CN1440278A - 2′-脱氧-2′-(氟亚甲基)胞嘧啶核苷的药物组合物 - Google Patents
2′-脱氧-2′-(氟亚甲基)胞嘧啶核苷的药物组合物 Download PDFInfo
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- CN1440278A CN1440278A CN01812316A CN01812316A CN1440278A CN 1440278 A CN1440278 A CN 1440278A CN 01812316 A CN01812316 A CN 01812316A CN 01812316 A CN01812316 A CN 01812316A CN 1440278 A CN1440278 A CN 1440278A
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Abstract
揭示了可口服的2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(“FMdC”)的药物组合物,以及在体内增强FMdC生物利用度的方法。
Description
发明背景
发明领域
本发明涉及可口服的2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(FMdC)的药物组合物,以及在体内增强FMdC生物利用度的方法。
特别地,本发明涉及含有FMdC的药物组合物,其成分被包裹进在pH小于2时不会溶解而当pH约为4-5或更高时很容易溶解的材料中。
本发明还涉及在体内提高FMdC的口服生物利用度的方法,方法是将FMdC包裹进在pH小于2时不会溶解而当pH约为4-5或更高时很容易溶解的材料中。
发明领域
这里引用了以下参考资料,在此全文并入以供参考:
McCarthy等的美国专利5,378,693号,发表于1/3/1995;
McCarthy等的美国专利5,508,393号,发表于4/16/1996;
McCarthy等的美国专利5,589,587号,发表于12/31/1996;
Snyder的美国专利5,595,979号,发表于1/21/1997;
Matthews等的美国专利5,607,925号,发表于3/4/1997;
Edwards等的美国专利5,616,702号,发表于4/1/1997;
McCarthy等的美国专利5,760,210号,发表于6/2/1998;
Edwards等的美国专利5,792,841号,发表于8/11/1998;
Handbook of Pharmaceutical Excipients,1986,美国药学协会出版,华盛顿,哥伦比亚特区,第251-252页。技术现状
2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(“FMdC”)是一种核苷类似物,它是核糖核苷酸还原酶的抑制剂和DNA链的终止剂。有这些活性的化合物可以抑制DNA的合成。因此,这些类型的化合物可有效抑制细胞生长和/或抑制病毒复制。由于这些性质,FMdC可用于肿瘤(癌症)和病毒性疾病的治疗。对肿瘤而言,FMdC可以单独使用或与放射疗法或化学疗法结合使用。对病毒性疾病而言,FMdC可以单独使用或与其它药物结合使用。
当用于这些目的时,此项技术指出,FMdC可以单独向患者施用或以与药学上可接受的载体或赋形剂结合的药物组合物的形式施用。例如,可以参见Synder的美国专利5,595,979号和McCarthy的美国专利5,378,693号,在此将这两者全文并入以供参考。美国专利5,378,693号中提到,FMdC可以一种使这种化合物以有效量被生物利用的形式或方式施用,包括口服。口服是优选的输递途径。
尽管这一技术已有这些指导,当以口服形式施用这种化合物还是遇到了一个问题。特别地,在哺乳类患者中,以常规的片剂形式口服施用这种化合物会使药物的吸收少于所需的全身摄入量,并且个体之间的差异性很大。这说明口服输递不能为这种药物提供可接受的生物利用度。
仔细分析后,确定FMdC在酸性条件下没有足够的稳定性以有效通过胃的酸性环境。低的生物利用度是因药物在胃中降解引起的。此外,所观察到的显著的各个患者之间的差异性是由胃的排空时间不同而造成的。
奇怪的是,缺乏酸稳定性的现象对这类药物中其它的成员并不典型。实际上,已经发现FMdC在pH9附近是最稳定的。例如,可参见图1,它描述了FMdC的pH稳定性曲线,同时还证明在pH2左右或更低时,这种化合物是非常不稳定的。然而,大多数哺乳动物胃中的pH在2附近或更低,在这种pH值下FMdC会明显的降解。
基于这些发现,本发明一方面在于以一种可防止FMdC因口服施用而发生酸降解的形式施用FMdC。然而,为获得这种药物的最大的生物利用度,仅仅防止FMdC发生酸降解是不够的。特别地,生物吸收开始于小肠的上端,这里的pH值可低至4-5左右。将FMdC包在可抵抗酸性pH的材料中会使其在肠胃道这部分中的生物吸收发生不希望的降低。
因此,例如,如美国专利5,378,693所述的以糖或虫胶作为包衣剂的包衣片或丸就并不理想。特别地,糖包衣是酸不稳定的,因此可在胃中溶解并使FMdC暴露于胃的酸性环境中。在酸性环境中暴露会使化合物降解由此降低FMdC的生物利用度。虫胶在酸性环境(例如pH5)下不溶而仅在碱性pH下溶解,因此虫胶包衣会使崩解延迟并使药物在较下面的肠的上部释放,故而降低了药物的生物吸收。另外,对虫胶包衣片进行USP崩解试验证实,将这些片剂贮存6个月后崩解时间显著增加。这种效应可能是由于长时间储存过程中虫胶聚合而产生的。参见
Handbook of Pharmaceutical Excipients,1986,第251-252页。
因此,尽管已有应用,口服施用时高生物利用度的缺乏严重降低了FMdC的效果。因此,提供一种能使FMdC安全输递至小肠(在这里被吸收至血液)的组合物是有用的。
发明概要
本发明涉及可口服输递的2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(FMdC)的药物组合物,以及可在体内提高FMdC生物利用度的方法。特别地,本发明涉及被包裹的2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(FMdC),其中被选择的包衣材料在pH4-5或更低时是不溶的,而在pH高于4-5时很容易溶解。
因此,在其组成的一方面,本发明涉及可口服输递的药物组合物,其中含有一种药学上可接受的赋形剂或多种赋形剂,以及可在哺乳动物中***或病毒性疾病的有效量的FMdC,其中所述的组合物被包在经选择在pH4-5或更低时不溶而在pH高于4-5时很容易溶解的材料中。
在一个实施方案中,药学上可接受的赋形剂或多种赋形剂仅仅由包囊材料组成。在另一个实施方案中,分离的药学上可接受的赋形剂和/或多种赋形剂包含在包囊材料中。
较好的,包囊材料选自邻苯二甲酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、聚(邻苯二甲酸醋酸乙烯酯)、琥珀酸酯酸羟丙基甲基纤维素、聚(甲基)丙烯酸酯类以及邻苯二甲酸醋酸纤维素/邻苯二甲酸二乙酯醋酸纤维素。更好的,包囊材料是甲基丙烯酸:丙烯酸甲酯的共聚物。
较好的,组合物中药学上可接受的赋形剂或多种赋形剂的重量约占50-99.5%,FMdC的重量约占0.5-50%。
在这一方法的一个方面,本发明涉及一种当向哺乳动物经口输递FMdC时提高口服生物利用度的方法,这种方法包括:
(a)将FMdC包在经选择在pH4-5或更低时不溶而在pH高于4-5时很容易溶解的药学上可接受的材料中;以及
(b)向所述哺乳动物经口输递上述(a)制备的产品。
附图简述
图1显示了在60℃的Britton-Robinson缓冲液(pH2-pH11)和0.1N HCl(pH1)中FMdC降解的pH-速度曲线。
发明详述
本发明涉及可口服的2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷(FMdC)的药物组合物,以及可在体内提高FMdC生物利用度的方法。
然而,在详细讨论本发明之前,要先定义以下术语:
这种化合物也可被称为氟亚甲基脱氧胞苷;(E)-2’-脱氧-2’-(氟亚甲基)胞苷和(E)-2’-脱氧-2’-氟亚甲基(fluoromethylidene)胞苷。无论用这些名称中的哪一个都是指FMdC。
“药学上可接受的盐”是指FMdC的药学上可接受的盐类,这些盐类衍生自各种在这一技术中已熟知的有机和无机离子,包括(只是为了举例)有机或无机酸的盐类,如氢氯化物、氢溴化物、酒石酸盐、甲磺酸盐、醋酸盐、马来酸盐和草酸盐等。
“小肠”和“肠的上端”是指位于胃和结肠之间的肠子。它包括十二指肠、空肠和回肠,并分泌消化酶类。这是吸收被消化的营养物质的主要部位。
“肿瘤”是指癌症,如血癌,比如白血病和淋巴瘤;实体瘤,比如脑、头颈部、***、胃、胰腺、肾脏、肝脏、结肠、卵巢、子宫和睾丸等处的癌;骨肉瘤、纤维肉瘤和卡波西肉瘤等;它们以不受控制或异常的细胞和/组织生长为特征。
“病毒性疾病”是指肝炎、HIV、巨细胞病毒(“CMV”)、庖疹病毒和流感等。
如上所述,已知在胃中等酸性条件下FMdC不稳定且会降解。图1描绘了FMdC的pH稳定性曲线,它显示FMdC在pH9左右最稳定。为获得口服施用的FMdC的高生物利用度,包在经选择在pH4-5或更低时不溶而在pH高于4-5时很容易溶解的材料中的FMdC被认为有较高的生物利用度。当被包在这种材料中时,摄取的FMdC剂型基本上完整并安全地通过胃并到达小肠,它在此处溶出。一旦FMdC剂型的包衣材料溶解,FMdC就可被穿过小肠吸收进血液。奇怪的是,尽管小肠上部的pH略呈酸性,FMdC在这种pH下的稳定性足以提高其生物利用度。药物组合物
本发明的组合物是由下列药物组合物获得的,其中包括被包在药学上可接受的在pH4-5左右或更高时溶解的材料中的FMdC。
用这一技术中所熟知的方法,本发明的组合物首先被制成片剂、胶囊或其它合适的剂型。在制造本发明的组合物时,FMdC(活性组分)通常与赋形剂或几种赋形剂混合,用赋形剂(类)稀释,或被装在可制成胶囊、片剂、颗粒剂、珠剂、丸剂等形式的载体中。当赋形剂用作稀释剂时,它最好是固体或半固体材料,起活性组分载色剂、载体或介质的作用。因此,组合物可以是片剂、胶囊、颗粒剂、珠剂等形式,其中含有(例如)多达50%或更多重量的活性化合物。
在制备制剂时,有必要在与其它成分混合之前研磨活性化合物以提供合适的粒度。如果是直接压制片剂,较好的是将活性组分研磨成粒度小于200目。如果活性化合物具水溶性,通常要通过研磨来调节粒度以使其在制剂中有基本一致的分布,例如约40目,特别是如果要使用制粒步骤。
合适的赋形剂的例子有乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、***树胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素和甲基纤维素。这种制剂还可以包括:润滑剂,如滑石、硬脂酸镁和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂,如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯;甜味剂;调味剂和着色剂。
组合物最好制成单位剂型,每一剂量约含0.5mg-500mg的活性组分,通常是约1mg-30mg。“单位剂型”是指适合作为人或其它哺乳动物单一剂量的物理上分离的单位,每一单位都含有通过计算可产生所需疗效的预定量的活性物质,并与合适的药物赋形剂混合。
活性化合物在很大的剂量范围都有效,它通常以药物有效量用药。然而,应理解是的,实际施用的化合物的量应由医师决定,这取决于相关的情况,包括治疗的疾病、所选用药途径、实际施用的化合物、年龄、体重、体表面积和各个患者的反应情况、患者症状的严重程度等。
较好的,FMdC将被制成含有药学上惰性载体或多种载体的组合物,包括常规的固体载体,如乳糖、淀粉、糊精、微晶纤维素、甘露醇等,这种组合物通常以片剂、胶囊、颗粒剂、珠剂等形式出现。
为制造片剂等固体组合物,将主要的活性成分与药学上可接受的赋形剂或多种赋形剂混合,以形成含有活性成分均匀混合物的固体预制剂组合物。当称这些预制剂组合物均匀时,这意味着活性成分已经均匀分散在整个组合物中,这样,这种组合物就可以容易地细分成同等有效的单位剂型,如片剂、胶囊以及颗粒剂或珠剂的集合。然后将这种固体预制剂细分成上述类型的单位剂型,其中含有(例如)约0.5-500mg本发明的活性成分。
本发明的片剂、胶囊、颗粒剂或珠剂然后被包衣或复合,以在pH小于2,较好的是小于4-5时提供良好的稳定性。
最优选的FMdC包衣方法是将含有FMdC的片剂、胶囊、颗粒剂或珠剂包以肠溶衣,这一方法在此技术中已熟知。优选的肠溶衣材料包括,例如,邻苯二甲酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、聚(邻苯二甲酸醋酸乙烯酯)、琥珀酸酯酸羟丙基甲基纤维素、邻苯二甲酸醋酸纤维素/邻苯二甲酸二乙酯醋酸纤维素,以及,更好的是,聚(甲基)丙烯酸酯类。后者包括甲基丙烯酸和丙烯酸酯和/或甲基丙烯酸酯的共聚物。当胶囊被包衣后,可以使用增塑剂(如琥珀酸酯酸羟丙基甲基纤维素/柠檬酸三乙酯,或者,尤其是邻苯二甲酸醋酸纤维素和醋酸纤维素邻苯二甲酸二乙酯)以减小包衣的脆性并抑制包衣破裂。也可以使用片剂或颗粒剂。
片剂、胶囊、颗粒剂或珠剂中还可以含有能提高FMdC吸收的物质和化合物。
还可以在片剂、胶囊、颗粒剂或珠剂中加入缓冲剂以降低小肠局部环境的酸性,从而保持FMdC的稳定性以便其通过小肠被吸收进入血液。
以下实施例阐述了本发明。
实施例
制剂实施例1
制造了含有以下成分的硬明胶胶囊:
成分
含量(mg/胶囊)
FMdC 30.0
淀粉 305.0
硬脂酸镁 5.0
将上述成分混合并填充进340mg的硬明胶胶囊中。需要的话,可再在硬明胶胶囊上包一层在pH约4-5以下不溶的药学上可接受的材料。
制剂实施例2
用以下成分制造了片剂制剂:
成分
含量(mg/片)
FMdC 1.0
微晶纤维素 90.0
胶体二氧化硅 6.0
硬脂酸 3.0
将组分混合并压制成片剂,每片的重量为100mg。在片剂上包一层在pH约4-5以下不溶的药学上可接受的材料。
制剂实施例3
用以下成分制造了片剂制剂:
成分
含量(mg/片)
FMdC 5.0
微晶纤维素 86.0
胶体二氧化硅 6.0
硬脂酸 3.0
将组分混合并压制成片剂,每片的重量为100mg。在片剂上包一层在pH约4-5以下不溶的药学上可接受的材料。
制剂实施例4
用以下配方制造每粒含30mgFMdC的片剂:
成分
含量(mg/片)
FMdC 30.0mg
淀粉 45.0mg
微晶纤维素 35.0mg
聚乙烯吡咯烷酮(10%的水溶液) 4.0mg
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石 1.0mg
总计 120mg
将FMdC、淀粉和纤维素通过美国20目的筛并完全混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,然后通过美国16目的筛。在50℃-60℃的温度下将制得的颗粒干燥并通过美国16目的筛。将羧甲基淀粉钠、硬脂酸镁和滑石先通过美国30目的筛,然后加到颗粒中,混合后,在压片机上压片以制得每片重150mg的片剂。然后在片剂上包一层在pH约4-5以下不溶的药学上可接受的材料。
制剂实施例5
用以下配方制造每粒含40mgFMdC的胶囊:
成分
含量(mg/胶囊)
FMdC 40.0mg
淀粉 109.0mg
硬脂酸镁 1.0mg
总计 150.0mg
将活性成分、纤维素、淀粉、硬脂酸镁混合,通过美国20目的筛,并填充进150mg的硬明胶胶囊中。需要的话,可再在硬明胶胶囊上包一层在pH约4-5以下不溶的药学上可接受的材料。
Claims (8)
1.一种用于治疗哺乳动物的肿瘤或病毒性疾病的含有有效量2’-脱氧-2’-(氟亚甲基)胞嘧啶核苷的口服输递的药物组合物,其中,所述组合物被包在经选择在pH4-5或更低时不溶而在pH高于4-5时容易溶解的材料中。
2.如权利要求1所述的口服输递的药物组合物进一步含有药学上可接受的一种赋形剂或多种赋形剂。
3.如权利要求2所述的口服输递的药物组合物,其中,药学上可接受的赋形剂或多种赋形剂仅仅由包衣材料组成。
4.如权利要求2所述的口服输递的药物组合物,其中,药学上可接受的赋形剂或多种赋形剂包括在包衣材料中。
5.如权利要求1、2、3或4中任何一项所述的口服输递的药物组合物,其中,包衣材料选自邻苯二甲酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、聚(邻苯二甲酸醋酸乙烯酯)、琥珀酸酯酸羟丙基甲基纤维素、聚(甲基)丙烯酸酯类以及邻苯二甲酸醋酸纤维素/邻苯二甲酸二乙酯醋酸纤维素。
6.如权利要求5所述的口服输递的药物组合物,其中,包衣材料选自甲基丙烯酸和丙烯酸酯的共聚物以及甲基丙烯酸和甲基丙烯酸酯的共聚物。
7.如权利要求1所述的口服输递的药物组合物,其中,组合物中药学上可接受的赋形剂的重量约占50-99.5%,2’-脱氧-2’-(氟亚甲基)胞苷的重量约占0.5-50%。
8.一种当向哺乳动物经口输递2’-脱氧-2’-(氟亚甲基)胞苷时提高其口服生物利用度的方法,这种方法包括:
(a)将2’-脱氧-2’-(氟亚甲基)胞苷包在经选择在pH4-5或更低时不溶而在pH高于4-5时容易溶解的药学上可接受的材料中;以及
(b)向所述哺乳动物经口输递上述(a)制备的产品。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US20859300P | 2000-06-02 | 2000-06-02 | |
US60/208,593 | 2000-06-02 | ||
US21196900P | 2000-06-16 | 2000-06-16 | |
US60/211,969 | 2000-06-16 |
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CN1440278A true CN1440278A (zh) | 2003-09-03 |
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CN01812316A Pending CN1440278A (zh) | 2000-06-02 | 2001-05-31 | 2′-脱氧-2′-(氟亚甲基)胞嘧啶核苷的药物组合物 |
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US (2) | US20020019365A1 (zh) |
EP (1) | EP1296659A4 (zh) |
JP (1) | JP2003534371A (zh) |
KR (1) | KR20030041866A (zh) |
CN (1) | CN1440278A (zh) |
AU (1) | AU2001265410A1 (zh) |
BR (1) | BR0111392A (zh) |
CA (1) | CA2410589A1 (zh) |
IL (1) | IL153203A0 (zh) |
MX (1) | MXPA02011905A (zh) |
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US20080113025A1 (en) * | 1998-11-02 | 2008-05-15 | Elan Pharma International Limited | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
JP2004035408A (ja) * | 2002-02-15 | 2004-02-05 | Chiron Corp | テザシタビンを含有する安定な組成物 |
US20050244490A1 (en) * | 2003-12-09 | 2005-11-03 | Michael Otto | Dosing methods for beta-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine antiviral therapy |
DE112006000873T5 (de) * | 2005-04-12 | 2008-03-06 | Elan Pharma International Ltd. | Zusammensetzungen mit modifizierter Freisetzung, umfassend ein Fluorcytidin-Derivate zur Behandlung von Krebs |
KR100846143B1 (ko) | 2007-02-28 | 2008-07-14 | (주) 유일팜테크 | 2'-데옥시-2',2'-디플루오로시티딘의 전구체 및 그의제조방법 |
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JPS517116A (en) * | 1974-06-11 | 1976-01-21 | Shinetsu Chemical Co | Choyoseihifukuyakuzaino seizohoho |
US4180559A (en) * | 1978-01-05 | 1979-12-25 | Richardson-Merrell Inc. | Coated 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine compositions |
US5607925A (en) * | 1988-11-15 | 1997-03-04 | Merrell Pharmaceuticals Inc. | Treatment of carcinoma by administration of 2'-halomethylidenyl-2'-deoxynucleosides |
US5616702A (en) * | 1988-11-15 | 1997-04-01 | Merrell Pharmaceuticals Inc. | 2-'-ethenylidene cytidine, uridine and guanosine derivatives |
MX9203459A (es) * | 1988-11-15 | 1992-08-01 | Merrell Pharma Inc | Nuevos derivados de 2'-halometilideno, 2'-etenilideno y 2'-etinilcitidina, uridina y guanosina. |
US5589587A (en) * | 1992-05-12 | 1996-12-31 | Merrell Pharmaceuticals Inc. | Process for the preparation of ribonucleotide reductase inhibitors |
AU2768295A (en) * | 1994-07-11 | 1996-02-09 | Hoechst Marion Roussel, Inc. | Method of treating a neoplastic disease state by conjunctive therapy with 2'-fluoromethylidene derivatives and radiation or chemotherapy |
US5665711A (en) * | 1995-12-12 | 1997-09-09 | Yoshitomi Pharmaceutical Industries, Ltd. | Antitumor composition for oral administration |
-
2001
- 2001-05-31 KR KR1020027016417A patent/KR20030041866A/ko not_active Application Discontinuation
- 2001-05-31 AU AU2001265410A patent/AU2001265410A1/en not_active Abandoned
- 2001-05-31 BR BR0111392-5A patent/BR0111392A/pt not_active IP Right Cessation
- 2001-05-31 JP JP2001587747A patent/JP2003534371A/ja active Pending
- 2001-05-31 IL IL15320301A patent/IL153203A0/xx unknown
- 2001-05-31 CA CA002410589A patent/CA2410589A1/en not_active Abandoned
- 2001-05-31 EP EP01939946A patent/EP1296659A4/en not_active Withdrawn
- 2001-05-31 CN CN01812316A patent/CN1440278A/zh active Pending
- 2001-05-31 US US09/867,770 patent/US20020019365A1/en not_active Abandoned
- 2001-05-31 MX MXPA02011905A patent/MXPA02011905A/es unknown
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IL153203A0 (en) | 2003-07-06 |
EP1296659A4 (en) | 2005-08-31 |
BR0111392A (pt) | 2004-10-05 |
JP2003534371A (ja) | 2003-11-18 |
KR20030041866A (ko) | 2003-05-27 |
MXPA02011905A (es) | 2004-09-06 |
CA2410589A1 (en) | 2001-12-06 |
AU2001265410A1 (en) | 2001-12-11 |
US20020019365A1 (en) | 2002-02-14 |
EP1296659A1 (en) | 2003-04-02 |
US20040265376A1 (en) | 2004-12-30 |
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