CN1160061C - 在口服途径给药之后延长释放甲磺吡脲的骨架片 - Google Patents
在口服途径给药之后延长释放甲磺吡脲的骨架片 Download PDFInfo
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Abstract
本发明涉及到延长释放甲磺吡脲的骨架片，它确保在口服途径给药之后活性成分连续和规律的释放，这种释放对于溶解介质pH的变动不敏感。
Description
本发明涉及到缓释甲磺吡脲的骨架片，这种释放对溶解介质的pH的变化不灵敏，并且在制剂形式口服途径吸收之后能保证规律的和连续的血药浓度
甲磺吡脲，化学式(I)的化合物：
是一种在通常给予人的剂量就具有抗糖尿病性能的磺脲化合物。
迄今甲磺吡脲通过含有80mg剂量的片剂形式由口服途径给药。常规的平均处方量是每天给药两片，分两次给药，但是取决于糖尿病的严重性，每天给药可从1到4片，分几次给药。
本发明的一项目的是获得一种可每天单次给药的口服剂型。一方面，这对于病人使用方便，另一方面，它更好的配合治疗。
本发明的另一项目的是这种口服剂型可缓释。的确，在一些病人中立即释放的剂型引起血液中短期高浓度。缓释剂型可避免血液中这样的峰值，并在人体血液中得到稳定的浓度。这可能减少由“峰效应”引起的不希望的作用，这种效应伴随着与活性成分在血浆中浓度变化有关的水电解-和代谢-型的紊乱。
本发明的主要目的是得到一种口服剂型，其中活性成分的释放是可控制和可重现的。事实上，当前剂型的活性成分的溶解随pH变化很大。这种性质，与甲磺吡脲自身有关，造成活性成分的吸收问题。活性成分的溶解度按照pH变化的现象如图1所示(附上)。溶解度在酸性pH值非常小，pH升高时提高。
因而，对于这种活性成分而言，开发一种新的可使甲磺吡脲释放独立于溶解介质pH的甲磺吡脲剂型是重要的。
更特别地，本发明描述了一种亲水性的骨架，它可通过口服途径给药，并延长和控制释放活性成分-甲磺吡脲，而且不具有所述骨架的pH影响的体外溶解动力学。
用于糖尿病治疗的甲磺吡脲延释剂型，可提供更稳定的血浆浓度和较小的Cmax-Cmin变化。释放速率是可再现的，并且与给药后观察到的血液浓度相关联。
在用于控制可溶的活性成分扩散的机理之中，选择一项最重要的机理，它是活性成分在亲水性聚合物与溶解液(体外)或胃-肠液(体内)接触并溶胀之后，通过凝胶的扩散。
曾经描述过许多适于制备这种凝胶的聚合物。主要的聚合物是纤维素化合物，特别是纤维素醚，例如羟丙基纤维素、羟乙基纤维素、甲基纤维素和羟丙基甲基纤维素，以及在那些醚的各种商品等级中，较高粘度的那些。应当注意地是，描述的系统并不具有在释放动力学方程中得到0级的理论上的可能性。
目前用于这种骨架片的制备工艺或者是在混合各种赋形剂和活性成分之后直接压片，或者湿法制粒。
本发明描述的甲磺吡脲骨架片以一种新方法组合了至少一种纤维素聚合物化合物和葡萄糖浆(玉米淀粉水解产物)，使得优选延长和控制的活性成分的释放成为可能。
这种控释在超过八小时的期间内是直线形的，在4和6小时之间释放了甲磺吡脲总量的50％。此外，按照本发明的骨架片能缓释甲磺吡脲，在含有30mg剂量的甲磺吡脲片的口服途径单次给药之后至多12小时，产生400至700ng/ml的人体血药浓度，以及在含有30mg剂量的甲磺吡脲片每天给药之后，浓度为250至1000ng/ml。
根据病人的年龄、体重、糖尿病的性质和严重性，可改变单位剂量。对于每天的治疗，单次给药通常的范围是30至120mg。骨架片中甲磺吡脲的百分数是片重的12至40％。按照本发明有益的实施方案，所述片含有60mg剂量的甲磺吡脲。本发明特别优选的实施方案是提供含有30剂量的甲磺吡脲片。在那些本发明有益的实施例中，对于每天单次给药，范围为30至120mg的单位剂量，与含30mg剂量的1至4片或者含60mg剂量1至2片的吸收相对应。一方面申请人描述的骨架片具有可每天单次给药的口服剂型，另一方面，令人惊奇地和特别有益地，减少每片中的活性成分含量而不更改和变动甲磺吡脲的血浆浓度。迄今这种制剂现有含有80mg甲磺吡脲剂量。
上述化合物的特定组合，令人惊奇地，使得所述骨架的体外溶解动力学不受pH的影响，尽管活性成分的溶解度随同样的pH变动。这一点通过图2介绍(附上)，它显示制备的胃架对于发生在肠内环境的范围为6.2至7.4的pH变动不敏感。因而，相对应于图1(附上)显示的上升曲线的pH6至8的范围内，可以观察到活性成分在0和12小时之间的释放曲线是相同的，与含有所述活性成分的骨架片的溶解介质的pH无关。
因而，通过至少一种纤维素聚合物化合物和葡萄糖浆的特征组合，申请人创造了一种亲水性骨架，在其组成和其功能方面它是创新的，由于，具体地，它能以延长和控制的方式释放所含的活性成分甲磺吡脲，且与溶解介质的pH无关。
亲水性骨架中使用的纤维素聚合物化合物是高粘度的纤维素醚。有益地，纤维素醚是羟丙基甲基纤维素，优选两种不同粘度的羟丙基甲基纤维素的组合。所述骨架组合物中另一化合物是葡萄糖浆，并且有益地，采用麦芽糖糊精，它是具有1至20右旋葡萄糖效价(ED)的葡萄糖浆。一方面这两种类型的化合物的组合物可得到活性成分释放曲线对溶解介质的pH变动不敏感的制剂，另一方面，得到了良好控制的释放动力学。纤维素聚合物化合物的百分数是片重的10至40％，按照特别有益的实施方案，是片重的16至26％。葡萄糖浆的百分数是片重的2至20％，优选片重的4至10％。
也可加入各种赋形剂以完善制剂。在常规使用的稀释剂中，优选的是采用磷酸氢钙二水合物，它能改善颗粒的流动性和获得改善的颗粒压片性。此外，磷酸氢钙二水合物能够放慢溶解动力学，该特征使得可以采用较小量的羟基丙基甲基纤维素控制活性成分的释放曲线。磷酸氢钙二水合物的百分数是片重的35至75％，优选片重的45至60％。润滑剂中，借助实例提到了硬脂酸镁、硬脂酸、甘油山萮酸酯和苯甲酸钠，在助流剂中，优选的是采用无水胶体二氧化硅。
本发明也涉及到骨架片的制备。通过混合活性成分、葡萄糖浆和磷酸氢钙二水合物，接着润湿混合物，进行湿法制粒。第一步在活性成分周围产生促进其良好溶解的亲水性环境，并且尽可能提供稳定的单位剂量。在第二步，以上得到的颗粒与纤维素醚混合。如果希望，纤维素醚在第一步可与活性成分一起直接制粒。接着通过加入胶体二氧化硅和硬脂酸镁润滑混合物。然后压片最终的润滑过的混合物。
下列实施例介绍本发明，但不是以任何方式限制本发明。
口服途径给药的延释片的制备按照以下生产工艺进行：
步骤A：
甲磺吡脲、麦芽糖糊精和磷酸氢钙二水合物的混合物，以纯水润湿混合物。所得的湿材接着制粒、干燥并随后分级，得到具有可良好填充快速压片机模的物理特征的颗粒。
步骤B：
步骤A得到的颗粒与羟丙基甲基纤维素混合。
步骤C：
以胶体二氧化硅和硬脂酸镁润滑步骤B得到的混合物。
步骤D：
采用旋转压片机压片步骤C得到的润滑的混合物，以获得具有大约6至10daN硬度(通过直径压碎测量)的片。
实施例1：
实施例1显示麦芽糖糊精对体外释放动力学的影响。麦芽糖糊精每片含量7.5至15mg，因而组成片重的4至10％。羟丙基甲基纤维素的量保持稳定，调节稀释剂磷酸氢钙二水合物的量，以获得具有160mg稳定重量的片。按照步骤A至D描述的程序进行制备。
表1：片剂的单位配制(mg每片)和特征
| 批 | ||
| 组分 | LP1 | LP2 |
| 甲磺吡脲 | 30 | 30 |
| 磷酸氢钙二水合物 | 87.4 | 79.9 |
| 麦芽糖糊精(*) | 7.5 | 15 |
| 羟丙基甲基纤维素 | 34 | 34 |
| 硬脂酸镁 | 0.8 | 0.8 |
| 胶体二氧化硅 | 0.32 | 0.32 |
| 最终重量 | 160 | 160 |
| 8小时溶解的活性成分(％) | 73 | 84 |
(*)麦芽糖糊精的量等于制粒材料(活性成分+磷酸氢钙二水合物+麦芽糖糊精)量的6至12％。
图3表示采用的两个制剂的溶解动力学曲线
麦芽糖糊精的量，在羟丙基甲基纤维素重量稳定时，影响大于4小时期的活性成分释放。溶解曲线通过麦芽糖糊精的增长量线性化。
实施例2：
实施例2显示羟丙基纤维素对体外释放动力学的影响。羟丙基甲基纤维素的用量为26至42mg。因而构成片重的16至26％。
表2：片剂的单位配制(mg每片)
| 批 | ||
| 组分 | LP3 | LP4 |
| 甲磺吡脲 | 30 | 30 |
| 磷酸氢钙二水合物 | 79.87 | 94.91 |
| 麦芽糖糊精(*) | 7.01 | 7.97 |
| 羟丙基甲基纤维素 | 42 | 26 |
| 硬脂酸镁 | 0.8 | 0.8 |
| 胶体二氧化硅 | 0.32 | 0.32 |
| 最终重量 | 160 | 160 |
| 4小时溶解的活性成分(％) | 35 | 52 |
(*)麦芽糖糊精的量等于制粒材料(活性成分+磷酸氢钙二水合物+麦芽糖糊精)的6％。
图4表示采用的两个制剂的溶解动力学曲线：
亲水性骨架中羟丙基甲基纤维素量强烈影响活性成分的释放。
实施例3：
实施例3显示采用的羟丙基甲基纤维素的级别对体外释放动力学的影响。每一批中，羟丙基纤维素的总重是稳定的，每种不同粘度的羟丙基甲基纤维素的相对量是变化的，因而，得到缓慢溶解批(LP5)和快速溶解批(LP7)，与对照批(LP6)比较。
表3：片剂的单位配制(mg)
| 批 | |||
| 组分 | LP5 | LP6 | LP7 |
| 甲磺吡脲 | 30 | 30 | 30 |
| 磷酸氢钙二水合物 | 83.64 | 83.64 | 83.64 |
| 麦芽糖糊精(*) | 11.24 | 11.24 | 11.24 |
| 羟丙基甲基纤维素4000cP | 24 | 16 | 8 |
| 羟丙基甲基纤维素100cP | 10 | 18 | 26 |
| 硬脂酸镁 | 0.8 | 0.8 | 0.8 |
| 胶体二氧化硅 | 0.32 | 0.32 | 0.32 |
| 最终重量 | 160 | 160 | 160 |
| 4小时溶解的活性成分(％) | 33 | 46 | 58 |
(*)麦芽糖糊精的量等于制粒材料(活性成分+磷酸氢钙二水合物+麦芽糖糊精)的9％。
图5表示采用的三种制剂的溶解动力学曲线：
曲线清楚地显示不仅亲水骨架中羟丙基甲基纤维素的用量，而且采用的羟丙基甲基纤维素的级别影响活性成分的溶解动力学。
在LP6片的单次给药之后，测量12受体中甲磺吡脲的血浆动力学。图6给出了平均血浆浓度。
该曲线显示骨架型溶解曲线(活性成分连续释放)具有单室血浆动力学。
实施例4：
实施例4显示60mg剂量片的体外释放动力学类似于含有同样剂量的羟丙基甲基纤维素和麦芽糖糊精骨架片中30mg剂量片(LP6批)的，
表4：片剂的单位配制(mg每片)
| LP8批 | |
| 组分 | |
| 甲磺吡脲 | 60 |
| 磷酸氢钙二水合物 | 53.64 |
| 麦芽糖糊精 | 11.24 |
| 羟丙基甲基纤维素 | 34 |
| 无水胶体二氧化硅 | 0.32 |
| 硬脂酸镁 | 0.8 |
| 最终重量 | 160mg |
| 4小时溶解的活性成分(％) | 45 |
Claims (15)
1.缓释甲磺吡脲骨架片，其特征在于它包括至少一种纤维素聚合物化合物和葡萄糖浆的组合，纤维素聚合物化合物的百分数是所述片总重的10至40％，葡萄糖浆的百分数是所述片总重的2至20％，这种组合能够控制甲磺吡脲的延长释放并使得甲磺吡脲的溶解释放动力学对pH的变动不灵敏。
2.按照权利要求1的甲磺吡脲骨架片，其特征在于纤维素聚合物化合物包括至少一种羟丙基甲基纤维素。
3.按照权利要求1或2的甲磺吡脲骨架片，其特征在于纤维素聚合物化合物包括两种不同粘度羟丙基甲基纤维素的混合物。
4.按照权利要求3的甲磺吡脲骨架片，其特征在于纤维素聚合物化合物包括4帕斯卡·秒粘度的羟丙基甲基纤维素和0.1帕斯卡·秒粘度的羟丙基甲基纤维素的混合物。
5.按照权利要求1的甲磺吡脲骨架片，其特征在于葡萄糖浆是麦芽糖糊精。
6.按照权利要求1的甲磺吡脲骨架片，其特征在于纤维素聚合物化合物的百分数是所述片总重的16至26％。
7.按照权利要求1的甲磺吡脲骨架片，其特征在于葡萄糖浆的百分数是所述片总重的4至10％。
8.按照权利要求1的甲磺吡脲骨架片，其特征在于磷酸氢钙二水合物用作稀释剂。
9.按照权利要求8的甲磺吡脲骨架片，其特征在于稀释剂的百分数是所述片总重的35至75％。
10.按照权利要求8的甲磺吡脲骨架片，其特征在于稀释剂的百分数是所述片总重的45至60％。
11.按照权利要求1的甲磺吡脲骨架片，其特征在于甲磺吡脲的量是所述片总重的12至40％。
12.按照权利要求1或11的甲磺吡脲骨架片，其特征在于其含有甲磺吡脲的总量为30mg。
13.按照权利要求1或11的甲磺吡脲骨架片，其特征在于其含有甲磺吡脲的总量为60mg。
14.按照权利要求1的甲磺吡脲骨架片的制备方法，其特征在于它采用湿法制粒技术和直接压片技术，包括下列步骤：
步骤A：
甲磺吡脲、麦芽糖糊精和磷酸氢钙二水合物的混合物，以纯水润湿混合物，所得的湿材接着制粒、干燥并随后分级，得到具有可良好填充快速压片机模的物理特征的颗粒；
步骤B：
步骤A得到的颗粒混合物与羟丙基甲基纤维素混合；
步骤C：
以胶体二氧化硅和硬脂酸镁润滑步骤B得到的混合物；
步骤D：
采用旋转压片机压片步骤C得到的润滑混合物，以获得通过直径压碎测量的、具有6×10-5牛顿至1.0×10-4牛顿硬度的片。
15.按照权利要求1的甲磺吡脲骨架片在制备治疗糖尿病的药物中的用途。
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| FR99/01082 | 1999-02-01 | ||
| FR9901082A FR2788981B1 (fr) | 1999-02-01 | 1999-02-01 | Comprime matriciel permettant la liberation prolongee de gliclazide apres administration par voie orale |
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| AU2004318976B2 (en) * | 2004-04-29 | 2009-04-09 | Lotus Pharmaceutical Co., Ltd. | Oral modified-release lozenges and their preparation method |
| CN100413491C (zh) * | 2004-06-14 | 2008-08-27 | 北京德众万全药物技术开发有限公司 | 一种难溶性药物的控释制剂 |
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| EP1946780B1 (en) | 2005-11-11 | 2012-01-11 | Asahi Kasei Chemicals Corporation | Controlled release solid preparation |
| US20080286343A1 (en) * | 2007-05-16 | 2008-11-20 | Dzenana Cengic | Solid form |
| TR200704897A1 (tr) * | 2007-07-13 | 2009-02-23 | Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� | Uzatılmış salım sağlayan gliklazid formülasyonları@ |
| TR200708938A2 (tr) * | 2007-12-26 | 2008-11-21 | Ali̇ Rai̇f İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Uzatılmış salım sağlayan gliklazid tablet |
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| FR2928836B1 (fr) * | 2008-03-21 | 2011-08-26 | Servier Lab | Forme galenique secable permettant une liberation modifiee du principe actif |
| WO2009140279A2 (en) * | 2008-05-12 | 2009-11-19 | Concert Pharmaceuticals, Inc. | Sulfonyl urea compounds |
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| TR201107482A1 (tr) | 2010-12-21 | 2012-07-23 | Sanovel İlaç San.Ve Ti̇c.A.Ş. | Vildagliptin ve gliklazidin iki tabakalı kombinasyon kompozisyonu. |
| TR201103946A1 (tr) | 2011-04-22 | 2012-11-21 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Kontrollü salım sağlayan gliklazid formülasyonları. |
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| US20150031737A1 (en) * | 2012-02-24 | 2015-01-29 | Ranbaxy Laboratories Limited | Stabilized controlled-release pharmaceutical composition comprising gliclazide |
| WO2014128116A1 (en) * | 2013-02-19 | 2014-08-28 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A production process for gliclazide formulations |
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