CN1302663A - 口服给药后能够长时间释放曲美他嗪的基质片 - Google Patents
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Abstract
本发明涉及一种基质片,在口服给药后能够长时间释放曲美他嗪或其与可药用酸的加成盐,其特征在于,这种长时间释放是通过纤维素衍生物聚合物的使用进行控制的。
Description
本发明涉及口服给药后能够长时间释放曲美他嗪或其与可药用酸的加成盐的基质片。
曲美他嗪，或1-(2,3,4-三甲氧基苄基)哌嗪，是一种通过使处于低氧或局部缺血的细胞保持能量代谢，避免腺苷三磷酸(ATP)的细胞内浓度突然下降的化合物。这种药由此确保离子泵的功能和钠-钾的跨膜流动并维持细胞内环境稳定。
曲美他嗪二盐酸盐近来用于心绞痛危险期的预防性治疗，脉络膜视网膜的发作和用于血管根源的眩晕(美尼尔眩晕，耳鸣)的治疗。
曲美他嗪二盐酸盐到目前为止，一直以40-60毫克/天的剂量(呈含有20毫克活性成分的片剂形式或每毫升含有20毫克活性成分的饮用液形式)经口服用药。这两种剂型都是即时释放型的。专利FR2 490 963描述了立即释放型的片剂。曲美他嗪二盐酸盐由身体迅速吸收和排除，其血浆半存留期(half-life)小于6小时，这意味着活性成分的服用必须每天分成2或3次以确保足够的血浆浓度。在治疗期间最常需要的给药剂量方案是每天3片。每天多次服用药物有被生活忙碌的病人或年老的服用几种药物的病人忘记的危险。
由于迅速的吸收和6-小时的半存留期，这种立即释放的剂型导致到下次服用时血液中浓度的下降。大家都知道，重要的是在整个24小时的期间内保持有效的心肌保护，尤其是局部缺血后果最严重的清晨。由于立即释放剂型不能达到全天完全的覆盖，本申请人开发了一种能够全天24小时覆盖的长时间释放的剂型，确保在两次服药期间足够的血浓度同时保持每次服药后高的血浆峰值，以保持曲美他嗪的疗效，维持处于低氧或局部缺血的细胞的能量代谢并且避免ATP细胞内浓度下降。
这种剂型还可以避免外周血管舒张作用，同时稳定血流速度和张力作用。
本发明的这种新制剂允许在专利FR 2 490 963所述配方中令人满意的特征继续保持，同时能够更好地覆盖全天，导致更好地遵从和持久的保护。
图1是曲美他嗪的血浆动力学曲线，清楚地显示了给12个键康的志愿者口服F3和IR型药物后曲美他嗪的平均血浆浓度(微克/升)随时间的变化。
更具体的说，本发明涉及一种通过口服途径服药后能够长时间释放曲美他嗪或其与可药用酸的加成盐的基质片，而这种基质片由一种亲水基质材料构成，其特征在于长时间释放通过使用纤维素衍生物聚合物来控制。
这种基质片，优选每天服用两次，能够延长活性成分的释放同时在每次服用后保持高的血浆峰值。这种片剂每次服药后能够使人体内血浆浓度大于70微克/升，并且使血浆浓度直到下一次服药保持大于或等于40微克/升，这与在专利FR 2 490 963中所描述的每天服用3次的片剂不同。
在用于本发明基质中的纤维素衍生物中，更具体可以指出的是纤维素醚，例如羟丙基纤维素、羟乙基纤维素、羟甲基纤维素、甲基纤维素和羟丙基甲基纤维素。
纤维素衍生物优选羟丙基甲基纤维素。纤维素衍生物聚合物的百分比为片剂总重量的25-50％。可以使用粘度是100 cP-100 000cP的羟丙基甲基纤维素。优选的粘度是4 000 cP。
各种赋形剂被加入到亲水基质中，例如，粘合剂、稀释剂、润滑剂和流动剂。在粘合剂中，优选使用聚乙烯吡咯烷酮(polyvidone)。聚乙烯吡咯烷酮的百分比为片剂总重量的3-12％。稀释剂优选磷酸氢钙二水合物，它具有比其它稀释剂如乳糖一水合物更好的流动性和可压缩性。磷酸氢钙的百分比为片剂总重量的25-75％。
在润滑剂中，没有任何限制，可以指出硬脂酸镁、硬脂酸、山萮酸甘油酯和苯甲酸钠。优选的润滑剂是硬脂酸镁。最后，优选使用胶体二氧化硅作为流动剂。
本发明的基质片中使用的曲美他嗪优选呈二盐酸盐的形式。
曲美他嗪二盐酸盐的百分比为片剂总重量的15-30％，优选15-18％。
本领域的技术人员通常认为基质片的释放动力学取决于基质(在此例中是纤维素衍生物)的基本成分的性质和含量。
令人惊异的是，本发明的基质片的释放动力学既不受所使用的纤维素衍生物的量的影响，也不受所使用的纤维素衍生物的等级的影响。
一方面，使用不同粘度的羟丙基甲基纤维素，另一方面，使用相同等级的羟丙基甲基纤维素的不同量，所制成的各种配方均表现出相同的释放动力学，这意味着在纤维素衍生物和曲美他嗪之间存在着一种特殊的协同作用。
本发明也涉及这种基质片的制备方法。这种基质片可以通过湿法造粒然后压制、通过干法造粒然后压制，或通过直接压制来制备。制备方法优选湿法造粒随后进行压制。
湿法造粒通过将曲美他嗪、聚乙烯吡咯烷酮和稀释剂混合然后将混合物湿润来进行。第一步骤能够在活性成分周围建立亲水性环境，这种亲水环境对于活性成分的溶解有好处，并且还能够使得到的单位剂量尽可能均匀。
在第二步骤中，先前得到的颗粒与纤维素衍生物混合。然后将润滑剂和流动剂加入混合物中。第三步是将先前得到的加入润滑过的混合物压片。
然后，如果需要，按照常规的包衣技术将这样制成的片剂进行包覆。
以下的实施例具体说明本发明但绝不限制本发明。在这些实施例中所描述的基质片按照下述方式制备
-步骤A：将曲美他嗪、聚乙烯吡咯烷酮和磷酸氢钙二水合物混合，然后用足量纯化水以湿润混合物，造粒并且将颗粒干燥。
-步骤B：将在步骤A中得到的颗粒与羟丙基甲基纤维素混合。
-步骤C：将在步骤B中得到的混合物用硬脂酸镁和胶态二氧化硅润滑。
-步骤D：将在步骤C中得到的经润滑的混合物在旋转制片机上压片以便得到硬度约40-160 N(通过沿直径破碎进行测量)的片剂。实施例1：不同含量的曲美他嗪的不同基质片的制剂
表1：3种片剂的单位配方
实施例2：实施例2显示不同量的羟丙基甲基纤维素对片剂的溶解动力学没有影响。
| 化合物 | 含量(毫克) | ||
| F1 | F2 | F3 | |
| 曲美他嗪二盐酸盐 | 60 | 30 | 35 |
| 羟丙基甲基纤维素 | 112 | 74 | 74 |
| 聚乙烯吡咯烷酮 | 13.3 | 8.7 | 8.7 |
| 磷酸氢钙二水合物 | 92 | 85.9 | 80.9 |
| 硬脂酸镁 | 2.2 | 1 | 1 |
| 无水胶态二氧化硅 | 0.5 | 0.4 | 0.4 |
| 片剂总重量 | 280 | 200 | 200 |
表2：单位配方/各种量的HPMC
表3显示配方F4和F5随时间释放的化合物的百分数。
| 化合物 | 含量(毫克) | |
| F4 | F5 | |
| 曲美他嗪二盐酸盐 | 35 | 35 |
| 羟丙基甲基纤维素 | 54 | 94 |
| 聚乙烯吡咯烷酮 | 10.1 | 7.3 |
| 磷酸氢钙二水合物 | 99.5 | 62.3 |
| 硬脂酸镁 | 1 | 1 |
| 无水胶态二氧化硅 | 0.4 | 0.4 |
| 片剂总重量 | 200 | 200 |
表3：释放动力学
实施例3：实施例3显示不同等级的羟丙基甲基纤维素对片剂的溶解动力学没有影响。
| 时间(小时) | 释放的化合物的百分数(％) | |
| F4 | F5 | |
| 1 | 41 | 38 |
| 2 | 59 | 59 |
| 3 | 80 | 77 |
| 4 | 97 | 96 |
表4：单位配方/各种等级的HPMC
表5显示配方F3、F6和F7随时间释放的化合物的百分数。
| 化合物 | 含量(毫克) | ||
| F3 | F6 | F7 | |
| 曲美他嗪二盐酸盐 | 35 | 35 | 35 |
| 羟丙基甲基纤维素4000 cP | 74 | - | - |
| 羟丙基甲基纤维素100 cP | - | - | 74 |
| 羟丙基甲基纤维素100 000 cP | - | 74 | - |
| 聚乙烯吡咯烷酮 | 8.7 | 8.7 | 8.7 |
| 磷酸氢钙二水合物 | 80.9 | 80.9 | 80.9 |
| 硬脂酸镁 | 1 | 1 | 1 |
| 无水胶态二氧化硅 | 0.4 | 0.4 | 0.4 |
表5：释放动力学
实施例4：血浆动力学研究
| 时间 | 释放的化合物的百分数(％) | ||
| F3 | F6 | F7 | |
| 1 | 43 | 41 | 40 |
| 2 | 62 | 59 | 60 |
| 3 | 86 | 83 | 83 |
| 4 | 105 | 102 | 100 |
给12个健康的志愿者服用实施例1所描述的配方F3的基质片后研究血浆动力学。
服药进行4天，每天服用两片。
配方F3的片剂的血浆动力学与以每天三片服用4天的立即释放(IR)片剂的动力学进行比较。立即释放(IR)片剂的单位配方如下：曲美他嗪二盐酸盐—————————————————————20毫克玉米淀粉—————————————————————————26毫克甘露糖醇—————————————————————————34毫克聚乙烯吡咯烷酮——————————————————————4毫克硬脂酸镁—————————————————————————1毫克滑石———————————————————————————5毫克
平均血浆浓度示于图1中。
这条曲线清楚地显示F3型能够获得曲美他嗪的长时间释放同时每次服用后保持高的血浆峰值。
每次服药后观察到的血浆浓度接近90微克/升且与服用IR型所得到的几乎没有差别。在24小时的最终血浆浓度大于40微克/升，而用立即释放的配方，该血浆浓度只有约25微克/升。
Claims (17)
1．用于长时间释放曲美他嗪或其可药用盐的基质片，其特征在于，长时间释放是通过纤维素衍生物聚合物的使用进行控制的。
2．根据权利要求1的基质片，其特征在于，纤维素衍生物聚合物是羟丙基甲基纤维素。
3．根据权利要求1或2的基质片，其特征在于，纤维素衍生物的百分含量是片剂总重量的25-50％。
4．根据权利要求1的基质片，其特征在于，它还含有粘合剂、稀释剂、润滑剂和流动剂。
5．根据权利要求4的基质片，其特征在于，粘合剂是聚乙烯吡咯烷酮。
6．根据权利要求5的基质片，其特征在于，聚乙烯吡咯烷酮的百分含量是片剂总重量的3-12％。
7．根据权利要求4、5或6的基质片，其特征在于，稀释剂是磷酸氢钙二水合物。
8．根据权利要求7的基质片，其特征在于，磷酸氢钙二水合物的百分含量是片剂总重量的25-75％。
9．根据权利要求4、5、6、7或8的基质片，其特征在于，润滑剂是硬脂酸钙而流动剂是无水胶态二氧化硅。
10．根据权利要求1的基质片，其特征在于，曲美他嗪为二盐酸盐的形式。
11．根据权利要求10的基质片，其特征在于，曲美他嗪二盐酸盐的百分含量是片剂总重量的15-30％。
12．根据权利要求10或11的基质片，其特征在于，曲美他嗪二盐酸盐的百分含量是片剂总重量的17.5％。
13．根据权利要求1至12任一项的基质片，其特征在于，它含有35毫克曲美他嗪二盐酸盐、74毫克羟丙基甲基纤维素、8.7毫克聚乙烯吡咯烷酮、80.9毫克磷酸氢钙二水合物、1毫克硬脂酸镁和0.4毫克无水胶态二氧化硅。
14．根据权利要求13的基质片，其特征在于，服药为每天两次。
15．根据权利要求1的基质片，其特征在于，每次服药后它能够在人体内得到大于70微克/升的血浆浓度，并且能够使血浆浓度直到下一次服药大于或等于40微克/升。
16-权利要求1-13中任一项的基质片的制备方法，其特征在于，
-通过将曲美他嗪、聚乙烯吡咯烷酮和稀释剂混合然后湿润这种混合物进行湿法造粒，
-将这样得到的颗粒与纤维素衍生物混合，
-然后加入润滑剂和流动剂，
-然后将上述混合物压片。
17．根据权利要求1-15中任一项的基质片，用于预防性治疗心绞痛、脉络膜视网膜的发作和用于血管根源的眩晕的治疗。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9915960A FR2802424B1 (fr) | 1999-12-17 | 1999-12-17 | Comprime matriciel permettant la liberation prolongee de trimetazidine apres administration par voie orale |
| FR9915960 | 1999-12-17 |
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| Publication Number | Publication Date |
|---|---|
| CN1302663A true CN1302663A (zh) | 2001-07-11 |
| CN1166408C CN1166408C (zh) | 2004-09-15 |
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| JP (2) | JP2001172181A (zh) |
| KR (1) | KR100456933B1 (zh) |
| CN (1) | CN1166408C (zh) |
| AR (1) | AR026968A1 (zh) |
| AT (1) | ATE296622T1 (zh) |
| AU (1) | AU780011B2 (zh) |
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| BR (1) | BR0005915A (zh) |
| CY (1) | CY2347B1 (zh) |
| CZ (1) | CZ299461B6 (zh) |
| DE (1) | DE60020501T3 (zh) |
| DK (1) | DK1108424T4 (zh) |
| EA (2) | EA008223B1 (zh) |
| ES (2) | ES2176106B1 (zh) |
| FR (1) | FR2802424B1 (zh) |
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| HK (1) | HK1036937A1 (zh) |
| HU (1) | HU226956B1 (zh) |
| IE (1) | IE20001017A1 (zh) |
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| OA (1) | OA12121A (zh) |
| PL (1) | PL206994B1 (zh) |
| PT (2) | PT102542A (zh) |
| SI (1) | SI1108424T2 (zh) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824644A (zh) * | 2012-09-13 | 2012-12-19 | 浙江诚意药业有限公司 | 使用羟丙基纤维素制备的高稳定性的缓释片 |
| CN109316455A (zh) * | 2017-07-31 | 2019-02-12 | 北京万生药业有限责任公司 | 一种盐酸曲美他嗪缓释片 |
| CN109908096A (zh) * | 2017-12-12 | 2019-06-21 | 武汉武药科技有限公司 | 一种盐酸曲美他嗪缓释片及其制备方法 |
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| EP1195160B1 (en) * | 2000-10-05 | 2009-09-16 | USV Ltd. | Sustained release trimetazidine pharmaceutical compositions and a method of their preparation |
| EP1652522A4 (en) | 2003-08-04 | 2008-11-26 | Kyorin Seiyaku Kk | PROLONGED RELEASE TABLET FOR ORAL ADMINISTRATION |
| SG126792A1 (en) * | 2005-04-27 | 2006-11-29 | Servier Lab | Matrix tablet enabling the prolonged release of trimetazidine after administration by the oral route |
| FR2885807B1 (fr) * | 2005-05-18 | 2008-05-16 | Mg Pharma | Composition pharmaceutique solide a liberation prolongee de 1-(2,3,4-trimethoxybenzyl) piperazine, et procede de preparation |
| CZ300307B6 (cs) * | 2006-01-04 | 2009-04-15 | Zentiva, A. S. | Tableta s obsahem trimetazidinu nebo jeho farmakologicky akceptovatelné soli s modifikovaným uvolnováním |
| EA009776B1 (ru) * | 2006-07-18 | 2008-04-28 | Мераб Ревазович Кокеладзе | Способ изготовления таблетированной лекарственной формы триметазидина дигидрохлорида и ее состав |
| EA009810B1 (ru) * | 2006-12-26 | 2008-04-28 | Закрытое Акционерное Общество "Канонфарма Продакшн" | Матрица для изготовления таблетированной лекарственной формы и способ лечения |
| EP2200591A2 (en) * | 2007-09-11 | 2010-06-30 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical dosage forms of trimetazidine |
| WO2010084397A2 (en) | 2009-01-20 | 2010-07-29 | Micro Labs Limited | Modified release solid pharmaceutical compositions of trimetazidine and process thereof |
| EP2391353B1 (en) * | 2009-01-30 | 2016-02-10 | Lupin Limited | Pharmaceutical compositions of trimetazidine |
| TR201001902A2 (tr) | 2010-03-12 | 2011-04-21 | Ali̇ Rai̇f İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Uzatılmış salınımlı trimetazidin tablet |
| RU2445958C2 (ru) * | 2010-04-20 | 2012-03-27 | Общество с ограниченной ответственностью "Озон" (ООО "Озон") | Матричная таблетка с основой для пролонгированного высвобождения триметазидина и способ ее изготовления |
| EP2394644B1 (en) | 2010-05-04 | 2014-07-09 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Trimetazidine Formulation With Different Release Profiles |
| EP2386302A1 (en) | 2010-05-11 | 2011-11-16 | Ranbaxy Laboratories Limited | A controlled release pharmaceutical dosage form of trimetazidine and processes for the preparation thereof |
| EP2491930A1 (en) | 2011-02-25 | 2012-08-29 | Deva Holding Anonim Sirketi | Pharmaceutical combination of betahistine and trimetazidine |
| FR2978916B1 (fr) * | 2011-08-10 | 2013-07-26 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| FR2986431B1 (fr) | 2012-02-03 | 2017-03-17 | Servier Lab | Composition pharmaceutique a liberation prolongee de trimetazidine, son procede de fabrication et son utilisation dans des traitements therapeutiques |
| KR20160118733A (ko) | 2015-04-03 | 2016-10-12 | 이인현 | 호스 권취용 호스 안내장치 및 이를 구비한 호스 권취기 |
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| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| FR2490963B1 (fr) * | 1980-09-30 | 1986-04-18 | Science Union & Cie | Nouvelle composition therapeutique a action anti-ischemique contenant de la trimethoxy 2, 3, 4-benzyl 1-piperazine |
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| RU2082400C1 (ru) * | 1993-12-16 | 1997-06-27 | Акционерное общество - Фармацевтическая фирма "Ник-Фарм" | Способ получения нитроглицерина пролонгированного действия |
| FR2717687B1 (fr) * | 1994-03-24 | 1996-06-14 | Adir | Compositions pharmaceutiques permettant la libération prolongée de trimétazidine après administration par voie orale. |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824644A (zh) * | 2012-09-13 | 2012-12-19 | 浙江诚意药业有限公司 | 使用羟丙基纤维素制备的高稳定性的缓释片 |
| CN109316455A (zh) * | 2017-07-31 | 2019-02-12 | 北京万生药业有限责任公司 | 一种盐酸曲美他嗪缓释片 |
| CN109908096A (zh) * | 2017-12-12 | 2019-06-21 | 武汉武药科技有限公司 | 一种盐酸曲美他嗪缓释片及其制备方法 |
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