CN113307787A - 一种橙皮素与胡椒碱的共晶及其制备方法 - Google Patents
一种橙皮素与胡椒碱的共晶及其制备方法 Download PDFInfo
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
本发明公开一种橙皮素与胡椒碱的共晶及其制备方法。所述的共晶中,橙皮素与胡椒碱的摩尔比为1:1,两者采用氢键相连,其共晶的分子式为C33H33NO9。运用X‑射线单晶衍射、X‑射线粉末衍射、热重分析、差示扫描量热分析对橙皮素和胡椒碱的共晶进行了全面表征。本发明所述的共晶溶解度和生物利用度均得到了提高。本发明还公开了该共晶的制备方法,该制备方法简单,具有可重复性和可控性强,易于扩大工业化生产,耗能低等优点。
Description
技术领域
本发明涉及橙皮素的共晶,具体涉及一种橙皮素与胡椒碱的共晶及其制备方法。
技术背景
由于疏水性取代基通常是药效学活性必不可少的元素,因此难溶性候选药物在研发渠道中占很大比例(80-90%)。而大多数候选物因其低溶解度而可能无法制造产品,所以水溶性差的活性药物成分(API)的增溶是科学家最重要和最主要的挑战。目前,已证明药物共晶是增强API理化性质的重要替代品。共晶是由两个或两个以上不同分子组成的晶体材料,一般是活性药物成分和共晶配体,通常具有相同的晶体结构。共晶已经被广泛应用改善药物的相关特性,例如溶解度、溶出度、生物利用度、稳定性以及可压缩性等。Entresto于2015 年获得美国食品和药物管理局(FDA)的批准,用于治疗慢性心力衰竭,它是首个将两种BCS II药物Sacubitril和valsartan结合使用的商业共晶药物。这样的药物-药物共晶不仅增加了两种药物的溶解度,而且还创造了双重药物的协同制剂。如曲马多-塞来昔布和TAK-020。
橙皮素(Hesperetin),5,7,3'-三羟基-4'甲氧基黄烷酮,如下式所示,是在柑橘类水果中发现的最丰富的类黄酮之一。它具有广泛的药理作用,包括抗氧化,抗炎,抗癌,神经保护,抗高血压和抗动脉粥样硬化活性。研究人员还发现,橙皮素可以抑制肿瘤细胞的生长。尽管它具有出色的生物活性,但其低水溶性限制了其临床应用。据报道,橙皮素与β-环糊精的络合物,胶束负载,脂质体制剂和基于聚环氧乙烷N10的熔铸基质薄膜等某些制剂可改善其溶解性和生物利用度;然而,由于这些制剂在水溶液中的稳定性差,其复杂性以及其高昂的制备成本,使这些制剂的使用受到限制。
胡椒碱别名1-胡椒酰哌啶、胡椒酰胺、胡椒辣碱,是从胡椒、荜茇及其他胡椒科植物果实中分离出的一种属于酰胺类的生物碱化合物。胡椒碱含有辛辣成分,常见于各种日常使用的食物和调味品中。在自然界中广泛存在。经过科学验证,胡椒碱可通过抑制代谢性CYP450酶(特别是CYP3A4,CYP2C9和 CYP1A2),刺激肠壁中的氨基酸转运蛋白和抑制P-糖蛋白来提高其他活性物质的生物利用度。
报道称,当白藜芦醇与胡椒碱同时口服时,白藜芦醇的生物利用度可被提高7 倍。
因此,制备橙皮素与胡椒碱的共晶,有利于改善橙皮素的溶解性能和生物利用度。
发明内容
基于以上事实,本发明提供一种橙皮素与胡椒碱的共晶及其制备方法,来提高橙皮素的溶解性能和体内的吸收,并对晶体进行了全面的表征。
1.本发明提供的橙皮素与胡椒碱的共晶晶体在X-射线粉末衍射图谱中2θ=7.65±0.2°、8.82±0.2°、9.52±0.2°、10.32±0.2°、12.12±0.2°、13.62±0.2°、 16.21±0.2°、17.45±0.2°、18.2±0.2°、18.82±0.2°、19.44±0.2°、20.26±0.2°、21.28±0.2°、22.42±0.2°、23.44±0.2°、24.38±0.2°、26.12±0.2°、27.18±0.2°、27.81±0.2°、29.30±0.2°、29.52±0.2°、32.08±0.2°处有特征峰,如附图1所示。
3.本发明提供的橙皮素与胡椒碱的共晶,所述共晶中的橙皮素与胡椒碱的比例为摩尔比1:1。
4.本发明提供的橙皮素与胡椒碱的共晶,用差示扫描量热仪(DSC)测定,在152.48±1℃一个熔化吸热峰,如附图2所示。测试条件范围40-500℃,升温 10℃/min,保护N2为50mL/min。
5.本发明提供的橙皮素与胡椒碱的共晶制备方法如下:将橙皮素和胡椒碱以摩尔比1:1的比例溶于有机溶剂中,0.22μm滤膜过滤后,将溶剂至于室温下挥发,析晶,干燥,得到橙皮素胡椒碱共晶。
6.所述有机溶剂为甲醇和乙醇,或是甲醇和乙醇以任意比例的混合体系。
7.所述橙皮素的浓度为0.5-2M,优选0.75-1.5M;胡椒碱的的浓度为0.5-2 M,优选0.75-1.5M。
8.所述析晶过程可根据获得晶体目的不同选择溶剂挥发方式,静置挥发可得到体积较大的晶体,而搅拌挥发溶剂可加快溶剂的挥发,获得颗粒较小的粉末晶体。
9.所述干燥温度为40-60℃,干燥时间为12-24h。
本发明提供的橙皮素与胡椒碱的共晶及其制备方法,解决了橙皮素溶解度差的问题,并具有以下优点:本发明制备的共晶在继承原料药物原有的活性外,其溶解性和生物利用度都明显提高。且制备方法简单,可重复性高,低能耗,易于工业化生产,获得的共晶晶体结晶度高,晶型完整。
附图说明:
图1为本发明实施例1制备的共晶化合物、橙皮素和胡椒碱的X-射线粉末衍射的对比图。
图2为本发明实施例1制备的共晶化合物、橙皮素和胡椒碱的DSC比图。
图3为本发明实施例1的共晶化合物和橙皮素新晶型溶出图。
图4为本发明实施例1的共晶化合物和橙皮素的生物利用度图。
具体实施方式
为了充分表达本发明的目的和优势,下面结合了优选的实施例和附图对本发明进行清楚、完整的描述。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1
将3.02g的橙皮素固体和2.85g胡椒碱加入10mL乙醇中,搅拌使其完全溶解后,放置室温,静置挥发溶剂,析晶后,45℃烘干,获得橙皮素和胡椒碱的共晶。这种方法获得的晶体体积较大,便于单晶结构的测试。
实施例2
将3.02g的橙皮素固体和2.85g胡椒碱加入10mL甲醇中,搅拌使其完全溶解待用,放置室温,静置挥发溶剂,析晶后,45℃烘干,获得橙皮素和胡椒碱的共晶。
实施例3
将6.04g的橙皮素固体和5.7g胡椒碱加入15mL甲醇与乙醇体积比为1:1 的溶剂体系中,搅拌使其完全溶解待用,放置室温,静置挥发溶剂,析晶后, 50℃烘干,获得橙皮素和胡椒碱的共晶。
实施例4
将1.51g的橙皮素固体和1.42g胡椒碱加入6mL乙醇中,搅拌使其完全溶解待用,放置室温,边搅拌边挥发,析晶后,40℃烘干,获得橙皮素和胡椒碱的粉末共晶。
制备得到的共晶样品进行溶出度测试和生物利用度研究
溶出测试条件:
样品:实施例4制备得到的橙皮素-胡椒碱共晶,以及与橙皮素单体进行对照。
测试方法:分别取一定质量的橙皮素-胡椒碱共晶和橙皮素(包含橙皮素 25mg)加入5mL的溶解介质(pH=6.8)中,分别于0.25,0.5,1,2,4,6,8, 12,24和48h取出样品,10,000rpm离心10min,HPLC分析上清液体中的橙皮素的溶解度。
附图3中所示,与橙皮素单体比较,橙皮素-胡椒碱共晶表现出更高的溶解度。
生物利用度测试方法:
将SD大鼠随机分为两组(n=6),并禁食过夜。将游离的橙皮素和橙皮素- 胡椒碱共晶以灌胃形式给予动物后,在指定的时间(0.25,0.5,1,2,4,6,8, 12,24和48h)收集血液样本。将血浆以10,000rpm离心10min。处理血浆样品以进行HPLC分析。结果如附图4所示。
附图4可以看出,橙皮素单体在0.5h达到最大血药浓度1.18μg/mL,而橙皮素-胡椒碱共晶中的橙皮素在1h达到最大血药浓度6.11μg/mL。
Claims (9)
1.一种橙皮素与胡椒碱的共晶,其特征在于该晶体在X-射线粉末衍射图谱中2θ=7.65±0.2°、8.82±0.2°、9.52±0.2°、10.32±0.2°、12.12±0.2°、13.62±0.2°、16.21±0.2°、17.45±0.2°、18.2±0.2°、18.82±0.2°、19.44±0.2°、20.26±0.2°、21.28±0.2°、22.42±0.2°、23.44±0.2°、24.38±0.2°、26.12±0.2°、27.18±0.2°、27.81±0.2°、29.30±0.2°、29.52±0.2°、32.08±0.2°处有特征峰。
3.根据权利要求2所述的橙皮素与胡椒碱共晶,其特征在于,所述共晶中的橙皮素与胡椒碱的比例为摩尔比1:1。
4.根据权利要求1-3中任意一项所述的橙皮素与胡椒碱共晶,其特征在于,所述共晶的熔点为152.48±1℃。
5.一种如权利要求1-4中任意一项所述的橙皮素与胡椒碱共晶的制备方法,其特征在于,将橙皮素和胡椒碱以摩尔比1:1的比例溶于有机溶剂中,将溶剂至于室温下挥发,析晶,干燥,得到橙皮素胡椒碱共晶。
6.根据权利要求5所述的橙皮素与胡椒碱共晶的制备方法,其特征在于,有机溶剂为甲醇和乙醇,或是甲醇和乙醇以任意比例的混合体系。
7.根据权利要求5所述的橙皮素与胡椒碱共晶的制备方法,其特征在于,橙皮素的浓度为0.5-2M,胡椒碱的的浓度为0.5-2M。
8.根据权利要求5所述的橙皮素与胡椒碱共晶的制备方法,其特征在于,析晶时可选择静置挥发溶剂,或边搅拌边挥发有机溶剂。
9.根据权利要求5所述的橙皮素与胡椒碱共晶的制备方法,其特征在于,干燥温度为40-60℃,干燥时间为12-24h。
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