CN101677986A - 多西紫杉在聚山梨醇酯80中的溶剂中的直接溶解 - Google Patents
多西紫杉在聚山梨醇酯80中的溶剂中的直接溶解 Download PDFInfo
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Abstract
本发明涉及多西紫杉在有机溶剂中增溶,其与聚山梨醇酯80的混合物和蒸发溶剂。
Description
本发明涉及用于制备多西紫杉在聚山梨醇酯80中的溶液的新型方法。
它涉更特别地及,根据本发明的第一实施方案,多西紫杉(docétaxel)在有机溶剂中的增溶,涉及它与聚山梨醇酯80混合和蒸发溶剂。
多西紫杉在聚山梨酸酯中的直接溶解,即使是可能的,也是困难步骤。它要求极其有效的搅拌系统或者对活性成分有害的温度升高。迄今为止,多西紫杉在聚山梨醇酯80中的溶液已经通过三步骤方法进行制备,第一步骤构成多西紫杉在乙醇中的溶解,然后与聚氧乙烯失水山梨醇单油酸酯混合,最后蒸发乙醇。
很明显的是在包含多西紫杉的商业化组合物的成品配制剂中使用的乙醇不是可用于本发明范围的唯一溶剂。因此,可以使用许多能够溶解多西紫杉的并按各种比例能与聚氧乙烯失水山梨醇单油酸酯混溶的溶剂。因此可以使用在大气压力下显示出40-153℃沸点的溶剂;在这些溶剂中可以提到氯烷烃(特别地二氯甲烷或者氯仿),酰胺(如二甲基甲酰胺或者二甲基乙酰胺),酯(如乙酸乙酯),酮(如丙酮或者甲基异丁基酮)或者腈(如乙腈)。优选的溶剂选自丙酮、乙腈、二氯甲烷或者二甲基甲酰胺。用作在本发明范围内的原材料的多西紫杉可以是无定形的多西紫杉或者以任何形式结晶的多西紫杉,如丙酮酸酯、醇化物、水合物或者与乙腈的晶体。
根据本发明的方法不限于固体形式的多西紫杉在溶剂中的溶解、然后加入聚氧乙烯失水山梨醇单油酸酯(polysorbate)和蒸馏溶剂,而还在于使用在纯化塔出口获得的多西紫杉溶液。这种溶液可以是多西紫杉在单一溶剂(如乙酸乙酯、丙酮、二氯甲烷或者四氢呋喃)中的溶液,而还可以是在上述溶剂的混合物中的溶液。这些柱通常由二氧化硅柱组成,但是可以使用任何其它可以用于该纯化的材料。在本发明范围中优选使用二氧化硅,特别地以Lichrospher商标进行销售的二氧化硅。完全优选地,使用显示出12μm粒径的Lichrospher二氧化硅。
待纯化的多西紫杉溶液优选地是多西紫杉在乙酸乙酯中或者在乙酸乙酯与烃(如环己烷、己烷或者甲苯)的混合物中的溶液。来自纯化塔的溶液,如果所包含的多西紫杉具有所要求的纯度,可以直接与聚氧乙烯失水山梨醇单油酸酯混合然后蒸发所述一种或多种溶剂而没有呈任何溶剂化物形式的多西紫杉的结晶。从经济的观点看其显示相当大的优点。
本发明通过以下实施例将更完全地进行描述,所述实施例不应该被认为是限制本发明。
实施例1(FTA 152)
将4.3320g多西紫杉三水合物溶于37.9g无水乙醇中,滴加108.0g聚山梨醇酯80,出现大量的泡沫。在50毫巴压力与40℃浴温下进行蒸馏。在蒸馏4小时10分钟之后,获得33.9g蒸馏物和167.8g(待被证实)多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液(soluté),所述溶液包含低于0.01%乙醇和0.28%杂质。
实施例2(FTA 153)
将4.2017g乙腈溶剂化物形式的多西紫杉溶于533ml乙腈(419.2g)中,滴加108.0ml聚山梨醇酯80。在55mPa的平均压力与40℃浴温下进行蒸馏。在蒸馏6小时25分钟之后,获得99.2g多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液,其包含0.06%乙腈和0.41%杂质。
乙腈溶剂化物用下列方式进行制备:
该方法包括使在7和10位双保护的多西紫杉去保护(détrocage)以得到多西紫杉,其通过在甲苯/乙腈混合物中结晶进行分离。
在1升反应器中,进料:900ml乙酸乙酯、7.8mg 4-甲氧基苯酚和78g用三氯乙氧基羰基进行双保护的多西紫杉。搅拌该反应介质然后在减压下蒸馏出120ml乙酸乙酯。返回到23℃,进料37g锌。然后在将温度保持在25±2℃同时倾倒74g乙酸。该倾倒持续1小时15分钟。维持搅拌1小时15分钟,在该时间结束时反应是完全的。
在氮气下过滤该反应介质(锌滤饼)并且该滤饼用乙酸乙酯洗涤三次。将母液和洗液合并然后它们用水洗涤然后用碳酸氢钠水溶液洗涤。将7.2mg 4-甲氧基苯酚在2ml乙酸乙酯中的溶液加入到有机相中,然后用水进行洗涤。
随后,将溶剂改为乙腈。在改变溶剂结束时,使温度返回到25℃然后在2小时期间倾倒113ml甲苯。在该温度下维持搅拌过夜然后在3小时期间将反应介质冷却至0℃。在0℃过滤获得的浆料。滤饼用冷甲苯冲洗。
由此获得的滤饼在烘箱中进行干燥至恒重(27小时)。
由此获得51.7g白色粉末。
测定 | 试验 |
测试的RR% | 87.8 |
水% | 0.6 |
乙腈 | 4.7 |
乙酸乙酯 | 0.2 |
溶剂总和 | 5.5 |
基于原样的含量% | 95.2 |
折干计算的含量% | 100.8 |
杂质的总和% | 0.73 |
实施例3(FTA 154)
将4.3324g三水合物形式的多西紫杉溶于85g二甲基甲酰胺中,滴加108.0g聚山梨醇酯80。在48mPa压力与67℃浴温下进行蒸馏。在蒸馏6小时15分钟之后,获得106.1g(待被证实)多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液,所述溶液包含0.01%二甲基甲酰胺和0.43%杂质。
实施例4(FTA 155)
将4.1792g丙酮酸酯形式的多西紫杉溶于21ml丙酮中,滴加108.0g聚山梨醇酯80。在46毫巴压力与38℃浴温下进行蒸馏。在蒸馏4小时45分钟之后,获得99.7g多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液,其包含0.01%丙酮和0.34%杂质。
实施例5(FTA 156)
将4.33g多西紫杉三水合物溶于165.4g二氯甲烷中,滴加108.0g聚山梨醇酯80。在84毫巴压力与38℃浴温下进行蒸馏。在蒸馏5小时5分钟之后,获得101.2g多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液,其包含0.11%二氯甲烷和0.35%杂质。
实施例6(FTA 151)
混合来自二氧化硅柱纯化的148.1g多西紫杉并且以浓度2.7%(重量/重量)溶于乙酸乙酯中,滴加108.2g聚山梨醇酯80。在55毫巴压力与40℃的浴温下进行蒸馏。在蒸馏3小时15分钟之后,获得95.1g多西紫杉在聚氧乙烯失水山梨醇单油酸酯中的溶液,其包含0.01重量%二氯甲烷和0.64%杂质。
Claims (4)
1.用于制备多西紫杉在聚山梨醇酯80中的溶液的方法,特征在于将多西紫杉溶于具有40-153℃沸点的除乙醇之外的有机溶剂中,将获得的溶液与聚山梨醇酯80混合并且在减压下蒸发溶解溶剂。
2.根据权利要求1的方法,特征在于多西紫杉为结晶形式。
3.根据权利要求2的方法,特征在于多西紫杉为三水合物形式、丙酮酸酯形式或者乙腈溶剂化物形式。
4.根据权利要求1的方法,特征在于溶解溶剂选自丙酮、乙腈、二氯甲烷或者DMF。
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FR0704095 | 2007-06-08 | ||
FR0704095A FR2917088B1 (fr) | 2007-06-08 | 2007-06-08 | Dissolution directe du docetaxel dans un solvant dans le polysorbate 80 |
PCT/FR2008/000766 WO2009004188A2 (fr) | 2007-06-08 | 2008-06-06 | Dissolution directe du docetaxel dans un solvant dans le poly sorbate 80 |
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CN2012103564971A Division CN102908309A (zh) | 2007-06-08 | 2008-06-06 | 多西紫杉在聚山梨醇酯80中的溶剂中的直接溶解 |
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CN2012103564971A Pending CN102908309A (zh) | 2007-06-08 | 2008-06-06 | 多西紫杉在聚山梨醇酯80中的溶剂中的直接溶解 |
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US (1) | US20100197776A1 (zh) |
EP (1) | EP2155189A2 (zh) |
JP (1) | JP2010529094A (zh) |
KR (1) | KR20100022033A (zh) |
CN (2) | CN101677986A (zh) |
AR (1) | AR066889A1 (zh) |
AU (1) | AU2008270141A1 (zh) |
BR (1) | BRPI0812438A2 (zh) |
CA (1) | CA2689466A1 (zh) |
CL (1) | CL2008001650A1 (zh) |
CO (1) | CO6260063A2 (zh) |
CR (1) | CR11144A (zh) |
DO (1) | DOP2009000249A (zh) |
EA (1) | EA200971137A1 (zh) |
EC (1) | ECSP099789A (zh) |
FR (1) | FR2917088B1 (zh) |
GT (1) | GT200900306A (zh) |
HN (1) | HN2009003363A (zh) |
IL (1) | IL202517A0 (zh) |
MA (1) | MA31671B1 (zh) |
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NI (1) | NI200900209A (zh) |
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PA (1) | PA8783101A1 (zh) |
SV (1) | SV2009003428A (zh) |
TN (1) | TN2009000396A1 (zh) |
TW (1) | TW200916095A (zh) |
UA (1) | UA99828C2 (zh) |
UY (1) | UY31129A1 (zh) |
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KR101752944B1 (ko) | 2010-05-03 | 2017-07-03 | 테이코쿠 팔마 유에스에이, 인코포레이티드 | 비수성의 탁산 프로에멀젼 제제, 및 그의 제조 및 사용 방법 |
JO3685B1 (ar) * | 2012-10-01 | 2020-08-27 | Teikoku Pharma Usa Inc | صيغ التشتيت الجسيمي للتاكسين غير المائي وطرق استخدامها |
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FR2678833B1 (fr) * | 1991-07-08 | 1995-04-07 | Rhone Poulenc Rorer Sa | Nouvelles compositions pharmaceutiques a base de derives de la classe des taxanes. |
US6040330A (en) * | 1999-01-08 | 2000-03-21 | Bionumerik Pharmaceuticals, Inc. | Pharmaceutical formulations of taxanes |
GB9920548D0 (en) * | 1999-08-31 | 1999-11-03 | Rhone Poulenc Rorer Sa | Treatment of hepatocellular carcinoma |
US20020041898A1 (en) * | 2000-01-05 | 2002-04-11 | Unger Evan C. | Novel targeted delivery systems for bioactive agents |
US6838569B2 (en) * | 2002-12-16 | 2005-01-04 | Dabur India Limited | Process for preparation of paclitaxel trihydrate and docetaxel trihydrate |
WO2006057429A1 (ja) * | 2004-11-24 | 2006-06-01 | Nanocarrier Co., Ltd. | ブロックコポリマーのモーフォロジ-の変化方法 |
BRPI0600194A (pt) * | 2006-01-30 | 2007-10-23 | Quiral Quimica Do Brasil S A | composições farmacêuticas contendo docetaxel e um inibidor de degradação e processo de obtenção das mesmas |
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