CN1764459A - 口服制剂 - Google Patents
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Abstract
本发明提供与3-羟基-2-(羟甲基)-2-甲基丙酸生成的雷帕霉素42-酯(CCI-779)的口服固体制剂。
Description
发明背景
本发明涉及与3-羟基-2-(羟甲基)-2-甲基丙酸生成的雷帕霉素42-酯(CCI-779)的口服固体制剂。
雷帕霉素是由吸水链霉菌产生的大环三烯类抗生素,在体内和体外具有抗真菌活性,特别是抑制白色念珠菌[C.Vezina等,J.Antibiot.28,721(1975);S.N.Sehgal et al.,J.Antibiot.28,727(1975);H.A.Baker et al.,J.Antibiot.31,539(1978);美国专利申请3,929,992;和美国专利申请3,993,749]。另外,雷帕霉素单独(美国专利申请4,885,171)或与溶链菌(美国专利申请4,401,653)联合均具有抗肿瘤活性。
FASEB 3,3411(1989)公开了雷帕霉素具有免疫抑制作用。环孢霉素A和FK-506、其他的大环分子,也显示出作为免疫抑制剂的有效性,因此其对于预防移植排斥是有用的[美国专利申请5,100,899]。R.Martel et al.[Can.J.Physio.Pharmacol.55,48(1977)]公开了雷帕霉素对于实验性变应性脑脊髓炎模型即一种多发性硬化症模型、佐剂(诱发的)关节炎模型即一种类风湿性关节炎模型的有效性;其还可有效地抑制IgE-样抗体的生成。
雷帕霉素还可用于预防或治疗全身性红斑狼疮[美国专利申请5,078,999]、肺炎[美国专利申请5,080,899]、胰岛素依赖型糖尿病[美国专利申请5,321,009]、皮肤病例如牛皮癣[美国专利申请5,286,730]、肠疾病[美国专利申请5,286,731]、平滑肌细胞增殖和血管损伤引起的内膜增厚[美国专利申请5,288,711和5,516,781]、成年人T-细胞白血球过多症/淋巴瘤[欧洲专利申请525,960A1]、眼部炎症[美国专利申请5,387,589]、恶性癌症[美国专利申请5,206,018]、心脏炎症[美国专利申请5,496,832]、和贫血[美国专利申请5,561,138]。
与3-羟基-2-(羟甲基)-2-甲基丙酸生成的雷帕霉素42-酯(CCI-779)是雷帕霉素酯,已证明其对于体内和体外模型均具有显著的肿瘤生长抑制作用。美国专利申请5,362,718公开了包括CCI-779的雷帕霉素酯的制备和应用。
CCI-779显示出与细胞毒素性质相反的细胞生长抑制作用,并且可以延缓肿瘤的演化时间或肿瘤复发时间。CCI-779被认为其作用机理与西罗莫司相似。CCI-779与细胞质蛋白FKBP连接并形成络合物,其可抑制一种酶、mTOR(哺乳动物体内雷帕霉素的靶点,也被称作伴随蛋白[FRAP]的FKBP12-雷帕霉素)。mTOR激酶的活性抑制作用抑制了多种信号转导途径,包括细胞因子-刺激的细胞增殖、用于调节细胞周期G1相的若干关键蛋白的mRNAs的翻译、和IL-2-诱导的转录其结果为抑制了细胞周期从G1相发展为S相。CCI-779的作用机理是造成了G1相发展为S相的阻断,这对于抗癌药而言是闻所未闻的。
CCI-779在体外显示出可抑制很多组织结构不同的肿瘤细胞的生长。中枢神经系统(CNS)癌、白血球过多症(T-细胞)、乳腺癌、前列腺癌和黑素瘤系对于CCI-779最为敏感。此化合物阻止了细胞周期中G1相的细胞。
裸鼠体内实验表明CCI-779可抑制人类不同组织学类型肿瘤的异种嫁接。神经胶质瘤对于CCI-779特别敏感,此化合物对于裸鼠的常位神经胶质瘤模型是有效的。体外人类成胶质细胞瘤细胞系由生长因子(血小板-衍生的)-诱导的刺激被CCI-779显著抑制。裸鼠中一些人类胰腺肿瘤的生长与体内研究的两个乳腺癌系之一一样也被CCI-779抑制。
制备CCI-779制剂的一个障碍就是其弱水溶性(小于1μg/ml),其导致生物利用度降低。另外,内酯键的分裂显示出CCI-779的水不稳定性,导致形成了开环的开环-CCI-779。直接压制非微粒化的CCI-779和标准辅料、填充剂制备CCI-779片剂,在存在或不存在表面活性剂的情况下制得的片剂不能达到迅速而完全的药物释放,因此这种方法制备的CCI-779制剂是不适合的。
发明概述
本发明通过使用水溶性聚合物如聚乙烯吡咯酮(PVP)、采用湿制粒法获得一种克服了溶解度和不稳定性缺陷的高生物利用度、非微粒化CCI-779制剂从而避免上述问题。对降解的抑制作用可通过使用一种或多种抗氧化剂和pH调节剂解决,保持pH值为约4-约6。
本发明的其他方面和优点在下文的详细描述中是显而易见的。
发明详述
相应地,本发明提供了一种包含通过湿制粒法制得的颗粒的固体制剂,所述颗粒包含CCI-779、水溶性聚合物、pH调节剂、表面活性剂和抗氧化剂。在一个具体的实施例中,制剂包含0.1-30%、0.5-25%、1-20%、5-15%或7-12%(wt/wt)的CCI-779,0.5-50%、1-40%、5-35%、10-25%或15-20%(wt/wt)的水溶性聚合物,0.5-10%、1-8%或3-5%(wt/wt)的表面活性剂和0.001%-1%、0.01%-1%或0.1%-0.5%(wt/wt)的抗氧化剂。然而,其他实施例中包含或多或少的这些组份。
制剂还可以包含适当的螯合剂、填充剂、粘合剂、表面活性剂和有助于成粒和压片过程的类似物质。优选的湿制粒法采用包含水和醇的含水酒精溶剂系统完成,优选的醇是乙醇。
典型的水溶性聚合物包括但不限于聚乙烯吡咯酮(PVP)、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)和环糊精或其混合物。优选的水溶性聚合物是PVP,其分子量为2.5-60千道尔顿。本发明所述的任何制剂中每一组分可包括多种成分。例如,一种制剂包括抗氧化剂,其可包括一种或多种抗氧化剂共同作为抗氧化剂组份。
可接受的pH调节剂包括但不限于柠檬酸、柠檬酸钠、稀HCl和其他能够将含有CCI-779的溶液缓冲至pH为约4-约6的弱酸或弱碱。
可接受的抗氧化剂包括但不限于柠檬酸、d,1-α-生育酚、BHA、BHT、二羟基丙硫醇、抗坏血酸和丙基没食子酸。预计本发明制剂中使用的抗氧化剂的浓度为0.001%-3%wt/wt。
螯合剂及其他能够结合金属离子的物质,例如乙二胺四乙酸(EDTA)及其盐能够增强CCI-779的稳定性。
表面活性剂可以包括土温80、月桂基硫酸钠、十二烷基硫酸钠、胆汁酸盐(牛磺胆酸盐、甘氨胆酸盐、胆酸盐、脱氧胆酸盐等),其可与卵磷脂结合。任选地,乙氧基植物油例如Cremophor EL、维生素E生育酚丙二醇丁二酸酯(Vitamin E TGPS)、聚氧乙烯聚氧丙烯嵌段共聚物和泊洛沙姆。
粘合剂、填充剂和崩解剂如蔗糖、乳糖、微晶纤维素、交联羧甲基纤维素钠、硬脂酸镁、阿拉伯胶、胆固醇、西黄蓍胶、硬脂酸、明胶、酪蛋白、卵磷脂(磷脂)、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙甲基纤维素邻苯二甲酸酯、非晶纤维素、十八醇十六醇混合物、鲸蜡醇、十六烷基酯蜡、葡聚糖结合剂、糊精、乳糖、葡萄糖、单油酸甘油酯、单硬脂酸甘油酯、甘油基棕榈(酰)硬脂(酰)甘油酯、聚氧乙烯烷基醚、聚乙二醇、聚氧乙烯蓖麻油衍生物、聚氧乙烯硬脂酸酯和聚乙烯醇,及可以混入制剂中的其他类似物。
制剂可通过下述方法制备:配制含有CCI-779和抗氧化剂的醇溶液和含水溶性聚合物、表面活性剂和pH调节剂的水溶液,pH调节剂的用量以使水溶液pH值为4-6为适宜。合适的醇包括甲醇、乙醇、异丙醇及其类似物,优选乙醇。混合两种溶液,加入含有颗粒内辅料的混合物中。任选地,醇溶液和水溶液也可以不混合,分别独立地加入。所述颗粒内辅料包括粘合剂和填充剂,其有助于增加溶解。典型的颗粒内辅料包括但不限于微晶纤维素、乳糖和交联羧甲基纤维素钠。固体颗粒内辅料是在搅拌机中由溶液形成颗粒,直至得到均匀的颗粒。搅拌机可能是带有强化棒的搅拌机、低切力制粒机或高切力制粒机。颗粒于约50℃下在流化床干燥器中干燥,然后使用适当的碾磨装置例如Fitz碾磨机进行碾磨。湿制粒和干燥步骤在流化床制粒机/干燥器中进行。湿制粒法可以使用支架干燥箱进行干燥。如有需要,干颗粒可在压片前进一步与颗粒外填充剂和粘合剂例如微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁在搅拌机中混合,例如V-搅拌机。
任选地,一些水溶性聚合物可以包含在颗粒内辅料中,水溶液和醇溶液逐步加入含有颗粒内辅料的混合物中。例如,加入混合器的顺序可以是先加入水溶液的一半,再加入全部醇溶液,再加入水溶液的剩余部分。在本发明范围内,其他的加入顺序都是可能和允许的。
下面提供了本发明制剂的有代表性的实施例。CCI-779的制备方法公开于美国专利申请5,362,718中,在此处引用作为参考。美国专利申请6,277,983公开了CCI-779的区域选择性制备方法,在此处引用作为参考。这些实施例仅仅用于说明本发明,而不对保护范围造成限制。
实施例
操作A
下述操作用于制备包含2mg CCI-779和下述组分的片剂;调节用量以说明其低效能:
组分 | 百分比wt/wt |
CCI-779 | 1.77 |
丁酸酯羟基苯甲醚 | 0.10 |
丁酸酯羟基甲苯 | 0.05 |
PVP,17PF | 8.85 |
乙二胺四乙酸 | 0.01 |
月桂基硫酸钠 | 3.0 |
柠檬酸钠(无水) | 0.75 |
柠檬酸(无水) | 0.25 |
微晶纤维素 | 50.4 |
交联羧甲基纤维素钠 | 4.0 |
无水乳糖 | 30.32 |
硬脂酸镁 | 0.5 |
无水醇(乙醇)* | |
纯水* |
*制备过程中使用,不出现在最终产物中。
微晶纤维素、无水乳糖和交联羧甲基纤维素钠使用20目筛进行筛选,加入带有强化棒的V-搅拌机中,混合。月桂基硫酸钠、乙二胺四乙酸、柠檬酸钠、柠檬酸和PVP溶于足够量的纯水中,形成溶液。丁酸酯羟基苯甲醚、丁酸酯羟基甲苯和CCI-779溶于足够量的无水乙醇中,形成溶液。醇溶液在搅拌下加入水溶液中。用无水乙醇洗涤盛醇溶液的容器,将洗涤液加入疏水性溶液中。搅拌该溶液直至澄清。将疏水性溶液加入V-搅拌机中,组分形成颗粒。使用10%乙醇溶液洗涤盛疏水性溶液的容器,将洗涤液加入颗粒中。混合颗粒直至颗粒均匀,然后在流化床干燥器中进行干燥。干颗粒经过30目筛,任何超尺寸的颗粒均通过Fitz碾磨机进行碾磨。碾磨后的颗粒装入V-搅拌机中。另加的微晶纤维素、无水乳糖和交联羧甲基纤维素钠通过20目筛,加入搅拌机中。混合混合物,硬脂酸镁(通过30目筛)加入搅拌机中,混合混合物。将得到的混合物压制为片剂。
下列表格说明了以下三种制剂在水中溶解性的比较:(a)纯CCI-779胶囊,(b)包含在颗粒中的相同组分干混合的片剂,和(c)根据上述方法制备的颗粒的片剂。结果清楚地表明本发明湿制粒法提高了药物在水中的溶解度,因而也提高了生物利用度。
CCI-779溶解百分率 | |||
时间(分钟) | CCI-779胶囊 | CCI-779干混合片剂 | CCI-779湿制粒法 |
10 | 4 | 31 | 96 |
20 | 9 | 42 | 104 |
30 | 14 | 50 | 104 |
45 | 21 | 56 | 104 |
操作B
下述操作用于制备包含25mg CCI-779和下述组分的片剂;调节用量以说明其低效能:
组分 | 百分比wt/wt |
CCI-779 | 4.0 |
丁酸酯羟基苯甲醚 | 0.10 |
丁酸酯羟基甲苯 | 0.05 |
PVP,17PF | 21.0 |
乙二胺四乙酸 | 0.01 |
月桂基硫酸钠 | 3.6 |
柠檬酸(无水) | 0.025 |
微晶纤维素 | 44.5 |
交联羧甲基纤维素钠 | 4.0 |
无水乳糖 | 22.17 |
硬脂酸镁 | 0.5 |
无水醇(乙醇)* | |
纯水* |
*制备过程中使用,不出现在最终产物中。
微晶纤维素、无水乳糖、大约一半的PVP和交联羧甲基纤维素钠使用20目筛进行筛选,装入带有强化棒的V-搅拌机中,混合。月桂基硫酸钠、乙二胺四乙酸、柠檬酸和剩余的PVP溶于足够量的纯水中,形成溶液。测量溶液的pH值,如果高于4.5,则使用0.1N HCl降低直至达到pH值为4.5。将丁酸酯羟基苯甲醚、丁酸酯羟基甲苯和CCI-779溶于足够量的无水乙醇中,形成溶液。向搅拌机中加入约一半的水溶液,颗粒混合约4分钟。将醇溶液加入搅拌机中,颗粒混合约4分钟。将剩余的水溶液加入搅拌机中,颗粒混合约4分钟。如果需要制备均匀的颗粒,再加入一些水。颗粒于约50℃下在流化床干燥器中干燥。干颗粒通过30目筛,任何超尺寸的颗粒均通过Fitz碾磨机进行碾磨。碾磨后的颗粒装入V-搅拌机中。另加的微晶纤维素、无水乳糖和交联羧甲基纤维素钠通过20目筛,加入搅拌机中。混合混合物,硬脂酸镁(通过30目筛)加入搅拌机中,混合混合物。将得到的混合物压制成片剂。
本说明书引用的文件均在此引入作为参考。上述详细描述的说明书和用于解释的实施例中公开的方法和原料的小的变化和修改对于本领域技术人员而言都是显而易见的,并且包含在本发明的保护范围之内。
Claims (19)
1.一种含有颗粒的用于口服的药物组合物,其特征在于所述颗粒包含CCI-779、水溶性聚合物、表面活性剂、抗氧化剂和pH调节剂。
2.权利要求1所述的组合物,其中水溶性聚合物是PVP、羟丙基甲基纤维素、聚乙二醇、环糊精或其混合物。
3.权利要求2所述的组合物,其中水溶性聚合物是PVP。
4.权利要求1至3任一项所述的组合物,其中表面活性剂是土温80、月桂基硫酸钠、十二烷基硫酸钠、胆汁酸盐、乙氧基植物油、聚氧乙烯-聚氧丙烯嵌段共聚物或泊洛沙姆。
5.权利要求4所述的组合物,其中表面活性剂是月桂基硫酸钠或十二烷基硫酸钠。
6.权利要求1至5任一项所述的药物组合物,其中pH调节剂选自柠檬酸钠、柠檬酸、稀盐酸和其混合物。
7.一种制备CCI-779口服组合物的方法,包括:
(a)将CCI-779和抗氧化剂溶于醇中;
(b)将PVP、pH调节剂和表面活性剂溶于水中;
(c)合并水溶液和醇溶液得到一种疏水性溶液;
(d)将疏水性溶液加入包含一种或多种颗粒内辅料的搅拌机中;
(e)将混合物制成颗粒;和
(f)干燥制得的颗粒。
8.一种制备CCI-779口服组合物的方法,包括:
(a)将CCI-779和抗氧化剂溶于醇中;
(b)将PVP、pH调节剂和表面活性剂溶于水中;
(c)向包含一种或多种颗粒内辅料的搅拌机中逐步加入水溶液和醇溶液各自的一个或多个部分;
(e)将混合物制成颗粒;和
(f)干燥制得的颗粒。
9.通过湿制粒法制备的一种CCI-779口服组合物。
10.一种通过下述方法制备的CCI-779口服组合物,包括:
(a)将CCI-779和抗氧化剂溶于醇中;
(b)将PVP、pH调节剂和表面活性剂溶于水中;
(c)合并水溶液和醇溶液得到一种疏水性溶液;
(d)将疏水性溶液加入包含一种或多种颗粒内辅料的搅拌机中;
(e)将混合物制成颗粒;和
(f)干燥制得的颗粒。
11.权利要求10所述的组合物,其中pH调节剂选自柠檬酸、柠檬酸钠、盐酸及其混合物。
12.权利要求10或11所述的组合物,其中醇是乙醇。
13.权利要求10至12任一项所述的组合物,其中抗氧化剂是丁酸酯羟基苯甲醚和丁酸酯羟基甲苯。
14.权利要求10至13任一项所述的组合物,其中表面活性剂是月桂基硫酸钠。
15.一种通过下述方法制备的CCI-779口服组合物,包括:
(a)将CCI-779和抗氧化剂溶于醇中;
(b)将PVP、pH调节剂和表面活性剂溶于水中;
(c)向包含一种或多种颗粒内辅料的搅拌机中逐步加入水溶液和醇溶液各自的一个或多个部分;
(e)将混合物制成颗粒;和
(f)干燥制得的颗粒。
16.权利要求15所述的组合物,其中pH调节剂选自柠檬酸、柠檬酸钠、盐酸及其混合物。
17.权利要求15或16所述的组合物,其中醇是乙醇。
18.权利要求15至17任一项所述的组合物,其中抗氧化剂是丁酸酯羟基苯甲醚和丁酸酯羟基甲苯。
19.权利要求18所述的组合物,其中表面活性剂是月桂基硫酸钠。
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DK1635830T3 (da) | 2009-02-23 |
DE60324609D1 (de) | 2008-12-18 |
WO2004026280A2 (en) | 2004-04-01 |
HK1084050A1 (en) | 2006-07-21 |
WO2004026280A3 (en) | 2005-12-01 |
PT1635830E (pt) | 2008-12-31 |
EP1635830B1 (en) | 2008-11-05 |
MXPA05002828A (es) | 2005-05-27 |
RU2005111222A (ru) | 2005-09-20 |
ATE413163T1 (de) | 2008-11-15 |
ES2315530T3 (es) | 2009-04-01 |
JP2006506353A (ja) | 2006-02-23 |
AU2003272489B2 (en) | 2008-11-13 |
CN100415233C (zh) | 2008-09-03 |
CA2496332A1 (en) | 2004-04-01 |
NO20050836L (no) | 2005-04-15 |
ECSP055731A (es) | 2005-07-06 |
KR20050084559A (ko) | 2005-08-26 |
NZ538781A (en) | 2007-11-30 |
US20040077677A1 (en) | 2004-04-22 |
UA81265C2 (en) | 2007-12-25 |
EP1635830A2 (en) | 2006-03-22 |
SI1635830T1 (sl) | 2009-02-28 |
RU2326654C2 (ru) | 2008-06-20 |
CR7791A (es) | 2007-10-01 |
ZA200502220B (en) | 2008-01-30 |
IL166824A0 (en) | 2006-01-15 |
BR0314397A (pt) | 2005-08-09 |
AU2003272489A1 (en) | 2004-04-08 |
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