CN1535139A - 阿伐他丁半钙形式ⅶ - Google Patents
阿伐他丁半钙形式ⅶ Download PDFInfo
- Publication number
- CN1535139A CN1535139A CNA018183840A CN01818384A CN1535139A CN 1535139 A CN1535139 A CN 1535139A CN A018183840 A CNA018183840 A CN A018183840A CN 01818384 A CN01818384 A CN 01818384A CN 1535139 A CN1535139 A CN 1535139A
- Authority
- CN
- China
- Prior art keywords
- calcium
- atorvastatin hemi
- form vii
- hydrate
- vii
- 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.)
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
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Images
Classifications
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Abstract
本发明提供了一种命名为形式VII的新形式的阿伐他丁半钙，以及其新的制备方法，其中将其它晶型的阿伐他丁半钙悬浮在乙醇、优选绝对乙醇中，并将其转化为新的形式，然后分离。本发明还提供了一种降低患有或易患心血管病患者血浆中低密度脂蛋白含量的方法，以及用于实现本发明的组合物和剂型。
Description
相关申请的交叉参考
本申请要求2000年11月3日提交的临时申请系列号60/245897的优先权，其在此引入作为参考。
技术领域
本申请涉及阿伐他丁(atorvastatin)半钙的结晶多晶形式及制备结晶固体的新方法。
背景技术
阿伐他丁，([R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸)，其呈式(I)所示内酯的形式和呈式(II)所示钙盐三水合物的形式在本领域中是周知的，描述于US4681893，5273995和2000年11月17日提交的共同转让、共同未决USSN60/166153中，所有这些均在此引入作为参考。
阿伐他丁是一类称作抑制素的药物，目前抑制素药物是降低患心血管疾病危险的患者血流中低密度脂蛋白(LDL)颗粒浓度最有效的治疗药物。血流中存在大量的LDL已经关联到形成冠状动脉病变，它会阻塞血液流动并可能破裂并促进血栓，参见Goodman和Gilman，ThePharmacological Basis of Therapeutics 879(第9版，1996年)。业已表明，降低血浆LDL含量会降低心血管病患者和没有心血管病但有高胆固醇血的患者发生临床事故的危险，参见ScandinavianSimvastatin Survival Study Group，1994；Lipid Research ClinicsProgram，1984a，1984b。
对于抑制素药物的作用机理已经进行了相当详细的描述。它们通过竞争性抑制3-羟基-3-甲基-戊二酰基-辅酶A还原酶(“HMG-CoA还原酶”)而干扰肝脏中胆固醇和其它固醇的合成。HMG-CoA还原酶催化HMG转化为甲羟戊酸酯，它是胆固醇生物合成中决定速度的步骤，所以，对它的抑制会降低肝脏中胆固醇的浓度。极低密度的脂蛋白(VLDL)是将胆固醇及三甘油酯从肝脏中转移到周围细胞中的生物载体。VLDL在外围细胞中分解代谢，会释放出脂肪酸，这种脂肪酸会贮存在adopcyte中或被肌肉氧化。VLDL转化为中密度脂蛋白(IDL)，它或者被LDL受体除去，或者转化为LDL。胆固醇的产生量降低会导致LDL受体数增多，并相应地降低被IDL代谢的LDL颗粒的产生量。
阿伐他丁半钙盐三水合物是由Warner-Lambert Co.以商品名LIPITOR上市的。在US4681893中首次公开并要求保护了阿伐他丁。式(II)所示的半钙盐公开于US5273995中，所述’995专利提出，半钙盐是从一种盐水溶液中结晶得到的，所述盐水溶液是用CaCl2对钠盐进行易位，之后通过用5∶3的乙酸乙酯与己烷混合物进行重结晶而进一步纯化获得的。
本发明提供阿伐他丁半钙的一种新的结晶形式。存在不同的晶形(多晶型)是某些分子及分子络合物的性质。作为单一分子，象式(I)的阿伐他丁或式(II)的盐络合物，可能形成各种各样物理性质如熔点、X-衍射图、红外吸收图谱和NMR谱明显不同的固体。多晶型体物理性质的不同是由于大块固体中相邻分子(络合物)的取向和分子间相互作用的结果。因此，多晶型体是具有相同分子式，但与多晶型体家族中其它形式相比，具有明显有利和/或不利物理性质的完全不同的固体。药用多晶型体的一个最重要的物理性质是其在水溶液中的溶解性，特别是其在患者胃液中的溶解性。例如，当通过胃肠道吸收慢时，对一种药物来说，通常希望它对患者的胃或肠部的条件不稳定，缓慢溶解，这样它就不会聚集在有害的环境中。另一方面，当药效与药物在血流中的最高含量(这是抑制素药物所共有的性质)相关，并且假设药物被GI系统迅速吸收时，对于相当量的溶解更慢的形式来说，更快溶解的形式很可能呈现提高的药效。
授权于Warner-Lambert的US5959156和6121461的主题是阿伐他丁半钙的晶形I、II、III和IV。阿伐他丁半钙的晶形V公开于普通所有、共同未决申请系列号09/714351中。在’156专利中主张，晶形I比已知的无定形阿伐他丁半钙具有更有利的过滤和干燥特性。尽管就可制造性而言，形式I弥补了无定形物质的某些缺陷，但仍需要进一步改善这些性质以及其它性质，如流动性、蒸汽渗透性和溶解性。发现药物的新的多晶形式扩大了物质的范围，配方科学家们用它来设计具有目标释放曲线或其它所需特性的药物剂形。
附图简述
图1是阿伐他丁半钙形式VII的特征粉末X-射线衍射图。
发明概述
本发明提供一种新的阿伐他丁半钙的结晶形式，命名为形式VII，其水合物和其新型的制备方法。
另一方面，本发明提供含有阿伐他丁半钙形式VII的组合物和剂型。
再一方面，本发明提供一种降低患有或易患有心血管病患者血浆较低密度脂蛋白含量的方法，它是通过向患者给以包含阿伐他丁半钙形式VII的药用剂型而实现的。
优选实施方案的详细描述
本发明提供一种阿伐他丁的新的结晶多晶形式，它已被命名为形式VII，与该有机盐已有命名一致。阿伐他丁半钙形式VII的特征且与其它形式的截然不同之处在于其粉末X-射线衍射图(附图1)在2θ角为18.5-21.8度及21.8-25.0度处具有两个宽峰，其它的宽峰出现在2θ角为4.7、7.8、9.3、12.0、17.1、18.2±0.2度处。形式VII的样品可以包含高达12％的水。根据从2θ角为7.8度和9.3±0.2度处的宽峰，形式VII可很容易地与已知形式的阿伐他丁半钙相区分。例如，根据美国专利5,969,156所提供的信息，形式I在2θ角为9.2，9.5，10.3，10.6，11.0和12.2度处有峰。在这一区域，形式II在2θ角为8.5度和9.0度处有两个锐峰而形式IV在2θ角为8.0度处有一个强峰。2θ角为15～25度区域内的其它宽峰将VII形式与所有其它形式区分开来。形式I，III和IV均在此区域内有锐峰。粉末X-射线衍射(“PXRD”)数据得自本领域内公知方法，使用了SCINTAG粉末X-射线衍射仪，其型号为X’TRA，配有固态检测器。使用铜射线，λ＝1.5418A。
阿伐他丁半钙形式VII可通过如下方法制备：用乙醇，优选无水乙醇处理阿伐他丁半钙形式I或V，温度为室温到回流温度，时间为约1至约24小时，优选2.5-16小时。形式I或V转化为形式VII的速率取决于温度。一个优选的操作温度范围为从约20℃至约78℃。在回流乙醇悬浮液中少至2.5小时内曾观测到完全的转化。如果操作在室温下进行则需要更长的时间。转化完成后，VII晶体可通过常规方法，如过滤分离并干燥。温度为约65℃，常压及24小时的干燥时间为干燥晶体的适合条件。
作为起始物料的阿伐他丁半钙形式I可通过美国专利5,969,156的实施例1的方法制备，该专利全文在此引用作为参考。根据一个方法，将根据美国专利5,273,995(其亦全文在此引用作为参考)所述过程制备的阿伐他丁内酯，甲基叔丁基醚(MTBE)和甲醇的混合物与氢氧化钠水溶液在48-58℃下反应40到60分钟以形成阿伐他丁游离酸钠盐。冷却到25-35℃后，弃去有机层，水层再用MTBE萃取。弃去有机层，将MTBE饱和的钠盐水溶液加热到47-52℃。在至少30分钟内向该溶液中加入乙酸钙半水化合物溶于水中的溶液。加入乙酸钙溶液后短时间内用阿伐他丁晶型I的浆液在该混合物中播种晶种。然后将混合物加热到51-57℃至少10分钟，然后冷却到15-40℃。过滤混合物，先用水和甲醇溶液而后用水洗涤。固体在真空下60-70℃干燥3至4天以得到阿伐他丁晶型I。
另一个适合的起始物料是阿伐他丁半钙形式V，可通过从四氢呋喃，甲醇或乙醇与水的混合物中结晶而制备。例如，阿伐他丁半钙可溶于甲醇(例如，0.025-0.050g/ml)中。溶液可加热到约60℃加入大致等体积或更少的水。然后冷却溶液，这一步骤与加入水一同使阿伐他丁半钙结晶为多晶形式V。此过程中可容易地用乙醇和THF替代甲醇，尽管在使用THF时优选加入体积过量的水。
阿伐他丁半钙形式VII用于降低血胆脂醇过多患者或易患血胆固醇过多症的患者血浆中低密度脂蛋白的含量。为此目的，一般给人类患者的一个单位剂量为约0.5mg到约100mg。对多数患者，每日约2.5至约80mg，更优选每日约2.5至约20mg的剂量就使人类患者血浆中低密度脂蛋白含量降低。这一降低是否足够或者剂量或给药频率是否应该提高是受到适当培训的医疗工作者的技能水平可以决定的。
本发明另一个方面是含有以本发明方法可实际给药的新形式阿伐他丁半钙的药学组合物及剂型。
本发明组合物包括含有新的阿伐他丁半钙形式VII的粉末，颗粒，聚集体和其它固体组合物。另外，本发明考虑的形式VII组合物还可包含稀释剂，如纤维素衍生的物质如粉末状纤维素，微晶纤维素，超细纤维素，甲基纤维素，乙基纤维素，羟乙基纤维素，羟丙基纤维素，羟丙基甲基纤维素，羧甲基纤维素盐和其它取代和未取代的纤维素；淀粉；预凝胶化淀粉；无机稀释剂如碳酸钙和磷酸氢钙及其它制药工业公知的稀释剂。其它适合的稀释剂包括蜡，糖和糖醇如甘露醇和山梨醇，丙烯酸酯聚合物和共聚物，以及胶质，糊精和明胶。
本发明考虑之内的其它赋形剂包括粘结剂，如阿拉伯树胶，预凝胶化淀粉，海藻酸钠，葡萄糖和其它用于湿法或干法造粒及直接压缩成片过程的粘结剂。还可出现在阿伐他丁半钙形式VII固体组合物中的赋形剂包括崩解剂如淀粉乙醇酸钠，crospovidone，低取代的羟丙基纤维素等。另外，赋形剂可包括压片润滑剂如硬脂酸镁和硬脂酸钙及硬脂酰富马酸钠；香料；甜味剂；防腐剂；制药学可接受的染料和助流剂如二氧化硅。
药剂包括适于经口，面颊，直肠，不经肠(包括皮下，肌肉和静脉)，吸入和经眼给药的药剂。尽管任何给定情况下最适合的途径取决于所治疗症状的性质及严重程度，但本发明最优选的途径是经口。药剂可方便地呈现为单位剂型，并通过制药技术领域内公知的任何方法制备。
药剂形式包括固体剂型，如片剂，粉末，胶囊，栓剂，袋装，锭剂和糖淀及液体悬浮体和酏剂。本说明书不是为了作为限制，同时本发明也不准备包括阿伐他丁半钙的真溶液，其中失去了区别固态阿伐他丁半钙的性质。但是，认为使用该新形式以制备这样的溶液(如，为了将阿伐他丁之外的溶剂化物以一定的比例同溶剂化物一同传送至所述溶液中)属于本发明考虑的范围。
胶囊药剂，当然，应在胶囊中含有固体组合物，其可由明胶或其它传统封装材料制得。片和粉可被包衣。片和粉可被肠衣包衣。肠衣包衣的粉末形式可具有含有邻苯二甲酸纤维素乙酸酯，邻苯二甲酸羟丙基甲基纤维素酯，邻苯二甲酸聚乙烯醇酯，羧甲基乙基纤维素，苯乙烯和马来酸共聚物，甲基丙烯酸和甲基丙烯酸甲酯共聚物等物质的涂层，且如果需要，其可与适合的增塑剂和/或延展剂一同使用。包衣的片可在片表面具有涂层或可以是含有带肠衣包衣的粉末或胶囊的片。
这样用特别优选的实施方案描述本发明后，进一步用以下实施例描述本发明。其不想以任何方式成为限制。
实施例
通例
含有少于0.2％水的绝对乙醇购自Biolab。其它试剂为试剂级且以购得的形式使用。
实施例1
阿伐他丁半钙形式V(1.00g)于室温下在绝对乙醇(400ml)中搅拌16小时。过滤收集固体并在65℃干燥24小时，得到阿伐他丁半钙形式VII(40mg，40％)。
实施例2
阿伐他丁半钙形式I(75mg)于室温下在绝对乙醇(30ml)中搅拌16小时。过滤收集固体并在65℃干燥24小时，得到阿伐他丁半钙形式VII(0.60g，80％)。
这样用特别优选的实施方案描述并用实施例描述本发明后，本领域技术人员可以理解对所描述的发明的修改不偏离权利要求所定义的本发明的实质及范围。
Claims (17)
1.阿伐他丁半钙形式VII及其水合物，其具有基本如图1所示的粉末X-射线衍射图案。
2.阿伐他丁半钙形式VII及其水合物，其特征在于在粉末X-射线衍射图中在2θ角为18.5-21.8度和21.8-25.0度范围内具有宽峰。
3.权利要求2的阿伐他丁半钙形式VII及其水合物，其进一步的特征在于在粉末X-射线衍射图中2θ角为4.7，7.8，9.3，12.0，17.1，18.2±0.2度处具有宽峰。
4.权利要求2的阿伐他丁半钙形式VII及其水合物，其含有高达约12％的水。
5.权利要求2的阿伐他丁半钙形式VII及其水合物，其每摩尔阿伐他丁半钙含有约一至约八摩尔水。
6.权利要求2的阿伐他丁半钙形式VII及其水合物，其具有窄的粒径分布。
7.权利要求6的阿伐他丁半钙形式VII及其水合物，其中所有粒子直径为100微米或更小。
8.权利要求7的阿伐他丁半钙形式VII及其水合物，其中所有粒子直径为50微米或更小。
9.制备阿伐他丁半钙形式VII的方法，其包括以下步骤：
a)将阿伐他丁半钙分散在乙醇中，时间足以将其转化为形式VII，和
b)从悬浮液中回收形式VII。
10.权利要求9的制备阿伐他丁半钙形式VII的方法，其中悬浮液保持在约20℃至约78℃的温度范围内，保持的时间使阿伐他丁半钙转化为形式VII。
11.权利要求9的方法，其中所述阿伐他丁半钙为形式I或形式V。
12.权利要求9的方法，其中乙醇含有低于约0.5％的水。
13.权利要求12的方法，其中乙醇含有低于约0.2％的水。
14.一种含有权利要求2的阿伐他丁半钙形式VII及其水合物的药物组合物。
15.一种含有要求权利保护的阿伐他丁半钙形式VII的药物组合物的药用剂型。
16.一种降低患有或易患有血胆固醇过多症患者的血浆低密度脂蛋白含量的方法，它是通过向患者给以权利要求15的药用剂型而实现的。
17.权利要求2的阿伐他丁半钙形式VII及其水合物在制备药用剂型中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24589700P | 2000-11-03 | 2000-11-03 | |
| US60/245,897 | 2000-11-03 |
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| Publication Number | Publication Date |
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| CN1535139A true CN1535139A (zh) | 2004-10-06 |
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| Country | Link |
|---|---|
| US (1) | US6605636B2 (zh) |
| EP (1) | EP1332130A4 (zh) |
| JP (1) | JP2004513956A (zh) |
| KR (1) | KR100704213B1 (zh) |
| CN (1) | CN1535139A (zh) |
| AU (1) | AU4150602A (zh) |
| CA (1) | CA2426632C (zh) |
| CZ (1) | CZ20031495A3 (zh) |
| HR (1) | HRP20030442A2 (zh) |
| HU (1) | HUP0303765A2 (zh) |
| IL (2) | IL155734A0 (zh) |
| IS (1) | IS6798A (zh) |
| MX (1) | MXPA03003900A (zh) |
| NO (1) | NO20031986D0 (zh) |
| PL (1) | PL362472A1 (zh) |
| SK (1) | SK6592003A3 (zh) |
| WO (1) | WO2002041834A2 (zh) |
| ZA (1) | ZA200303972B (zh) |
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| CN1997651B (zh) * | 2004-07-16 | 2012-06-06 | 力奇制药公司 | 阿托伐他汀钙的氧化降解产物 |
| US8026376B2 (en) * | 2004-07-20 | 2011-09-27 | Pfizer, Inc. | Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) |
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| WO2011028309A1 (en) | 2009-09-04 | 2011-03-10 | University Of Toledo | PROCESSES FOR PRODUCING OPTICALLY PURE β-LACTONES FROM ALDEHYDES AND COMPOSITIONS PRODUCED THEREBY |
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| CA2622477A1 (en) * | 2000-12-27 | 2002-07-04 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of atorvastatin |
| WO2002057229A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| EP3009423A3 (en) * | 2001-06-29 | 2016-12-28 | Warner-Lambert Company LLC | Crystalline forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
| KR20040019043A (ko) * | 2001-07-30 | 2004-03-04 | 닥터 레디스 레보러터리즈 리미티드 | 아토바스탄틴 칼슘의 결정형 ⅵ 및 ⅶ |
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2001
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- 2001-11-05 CZ CZ20031495A patent/CZ20031495A3/cs unknown
- 2001-11-05 WO PCT/US2001/043947 patent/WO2002041834A2/en not_active Application Discontinuation
- 2001-11-05 JP JP2002544015A patent/JP2004513956A/ja not_active Withdrawn
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- 2001-11-05 CA CA 2426632 patent/CA2426632C/en not_active Expired - Fee Related
- 2001-11-05 SK SK659-2003A patent/SK6592003A3/sk not_active Application Discontinuation
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- 2001-11-05 AU AU4150602A patent/AU4150602A/xx active Pending
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- 2003-05-04 IL IL155734A patent/IL155734A/en not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA200303972B (en) | 2004-08-23 |
| HUP0303765A2 (hu) | 2004-03-01 |
| CA2426632C (en) | 2008-08-05 |
| WO2002041834A2 (en) | 2002-05-30 |
| NO20031986L (no) | 2003-05-02 |
| NO20031986D0 (no) | 2003-05-02 |
| JP2004513956A (ja) | 2004-05-13 |
| IL155734A0 (en) | 2003-11-23 |
| CA2426632A1 (en) | 2002-05-30 |
| SK6592003A3 (en) | 2004-01-08 |
| HRP20030442A2 (en) | 2005-06-30 |
| WO2002041834A8 (en) | 2003-01-03 |
| IS6798A (is) | 2003-04-30 |
| EP1332130A2 (en) | 2003-08-06 |
| MXPA03003900A (es) | 2005-02-17 |
| CZ20031495A3 (cs) | 2004-01-14 |
| IL155734A (en) | 2008-11-26 |
| EP1332130A4 (en) | 2004-01-21 |
| WO2002041834A3 (en) | 2002-07-18 |
| PL362472A1 (en) | 2004-11-02 |
| AU4150602A (en) | 2002-06-03 |
| KR100704213B1 (ko) | 2007-04-10 |
| US20020115709A1 (en) | 2002-08-22 |
| KR20040005854A (ko) | 2004-01-16 |
| US6605636B2 (en) | 2003-08-12 |
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