CN102170786B - 药物组合物和产生低杂质浓度的药物组合物的方法 - Google Patents
药物组合物和产生低杂质浓度的药物组合物的方法 Download PDFInfo
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- CN102170786B CN102170786B CN200980139203.6A CN200980139203A CN102170786B CN 102170786 B CN102170786 B CN 102170786B CN 200980139203 A CN200980139203 A CN 200980139203A CN 102170786 B CN102170786 B CN 102170786B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
描述了含有氯维地平作为活性成分的组合物。该组合物包含作为活性成分的氯维地平和不高于约1.5%的量的杂质H168/79,或其中氯维地平和H168/79之间的比值等于或大于60比1。
Description
发明领域
本发明涉及药物组合物,特别涉及含有减少水平杂质的氯维地平的组合物,和维持此类药物组合物稳定性的方法。
发明背景
氯维地平(Clevidipine),也称作CleviprexTM,是短效的血管选择性钙拮抗剂,已显示其降低动脉血压,同时由于血液和组织酯酶的代谢,该效果迅速终止。作为动脉-选择性血管扩张剂,氯维地平直接降低外周血管阻力,而不扩张静脉容量床(venous capacitance bed)。
氯维地平的化学名称是4-(2′,3′-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸丁酰氧甲基甲酯(C21H23Cl2NO6)。它的结构如下:
氯维地平典型地制成适合于静脉内施用的液体乳剂。脂质乳剂在胃肠外营养应用中广泛使用了约30年,并在最近已被用作不溶性药物如丙泊酚(propofol)(得普利麻 (Diprivan) )和地西泮(diazepam)的药物载体。除了它们能够递送不溶性药物,乳剂也是药物如氯维地平的合适剂型,其易于水解分解。还报道了乳剂防止药物与在静脉注射期间所用的塑料施用器具粘附,并减少输液的局部毒性。
作为药物组合物,氯维地平必需维持其稳定性。在过去的数年中,在含有氯维地平作为活性成分的组合物中已经鉴定了多种杂质。例如,一些杂质来自于用于制造氯维地平的过程,而另一些则是由于活性成分的逐步降解。作为药物组合物,必需维持稳定性并使杂质的量最小化,而不论该杂质的来源或降解的机制。因此,存在对这样的氯维地平的组合物的需要,该组合物针对其最终效力和杂质水平具有可接受的稳定性特征(profiles)。也存在对这样的方法的需要,该方法用于维持含有氯维地平作为活性成分的组合物的稳定性。
发明概述
本发明的第一方面描述了许多杂质,其可以由氯维地平通过水解、脱羧作用和缩合反应产生。描述了这些杂质的结构和检测与分析这些杂质的方法。
本发明的第二方面描述了减少含有氯维地平作为活性成分的药物组合物中的此类杂质的量的方法。
本发明的第三方面描述了使用本文描述的方法制备或储存的药物组合物,其中某些杂质的水平被最小化或降低。
特别地,本发明描述了药物组合物,其含有作为活性成分的氯维地平,并含有降低水平的一种或多种杂质,该杂质选自由物质23、物质24、物质25和H 168/79组成的组。
更特别地,本发明描述了含有氯维地平作为活性成分的药物组合物,其中该组合物包含等于或不超过0.2%的杂质(基于杂质比氯维地平的重量-比-重量),该杂质选自由物质23、24和25组成的组。
甚至更特别地,本发明描述了含有氯维地平或其任何药用盐形式作为活性成分的药物组合物,其中对于每种杂质,即物质23、24和25而言,该组合物包含等于或不超过0.2%的杂质(基于杂质比氯维地平的重量-比-重量)。
本发明包括含有氯维地平作为活性成分的组合物,其中该组合物包含降低水平的量的杂质H168/79,该杂质不高于约1.5%(基于杂质比氯维地平的重量-比-重量),或其中氯维地平和H168/79之间的色谱曲线下面积的比值等于或高于60比0.9。
本发明也包括含有氯维地平或其任何药用盐形式作为活性成分的组合物,其中该组合物包含降低水平的量的杂质H168/79、物质23、物质24和物质25,H168/79的水平为不高于约1.5%(基于杂质比氯维地平的重量-比-重量),或其中氯维地平和物质23、物质24和/或物质25中的每种之间的色谱曲线下面积的比值等于或高于500比1,并且氯维地平和H168/79之间的色谱曲线下面积的比值等于或高于60比0.9。
本发明也描述了制造这样的组合物的方法,所述组合含有氯维地平作为活性成分,和不高于约1.0%(基于杂质比氯维地平的重量-比-重量)的量的杂质H168/79,或其中氯维地平和H168/79之间的比值等于或高于100比1。
本发明的第四方面是治疗或减轻有其需要的受试者中的疾病或病症的方法,其包括向受试者施用有效量的含有氯维地平或其任何药用盐形式作为活性成分的药物组合物,其中对于物质23、物质24和物质25任何一种而言将杂质的水平降低或最小化到不超过0.2%(基于杂质比氯维地平的重量-比-重量),并且对于H168/79而言将杂质的水平降低或最小化到不超过1.5%(基于杂质比氯维地平的重量-比-重量)。用于本文中时,疾病或病症是指任何可以使用选择性钙通道阻断剂,如氯维地平进行治疗的疾病或病症。此类疾病或病症的例子包括,但不限于,高血压(hypertension)诸如原发性高血压(primary hypertension)、继发性高血压(secondary hypertension)、急性高血压(acute hypertension)、慢性高血压(chronic hypertension)、高血压(high blood Pressure)、胸痛(心绞痛)(chest pain(angina))、偏头痛(migraine)、脑动脉瘤并发症(brain aneurysm complications)、不规则心跳(心律失常)(irregular heartbeats(arrhythmia))和雷诺氏病(Raynaud′s disease)。
附图说明
将本发明的下列实施方案的详细描述与附图结合起来考虑有助于理解本发明,其中相同的数字指相同的部分,且其中:
图1图示提出的氯维地平的降解途径。
优选实施方案的详细描述
应当理解,对本发明的附图和描述进行了简化,以便说明与清楚理解本发明相关的要素,同时为了清楚的目的,去除了典型的药物组合物和稳定方法中存在的很多其他要素。本领域的普通技术人员将认识到其他要素和/或步骤在实施本发明中是可取的和/或必需的。然而,因为此类要素和步骤在本领域是众所周知的,并且因为它们无助于更好的理解本发明,所以本文中未提供此类要素和步骤的讨论。本文的公开涉及本领域技术人员已知的对此类要素和方法的所有此类变体和修改。而且,本文鉴定和说明的实施方案仅是出于示例性目的,在其对本发明的描述中无排除或限制之意。
如前所述,氯维地平是速效的二氢吡啶钙通道阻断剂,其开发用于治疗各种病症,例如高血压,包括原发性高血压、继发性高血压、急性高血压、慢性高血压和心脏手术中的围手术期高血压、高血压、胸痛(心绞痛)、偏头痛、脑动脉瘤并发症、不规则心跳(心律失常)和雷诺氏病。作为动脉-选择性血管扩张剂,氯维地平直接降低外周血管阻力,而不扩张静脉容量床(venous capacitance bed)。最终的效果可以是收缩压的降低。关于短效二氢吡啶及其临床适应证的更详细信息可以在美国专利5,856,346中找到,该专利的全部公开通过引用并入本文,如同在本文中叙述其全文一样。
用于本文中时,术语“氯维地平”意指并包括氯维地平的所有变化形式。除非另有说明,此类形式的例子包括所有药用盐、酯、异构体、立体异构体、晶体和无定形形式。
用于本文中时,术语“药用盐”指的是从药用无毒碱或酸,包括无机碱或有机碱和无机酸或有机酸中制备的盐。来自无机碱的盐的例子包括铝、铵、钙、铜、高铁、亚铁、锂、镁、锰(manganic)盐、亚锰(manganous)、钾、钠、锌等等。特别优选的是铵、钙、镁、钾和钠盐。来自药用有机无毒碱的盐包括以下各项的盐:伯胺、仲胺和叔胺,取代胺包括天然存在的取代胺、环胺、和碱性离子交换树脂,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨乙醇、乙醇胺、乙二胺、N-乙基-吗啉、N-乙基哌啶、葡萄糖胺(glucamine)、葡糖胺(glucosamine)、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡 萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等等。
氯维地平通过4-(2’,3’-二氯苯基)-1,4-二氢-5-甲氧羰基-2,6-二甲基-3-吡啶羧酸与丁酸氯甲酯(chloromethyl butyrate)反应进行制造以获得氯维地平。这种反应可以任选地在相应碳酸氢盐(如KHCO3)存在下在回流的乙腈中进行。无机盐可通过过滤除去,且产物通过加入异丙醇和水及随后冷却进行结晶。它也可以通过将溶剂从乙腈交换为醇(如乙醇或异丙醇)的混合物和水以及反复蒸发进行结晶。在该产物的进一步纯化中,该晶体用水和乙醇或异丙醇的混合物进行洗涤。该产物可溶解在回流的异丙醇中,通过冷却进行结晶,通过过滤进行分离并最后用水和异丙醇混合物进行洗涤。氯维地平制造过程的更详细描述可在美国专利6,350,877中找到,该专利的全部公开通过引用并入本文,如同在本文中叙述其全文一样。
氯维地平实际上不溶于水,因此典型地制成适合于静脉施用的液体乳剂。典型地,每毫升可以包含0.5毫克氯维地平,其处于约20%大豆油乳剂中,以用于静脉施用。其他成分可包括甘油、水、纯化的蛋黄磷脂和用于调节pH值的氢氧化钠。
乳剂能比传统的溶液提供好的多的溶解性、更少的载体副作用和更好的稳定性。水包油乳剂也防止化合物粘附到在施用该化合物时使用的塑料输液器具。这些乳剂提供快速的释放和衰减,并提供比传统溶液好的多的体内溶解属性,更少的载体副作用和更好的稳定性。关于氯维地平制剂的更多信息可在美国专利5,739,152中找到,该专利的全部公开通过引用并入本文,如同在本文中叙述其全文一样。
以前不知道含有氯维地平作为活性成分的组合物是热不耐受的并对含水量敏感。然而,基于下述发现,即此类不利条件可从含有氯维地平作为活性成分的药物组合物中产生不可接受水平的杂质,本发明提供这样的组合物,其包括氯维地平和最小化的杂质水平,以及制造和保存这些药物组合物的方法。
已经发现氯维地平在不利条件下降解为数种杂质,该杂质危害纯度并最终危害氯维地平的效力。例如,在不利条件下,氯维地平代谢为H168/79, 其也被称为4-(2’,3’-二氯苯基)-1,4-二氢-2,6,-二甲基-5-吡啶-甲酸甲酯,并显示于下式中:
基于这种发现,提出了氯维地平的降解途径并显示于图1中。这种途径包括许多的氯维地平降解产物,如例如H324/78、H152/66、H152/81、H168/79、H207/59和H207/36。该途径也说明了H168/79通过水解和缩合的方式的进一步降解为物质23、物质24和/或物质25。物质23、物质24和物质25的组成如下:
物质23(1,6顺式) 物质25(1,6反式)
物质24(1,6反式)
对杂质水平进行评估以确定氯维地平乳剂的稳定性和它们暴露在光下使氯维地平的降解最小化的能力。此外,H152/81,H168/79和H207/59是氯维地平的代谢物。H324/78是活性成分的吡啶类似物并通过氯维地平的氧化形成。降解产物H152/81是二氢吡啶羧酸并由氯维地平的水解形成。H152/81可顺序经历脱羧和氧化以分别形成H168/79和H207/59。降解产物H168/79可进行水解以形成二酮酯H207/36,其可进一步环化以形成取 代的环己烯酮衍生物杂质例如物质23和物质25。在这种反应中也可形成物质24,其是物质23的非对映体。
如关于本文描述的药物组合物的任何一种示例性实施方案,优选的是组合物中杂质的水平尽可能低。因此,虽然各种药物组合物的示例性实施方案包括对于组合物作为一个整体而言在可接受和有效的范围内的杂质量,但是组合物越纯,意味着氯维地平或其任何可接受的盐形式的百分比越高,就越好。
物质23是通过H168/79的降解产生的杂质。与温度低于5℃相比,当暴露于超过25℃的温度时H168/79的降解加速。因此,物质23的水平在较高的温度下增加。
类似地,物质25是通过H168/79的降解产生的杂质,并且随着H168/79降解质量可增加。
以前未被鉴定的物质24也是H168/79的降解产物。假设物质24是物质23的非对映体,开发了一种单独的HPLC法来验证和定量物质24。
本发明进一步包括鉴定和定量含有氯维地平作为活性成分的药物样品中的物质24的水平的方法。在一个实施方案中,检测含有氯维地平作为活性成分的药物样品中的物质24的方法包括分离单个的化学化合物的步骤,该化合物构成在氯维地平降解途径中存在的降解物(degradant)或杂质。这可通过柱色谱法,如例如高压液相色谱法(″HPLC″)来完成。含有氯维地平作为活性成分的药物样品可以以小体积引入到柱中并且由此产生的洗脱液的分析可以举例说明代表物质24的峰的分离和鉴定。正如本领域技术人员所理解的,可进行HPLC法的任何优化以产生氯维地平降解中存在的各种杂质之间的峰的最佳分离。用于本发明的典型HPLC法显示在实施例1和2中。基于这种检测物质24的方法,物质24的检测下限,或最小可检测水平,可以是含有氯维地平作为活性成分的药物组合物的约0.01%的面积。备选地,可以存在物质24的下限,其中氯维地平比物质24的比值可以等于或类似于9000比1,其等于或类似于0.01%。类似地,物质25或物质23检测的下限可表述为氯维地平比物质25或物质23的比值,其中氯维地平比物质25或物质23的比值可以等于或类似于9000比1,其等于或类似于0.01%。
实施例1HPLC过程
在每个时间点通过稳定性指示法对氯维地平测定和相关物质进行测试。这种方法是等度、正相HPLC法,具有在220nm波长处的峰值检测。
柱温:35-40℃。
注射体积:20微升。
流速:1.0毫升/分钟。
运行时间约25分钟。
使用庚烷∶乙醇(90∶10)的流动相并将其用于氯维地平和除物质24之外的降解产物的测定。
柱子通过使用氯维地平流动相以1.0毫升/分钟老化(condition)4小时。
新的柱子应以0.2毫升/分钟老化过夜。
当降解产物被洗脱时,可用过滤的乙醇以1.0毫升/分钟洗涤柱子约2小时,然后继续进行平衡。
柱的实例:PVA硅柱4.6毫米x 150毫米,5微米PV12s051546WT或等同物。
实施例2物质24的HPLC过程
这种方法是等度、正相HPLC法,具有在220nm波长处的峰值检测。
柱温:35-40℃。
注射体积:20微升至100微升。
运行时间约60分钟。
使用庚烷∶异丙醇(95∶5)的流动相并将其用于物质24的测定。
柱子通过使用庚烷∶异丙醇95∶5的流动相以1.0毫升/分钟进行老化,直到空白注射基线稳定。新的柱子应以0.2毫升/分钟老化过夜。
柱的实例:两个PVA硅柱4.6毫米x 150毫米,5微米PV12s051546WT或等同物。
流速:1.0毫升/分钟。
基于总的峰面积计算杂质百分比:
杂质峰面积(100)
(降解产物的总的峰面积+H324/38峰面积(氯维地平峰面积))
基于总的峰面积使用H168/79作为杂质的例子计算杂质百分比:
H168/79峰面积(100)
(降解产物的总的峰面积+H324/38峰面积(氯维地平峰面积))
当可获得特定分解产物的标准时,杂质的量化可通过本领域已知的标准程序,如构建标准曲线或通过计算相对响应因子(RRF)来完成。当不可获得标准时,在假设预先计算RRF条件下可以使用杂质比氯维地平的曲线下面积的比值,或如果不知道RRF,使用RRF 1.0来计算杂质百分比。
本发明包括含有氯维地平作为活性成分的药物组合物,其中杂质H168/79的水平是不超过1.5%(基于重量-比-重量)。在本发明的一个实施方案中,该药物组合物包含作为活性成分的氯维地平和不高于约1.2%的量的H168/79。在其他实施方案中,H168/79的量优选不高于约1.0%,和最优选不高于约0.5%。这些组合物可进一步包括如本文所述的可变量的其他降解物,条件是所需的氯维地平的效力水平保持对用于治疗如本文所述的或通过引用并入本文的任何适应证是令人满意且有效的。
表1、2、和3中例示的药物组合物是乳剂。该乳剂包含:氯维地平0.5毫克/毫升,蛋黄磷脂1.2%,大豆油20%,甘油2.25%。剩余物是水,调节pH在6和8.8之间。将产物包装在带有28毫米West compound 1821黑色塞子和铝封口的100毫升的II型玻璃瓶中。
在本发明的另一个实施方案中,药物组合物包括作为活性成分的氯维地平和H168/79,其中氯维地平和H168/79之间的HPLC色谱图的峰下面积的比值等于或高于60比0.9。备选地,氯维地平和H168/79之间的比值可以等于或高于100比1、200比1、或1000比1。在其他实施方案中,氯维地平和H168/79之间的比值可以是在2000比1和1000比1之间。这些组合物可进一步包括如本文所述的可变量的其他降解物,条件是所需的氯维地平的效力水平保持对用于治疗如本文所述的或通过引用并入本文的任何适应证是令人满意且有效的。
在接近约5℃的较低温度时H168/79的百分比增加并稳定,而在接近例如约25℃至约40℃的温度时H168/79的百分比减少。这种趋势表明更 高的温度,H168/79通过中间体H207/36的方式进一步降解为物质23、物质24和/或物质25,如图1所示。
因此,如下列的表1、表2和表3所示,降低温度也为H168/79提供稳定性,并因而降低且抑制由此产生的二级杂质的量。
表1-H168/79的百分比
表2-物质23的百分比
表3-物质25的百分比
根据本发明的一个方面,当储存在约2℃至8℃时,上述提到的稳定含有氯维地平作为活性成分的药物化合物的方法为该组合物提供至少36个月的储存期(shelf life)。从这种冷藏的条件移出并放置在大概室温(15℃至30℃)后,该组合物在长达至少额外的2个月保持稳定。
本发明也包括维持含有氯维地平作为活性成分的药物组合物的稳定性的方法,包括通过减少或抑制制造组合物过程和最后制剂的乳化过程中的水量而减缓或否则抑制氯维地平的水解途径。
在本发明的一个实施方案中,氯维地平通过4-(2’,3’-二氯苯基)-1,4-二氢-5-甲氧羰基-2,6-二甲基-3-吡啶羧酸与丁酸氯甲酯(chloromethyl butyrate)反应进行制造以获得氯维地平。这种反应可以任选地在相应碳酸氢盐(如KHCO3)存在下在回流的乙腈中进行。无机盐可通过过滤除去,且产物通过加入异丙醇及随后冷却进行结晶。它也可以通过将溶剂从乙腈交换为醇(如乙醇或异丙醇)的混合物以及反复蒸发进行结晶。在该产物的进一步纯化中,该晶体用乙醇或异丙醇的混合物进行洗涤。该产物可溶解在回流的异丙醇中,通过冷却进行结晶,通过过滤进行分离并最后用异丙醇混合物进行洗涤。氯维地平制造过程的更详细描述可在美国专利6,350,877中找到,该专利的全部公开通过引用并入本文,如同在本文中叙述其全文一样
氯维地平通常制成适合于静脉施用的液体乳剂。脂质乳剂在胃肠外营养应用中广泛使用了约30年,并在最近已被用作不溶性药物如丙泊酚(得普利麻, )和地西泮的药物载体。除了它们能够递送不溶性药物, 乳剂也是药物如氯维地平的合适剂型,其易于水解分解。还报道了乳剂防止药物与在静脉注射期间所用的塑料施用器具粘附,并减少输液的局部毒性。
典型地,每毫升可以包含0.5毫克氯维地平,其处于约20%大豆油乳剂中,以用于静脉施用。其他成分可包括甘油、纯化的蛋黄磷脂和用于调节pH值的氢氧化钠。通常,在约74℃至约78℃将注射用水分配到混合槽。加入甘油,并且在加入油相前将水相冷却到约60℃至约70℃。对于油相而言,将大豆油分配到溶解槽中、混合并加热到约70℃至约82℃。然后将氯维地平加入到大豆油混合物并加热到约78℃至约82℃。然后将蛋黄磷脂加入到该混合物。将水相和油相混合在一起以形成乳剂,并用1N氢氧化钠调节pH到约6至约8.8的pH。然后使乳剂在约500至8000psi的压力和约50℃至约55℃的温度下均质化为精细粒度。优选地,乳剂在约25℃,更优选地在约15℃,还更优选地在约10℃和最优选地在约5℃进行均质化。将样品过滤并分配到50毫升或100毫升瓶中并盖上硅化处理的橡皮塞子,并用铝顶封(overseal)进行锯齿形焊缝(crimp sealed)。关于氯维地平制剂的更多信息可在美国专利5,739,152中找到,该专利的全部公开通过引用并入本文,如同在本文中叙述其全文一样。
本发明的乳剂包含水包油乳剂,其含有:a)氯维地平,b)脂相,c)乳化剂,和d)水或缓冲剂。该乳剂也可包含助溶剂或其他溶解度增强剂、抗氧化剂、稳定剂、pH调节剂或张力改性剂(tonicity modifying agents),如甘油。
在本发明的乳剂中,氯维地平以约0.4毫克/毫升至约0.6毫克/毫升存在。优选氯维地平以约0.45毫克/毫升至约0.55毫克/毫升存在。脂相以约1%至约35%存在,优选以约18%至约22%存在。乳化剂以脂相重量的约0.01倍至约2倍存在,优选以约0.5%至约4%并更优选以约1%至约1.32%存在。乳剂的剩余物是水或缓冲剂。水或缓冲剂的优选范围是约75%至约90%。将乳剂的pH调整到约6至约8.8,优选约7.5至约8.8。在存在时,甘油以约2%至约2.5%存在。乳剂组合物的百分比以重量/重量表示。
乳剂中的脂相是任何药用油,优选甘油三酯例如大豆油、红花籽油、橄榄油、棉籽油、向日葵油、芝麻油、花生油、玉米油、中链甘油三酯(如 Miglyol.RTM.812或810)或乙酸甘油酯。脂相也可是丙二醇二酯(propylene glycol diesters)或甘油单酯(如acetylareal monoglycerides)。脂相也可是所述成分的混合物。最优选的脂相是大豆油。
乳化剂是任何药用乳化剂,优选提取自蛋黄或大豆的磷脂、合成的磷脂酰胆碱或来自植物来源的纯化的磷脂酰胆碱。也可使用氢化的衍生物,例如氢化磷脂酰胆碱(蛋)和氢化磷脂酰胆碱(大豆)。乳化剂也可以是非离子型表面活性剂如泊洛沙姆(poloxamer)(例如泊洛沙姆188和407)、泊洛沙胺(poloxamine)、聚氧乙烯硬脂酸酯、聚氧乙烯失水山梨糖醇脂肪酸酯或失水山梨糖醇脂肪酸酯。也可使用离子型表面活性剂例如胆酸和脱氧胆酸或其表面活性衍生物或盐。乳化剂也可以是所述成分的混合物。最优选的乳化剂是蛋黄磷脂。
本领域的那些普通技术人员将认识到本发明的很多修改和变体可以在不脱离本发明的精神或范围的情况下实施。因此,本发明意在涵盖本发明的修改和变体,只要它们在所附的权利要求及其等同物的范围内。
Claims (15)
1.一种药物组合物,其包含作为活性成分的氯维地平或其任何药用盐,并且包含降低水平的一种或多种选自由以下物质组成的组的降解物:
其中基于重量-比-重量,所述降解物的量是等于或低于0.2%,并且其中所述药物组合物被制备成pH为6至8.8的乳剂,所述乳剂包含0.4mg/ml-0.6mg/ml的氯维地平,1%-35%的脂相,脂相重量的0.01倍至2倍的乳化剂,和水或缓冲剂,其中百分比以重量/重量表示。
2.权利要求1的组合物,其中当所述组合物保存在有效温度下时所述组合物中的具有下式的降解物的水平等于或低于1.5%
。
3.药物组合物,所述组合物包含作为活性成分的氯维地平或其任何药用盐,所述组合物通过包括下述步骤的方法制备:
将油加热到70℃至82℃之间;
将氯维地平加入到加热的油中并将混合物加热到78℃;
将蛋黄磷脂加入到混合物中;和
加入水相;
其中水相由甘油和水或甘油和缓冲液组成,并且将pH调节到6至8.8;和
其中一种或多种选自由以下物质组成的组的降解物的量等于或低于0.2%:
4.权利要求1至3中任一项的组合物,其中所述具有下式的降解物的
量为等于或低于1.0%
。
5.权利要求4的组合物,其中所述降解物H168/79的量为等于或低于0.5%。
6.权利要求1至3中任一项的组合物用于制造治疗或预防高血压的药物的用途。
7.一种减少权利要求1-2和引用权利要求1的权利要求4-5中任一项的组合物中杂质的方法,其包括:
将油加热到70℃至82℃之间;
将氯维地平加入到加热的油中并将混合物加热到78℃;
将蛋黄磷脂加入到混合物中;和
加入水相;
其中将pH调节到6至8.8;
均质化乳液;和
其中具有下式的降解物的量等于或低于1.5%:
8.权利要求7的方法,其中所述降解物H168/79的量为等于或低于1.0%。
9.权利要求8的方法,其中所述降解物H168/79的量为等于或低于0.5%。
10.权利要求7至9中任一项的方法,其中所述水相由甘油和水或甘油和缓冲液组成。
11.权利要求7至9中任一项的方法,其中pH为7.5-8.8。
12.权利要求7至9中任一项的方法,其中所述混合物在25℃下均质化。
13.权利要求7至9中任一项的方法,其中所述混合物在15℃下均质化。
14.权利要求7至9中任一项的方法,其中所述混合物在10℃下均质化。
15.权利要求7至9中任一项的方法,其中所述混合物在5℃下均质化。
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WO2019123221A1 (en) * | 2017-12-20 | 2019-06-27 | Aurobindo Pharma Limited | Pharmaceutical composition comprising clevidipine and process for preparation thereof |
CN109956943B (zh) * | 2019-04-18 | 2021-07-20 | 合肥合源药业有限公司 | 一种二氢吡啶类药物中脱羧缩合杂质及其制备、控制方法 |
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