CN111787909B - 包含小檗碱的组合物 - Google Patents
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Abstract
本发明涉及包含小檗碱与豌豆蛋白和一种或多种表面活性剂的组合的组合物。本发明还涉及制备所述组合物的方法,以及其制剂和用途。
Description
技术领域
本发明涉及用于预防和/或治疗血脂异常、高胆固醇血症、代谢综合征和心血管疾病、包含小檗碱的组合物。
现有技术
小檗碱(以下简称BBR)是存在于各种植物中的生物碱,如具芒小檗(Berberisaristata)、黄连(Coptis chinensis)和白毛茛(Hydrastis canadensis),它们因其抗寄生虫、抗菌和抗炎性质而广泛用于中国和印度传统药物中。
许多更近期的研究已经突出了BBR的非常广谱的药理学活性,这表明其可能临床用于各种治疗领域,包括控制代谢综合征。后一种应用特别与在临床前和临床水平均观察到的主要抗血脂异常和降血糖作用有关[1,2]。
BBR的抗血脂异常和降血糖(餐后血糖)活性已经在许多临床试验中得到证实[1,2]。
还观察到对血管壁和与代谢综合征中的心血管并发症相关的炎性机制的重要作用[1,2]。
BBR在动脉粥样硬化过程中发挥保护作用的主要机制是通过诱导肝脏LDL-R受体的合成和抑制PCSK9酶的表达和分泌来降低LDL-C水平[3]。后一种机制目前代表了开发最新一代抗血脂异常药物的优先靶点。用于治疗家族性高胆固醇血症的抗PCSK9单克隆抗体最近上市,但其具有非常高的治疗成本和显著的副作用[2]。
关于BBR的降血糖作用,大量临床出版物证明T2DM患者血糖参数(与体重降低有关)或多囊卵巢综合征患者的代谢参数的改善。
BBR对与AMPk酶有关的细胞能量调节机制的调节活性也已被证明,AMPk酶已成为最重要和广泛研究的血糖调节的靶标。
口服给药后,BBR在被全身代谢前被肠道细菌菌群代谢形成主要代谢物小檗红碱,然后其被吸收并在肝脏中再转化成BBR,并通过胆汁途径排泄[4]。
因此,从药物动力学和药效学的观点来看,肝脏似乎是BBR的主要靶器官,因为它将主要吸收的代谢物小檗红碱再转化成BBR。LDL-R受体(BBR的主要靶标之一)在肝细胞中表达;肝脏在碳水化合物代谢中起到重要作用,并且是BBR结合并通过胆汁排出的器官。
BBR的肝活性也已经在体内实验模型中被证明是显著的,用于控制影响肝实质的变性过程,主要是与代谢综合征诱导的肥胖相关的脂肪变性[5]。因此BBR作为代谢综合征的一线产品日益增加,因为它对抗所述综合征的几种原因,所述综合征通常对健康具有严重后果,特别是对心血管风险。
使用BBR的主要问题是其非常低的口服吸收,其不超过给药剂量的0.5%,仅有0.36%的剂量到达体循环[6]。这是由于几个因素:肠吸收差、由渗透性糖蛋白(Pgp)消除、由细菌菌群的系统前代谢、肝代谢和胆汁消除。因此,必须每天数次给予大剂量(500-2000mg),以患者的依从性和胃肠副作用为代价。已经进行了许多尝试,通过制剂方法或使用从肠细胞中消除BBRs的特异性Pgp抑制剂来增加BBR的血浆水平。特别地,从科学文献中已知,一些含有来自柑桔属物种的柚皮苷[7]和来自葡萄籽的矢车菊苷配质[8]的植物提取物抑制Pgp活性。
欧洲专利EP2149377[9]描述了用于治疗高血糖的组合物,包含BBR或包含BBR的提取物与水飞蓟素或与含有水飞蓟素的水飞蓟(Silybum marianum)提取物的组合。
然而,仍然需要获得能够增加BBR的口服生物利用度和改善其治疗指数的制剂。
附图列表
图1显示了根据本发明的与豌豆蛋白和卵磷脂组合的BBR样品的色谱图(甲醇溶液,~0.15mg/ml)。
图2显示BBR氯化物的标准溶液(甲醇溶液,~0.05mg/ml)的色谱图。
发明简述
本发明涉及一种组合物,其包含:
a)小檗碱(BBR);
b)豌豆蛋白;
c)一种或多种表面活性剂;和任选地
d)葡萄属物种(Vitis species)或柑桔属物种(Citrus species)的植物提取物或其组合。
本发明还涉及制备所述组合物的方法、包含所述组合物的药物或保健(nutraceutical)制剂,以及所述组合物用于预防和/或治疗血脂异常、高胆固醇血症、代谢综合征和心血管疾病的用途。
发明详述
已经发现,当BBR与豌豆蛋白在至少一种表面活性剂存在下联合时,BBr在水溶液中的溶解度大于单独BBR的溶解度。当BBR与豌豆蛋白、表面活性剂和葡萄属物种的提取物、优选葡萄提取物和/或柑桔属物种的提取物、优选佛手柑(Citrus bergamia)提取物联合时,观察到进一步的增加。不受理论束缚,认为至少一种表面活性剂的存在促进BBR、豌豆蛋白和葡萄属和/或柑桔属物种提取物(如果使用)之间的协同相互作用,这反过来导致BBR的溶解度和吸收的增加。
因此,在其第一方面,本发明涉及一种组合物,其包含:
a)小檗碱(BBR);
b)豌豆蛋白;
c)一种或多种表面活性剂;和任选地
d)葡萄属物种或柑桔属物种的植物提取物或其组合。
对于本发明的目的,BBR可以以通过水提取(水提取物)可从具芒小檗、黄连或白毛茛的根获得的提取物的形式使用,更优选以具芒小檗的根的水提取物形式使用。水提取物的BBR含量优选在30-70%(w/w)之间,更优选50%w/w。提取物可通过常规方法获得,包括研磨根、在水性介质中提取、沉淀和干燥。
甚至更优选地,BBR可以以提取物的形式使用,在下文中称为“纯BBR”,其具有大于85%w/w的小檗碱含量,可通过在树脂柱上进一步纯化50%w/w的水提取物而获得。
同样适用于本发明实施方案的BBR提取物和纯BBR是可商购的,例如得自IndianHerbs Extractions。
表述“豌豆蛋白”是指通过水提取从干豌豆(Pisum sativum)获得的蛋白。它们可商购自例如Roquette(法国),商标为并且特征在于高溶解度(≥50%)、高消化性和平衡的氨基酸分布。
表述“葡萄属物种提取物”是指具有大于90重量%的原花色素含量的一种或多种葡萄属物种的提取物。优选使用如WO2007/017037[10]或EP0348781[11]所述可获得的葡萄(Vitis vinifera)籽提取物,其原花色素含量等于或大于95%重量,儿茶素和表儿茶素含量≥5%重量且≤15%重量。所述提取物可以以商标从Indena S.P.A.商购获得。
表述“柑桔属物种提取物”表示一种或多种具有等于或大于25重量%的黄烷酮含量的柑桔属物种提取物。优选使用如WO2010/055490[12]所述可获得的黄烷酮含量大于28重量%且呋喃骈香豆精(佛手柑内酯和香柠檬亭)含量减少的佛手柑提取物(香柠檬柑(bergamot orange)提取物)。
含有BBR的提取物和豌豆蛋白之间的比例范围优选在1:1w/w和10:1w/w之间,更优选达到4:1w/w,或者纯BBR和豌豆蛋白之间的比例范围在1:1w/w和10:1w/w之间,更优选达到3:1w/w。
在本发明的除了豌豆蛋白之外还含有葡萄属物种提取物和/或柑桔属物种提取物的组合物中,含有BBR的提取物或纯BBR与豌豆蛋白和葡萄属物种提取物和/或柑桔属物种提取物的总重量的重量比范围为1:1w/w和5:1w/w之间。豌豆蛋白与葡萄属物种提取物和/或柑桔属物种提取物之间的比例范围在1:3w/w和3:1 w/w之间。
对于本发明的目的,表述“表面活性剂”表示一种或多种包含极性基团(或头)和非极性基团(或尾)的药理学上可接受的物质。适用于制备本发明组合物的表面活性剂可以是非离子、阳离子、阴离子或两亲的,并且可以选自Remington:“The Science and Practiceof Pharmacy”,第22版,Pharmaceutical Press,2013。表面活性剂优选选自磷脂、蔗糖酯、聚山梨醇酯、聚氧乙烯蓖麻油衍生物、D-α-生育酚-聚乙二醇琥珀酸酯(维生素E TPGS)或其混合物。更优选地,表面活性剂是卵磷脂,特别是磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺或其混合物;甚至更优选地,卵磷脂是大豆或向日葵卵磷脂。在本发明的组合物中,表面活性剂的含量范围是BBR提取物或纯BBR和豌豆蛋白、以及如果使用的话葡萄属物种提取物和/或柑桔属物种提取物的总重量的5-30%w/w。
根据本发明的组合物优选不包括水飞蓟素或含有水飞蓟素的水飞蓟提取物。
本发明的组合物可以含有其它植物来源的活性成分;然而,在优选的实施方案中,组合物由以下组成:
a)BBR;
b)豌豆蛋白;
c)一种或多种表面活性剂;和任选地
d)葡萄属物种或柑桔属物种的植物提取物或其组合。
本发明的组合物可任选地含有适于获得口服给药制剂的药学上可接受的赋形剂,例如片剂、胶囊和颗粒剂。所述赋形剂包括例如:
·不溶性和可溶性稀释剂,例如微晶纤维素、磷酸钙、碳酸钙、甘露醇、麦芽糖糊精、异麦芽酮糖醇(isomalt)或其组合;
·润滑剂和/或助流剂,例如二氧化硅、滑石、硬脂酸、硬脂酸镁或其组合。
这些和其它赋形剂描述于Remington:“The Science and Practice ofPharmacy”,第22版,Pharmaceutical Press,2013。
通常,制剂包含根据本发明的组合物,优选其量为500至2000mg,更优选其量达到500mg,以及至少一种赋形剂。典型地,剂型中的根据本发明的组合物与至少一种赋形剂之间的重量比范围在1:5和5:1 w/w之间。
在其第二方面,本发明涉及一种获得本发明组合物和制剂的方法[方法(P-1)]。这些组合物和制剂可通过将BBR、豌豆蛋白和任选的葡萄属物种提取物或柑桔属物种提取物和/或赋形剂加入到表面活性剂溶液或分散体中获得。BBR、豌豆蛋白和任选的葡萄属物种提取物或柑桔属物种提取物和/或赋形剂可以在连续的步骤中或在单一步骤中加入。
第一种优选的方法[方法(P-1)]包括下列步骤:
a-1)将表面活性剂或表面活性剂的混合物溶解或分散在50-100体积的有机溶剂中,所述有机溶剂优选选自乙醇、乙酸乙酯和丙酮,直到获得溶液或均匀分散体;
b-1)将BBR,以及任选的葡萄属物种提取物和/或柑桔属物种提取物加入到步骤a-1)中获得的溶液或分散体中,加热至优选40℃至70℃、更优选60℃的温度,以获得分散体;
c-1)将步骤b-1)中获得的分散体冷却至室温,并在搅拌下加入豌豆蛋白,优选约10-15分钟,直至获得分散体;
d-1)任选地将稀释剂、优选微晶纤维素或稀释剂的混合物加入到步骤c-1)中获得的分散体中;
e-1)通过低压蒸发、优选100至500毫巴,从步骤c-1)中获得的混合物中除去溶剂,保持优选50℃至75℃、更优选≤65℃的温度,任选地终止在设定为60-65℃温度的烘箱中的真空干燥,直到获得优选<1.2%w/w的溶剂残留物;
f-1)在10目筛上校准步骤e-1)结束时获得的组合物,并任选地加入润滑剂和/或助流剂,所述润滑剂和/或助流剂优选选自硬脂酸、硬脂酸镁和二氧化硅,优选二氧化硅。
第二种优选的方法[方法(P-2)]包括下列步骤:
a-2)将表面活性剂或表面活性剂的混合物溶解或分散在5-10体积的有机溶剂中,所述有机溶剂优选选自乙醇、乙酸乙酯和丙酮,优选乙醇,直到获得溶液或均匀悬浮液;
b-2)与步骤a-2)中获得的溶液或悬浮液分开,将含有BBR的提取物与豌豆蛋白、任选地葡萄属物种提取物和/或柑桔属物种提取物以及稀释剂、优选微晶纤维素混合,直到获得均匀的混合物,通常混合约5分钟;
c-2)将步骤b-2)中获得的混合物加入到步骤a-2)中获得的溶液或悬浮液中以获得混合物;将所得混合物在搅拌下保持约10-15分钟;
d-2)在约60-65℃的温度下、在真空下烘箱干燥步骤c-2)中获得的混合物,直到获得<1.2%w/w的残余溶剂含量;
e-2)在10目筛上校准步骤d-2)结束时获得的组合物,并任选地加入一种或多种润滑剂和/或助流剂,优选选自硬脂酸、硬脂酸镁和二氧化硅,优选二氧化硅。
对于本发明的目的,术语“溶液”表示在视觉检查时看起来澄清的液体组合物;术语“分散体”表示液体组合物,其在视觉检查时呈现悬浮的颗粒并且看起来不透明和混浊;术语“混合物”表示除了溶液或分散体之外的固体和液体的均匀混合物,其表现为柔软的和可延展的。
此外,为了避免疑惑,在本说明书和权利要求书中指定了数值范围的情况下,应当认为包括了这些范围的端值。
BBR、豌豆蛋白和任选的葡萄属物种提取物和/或柑桔属物种提取物之间的协同相互作用可通过在模拟生物流体如模拟胃液中的溶解度试验来证实。该测试可以通过本领域技术人员已知的方法进行,例如如以下实验部分中所报道。当观察到溶解度增加至至少约三倍于未组合的BBR所获得的溶解度时,认为发生了相互作用。溶解度参数被认为是预测了增加的吸收。
在其另一方面,本发明涉及组合物(C)作为药物的用途,特别是用于预防和/或治疗血脂异常、高胆固醇血症、代谢综合征和心血管疾病。
在以下实验部分中列出的实施例进一步说明本发明。
实施例部分
材料
从Indian Herbs Extractions,Ramnagar获得BBR含量约50%的具芒小檗根的植物提取物和纯BBR。
豌豆蛋白从Roquette,France获得
葡萄提取物可从Indena S.P.A.以商标购得,并且通过水-醇提取、过滤、在树脂柱上纯化和干燥而获得。
佛手柑(香柠檬柑)提取物得自H&AD Herbal and Antioxidant Derivatives。
大豆卵磷脂得自
根据实施例的组合物中各成分的百分比以重量表示,为组合物总重量的比例。
制备实施例
实施例1-含有滴定至50%w/w的BBR提取物、豌豆蛋白和卵磷脂的组合物
该组合物通过包括以下步骤的以下方法(P-1)获得。
1.将聚山梨醇酯80和羟丙基纤维素溶于乙醇中直到得到溶液。
2.在磁力搅拌下,将滴定至50%w/w的BBR提取物加入到步骤1中获得的溶液中,并加热至60℃直至获得分散体。
3.在磁力搅拌下将卵磷脂加入步骤2中获得的分散体中,并加热至60℃。
4.将步骤3中获得的分散体冷却至室温,并加入豌豆蛋白以获得分散体。
5.通过低压蒸发从步骤4中获得的分散体中除去溶剂,同时保持温度≤65℃。
6.将步骤5中获得的产物在65℃真空烘箱干燥,直到乙醇残留物<1.2%。
7.将步骤6中获得的产物在10目筛上校准,并加入通过50目筛预筛分的二氧化硅。
实施例2--含有滴定至50%w/w的BBR提取物、豌豆蛋白、卵磷脂和佛手柑提取物的
组合物
该组合物是按照实施例1所述的方法获得,不同之处在于在步骤2中还加入了佛手柑提取物。
实施例3-含有50%w/w BBR提取物、豌豆蛋白、卵磷脂和葡萄籽提取物的组合物
该组合物是按照实施例1所述的方法获得,不同之处在于葡萄籽提取物也在步骤2中加入。
实施例4-包衣片
实施例5-硬明胶胶囊
实施例6-水分散性颗粒
测定
在模拟生物流体中的溶解度测试
通过比较含有等量BBR的样品进行溶解度测试。
通过与纯BBR(参照1)和与含有33%滴定到50%w/w的BBR提取物、65%卵磷脂和2%二氧化硅(参照2)但不含豌豆蛋白的组合物比较,测定如实施例1、2和3所述制备的组合物,以评价在模拟生物液体中增加的溶解度。
通过如下所述的UPLC(超高效液相色谱)方法进行分析:
装置:AcquityH-Class System。
Empower软件(Empower System Enterprise Client/Server)。
柱:固定相:AcquityCSHTM C18;尺寸:l=100mm;I.D=2.1mm;粒度:1.7μm;制造商:Waters。
流动相:溶剂A:0.5%磷酸(w/v);溶剂B:乙腈。
线性梯度
表1
时间(min) | 溶剂A*(%) | 溶剂B(%) |
0.0 | 95 | 5 |
6.0 | 50 | 50 |
6.5 | 0 | 100 |
7.5 | 0 | 100 |
8.0 | 95 | 5 |
10.0 | 95 | 5 |
*溶剂A和B的百分数以相比于总量的体积表示。
分析条件:流速:0.4ml/分钟;检测:348nm。
增溶溶剂:80%甲醇
空白溶液:80%甲醇
样品溶液:30mg/200ml(~0.15mg/ml典型样品的色谱图,见图1)。
标准溶液:10mg纯参比BBR在200ml甲醇中的溶液(标准溶液~0.05mg/ml,图2中的典型色谱图)。
溶解度测试使用如下报道制备的禁食状态模拟胃液(FaSSGF)作为溶剂进行。
1)制备NaCl/HCl溶液用于FaSSGF(1L):
将2g NaCl溶解在0.9L纯化水中,用HCl将pH调节至1.6,并用纯化水将混合物补足体积(1L)。
2)在室温将0.06g粉末物*(FassGF-Biorelated介质)加入到约500ml NaCl/HCl溶液中,用NaCl/HCl溶液补足体积(1L),得到澄清的备用液体。
*最终牛磺胆酸钠0.08mM,最终卵磷脂0.02mM
下表2显示测试结果:
表2
表2中列出的结果表明,本发明的组合物在模拟胃液中的溶解度大于纯BBR,无论单独使用还是仅与卵磷脂组合使用。豌豆蛋白的添加明显地引起溶解度的进一步增加。加入佛手柑提取物或葡萄籽提取物引起BBR溶解度的进一步增加。特别是,当BBR仅与豌豆蛋白和卵磷脂结合时,BBR的溶解度增加至约三倍,但是当它还与佛手柑提取物或葡萄籽提取物结合时,BBR的溶解度增加至约四倍。这些发现证明,本发明的组合物增加了构成其肠吸收最大障碍的BBR在水性介质中的溶解度。
仅含有BBR提取物和卵磷脂的参照组合物以及含有本发明BBR的组合物(如实施例
3所述的BBR)的生物利用度和对肠粘膜的影响的比较评价
BBR的吸收和生物利用度是用基于Caco-2人肠腺癌细胞(ATCC,HTB-37TM)的人肠上皮体外模型测定的,所述细胞在插入物上组织为功能性单层。插入物的特征在于两个室,顶端(或腔)和基底外侧(或浆膜),由微孔膜分开。
为确定糖蛋白-P(P-gp)潜在牵涉于BBR吸收,糖蛋白-P是一种将大量肠上皮细胞吸收的底物驱除进入肠腔的膜泵,在一种选择性糖蛋白-P(P-gp)抑制剂维拉帕米(Verapamile)存在下进行了体外吸收实验。
在进行体外吸收试验之前,将一剂由滴定至50%w/w的BBR提取物和卵磷脂组成的组合物(参照2)和一剂实施例3的组合物暴露于模拟生理消化的体外消化过程3小时。然后将两种经消化的制剂在体外加入肠上皮的顶端区室以进行吸收测试。如表3所示,实施例3组合物的BBR吸收显著高于参照2组合物的BBR吸收。
表3
吸收(μM) | |
参照2 | 0.65±0.06 |
实施例3的组合物 | 1.20±0.12 |
在暴露于经消化的制剂后,用MTS分析法评价肠上皮模型的细胞生存力,该分析法基于MTS四唑化合物被活细胞还原产生有色产物甲臜(formazan),可通过测量490nm处的吸光度来定量。获得的剂量(浓度(mg/ml))-反应(肠上皮的活力%)值在下表4和5中列出:
表4
表5
获得的剂量-反应值证明,在BBR的最大浓度(8.2mg/mL)下,参照2诱导肠上皮活力降低46.6%,显著高于实施例3的组合物诱导的活力降低(21.9%)。
这表明,本发明的组合物,特别是实施例3的组合物,与未与豌豆蛋白组合的提取物不同,保证了在P-gp抑制剂维拉帕米存在下活性成分BBR的更高的生物利用度,证实了该细胞机制在BBR的低肠吸收中的重要性。
此外,BBR浓度相同时,实施例3的组合物证明比参照2更安全,如肠粘膜的更强存活力所显示,因此尽管吸收增加,但令人惊讶地确保了对BBR典型的胃肠道病症的较低的潜在影响。
大鼠中的药代动力学试验
对大鼠进行药物动力学试验,以评价使用实施例1所述组合物可获得的吸收增加。
通过给三只Sprague Dawley大鼠口服给予1000mg/kg实施例1的组合物——相当于100mg/kg纯BBR进行试验,并给三只大鼠100mg/kg纯BBR。将产品在含有1重量%的甲基纤维素作为增溶剂的蒸馏水中给药。然后在15分钟、30分钟、1小时、2小时、4小时和6小时后从眼后窦(retroocular sinus)中采集血样,达到肝素化试管中0.5ml体积。
在提取和用葡糖醛酸糖苷酶和芳基硫酸酯酶处理后,通过标准HPLC方法偶联质谱/质谱检测器分析由此获得的样品。
出乎意料地发现,与给予等摩尔剂量BBR提取物后获得的结果相比,BBR的最大血浆水平增加约六倍。
与代表化合物总吸收的曲线下面积(AUC)相比,观察到约三倍的增加。
这些数据证明了溶解度测试的预测价值,并证实了体内药物动力学参数和生物利用度的改善。
参考文献
1)Alberico Luigi Catapano,Berberine,a plant alkaloid with lipid-andglucose-lowering properties:From in vitro evidence to clinical studiesAtherosclerosis Volume 243,Issue 2,2015年12月,449–461页.
2)Anil Kumar,Current knowledge and pharmacological profile ofberberine:An update European Journal of Pharmacology 761(2015)288–297.
3)Jin~lwen Liu,Inhibition of PCSK9 Transcription by BerberineInvolves Down-regulation of Hepatic HNF1 a Protein Expression through theUbiquitin-Proteasome Degradation Pathway The Journal of Biological Chemistryvol.290,no.7,pp.4047-4058,13,2015.
4)Jian-Dong Jiang,Transforming berberine into its intestine-absorbable form by the gut Microbiota Scientific Reports|5:12155|DOI:10.1038/srep12155 2015).
5)Ting Guo,Berberine Ameliorates Hepatic Steatosis and SuppressesLiver and Adipose Tissue Inflammation in Mice with Diet-induced ObesityScientific Reports 6:22612(2016).
6)Xiao-Ying Long,Research progress on berberine with a special focuson its oral bioavailability Fitoterapia 109(2016)274–282.
7)De Castro,Whocely Victor等人,“Effect of grapefruit juice,naringin,naringenin,and bergamottin on the intestinal carrier-mediated transport oftalinolol in rats.”Journal of agricultural and food chemistry 56.12(2008):4840-4845.
8)Zhao,Bo-xin等人,“Grape seed procyanidin reversal of p-glycoproteinassociated multi-drug resistance via down-regulation of NF-κB and MAPK/ERKmediated YB-1 activity in A2780/T cells.”PloS one 8.8(2013):e71071.
9)EP 2 149 377(Velleja Research SRL),公开于03/02/2010,授权于14/09/2016
10)WO 2007/017037(A1)(Indena S.p.A.),公开于15/02/2007.
11)EP 0348781(TECNOFARMACI S.p.A.和INDENA S.p.A.),公开于03/01/1990,授权于30/09/1992.
12)WO 2010/055490(A1)(Herbal&Antioxidant Derivatives S.r.L.),公开于20/05/2010。
Claims (15)
1.组合物,其包含:
a)小檗碱(BBR);
b)豌豆蛋白;
c)表面活性剂;和任选地
d)葡萄属或柑桔属物种植物提取物或其组合,
其中所述表面活性剂是卵磷脂,且含有BBR的提取物和豌豆蛋白之间的比例范围在1:1w/w和10:1w/w之间。
2.根据权利要求1的组合物,其中小檗碱以具芒小檗、黄连或白毛茛的根的水提取物的形式使用。
3.根据权利要求2的组合物,其中所述水提取物获自具芒小檗的根。
4.根据权利要求2的组合物,其中所述提取物含有30%w/w至70%w/w的量的小檗碱。
5.根据权利要求3的组合物,其中所述提取物含有30%w/w至70%w/w的量的小檗碱。
6.根据权利要求4的组合物,其中所述提取物含有等于50%w/w的量的小檗碱。
7.根据权利要求5的组合物,其中所述提取物含有等于50%w/w的量的小檗碱。
8.根据权利要求1的组合物,其中小檗碱以提取物的形式使用,所述提取物具有大于85%w/w的小檗碱含量。
9.根据权利要求1-8中任一项的组合物,其中所述卵磷脂是大豆卵磷脂或向日葵卵磷脂。
10.根据权利要求1-8中任一项的组合物,其包含葡萄籽提取物或佛手柑提取物或其组合。
11.根据权利要求9的组合物,其包含葡萄籽提取物或佛手柑提取物或其组合。
12.根据权利要求1-11中任一项的组合物在制备药物中的用途,其中所述药物用于预防和/或治疗血脂异常、高胆固醇血症、代谢综合征和心血管疾病。
13.制备根据权利要求中1-11任一项的组合物的方法或制备包含根据权利要求1-11任一项的组合物和至少一种药学可接受赋形剂的制剂的方法,所述方法包括制备表面活性剂的溶液或分散体,并在一个或多个连续步骤中加入BBR、豌豆蛋白、任选地葡萄属物种的提取物和/或柑桔属物种的提取物、和任选地至少一种药学可接受的赋形剂。
14.通过权利要求13的方法可获得的组合物或制剂。
15.制剂,其包含根据权利要求1-11中任一项的组合物和至少一种合适的药学可接受的赋形剂。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101606622A (zh) * | 2008-06-22 | 2009-12-23 | 张成华 | 一种凤头百灵鸟饲养料的配制方法 |
EP2149377A1 (en) * | 2008-07-29 | 2010-02-03 | Velleja Research SRL | Compositions containing berberine and/or analogues thereof or extracts containing it, for the prevention and treatment of alterations of the lipid and carbohydrate balance |
CN102702190A (zh) * | 2012-07-02 | 2012-10-03 | 东北制药集团股份有限公司 | 一种小檗碱静电复合物及其制备方法 |
CN104273522A (zh) * | 2013-07-03 | 2015-01-14 | 江南大学 | 一种姜黄素纳米复合物及其制备方法 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1219732B (it) | 1988-06-28 | 1990-05-24 | Tecnofarmaci Spa | Frazioni oligomeriche procianidoliche,loro procedimento di preparazione e composizioni farmaceutiche che le contengono |
ITMI20051485A1 (it) | 2005-07-29 | 2007-01-30 | Indena Spa | Estratto da semi d'uva ottenibile per frazionamento su resina |
US20100189857A1 (en) * | 2006-10-17 | 2010-07-29 | Theodorus Berend Jan Blijdenstein | Aerated food product and process for preparing it |
IT1392535B1 (it) | 2008-11-17 | 2012-03-09 | Herbal & Antioxidant Derivatives S R L In Forma Abbreviata H&Ad S R L | Fitocomplesso da frutto di bergamotto, procedimento di preparazione e impiego quale integratore alimentare e nel settore farmaceutico. |
DK2648809T3 (da) * | 2010-12-09 | 2019-07-15 | Y&B Mothers Choice Ltd | Naturlige formuleringer |
CN102949375B (zh) * | 2012-11-28 | 2015-04-08 | 厦门大学附属第一医院 | 一种盐酸小檗碱固体脂质纳米制剂及其制备方法 |
ES2863561T3 (es) | 2014-03-10 | 2021-10-11 | Esserre Pharma Soc A Responsabilita Limitata | Fitocomplejos de Citrus bergamia |
US20160015813A1 (en) * | 2014-06-16 | 2016-01-21 | Laila Pharmaceuticals Pvt. Ltd. | Novel and synergistic composition of lecithin and lysolecithin for improving bioavailability and solubility of hydrophobic compounds and extracts |
US9446100B2 (en) | 2015-02-13 | 2016-09-20 | Eastern Vision Limited | Dietary supplements and formulations |
ITUB20150541A1 (it) | 2015-03-03 | 2016-09-03 | Acraf | Composizione comprendente sostanze e/o estratti naturali |
CA2979690A1 (en) * | 2015-03-16 | 2016-09-22 | Nature's Sunshine Products, Inc. | Phytocomplexes exhibiting multiple, synergistic antioxidant activities useful in foods, dietary supplements, cosmetics and pharmaceutical preparations |
EP3118215A1 (en) | 2015-07-16 | 2017-01-18 | Nuritas Limited | Anti-inflammatory peptides, and uses thereof |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101606622A (zh) * | 2008-06-22 | 2009-12-23 | 张成华 | 一种凤头百灵鸟饲养料的配制方法 |
EP2149377A1 (en) * | 2008-07-29 | 2010-02-03 | Velleja Research SRL | Compositions containing berberine and/or analogues thereof or extracts containing it, for the prevention and treatment of alterations of the lipid and carbohydrate balance |
CN102702190A (zh) * | 2012-07-02 | 2012-10-03 | 东北制药集团股份有限公司 | 一种小檗碱静电复合物及其制备方法 |
CN104273522A (zh) * | 2013-07-03 | 2015-01-14 | 江南大学 | 一种姜黄素纳米复合物及其制备方法 |
Non-Patent Citations (3)
Title |
---|
A 13-week,randomized,pilot trial of a low glycemic load diet and lifestyle modification program combining low glycemic load protein shakes and targeted nutraceuticals improved weight loss and cardio-metabolic risk factors over a low glycemic load diet;Dahlberg CJ,et al;《Can J Physiol Pharmacol》;20171231;第95卷(第12期);第1414-1425页 * |
Food protein-based materials as nutraceutical delivery systems;L. Chen et al;《Trends in Food Science & Technology》;20061231(第17期);第272-283页 * |
助剂对小鼠吸收黄连总生物碱的影响及药代动力学的研究;李亚梅等;《中国中药杂志》;20090229(第03期);第344-348页 * |
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