CN112955151A - 异槲皮素组成物 - Google Patents
异槲皮素组成物 Download PDFInfo
- Publication number
- CN112955151A CN112955151A CN202080005307.4A CN202080005307A CN112955151A CN 112955151 A CN112955151 A CN 112955151A CN 202080005307 A CN202080005307 A CN 202080005307A CN 112955151 A CN112955151 A CN 112955151A
- Authority
- CN
- China
- Prior art keywords
- water
- vitamin
- composition
- pharmaceutical composition
- isoquercetin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000000203 mixture Substances 0.000 title claims description 67
- GXMWXESSGGEWEM-UHFFFAOYSA-N isoquercitrin Natural products OCC(O)C1OC(OC2C(Oc3cc(O)cc(O)c3C2=O)c4ccc(O)c(O)c4)C(O)C1O GXMWXESSGGEWEM-UHFFFAOYSA-N 0.000 title description 14
- OVSQVDMCBVZWGM-QCKGUQPXSA-N isoquercetin Natural products OC[C@@H]1O[C@@H](OC2=C(Oc3cc(O)cc(O)c3C2=O)c4ccc(O)c(O)c4)[C@H](O)[C@@H](O)[C@@H]1O OVSQVDMCBVZWGM-QCKGUQPXSA-N 0.000 claims abstract description 51
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- -1 alkali metal salt Chemical class 0.000 claims abstract description 19
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- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 3
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Images
Classifications
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
一种水溶性药学组成物,其包含异槲皮素、L‑精氨酸,以及抗坏血酸或抗坏血酸的碱金属盐,其中异槲皮素、L‑精氨酸以及抗坏血酸或抗坏血酸的碱金属盐之间的摩尔比为1:1.6‑2.6:0.16‑1.95。
Description
技术领域
相关申请案的交互参照
此申请案主张2019年1月24日所提申之美国临时申请案第62/796,126号之优先权。此先前的申请案之内容以其整体并入本文中以作为参考资料。
背景技术
异槲皮素是槲皮素的3-O-糖苷,而许多意想不到的生物活性已被归因于此。例如,已有报导,异槲皮素可抑制蛋白质双硫键异构酶(PDI),其为一种强烈涉及血栓形成的酵素。参见Flaumenhaft et al.,Arteriosclerosis,Thrombosis,and Vasc.Biol.,2015,35:16-23。人们认为,PDI的抑制剂(例如,异槲皮素)可预防或阻止血栓形成。
为了测试异槲皮素抑制癌症-相关的血栓形成的能力,第II/III期临床试验正在进行中。参见于全球信息网clinicaltrials.gov上的CAT IQ试验。值得注意的是,在该试验中所投予的异槲皮素的每日剂量为500mg与1000mg。这些剂量相较于常用的药学剂量异常地高。可能的是,由于相对低的口服吸收,需要高剂量的异槲皮素来达至足够的生物可利用性。
经酵素改质的具有较高水溶度的异槲皮素(EMIQ)已被开发来改善异槲皮素的生物可利用性。参见Murota et al.,Arch.Biochem.Biophys.,2010,501:91-97。然而,EMIQ是至少五种具生物活性的异槲皮素衍生物的混合物。参见Akiyama et al.,J.FoodHyg.Soc.Japan,1999,41:54-60。依据目前美国联邦药品管理局规范,不能将此种活性成分的混合物用作人类药物使用。
有需要去发展一通过改善水溶解度而具有较高口服吸收且没有上述缺点的异槲皮素。
发明内容
为了满足上述需要,提供一种水溶性药学组成物,其包含异槲皮素、L-精氨酸,以及抗坏血酸的碱金属盐。在此组成物中,异槲皮素、L-精氨酸以及抗坏血酸的碱金属盐之间的摩尔比为1:1.6-2.6:0.16-1.95。
本发明的详细内容已描述于下面的说明中。由详细说明、附图以及所附的权利要求书,本发明的其他特征、目的以及优点将变得明显。
附图说明
图1为投予500mg的异槲皮素(IQC 500mg)以及以异槲皮素/L-精氨酸(IQC 250mg/Arg)的方式投予250mg的异槲皮素之后血浆浓度对时间的图式。
具体实施方式
较佳实施例的详细说明
如上所述,本文揭示一种水溶性组成物,其包含L-精氨酸、异槲皮素,以及抗坏血酸碱金属盐。这三种组分之间的摩尔比为1:1.6-2.6:0.16-1.95,较佳地,1:1.8-2.5:0.36-1.25。一种示范性水溶性组成物包含摩尔比为1:2.3:0.42的异槲皮素、L-精氨酸以及抗坏血酸的碱金属盐。
特别地,该抗坏血酸的碱金属盐可为钠盐或钾盐。在一个特定的组成物中,该碱金属盐为钠盐。
除了异槲皮素、L-精氨酸以及抗坏血酸的碱金属盐,该水溶性药学组成物也可包含维生素B1、维生素B3、维生素B6、维生素B9,或者维生素B12。异槲皮素对于在该组成物中的各个水溶性维生素的摩尔比可为1;0.01-0.1。
该水溶性药学组成物可配制来供口服投药或局部投药。例如,供口服投药的组成物可为一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。若配制来供局部投药,该组成物可为一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
可由在美国专利申请案第62/661,255号与第62/720,651号中所描述的方法来生产上述异槲皮素、L-精氨酸以及抗坏血酸的碱金属盐的水溶性组成物,这些专利案的内容以其整体并入本文中。
在水溶性组成物中,异槲皮素通常以10wt%以上(例如,20wt%以上、30wt%以上,以及50wt%以上)的含量而存在。L-精氨酸也存在有10wt%以上(例如,20wt%以上、30wt%以上,以及50wt%以上)。抗坏血酸的碱金属盐存在有2wt%以上(例如,4wt%以上、6wt%以上,以及10wt%或更高)。
异槲皮素可呈水合物形式或无水形式。相似地,L-精氨酸亦可呈水合物形式或无水形式。
水溶性组成物(无论固态形式或水性形式)可呈供药学、医学或化妆品用途的各种不同的配方。
在一个具体例中,该组成物是呈口服配方,例如,一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。一示范性组成物是呈分别由肠溶包衣所形成的胶囊或锭剂。该组成物可进一步含有一药学活性剂、一药学上可接受的赋形剂,或者它们的组合。此具体例包括一属于药品、膳食补充品、天然健康产品、化妆产品、食品产品或饮料的组成物。
在另一个具体例中,该组成物是呈局部配方,例如,溶液、擦剂、乳液、乳霜、软膏、糊剂、凝胶以及乳胶中的一者。该组成物可进一步含有一药学活性剂、一局部可接受的赋形剂,或者它们的组合。此具体例包括一属于化妆产品、护肤产品或药品的组成物。
在没有进一步阐明的情况下,可以确定的是,熟习此技艺者可基于上述说明将本发明利用至最充分的程度。因此,下面的具体实例应被理解仅为例示性,而不以任何方式限制本发明的其余部分。此处所引用的出版物以其整体并入本发明作为参考资料。
实施例1:制备异槲皮素/L-精氨酸样品
由以下来制备一示范性异槲皮素/L-精氨酸混合物:将0.01mol的异槲皮素与一含有0.02mol的L-精氨酸的水溶液进行混合,将该混合物加热至80℃直到异槲皮素完全溶解,然后添加0.001mol的抗血酸钠。冷却后,由以下方法来测试异槲皮素的安定性:将该混合物加热至50℃并且由HPLC来定量在0h、5h以及24h后剩余的完整异槲皮素的含量。结果显示,在50℃下5h与24h后之时完整异槲皮素的含量分别为异槲皮素在该溶液中的初始含量的100%与98.1%。进行类似的研究来分析与异槲皮素有关的类黄酮(即儿茶素)在以L-精氨酸以及抗坏血酸钠溶解后的安定性。在50℃下5h与24h后在溶液中剩余的完整儿茶素的含量分别为30.8%与2.3%。意想不到的是,24h后只有1.9%的异槲皮素降解,相对地在相同条件下有97.7%的儿茶素降解。
由以下来制备第二个示范性异槲皮素/L-精氨酸混合物:首先将105.5g的L-精氨酸(0.61mol)溶解于845ml加热至45℃的H2O中,接着添加20.9g的L-抗坏血酸钠盐(0.11mol)与46.5g的氢化聚糊精并且搅拌至完全溶解。
对上面的溶液添加127g的异槲皮素一水合物(0.26mol),并且将所形成的混合物于80℃加热30分钟。当异槲皮素完全溶解,将该溶液进行喷雾干燥并且以80筛目过筛。于真空下将残余的H2O蒸发而残留黏性油,继而于60℃进行真空干燥8小时,从而提供一黄橙色固态组成物(253.9g)。
实施例2:胶囊配方制备
使用下面表1中所示的组分来制备异槲皮素与异槲皮素/L-精氨酸的配方。针对溶解研究,该等配方依其原样来使用。针对临床研究,将该等配方包覆于Capsugel所制造的尺寸#1抗酸缓释羟丙基甲基纤维素胶囊(DRcapsTM)。
表1.配方内容物
成分 | 配方1 | 配方2 | 配方3 |
异槲皮素(mg)/(w/w%) | 250/77.9 | 125/32.2 | 62.5/19.9 |
L-精氨酸(%) | —— | 26.7% | 16.6% |
抗坏血酸Na盐(w/w%) | —— | 5.3% | 3.2% |
糊精(w/w%) | 15.8% | 11.8% | 7.3% |
结晶纤维素(w/w%) | —— | 19.0% | 46.7% |
甘油脂肪酸酯(w/w%) | 6.3% | 5.0% | 6.3% |
加总(w/w%) | 100% | 100% | 100% |
实施例3:溶解度测试
异槲皮素从配方1与配方2溶解至H2O中的能力被测量如下。
将适量的含有500mg异槲皮素的配方1与适量的含有250mg异槲皮素的配方2分别添加至25mL蒸馏H2O水中并搅拌历时30s。在移除未溶解部分(0min.)后,在缓慢搅拌下于37℃下对各个混合物进行加热。在开始热处理后的5min.与30min.时从各个混合物中收取未溶解部分。将各个未溶解部分通过0.45μm过滤器并且由HPLC来量测滤液中的异槲皮素浓度。结果显示于下面的表2中。
表2.异槲皮素的水溶解度
培育时间 | 配方1 | 配方2 | 倍数差异 |
0min | 0.02mg/ml | 7.9mg/ml | 395 |
5min | 0.06mg/ml | 9.9mg/ml | 165 |
30min | 0.07mg/ml | 9.8mg/ml | 140 |
结果显示,从配方2(即异槲皮素/L-精氨酸/抗坏血酸盐)溶出的异槲皮素的含量比从配方1(其没有L-精氨酸与抗坏血酸盐)溶出的异槲皮素的含量高140至395倍。明显地,相较于配方1,配方2含有显著更可溶的异槲皮素。
实施例4:Caco-2细胞的通透研究
通过量测药物在培养的肠道Caco-2细胞中的通透量,以预测当口服给药时药物的相对吸收率。
将在实施例2中的上述配方1与2分别添加至一溶液中。将各个样品的500μL的未溶解部分添加至已培养19天的Caco-2细胞的顶侧,以及将2,000μL的HBSS缓冲液至于细胞的基底侧。将细胞培育于培养箱中于37℃下历时2小时,之后从细胞的顶侧与基底侧这两者取出培养基。培养基中的异槲皮素浓度是由HPLC来进行测定,从顶侧吸收至基底侧的程度是藉由下列方程式来计算出:
结果显示,含有异槲皮素而没有L-精氨酸与抗坏血酸盐的配方1具有0.008%的通透率,而含有异槲皮素、L-精氨酸以及抗坏血酸盐的配方2在通透(吸收)率上展现出37-倍显著提升至0.298%。
实施例5:临床药物动力学研究
进行随机化临床药物动力学研究来比较在实施例2中的上述三种不同的异槲皮素配方,其以单一剂量投药给10位在禁食条件下的自愿受试者。在年龄为24岁与39岁之间且身体质量指数数值在19.6-24.3的范围内的健康男性参予此研究。
如上所述来制备在表1中所示的含有配方1-3的胶囊。各个自愿受试者在三个试验日服用两个胶囊,其含有(i)配方1(IQC;一共500mg异槲皮素)、(ii)配方2(IQC/Arg;一共250mg异槲皮素)或者(iii)配方3(IQC/Arg;一共125mg异槲皮素),依据先前的随机化顺序来进行投药。
在投药之前(0h)以及投药之后的第0.5、1、2、4与8h,依据已确立的操作程序测量从受试者取出的血液样品中的异槲皮素为准。更具体地,为了测定异槲皮素,首先对由各个血液样品所制得的血浆进行处理以将异槲皮素代谢物解离为糖苷配基槲皮素以及异鼠李素,进而由HPLC来定量。
简言之,将200μl的血将样品与10μl的10%二硫苏糖醇以及50μl的0.58mol/L乙酸进行混合。于37℃下将混合物处理以配于0.1M乙酸钠缓冲液(pH5.0)中1000U的β-葡萄糖醛酸酶以及100U/mL的硫酸酯酶[这两者皆源自于HP-2型罗马蜗牛(Helixpomatia)]历时120min。
在解离之后,将500μl的10mM草酸添加至各个样品中,接着将混合物于10,000g下离心历时5min。使用预先准备的Oasis HLB萃取柱并依据制造商(Waters,MilfordMAUSA)的指引来对所有的处理样品进行固相萃取。在氮气下蒸发所萃取出的洗出物,回溶于甲醇中,并且拿来进行以下的HPLC分析:将各个洗出物进样至一C18柱(WatersACQUITYUPLC BEH;1.7μm,2.1×100mm)中,使用0.1%甲酸(配于H2O中)/0.1%甲酸(配于乙腈)的HPLC梯度溶剂系统,并且使用Ultimate 3000快速分离LC Q Exactive光谱仪来检测槲皮素与异鼠李素的存在。各个糖苷配基的浓度是使用可信的槲皮素与异鼠李素内部标准所制得的标准曲线来计算出。在上面的情况下槲皮素与异鼠李素的分析限制为4℃0.03μM。
药物动力学图谱显示于图1中。需要注意的是,投予IQC/Arg 125mg所得到的药物动力学图谱是相似于IQC/Arg 250mg,但Cmax与AUCs数值大约为较高剂量所具者的一半,显示出剂量-依赖的关联性。
从相似于图1所绘的图谱而计算出的药物动力学数值显示于下面表3中。
表3.药物动力学
结果显示,无法预期地,IQC/Arg 250mg达至4.2μM的最大的血浆浓度(Cmax),几乎是IQC 500mg所显示出的2.2μM的2-倍高。亦令人意外的是,对QC/Arg 250mg而言,外推至无限大的曲线下面积[AUC(0-∞h)](总药物可利用性的估算值)几乎是IQC 500mg的8-倍多,尽管实际上仅投予一半多的异槲皮素。明显地,数据显示出异槲皮素当与L-精氨酸结合时在吸收上有统计显著性的增进。
此外,先前所述的经酵素改质的异槲皮素(以2mg槲皮素糖苷配基/kg体重来投药)的Cmax与AUC(0-6h)分别为1.84μM与5.99μmol·hr/L。参见Murota等人。相对地,对IQC/Arg250mg(以2.56mg槲皮素糖苷配基/kg体重来投药)而言,Cmax与AUC(0-6h)数值分别为3.32μM与9.27μmol·hr/L,显示出尽管投予相同剂量的异槲皮素,IQC/Arg配方的异槲皮素相较于经酵素改质的异槲皮素具有更高的生物可利用性。
其他具体例
在本说明书中所揭示的所有特征可以任何结合方式来进行组合。在本说明书中所揭示的各个特征可置换为起到相同、等效或相似目的之替代特征。因此,除非另外明确指出,所揭示的各个特征仅为一系列等效或相似特征中的一个实例。
再者,透过上面的说明,熟习此技艺者可轻易地确知本发明的必要特征,并且可在没有背离其精神与范畴下,对本发明做出各种不同的改变与修改以使其适用于各种不同的用途与情况。因此,其他具体例亦是在申请专利范围内。
Claims (20)
1.一种水溶性药学组成物,包含异槲皮素、L-精氨酸,以及抗坏血酸或抗坏血酸的碱金属盐,其中异槲皮素、L-精氨酸以及该抗坏血酸的碱金属盐之间的摩尔比为1:1.6-2.6:0.16-1.95。
2.如权利要求1所述的水溶性药学组成物,其中该组成物包括该抗坏血酸的碱金属盐,该碱金属盐为一钠盐或一钾盐。
3.如权利要求2所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
4.如权利要求2所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
5.如权利要求1所述的水溶性药学组成物,其进一步包含维生素B1、维生素B3、维生素B6、维生素B9,或者维生素B12。
6.如权利要求5所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
7.如权利要求5所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
8.如权利要求2所述的水溶性药学组成物,其进一步包含维生素B1、维生素B3、维生素B6、维生素B9,或者维生素B12。
9.如权利要求8所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
10.如权利要求8所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
11.如权利要求1所述的水溶性药学组成物,其中异槲皮素、L-精氨酸以及该抗坏血酸的碱金属盐之间的摩尔比为1:1.8-2.5:0.36-1.25。
12.如权利要求11所述的水溶性药学组成物,其中该抗坏血酸的碱金属盐为一钠盐或一钾盐。
13.如权利要求12所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
14.如权利要求12所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
15.如权利要求11所述的水溶性药学组成物,其进一步包含维生素B1、维生素B3、维生素B6、维生素B9,或者维生素B12。
16.如权利要求15所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
17.如权利要求15所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
18.如权利要求12所述的水溶性药学组成物,其进一步包含维生素B1、维生素B3、维生素B6、维生素B9,或者维生素B12。
19.如权利要求18所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的口服配方:一液体、一胶囊、一锭剂、一丸剂,以及一凝胶。
20.如权利要求18所述的水溶性药学组成物,其中该组成物是一选自于由下列所构成的群组中的局部配方:一溶液、一擦剂、一乳液、一乳霜、一软膏、一糊剂、一凝胶,以及一乳胶。
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RU2545905C1 (ru) * | 2013-12-16 | 2015-04-10 | Гарри Захарович Казиев | Водорастворимая фармацевтическая композиция l-аргинин-дигидрокверцетин и способ ее получения |
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US7691425B2 (en) * | 2003-09-29 | 2010-04-06 | San-Ei Gen F.F.I., Inc. | Method for manufacturing α-glycosylisoquercitrin, intermediate product and by-product thereof |
WO2007114304A1 (ja) * | 2006-03-29 | 2007-10-11 | San-Ei Gen F.F.I., Inc. | ベンゼン生成抑制剤およびベンゼン生成抑制方法 |
DE602007013691D1 (de) | 2007-03-06 | 2011-05-19 | Rachid Ennamany | Zusammensetzung auf Basis von Rutin und L-Lysin |
WO2009158031A2 (en) * | 2008-06-27 | 2009-12-30 | Limerick Biopharma, Inc. | Methods and compositions for therapeutic treatment |
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US10391096B2 (en) * | 2011-10-13 | 2019-08-27 | Quercegen Pharmaceuticals Llc | Method for treating thrombotic disorders using quercetin-containing compositions |
BE1023772B9 (fr) | 2013-05-17 | 2017-08-02 | Valore | Composition a base d'un complexe de (+)-catechine et d'acide amine pour le traitement et la prevention du cancer |
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