CN1039673C - 阿糖胞苷十八烷基磷酸盐硬胶囊 - Google Patents
阿糖胞苷十八烷基磷酸盐硬胶囊 Download PDFInfo
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Abstract
本发明涉及适用作口服抗白血病药物的阿糖胞苷十八烷基磷酸盐的硬胶囊，包含有(1)阿糖胞苷十八烷基磷酸盐，(2)作为崩解剂的高分子化合物和(3)碱，可由此提供的药物制剂具有优异的崩解性和稳定性。阿糖胞苷十八烷基磷酸盐的硬胶囊适用于临床。
Description
本发明涉及用作口服抗白血病药物的阿糖胞苷十八烷基磷酸盐(4-氨基-1-β-D-阿糖呋喃-2(1H)-嘧啶酮-5′-(十八烷基磷酸钠)的硬胶囊。
阿糖胞苷十八烷基磷酸盐(以下称COP)载于美国专利Nos.4812560和5049663等。阿糖呋喃胞苷-5′-磷酸(Ara-CMP)胶囊叙述于美国专利№.4542021。在这些药物制剂中，加入了马铃薯淀粉和乳糖以制备胶囊。
当试图将COP制成口服制剂如胶囊等时，常规的方法是将淀粉和乳糖加入其中，加入淀粉和乳糖的量应相当大；当需要服用治疗所必需剂量的COP时，由于可分散性差，制剂规格增加得难以口服COP制剂。另外，为使胶囊可适当地崩解，必须加入大量的淀粉和乳糖，以致破坏了COP的稳定性，生成了分解产物。在这种情况下，遇到了COP含量降低等问题。此外，COP在pH低于4的酸性溶液中有极其微小的溶解性。COP压成片剂或装入胶囊，其缺点是在酸性溶液中崩解极其缓慢。考虑到胃中生理pH，希望能提供即使在酸性环境中也易于崩解的药物制剂。
本发明的目的是提供硬胶囊，它使COP有优良的稳定性，即使在酸性溶液中也不会损坏其崩解性。
本发明者经广泛的研究，了解是否向COP中加入各种添加剂可以得到良好的崩解和稳定这两种性质。因而发现作为崩解剂的高分子化合物，特别是选自低取代的羟丙基纤维素、羧甲基淀粉钠，部分预凝胶化的淀粉和交联的聚乙烯吡咯烷酮等高分子化合物加到COP中，可得到对COP有良好稳定性的具有良好崩解性的硬胶囊。还发现加入碱会进一步改善稳定性。因而完成了本发明。
所以，本发明涉及的阿糖胞苷十八烷基磷酸盐硬胶囊包含有(1)阿糖胞苷十八烷基磷酸盐，(2)作为崩解剂的高分子化合物，(3)一种碱。
下面详述本发明。本发明中作为崩解剂的高分子化合物，只要是崩解剂并且是药剂学中可接受的任何高分子化合物均可使用。这样的高分子化合物例如有化学改性的淀粉，纤维素衍生物，聚乙烯吡咯烷酮衍生物等。具体的实例包括有：低取代的羟丙基纤维素，羧甲基淀粉钠，部分预凝胶化淀粉，交联的聚乙烯吡咯烷酮，交联的羧甲基纤维素钠，羟丙基淀粉等。在这些高分子化合物中，优选的是低取代的羟丙基纤维素，羧甲基淀粉钠，部分预凝胶化的淀粉和交联的聚乙烯吡咯烷酮，而更为优选的是低取代的羟丙基纤维素，羧甲基淀粉钠和部分凝胶化的淀粉。
用于本发明的高分子化合物范例的低取代的羟丙基纤维素是以低取代程度被羟丙基取代的纤维素，可以是在日本药典(1986)收载的一种，其羟基的丙基化率为7-16％。羧甲基淀粉钠是水溶性淀粉型的高分子化合物，可以是在日本药典(1986)中“药物成分标准”未曾收载的一种，优选的羧甲基取代程度大约为0.3-0.5。
部分预凝胶化淀粉是在日本药典(1986)中“药物成份标准”未曾收载的转变成a-型的淀粉。
交联的聚乙烯吡咯烷酮是指一种交联的水不溶性的乙烯吡咯烷酮的高分子化合物。市场有售，商品名例如是Kollidon CL(BASF)。
交联的羧甲基纤维素是指部分地自交联的羧甲基纤维素钠，例如是交联羧甲基纤维素钠。
羟丙基淀粉是指淀粉的羟丙基醚，特别是例如在日本药典(1986)的“药物成分标准”中未收载的一种。
这些高分子化合物作为崩解剂加入到COP中的量，以1重量份的COP计，通常大约为0.5到4重量份，优选为1到3.5重量份，更为优选的是1.3-3.0重量份。崩解剂可以单用或两个或多个合用。
本发明所用的碱，无特殊限制，只要是在医用上可用作添加剂的碱均可使用。具体的实例包括有碳酸钠，碳酸钾，碳酸氢钠，氢氧化钠，氢氧化钾等。这些碱可以单用也可以两个或多个合用。一般优选使用的是碳酸钠或碳酸钾。加到COP中的碱量，若以1重量份的COP计，一般大约为0.002到0.3重量份，优选为0.005到0.2重量份，更为优选的是0.007到0.07重量份。
装入本发明的硬胶囊中成分的比例如下：COP大约为5到50％(重量/重量)，优选为10到47％(重量/重量)，更为优选的是20到40％(重量/重量)；作为崩解剂的高分子化合物为10到80％(重量/重量)，优选为15到75％(重量/重量)，更为优选的是30到70％(重量/重量)；碱为0.1到8.0％(重量/重量)，优选为0.2到4.0％(重量/重量)。用其它的添加剂加以平衡，这些添加剂用量大约为0到84％(重量/重量)，优选为1到74％(重量/重量)。
为制得本发明的硬胶囊，其它适宜的添加剂例如赋形剂，粘合剂和润滑剂等也可装入到硬胶囊中。赋形剂的实例包括淀粉(如玉米淀粉，马铃薯淀粉，小麦淀粉等)，糖类(如乳糖，甘露醇，葡萄糖等)。加入到COP中的赋形剂量若以1重量份的COP计，大约为0.5到7重量份，优选为1到5重量份。
粘合剂实例有水溶性的纤维素醚衍生物，如羟丙基纤维素，甲基纤维素等，聚乙烯吡咯烷酮，藻酸钠，淀粉胶，异丁烯酸氨烷基酯共聚物(Eudragit)，阿拉伯树胶等。加入到COP中的粘合剂量以1重量份COP计，大约为0.005到0.2重量份，优选为0.01到0.1重量份。
用作润滑剂的有硬脂酸和硬脂酸盐，如硬脂酸镁等，滑石粉，亮氨酸，巴西棕榈蜡，可可脂，聚乙二醇，鲸蜡醇，石蜡等。加入到COP中的润滑剂量，以1重量份COP计，大约为0.005到0.10重量份，优选为0.009到0.05重量份。
用于制备本发明硬胶囊的COP，是非收湿性和稳定的晶体，叙述于美国专利Nos.4812560和5049663。为将各个组分装入胶囊内，通常用湿法或干法将其制成颗粒，然后装入胶囊，得到本发明的硬胶囊。
湿法制粒是将COP与添加剂均匀混合，将混合物在适宜溶剂中捏和，制粒，干燥，磨成颗粒等，必要时磨成适当的直径，一般低于8目，优选为低于20目。可用的溶剂例如是乙醇，甲醇，丙酮，乙酸乙酯，二氯甲烷，环己烷等。从残留的溶剂看，乙醇是所希望的，水合乙醇更好，这在处理上是安全的。
干法制粒是将COP与添加剂均匀混合，将混合物压制成形为片状或丸状，再磨成颗粒，磨成适当的直径，一般低于8目，优选为低于20目。
下面用实施例对本发明作具体说明。实施例1
将25份COP，35份低取代的羟丙基纤维素(Shin-EtsuKagaku：L-HPC)，55份甘露醇，68份马铃薯淀粉，2份羟丙基纤维素和4份碳酸钠混合后，用60％乙醇捏合并制粒。将颗粒于50℃干燥，干后，将颗粒磨成20目以下的颗粒，然后掺加1份硬脂酸镁。将190mg混合物装入3号硬胶囊内，制成本发明的硬胶囊。实施例2
将50份COP，80份低取代的羟丙基纤维素(Shin-EtsuKagaku：L-HPC)，55份甘露醇，2份甲基纤维素和2份碳酸钠混合后，用70％乙醇捏合并制粒。60℃干燥后，将颗粒磨成16目以下的颗粒，再与1份硬脂酸镁混合。将190mg的混合物装入3号硬胶囊内，制成本发明的硬胶囊。实施例3
将50份COP，150份部分预凝胶化的淀粉(Asahi Chemical：PCS)，4份聚乙烯吡咯烷酮和2份碳酸钠混合后，压模制成片状，用干制粒机(Turbo Industry：滚筒压榨机)制粒，磨成低于20目的颗粒，再加入1份硬脂酸到颗粒中，将207mg混合物装入3号硬胶囊中，制成本发明的硬胶囊。实施例4
100份COP，220份交联型聚乙烯吡咯烷酮(BASF：KollidonCL)和3份碳酸钠混合，压模制成片状，用干制粒机(TurboIndustry：滚筒压榨机)制粒，磨成低于20目的颗粒，再向颗粒中加入2份滑石粉，将325mg混合物装入1号硬胶囊中，制成本发明的硬胶囊。实施例5
100份COP，165份低取代的羟丙基纤维素(Shin-EtsuKagaku：L-HPC)，1份碳酸钠和3份羟丙基纤维素混合物，用70％乙醇捏合并制粒。于60℃干燥颗粒，干后，将颗粒磨成低于16目的颗粒，再混入1份硬脂酸镁。将270mg混合物装入2号硬胶囊内，制成本发明的硬胶囊。实施例6
25份COP，35份羧甲基淀粉钠，55份甘露醇，68份马铃薯淀粉，2份羟丙基纤维素和4份碳酸钠混合后，用60％乙醇捏合后制成颗粒。颗粒于50℃干燥，干后，磨成低于20目的颗粒，再混入1份硬脂酸镁。将190mg混合物装入3号硬胶囊内，制成本发明的硬胶囊。
下面是检查本发明的硬胶囊的崩解性和稳定性。实验1：崩解性试验
用崩解试验装置，按照日本药典(1986)所述崩解试验的改良方法，测定本发明的硬胶囊的崩解时间，每组6只胶囊。初始液(将24.0ml稀盐酸和水加到2.0g氯化钠中，使氯化钠溶解，加水至1000ml，pH大约为1.2)用作试验溶液，在溶液温度为37℃时进行测定，结果见表1。样品 崩解所需时间(平均)实施例1硬胶囊 3分50秒到6分40秒(5分13秒)实施例2硬胶囊 4分20秒到6分40秒(5分22秒)实施例3硬胶囊 3分18秒到3分45秒(3分25秒)实施例4硬胶囊 3分35秒到4分20秒(3分53秒)实施例5硬胶囊 5分0秒到8分0秒(6分15秒)实施例6硬胶囊 3分05秒到3分57秒(3分29秒)
本发明的硬胶囊均显示良好的崩解性，崩解时间都在10分钟以下。结果表明，甚至在胃中的生理pH，即在酸性情况下，这些制剂均有良好的崩解性。实验2：稳定性试验
关于本发明的硬胶囊的稳定性，下面的试验是在剧烈的条件下和在长时间存贮条件下进行的。1.剧烈条件：
在65℃和相对湿度为73％的剧烈条件下存贮本发明的硬胶囊和比较用的胶囊。然后测定阿糖胞苷十八烷基磷酸盐的含量。含量测定是根据液相层析的阿糖胞苷十八烷基磷酸盐及其分解产物峰面积的百分数。结果列于表2。
表 2样品 含量(％)实施例1的硬胶囊 100.0实施例2的硬胶囊 100.0实施例3的硬胶囊 100.0实施例4的硬胶囊 100.0实施例5的硬胶囊 100.0实施例6的硬胶囊 100.0比较用胶囊* 87.5
*比较用的硬胶囊的组成：
10份COP，50份结晶性纤维素，3份硬脂酸镁，100份乳糖和100份马铃薯淀粉混合后，将263mg混合物装入一胶囊内，制成胶囊。
本发明的硬胶囊中COP含量为100％，而比较用的硬胶囊中COP含量明显地降到87.5％。2.长时间贮存
本发明的硬胶囊于室温下存放42个月后，测定COP含量。本发明的每个硬胶囊中COP含量均未降低。
以上结果清楚表明，本发明的硬胶囊提供的药物制剂，因加入了高分子化合物作为崩解剂和加入了碱，具有优异的崩解性和稳定性。此外，本发明提供的制剂含有高剂量的COP，该高剂量COP制剂具有临床用途。
Claims (8)
1.一种阿糖胞苷十八烷基磷酸盐的硬胶囊，包含有(1)阿糖胞苷十八烷基磷酸盐，(2)作为崩解剂的高分子化合物和(3)碱。
2.按照权利要求1的硬胶囊，其中所说的作为崩解剂的高分子化合物选自低取代的羟丙基纤维素，羧甲基淀粉钠，部分预凝胶化淀粉和交联型聚乙烯吡咯烷酮。
3.按照权利要求1的硬胶囊，其中所说的作为崩解剂的高分子化合物选自低取代的羟丙基纤维素，羧甲基淀粉钠和部分预凝胶化淀粉。
4.按照权利要求1的硬胶囊，其中所说的作为崩解剂的高分子化合物的用量以1份(重量)的阿糖胞苷十八烷基磷酸盐计，为0.5到4份(重量)。
5.按照权利要求1的硬胶囊，其中所说的碱的用量以1份(重量)的阿糖胞苷十八烷基磷酸盐计，为0.002到0.3份(重量)。
6.按照权利要求1的硬胶囊，其中所说的作为崩解剂的高分子化合物的用量是基于组合物重量的10到80％(重量/重量)。
7.按照权利要求1，2和3的任一项的硬胶囊，其中每个成分的比例是：(1)阿糖胞苷十八烷基磷酸盐为5到50％(重量/重量)，(2)作为崩解剂的高分子化合物为10到80％(重量/重量)，(3)碱为0.1到8.0％(重量/重量)。
8.按照权利要求1的硬胶囊，包含有(1)5到50％(重量/重量)的阿糖胞苷十八烷基磷酸盐，(2)10到80％(重量/重量)的低取代的羟丙基纤维素和(3)0.1到8.0％(重量/重量)的碳酸钠，每个成分的比例是基于组合物的重量。
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| EP (1) | EP0563697B1 (zh) |
| KR (1) | KR100267525B1 (zh) |
| CN (1) | CN1039673C (zh) |
| AU (1) | AU657044B2 (zh) |
| BR (1) | BR9301373A (zh) |
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| US7576216B2 (en) | 2004-07-30 | 2009-08-18 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
| US7524831B2 (en) | 2005-03-02 | 2009-04-28 | Schering Corporation | Treatments for Flaviviridae virus infection |
| EP1872798B1 (en) * | 2005-04-06 | 2013-06-05 | Kabushiki Kaisha Sangi | Intestinal absorptive anti-tumor agent |
| PT1868581E (pt) * | 2005-04-11 | 2012-06-22 | Abbott Lab | Composições farmacêuticas que possuem perfis de dissolução melhorados para fármacos pouco solúveis |
| RU2657833C2 (ru) | 2015-12-01 | 2018-06-15 | Общество С Ограниченной Ответственностью "Остерос Биомедика" | Стабилизированная лекарственная форма конъюгата этидроната с цитарабином и её применение |
| EA030671B1 (ru) | 2016-07-20 | 2018-09-28 | Общество С Ограниченной Ответственностью "Остерос Биомедика" | Препарат для лечения костных поражений, вызванных злокачественными новообразованиями |
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| US3859431A (en) * | 1973-01-04 | 1975-01-07 | Lilly Industries Ltd | Drug formulations |
| US4542021A (en) * | 1978-06-20 | 1985-09-17 | Yamasa Shoyu Kabushiki Kaisha | Antitumor compositions for non-injection administration |
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| US4681765A (en) * | 1984-09-13 | 1987-07-21 | American Home Products Corporation | Rapid releasing triamterene containing gelatin capsule dosage forms for once daily antihypertensive use |
| EP0239015B1 (en) * | 1986-03-24 | 1991-10-16 | Nippon Kayaku Kabushiki Kaisha | Process for producing 1-beta-d-arabinofuranosylcytosine-5'-stearylphosphate monosodium salt and monohydrate thereof, and pharmaceutical composition containing the latter |
| AU7084587A (en) * | 1986-04-01 | 1987-10-20 | Upjohn Company, The | Methylprednisolone/sodium carboxymethyl starch tablet composition |
| US5223503A (en) * | 1991-04-29 | 1993-06-29 | Eli Lilly And Company | 6-substituted pyrido[2,3-d]pyrimidines as antineoplastic agents |
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- 1993-03-19 DE DE69330392T patent/DE69330392T2/de not_active Expired - Fee Related
- 1993-03-19 EP EP93104505A patent/EP0563697B1/en not_active Expired - Lifetime
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- 1993-03-29 AU AU35558/93A patent/AU657044B2/en not_active Ceased
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3859431A (en) * | 1973-01-04 | 1975-01-07 | Lilly Industries Ltd | Drug formulations |
| US4542021A (en) * | 1978-06-20 | 1985-09-17 | Yamasa Shoyu Kabushiki Kaisha | Antitumor compositions for non-injection administration |
Non-Patent Citations (3)
| Title |
|---|
| US3859431 1975.01.07 A61J3/07 * |
| US3859431 1975.01.07 A61J3/07;US4542021 1985.09.17 H61K31/71 * |
| US4542021 1985.09.17 H61K31/71 * |
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| BR9301373A (pt) | 1993-10-13 |
| DE69330392T2 (de) | 2001-11-08 |
| HU9300974D0 (en) | 1993-06-28 |
| EP0563697A2 (en) | 1993-10-06 |
| HUT65314A (en) | 1994-05-02 |
| CA2093258C (en) | 2003-01-14 |
| ES2160582T3 (es) | 2001-11-16 |
| TW266160B (zh) | 1995-12-21 |
| PL298338A1 (en) | 1993-12-13 |
| EP0563697B1 (en) | 2001-07-04 |
| CN1077888A (zh) | 1993-11-03 |
| KR930021206A (ko) | 1993-11-22 |
| AU657044B2 (en) | 1995-02-23 |
| RU2116069C1 (ru) | 1998-07-27 |
| KR100267525B1 (ko) | 2000-12-01 |
| US5512298A (en) | 1996-04-30 |
| EP0563697A3 (en) | 1994-06-01 |
| CZ57793A3 (en) | 1994-02-16 |
| DE69330392D1 (de) | 2001-08-09 |
| PL171011B1 (pl) | 1997-02-28 |
| HU217810B (hu) | 2000-04-28 |
| CA2093258A1 (en) | 1993-10-04 |
| CZ282844B6 (cs) | 1997-10-15 |
| AU3555893A (en) | 1993-10-07 |
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