CN1876657B - 大环内酯的稳定化 - Google Patents
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Abstract
本发明涉及多烯大环内酯的稳定方法和涉及以结晶形式得到的特定大环内酯。
Description
本申请是中国发明专利申请no.99814124.0的分案申请，享有1998年12月7日的优先权。
本发明涉及氧化敏感性药物活性成分的稳定化作用，其中所述对氧化敏感的药物活性成分例如是多烯大环内酯，优选具有免疫抑制特性多烯大环内酯，特别优选雷帕霉素。
我们难以处理和储存氧化敏感性药物活性成分，特别是散装形式的药物活性成分。因此需要特别处理，并且药物活性成分通常在保护性气体下的气体密封装置中保存。在这些药物活性成分的配制期间加入大量稳定剂。
多烯大环内酯具有令人满意的稳定特性。然而，目前发现：在其分离步骤期间，通过加入稳定剂例如抗氧化剂能够大大地增加其稳定性。
本发明提供：
1、稳定多烯大环内酯的方法，包括：把抗氧化剂加入到纯化的大环内酯中，优选在分离步骤开始时进行。
该方法特别用于生产散装的稳定化多烯大环内酯。方便地，抗氧化剂的用量可以最高达1％、更优选0.01-0.5％(基于大环内酯的重量)。下文中把这样小的量称为催化量。
作为替代上述的选择，本发明还提供：
2、含有多烯大环内酯和(优选催化量)抗氧化剂的混合物，例如散装混合物，优选固体形式。
上述混合物可以是颗粒状，例如结晶或无定形。其可以在无菌或基本上无菌条件下，例如在适合药用的条件下。
3、上述2.定义的混合物在制备药物组合物中的应用。
多烯大环内酯的实例如下：例如含有双键优选共轭双键的分子，例如具有抗生素和/或免疫抑制特性的物质；含有内酰胺或内酯键的大环内酯及其衍生物；生物活性性质上类似于天然大环内酯的化合物；化学取代的大环内酯。合适的例子包括雷帕霉素和子囊霉素类(ascomycins)。优选的多烯大环内酯是包含至少二个共轭双键，例如三个共轭双键的大环内酯。
雷帕霉素是例如可由Streptomyces hygroscopicus制得的已知内酰胺大环内酯。雷帕霉素的结构在Kessler，H等，1993；Helv.Chim.Acta(瑞士化学学报)，76：117中有述。雷帕霉素具抗素和免疫抑制特性。其中雷帕霉素衍生物例如16-氧取代的雷帕霉素是已知的，例如记载于WO94/02136和WO96/41807；例如40-O-取代的雷帕霉素，例如记载于WO94/09010、WO92/05179、WO95/14023、94/02136、WO94/02385和WO96/13273中，所有这些出版物在此引入作为参考。优选的雷帕霉素衍生物例如：WO94/09010第1页所示式A的40位羟基被-OR所取代的雷帕霉素，其中R为羟烷基、羟基烷氧基烷基、酰基氨基烷基或氨基烷基，例如40-O-(2-羟基)乙基雷帕霉素、40-O-(3-羟基)-丙基雷帕霉素和40-O-[2-(2-羟基)乙氧基]乙基-雷帕霉素。
FK-506和子囊霉素的子囊霉素类是人们所熟知的，它们组成另一类内酰胺大环内酯类，许多这些化合物具有有效的免疫抑制和抗炎活性。FK506是由Streptomyces tsukubaensis产生的内酰胺大环内酯。在第11版默克索引(Merck Index，1989年)附录第A5项中记载了FK506的结构。子囊霉素也记载于现有技术中，例如记载在USP3,244,592中。子囊霉素、FK506、具有类似生物活性的其它天然大环内酯类及其衍生物例如合成类似物和衍生物在此统称为“子囊霉素类”。合成类似物或衍生物的例子为例如：卤化子囊霉素类如：33-表-氯-33-脱氧子囊霉素，如其记载于EP-A-427,680中；四氢吡喃衍生物，例如记载于EP-A-626,385中。
特别优选的大环内酯为雷帕霉素和40-O-(2-羟基)乙基-雷帕霉素。
优选的抗氧化剂例如是2，6-二叔丁基-4-甲基苯酚(下文称BHT)、维生素E或C，其中BHT是特别优选的抗氧化剂。
本发明特别优选的混合物是雷帕霉素或40-O-(2-羟基)乙基-雷帕霉素和0.2％(基于大环内酯重量)抗氧化剂优选BHT的混合物。
可以在分离步骤(优选最终的分离步骤)开始时，更优选刚好在最终分离步骤之前把抗氧化剂加入到多烯大环内酯中。所述大环内酯优选在纯化状态。可以将其溶解在惰性溶剂中，然后往所得溶液中加入抗氧化剂，之后，进行稳定的大环内酯例如无定形或晶体形式大环内酯的沉淀步骤。本发明的混合物优选无定形。
所得稳定的大环内酯对于氧化显示令人惊奇的稳定性，并且例如在进一步加工如加工成盖仑组合物之前的散装形式处理和储存变得更容易。无定形大环内酯是特别令人感兴趣的。
可以应用本发明稳定的大环内酯本身来制备需要的盖仑制剂。这样的制剂可以按照本领域已知的方法制备，所述方法包括：加入一种或多种可药用的稀释剂或载体，包括再加入稳定剂(如果需要)。
因此，本发明还提供：
4、药物组合物，包括：作为活性成分的上述稳定的混合物和一种或多种可药用稀释剂或载体。
本发明组合物可以适合口服、胃肠外给药、局部(例如皮肤)给药、眼、鼻或吸入(如肺)给药。优选的组合物为口服组合物，当活性成分为内酯大环内酯时，优选不含水的组合物。
本发明的药物组合物可以含有另外的赋形剂，例如润滑剂、崩解剂、表面活性剂、载体、稀释剂和调味剂等。其可以是液体形式，例如溶液、悬浮液或乳液例如微乳液，如在USP5,536,729中所公开的形式；或者可以是固体形式，例如胶囊、片剂、糖衣丸、粉剂(包括微粒化或其它减小的颗粒)、固体分散体和粒剂等，例如WO97/03654所记载的形式，该文内容在此引入作为参考；或者可以是半固体形式例如软膏、凝胶、乳膏和糊剂。这些组合物优选适合口服给药的形式。优选地它们是固体形式。可以按照已知方法制备本发明的药物组合物：在搅拌下，把本发明的稳定大环内酯同另外的成分混合；这些成分可以粉碎或磨碎，如果需要，可以进行压制，例如压成片剂。
液体或固体形式的雷帕霉素组合物在本发明中是特别令人感兴趣的。特别优选的组合物是固体分散体，例如含有本发明稳定的雷帕霉素和载体介质例如水溶性聚合物如羟丙基甲基纤维素，如公开在WO97/03654中。
本发明组合物可以用于其所含的大环内酯(例如在已知剂量下)所已知治疗的适应症。例如，大环内酯如雷帕霉素或雷帕霉素衍生物具有免疫抑制活性，该组合物可以用于例如治疗或预防器官或组织中急性或慢性异体移植排斥或异种移植排斥、自身免疫性疾病或炎症、哮喘、增生性疾病如肿瘤，或超增生性血管疾病，优选用于治疗或预防移植排斥。
所述组合物和大环内酯的给药量取决于许多因素，例如所用的活性成分、所治疗的疾病和治疗持续时间等。例如，对于雷帕霉素或40-O-(2-羟基)乙基雷帕霉素来说，合适的口服每日剂型含有0.1-10mg，一次给药或分次给药。
另一方面，本发明还提供晶体形式的40-O-(2-羟基)乙基-雷帕霉素，特别是基本上纯净的晶体形式。优选地，该晶体形式的特点在于不含有或基本上不含有任何溶剂成分；其为非溶剂化物。
40-O-(2-羟基)乙基-雷帕霉素晶型属于单斜晶系。得到的晶体熔点为146-147℃、特别是146.5℃。为了有助于新晶型的鉴定，此处提供了X-射线衍射分析数据。获得这些数据所采用的条件如下：
温度 293(2)K
波长 1.54178
空间群 P21
晶胞尺寸
a 14.378.(2)
b 11.244(1)
c 18.310(2)
β 108.58(1)°
体积 2805.8(6)
Z 2
密度(计算值) 1.134g/cm3
吸收系数 0.659mm-1
F(000) 1040
晶体大小 0.59×0.11×0.03mm
数据收集的θ范围 2.55-57.20°
收集的反射 4182
独立的反射 4037[R(int)＝0.0341]
强度衰减 32％
精化方法 F2的满矩阵法最小平方分析
数据/抑制
(restraints)/参数 3134/1/613
F2拟合优度
(Goodness-of-fit on F2) 1.055
最终R指数[I＞2sigma(I)] R1＝0.0574，wR2＝0.1456
最大区别的峰和谷 0.340和-0.184e/
晶体形式的40-O-(2-羟基)乙基-雷帕霉素可以这样制备：把无定形化合物溶解于溶剂例如乙酸乙酯中，然后加入脂族烃CnH2n+2(n＝5、6或7)。加入烃后，在温度为25-50℃下温热得到的混合物，例如高达30-35℃。然后可以在低温下例如低于25℃、优选从0-25℃储存得到的混合物。过滤出晶体，干燥。庚烷为优选的脂族烃。如果需要，可以通过声处理或引晶技术开始成核步骤。
本发明还提供纯化40-O-(2-羟基)乙基-雷帕霉素的方法，包括：从含有晶体的介质(例如如上所述)中，结晶40-O-(2-羟基)乙基-雷帕霉素，然后回收得到的晶体。含有晶体的介质可以包括除上述物质之外的一种或多种组份。已经发现含有晶体的介质特别合适是含有约2份乙酸乙酯和约5份脂族烃例如庚烷。
业已发现：晶体形式的40-O-(2-羟基)乙基-雷帕霉素具有同无定形式相当的体外和体内免疫抑制活性。在局部化GvHD中，应用3mg剂量的晶体形式的40-O-(2-羟基)乙基-雷帕霉素，可以达到淋巴结肿大的最大抑制(70-80％)。
40-O-(2-羟基)乙基-雷帕霉素可以用于与无定形化合物已知治疗的相同适应症，例如：预防或治疗急性和慢性异体或异种移植排斥、自身免疫性疾病或炎症、哮喘、增生性疾病如肿瘤或超增生性血管疾病，例如WO94/09010或WO97/35575中所公开的疾病，这些文献在此引入作为参考。一般来说，口服剂量为0.05-5或最高达20mg/kg/天、例如0.1-2或最高达7.5mg/kg/天数量级和给药一次或每天分2次至4次给药可以达到令人满意的效果。因此，用于病人的合适日剂量为最高达10mg数量级，例如0.1-10mg。
晶体形式的40-O-(2-羟基)乙基-雷帕霉素可以经任意常规途径给药，例如口服(如片剂或胶囊)、或者鼻或肺给药(吸入)。其可以作为单一活性成分给药，也可以同其它药物联合给药，其中所述其它药物例如是免疫抑制剂和/或免疫调节剂和/或抗炎剂，例如公开于WO94/09010中的药物。
根据上述内容，本发明还提供：
5、在需要治疗的患者中治疗或预防急性或慢性异体-或异种-移植排斥、自身免疫性疾病或炎症、哮喘、增生性疾病或超增生性血管疾病的方法，该方法包括：对所述患者给药治疗有效量的晶体形式的40-O-(2-羟基)乙基-雷帕霉素；
6、晶体形式的40-O-(2-羟基)乙基-雷帕霉素作为药物的应用，如在上述方法中；
7、含有晶体形式的40-O-(2-羟基)乙基-雷帕霉素和可药用稀释剂或载体的药物组合物；
8、用于免疫抑制或炎症的试剂盒或包装，包括：上述药物组合物和含有免疫抑制或免疫调节药物或抗炎剂的药物组合物。
下列实施例举例说明本发明，而不是对本发明进行限制。
实施例1：结晶
在40℃下，把0.5g无定形40-O-(2-羟基)乙基-雷帕霉素溶解于2.0ml乙酸乙酯中。加入5.0ml庚烷，溶液成“乳状”。温热至30℃后，溶液又变澄清。冷却到0℃，在刮擦的情况下，溶液中出现油。封闭该试管，在10℃下储存过夜。然后过滤出产生的白色大体积固体，用0.5ml乙酸乙酯/庚烷(1∶2.5)混合物洗涤，在5毫巴压力和40℃温度下，把所得到的晶体干燥16小时。这样得到晶体形式的40-O-(2-羟基)乙基-雷帕霉素，熔点为146.5℃。
大规模的结晶可如下进行：
在氩气保护并缓慢搅拌下，把250g无定形40-O-(2-羟基)乙基雷帕霉素溶解于1.0升乙酸乙酯中。在30℃下加热该溶液，持续45分钟，滴入1.5升庚烷。把如上制备的0.25g种晶在同样条件下分次加入上述混合物中。然后把得到的混合物在30℃温度下搅拌2小时。冷却结晶混合物至25℃，持续1小时。然后冷却至10℃持续30分钟，过滤。用100ml乙酸乙酯/庚烷(2∶3)混合物洗涤晶体。然后在50℃温度和约5毫巴压力下干燥。熔点146.5℃。
IR in KBr：3452，2931，1746，1717，1617，1453，1376，1241，1191，1163，1094，1072，
1010，985，896cm-1
在下面图1-图3中显示带坐标的单晶X-射线结构。
实施例2：制备稳定的40-O-(2-羟基)乙基-雷帕霉素
把100g 40-O-(2-羟基)乙基-雷帕霉素溶解于600升无水乙醇中。加入0.2g BHT，在搅拌下在1小时时间内把得到的溶液滴入到3.0升水中。继续搅拌得到的悬浮液30分钟。过滤后洗涤(3×200ml水/乙醇，体积比为5∶1)，得到湿白色产品，在30℃温度下真空(1毫巴)干燥48小时。所得干燥产品中含有0.2％(w/w)BHT。
所得产品在储存时显示增高的稳定性。储存1周后，副产品和降解产品百分数之和如下：
化合物 50℃在开口瓶中
实施例2(0.2％BHT) 1.49
不含BHT ＞10
可以应用活性成分雷帕霉素重复上述实施例的方法。
Claims (7)
1.晶体形式的40-O-(2-羟基)乙基-雷帕霉素，其具有晶格：a＝14.37
b＝11.24
c＝18.31
体积为2805
2.权利要求1的晶体形式的40-O-(2-羟基)乙基-雷帕霉素，特征在于熔点为146-147℃。
3.药物组合物，含有权利要求1或2的化合物和一种或多种可药用稀释剂或载体。
4.权利要求1或2的化合物在制备用于治疗急性或慢性异体或异种移植排斥、自身免疫性疾病或炎症、哮喘、增生性疾病或超增生性血管疾病的药物中的应用。
5.权利要求3的组合物在制备用于治疗急性或慢性异体或异种移植排斥、自身免疫性疾病或炎症、哮喘、增生性疾病或超增生性血管疾病的药物中的应用。
6.纯化40-O-(2-羟基)乙基-雷帕霉素的方法，包括：从溶剂中结晶40-O-(2-羟基)乙基-雷帕霉素，然后回收得到根据权利要求1的晶体，其中所述溶剂由乙酸乙酯和脂族烃组成。
7.根据权利要求6的方法，其中所述溶剂由2份乙酸乙酯和5份脂族烃CnH2n+2组成，其中n＝5，6或7。
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| KR100400620B1 (ko) * | 1995-06-09 | 2004-02-18 | 노파르티스 아게 | 라파마이신유도체 |
| NZ333657A (en) * | 1996-07-30 | 2000-05-26 | Novartis Ag | A pharmaceutical composition comprising cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin |
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1998
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1999
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| CN1195289A (zh) * | 1995-07-14 | 1998-10-07 | 诺瓦蒂斯有限公司 | 药物组合物 |
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