸香苷及一抗坏血酸碱盐。此等3种成分之间的摩尔比率为1:1.6-3.0:0.1-2.0。在本发明的另一组成物中，该比率为1:1.8-2.8:0.2-1.5。一例示性水溶性组成物含有芸香苷、L-精氨酸及一抗坏血酸的碱盐，其摩尔比率为1:2.3:0.42。
值得注意地，该抗坏血酸的碱盐可以为一钠盐或一钾盐。在一特定的组成物中，该碱盐为一钠盐。
除了芸香苷、L-精氨酸及一抗坏血酸的碱盐以外，该水溶性医药组成物也可以包括维生素B1、维生素B3、维生素B6、维生素B9或维生素B12。在该组成物中芸香苷与每种水溶性维生素的摩尔比率可以为1:0.01-0.1。
上述该等具有芸香苷、L-精氨酸及抗坏血酸的碱盐的水溶性组成物可以藉由在美国专利申请案第62/661,255号及第62/720,651号，以及国际申请案第PCT/JP2019/017262号中所述的方法制备，其全部内容并入本文中。
在该水溶性组成物中，芸香苷可以为以10wt％或更高(例如，20wt％或更高，30wt％或更高，及50wt％或更高)的含量存在。L-精氨酸也为以10wt％或更高(例如，20wt％或更高，30wt％或更高，及50wt％或更高)存在。该抗坏血酸的碱盐为以2wt％或更高(例如，4wt％或更高，6wt％或更高，及10wt％或更高)存在。
该水溶性组成物可以为以固体形式或水溶液形式被掺入用于医药、医疗、食品保存或化妆用途的调配物中。
举例而言，该水溶性组成物可以被调配成一液体、一胶囊、一锭剂、一丸剂或一凝胶以用于口服投药。该呈胶囊或锭剂形式的组成物可以具有一肠溶膜衣。
该等用于口服投药的调配物也可以含有一医药活性剂、一医药可接受的赋形剂或其等的组合。此等调配物可以为一药物、一膳食补充品、一天然保健品、一化妆品、一食品或一饮料。
若被调配用于局部投药，该组成物可以为一溶液、一擦剂、一洗剂、一乳剂、一软膏、一糊剂、一凝胶或一乳胶(emulgel)。局部调配物也可以含有一医药活性剂、一局部可接受之赋形剂或其等的组合。此等调配物可以为一化妆品、一护肤品或一药物。
无需进一步阐述，相信本发明所属技术领域中具有通常知识者可以基于以上描述最大程度地利用本发明。因此，以下具体实施例应被解释为仅用于说明，而不以任何方式限制本揭露内容的其余部分。在本文中所引用的所有公开文献均以全文引用的方式并入本文中。
实施例1：一水性芸香苷/L-精氨酸/抗坏血酸钠组成物的制备
藉由将0.0071mol芸香苷与一含有0.020mol L-精氨酸的水溶液混合，将该混合物加热至80℃直至该芸香苷完全地溶解，并添加0.0010mol抗坏血酸钠，以在水中制备一含有芸香苷、L-精氨酸及抗坏血酸钠的组成物。
在冷却上述溶液之后，藉由将该混合物加热至50℃，并在0小时、5小时及24小时之后藉由HPLC定量余留的完整芸香苷的量，以测试芸香苷的稳定性。结果显示在该溶液中完整芸香苷的量在50℃下在第5小时及第24小时分别为芸香苷之初始量的100％及97.2％。
进行一类似的研究以评估一与芸香苷相关的类黄酮，也即儿茶素的稳定性，在使用L-精氨酸及抗坏血酸钠将其溶解之后。余留在该溶液中的完整儿茶素的量在50℃下在5小时及24小时之后分别为30.8％及2.3％。出乎意料的是在相同的条件下，在24小时之后仅有2.8％的芸香苷降解，相较于97.7％的儿茶素降解。
实施例2：一固体芸香苷/L-精氨酸/抗坏血酸钠组成物的制备
藉由将125.0g的L-精氨酸(0.72mol)溶解于经加热至45℃的650ml水中，添加22.9g的L-抗坏血酸钠盐(0.12mol)及29.9g的氢化糊精，并搅拌直至完全地溶解，以制备第二种芸香苷/L-精氨酸/抗坏血酸盐组成物。将170.3g的芸香苷三水合物(0.26mol)添加至该溶液中，并将所得的混合物在80℃下加热30分钟。该芸香苷完全溶解后，对该溶液进行喷雾干燥并以80网目筛分，得到一黄橙色固体组成物(326.9g)。
实施例3：芸香苷医药调配物的制备
使用在下列表1中所示的成分制备芸香苷/抗坏血酸钠以及芸香苷/L-精氨酸/抗坏血酸盐的调配物。针对溶解研究，该等调配物为按原样使用。针对临床研究，该等调配物被囊封于由Capsugel所制造的尺寸#1耐酸延迟释放羟丙基甲基纤维素胶囊(DRcapsTM)中。
表1.芸香苷调配物成分
组分 调配物1 调配物2
芸香苷(mg)/(w/w％) 250mg/56.7％ 250mg/42.4％
L-精氨酸(％) - 31.0％
抗坏血酸钠(w/w％) 7.7％ 5.8％
糊精(w/w％) 29.7％ 16.4％
脂肪酸甘油酯(w/w％) 5.9％ 4.4％
总和(w/w％) 100％ 100％
实施例4：溶解度测试
如下所述，测试来自于调配物1及调配物2的芸香苷溶解于水中的能力。
将一定量的含有250mg芸香苷的调配物1以及一定量的含有250mg芸香苷的调配物2分别添加至单独的25mL蒸馏水中，并搅拌30秒。在取出一等分试样之后(0分钟)，在缓慢搅拌下在37℃下加热每个混合物。在热处理开始之后的第5分钟及第30分钟，从每个混合物收集等分试样。使每个等分试样通过一0.45μm过滤器，并藉由HPLC测量在该滤液中的芸香苷浓度。该等结果显示于下列表2中。
表2.芸香苷的水溶解度
培养时间 调配物1 调配物2 倍数差异
0分钟 0.036mg/ml 8.4mg/ml 233
5分钟 0.064mg/ml 9.6mg/ml 150
30分钟 0.073mg/ml 9.8mg/ml 134
结果显示，来自于调配物2的芸香苷所溶解的量，即芸香苷/L-精氨酸/抗坏血酸盐，高于来自于不含L-精氨酸之调配物I的芸香苷所溶解的量134至233倍。显然，相较于调配物1，调配物2含有显著较多的可溶性芸香苷。
实施例5：在Caco-2细胞中的渗透作用研究
测量一药物至经培养的肠道Caco-2细胞中的渗透作用，以预测口服给药时该药物的相对吸收速率。
将上述实施例3中的该等调配物单独地溶解于一溶液中。将每种溶液的一500μL等分试样添加至已培养19天的Caco-2细胞的顶面，并将2,000μL的HBSS缓冲液置于该等细胞的底侧面。将该等细胞在一培养箱中在37℃下培养2小时，之后从该等细胞的顶面及底侧面回收培养基。藉由HPLC测定在培养基中的芸香苷浓度，并藉由以下方程式确定从顶面至底侧面的吸收程度：
Figure GDA0003463040670000071
该等结果显示于图1中。相较于含有芸香苷及抗坏血酸盐但缺乏L-精氨酸的调配物1，含有芸香苷、L-精氨酸及抗坏血酸盐的调配物2的渗透(吸收)速率显著增加18倍。
实施例6：临床药物动力学研究
进行一随机临床药物动力学研究，以比较在禁食条件下以单剂量对8名志愿者投予上述实施例3中的2种不同芸香苷调配物。年龄介于25至39岁之间且具有身体质量指数数值在18.6-24.7的范围内的健康男性参与本研究。
如上所述制备含有在表1中所显示的调配物1及调配物2的胶囊。每位志愿者服用(i)4个含有调配物1的胶囊(芸香苷/抗坏血酸盐；总计1000mg芸香苷)，(ii)2个含有调配物2的胶囊(芸香苷/L-精氨酸/抗坏血酸盐；总计500mg芸香苷)，或(iii)根据先前随机的顺序在3个测试日投予4个调配物2的胶囊(芸香苷/L-精氨酸/抗坏血酸盐；1000mg芸香苷)。
按照既定程序，测量在服药之前(0小时)以及在服药之后0.5小时、1小时、2小时、4小时及8小时从该等参与者取出的血液样品中的芸香苷水平，而某些样品在服药之后48小时被取出。更具体地，为了测量芸香苷水平，首先处理从每个血液样品所制备的血浆，以将芸香苷及其代谢物去共轭(deconjugate)成糖苷配基(aglycones)、槲皮素(quercetin)及异鼠李素(isorhamnetin)，随后藉由HPLC对其进行定量。
简言之，将200μl血浆样品与10μl 10％二硫苏糖醇及50μl 0.58mol/L醋酸混合。在37℃下在0.1M醋酸钠缓冲液(pH5.0)中以100U的β-葡萄糖醛酸酶H-5型(其具有β-葡萄糖醛酸酶及硫酸酯酶，亦即去共轭作用活性)处理该混合物120分钟。
在去共轭作用之后，将500μl的10mM草酸添加至每个样品中，并将该混合物以10,000mg离心5分钟。按照制造商(Waters,Milford MA USA)指示，使用预调节的Oasis HLB萃取柱对所有经处理的样品进行固相萃取。经萃取的析出液在氮气下蒸发，在甲醇中复原，并将每个析出液装载至一C18管柱(Waters ACQUITY UPLC BEH；1.7μm,2.1×100mm)以进行HPLC分析，运用0.1％甲酸水溶液/0.1％甲酸乙腈溶液HPLC中的梯度溶剂系统，并使用ACQUITY UPLC I-class Plus·Xevo TQ-S micro(Waters)检测槲皮素及异鼠李素的存在。使用由真实的槲皮素及异鼠李素内标(internal standards)制成的标准曲线计算每种糖苷配基的浓度。在上述条件下，槲皮素及异鼠李素的分析极限为3.3nM。
该等结果显示于图2及图3中。
图2显示在摄入500mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷以及摄入1000mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷之后的48小时期间，共轭芸香苷代谢物的血浆浓度的时间进程(time course)。该等代谢物的血浆浓度稳定地增加，在摄入之后的第8.5小时(500mg)及第9.3小时(1000mg)达到最高水平。在24小时之后水平降低至背景。
由与图2所描绘相似的曲线所计算的药物动力学数值系显示于下列表3中。
表3.芸香苷组成物的药物动力学
Figure GDA0003463040670000091
图3显示在服用500mg芸香苷/抗坏血酸盐的芸香苷、500mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷、及1000mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷之后的8小时期间，共轭芸香苷代谢物的血浆浓度的时间进程。500mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷及1000mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷两者在第8小时的药物动力学曲线显示，血浆中芸香苷代谢物的出现速度明显快于不含L-精氨酸的芸香苷。
由与图3所描绘相似的曲线所计算的药物动力学数值系显示于下列表4中。
表4.芸香苷及芸香苷组成物的比较药物动力学
Figure GDA0003463040670000092
Figure GDA0003463040670000101
500mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷及1000mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷的经计算的曲线下的面积(AUCs)显示剂量依赖关系。进一步，500mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷及1000mg芸香苷/L-精氨酸/抗坏血酸盐的芸香苷从0-8小时的AUCs分别比不含L-精氨酸的芸香苷的AUCs高约2.5倍及4.0倍。显然，芸香苷与L-精氨酸及抗坏血酸盐结合可显著地改善芸香苷的口服吸收。
在此说明书中所揭露的所有特征可以以任何组合来组合。在此说明书中所揭露的每个特征可以由具有相同、等同或相似目的的替代特征所代替。因此，除非另有明确说明，否则所揭露的每个特征仅是一系列等同或相似特征的一范例。
此外，根据以上描述，本发明所属技术领域中具有通常知识者可以容易地确定本发明的必要特征，并且在不脱离本发明的精神及范围的情况下，可以对本发明进行各种改变及修改以使其适应各种用途及条件。因此，其他实施态样亦在申请专利范围之内。

Claims (16)

1.一种包含芸香苷、L-精氨酸及一抗坏血酸的碱盐的水溶性组成物，其中该芸香苷、L-精氨酸及该抗坏血酸的碱盐之间的摩尔比率为1:1.6-3.0:0.1-0.46。
2.如权利要求1所述的水溶性组成物，其中所述抗坏血酸的碱盐为一钠盐或一钾盐。
3.如权利要求2所述的水溶性组成物，其中所述组成物为一选自于由一液体、一胶囊、一锭剂、一丸剂及一凝胶所组成的群组的口服调配物。
4.如权利要求2所述的水溶性组成物，其中该组成物为一选自于由一溶液、一擦剂、一洗剂、一乳剂、一软膏、一糊剂、一凝胶及一乳胶所组成的群组的局部调配物。
5.如权利要求1所述的水溶性组成物，其进一步包含维生素B1、维生素B3、维生素B6、维生素B9或维生素B12。
6.如权利要求5所述的水溶性组成物，其中该组成物为一选自于由一液体、一胶囊、一锭剂、一丸剂及一凝胶所组成的群组的口服调配物。
7.如权利要求5所述的水溶性组成物，其中该组成物为一选自于由一溶液、一擦剂、一洗剂、一乳剂、一软膏、一糊剂、一凝胶及一乳胶所组成的群组的局部调配物。
8.如权利要求2所述的水溶性组成物，其进一步包含维生素B1、维生素B3、维生素B6、维生素B9或维生素B12。
9.如权利要求1所述的水溶性组成物，其中该芸香苷、L-精氨酸及该抗坏血酸的碱盐之间的摩尔比率为1:1.8-2.8:0.2-0.46。
10.如权利要求9所述的水溶性组成物，其中该芸香苷、L-精氨酸及该抗坏血酸的碱盐之间的摩尔比率为1:2.3:0.42。
11.如权利要求9所述的水溶性组成物，其中该抗坏血酸的碱盐为一钠盐或一钾盐。
12.如权利要求9所述的水溶性组成物，其中该组成物为一选自于由一液体、一胶囊、一锭剂、一丸剂及一凝胶所组成的群组的口服调配物。
13.如权利要求9所述的水溶性组成物，其中该组成物为一选自于由一溶液、一擦剂、一洗剂、一乳剂、一软膏、一糊剂、一凝胶及一乳胶所组成的群组的局部调配物。
14.如权利要求9所述的水溶性组成物，其进一步包含维生素B1、维生素B3、维生素B6、维生素B9或维生素B12。
15.如权利要求14所述的水溶性组成物，其中该组成物为一选自于由一液体、一胶囊、一锭剂、一丸剂及一凝胶所组成的群组的口服调配物。
16.如权利要求14所述的水溶性组成物，其中该组成物为一选自于由一溶液、一擦剂、一洗剂、一乳剂、一软膏、一糊剂、一凝胶及一乳胶所组成的群组的局部调配物。
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