CN1275597C - 含有山楂叶提取物的可延长释放的给药系统 - Google Patents
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Abstract
本发明涉及到能延长释放的含有山楂叶提取物的活性成份的的口服给药系统，它通过纤维素化合物和可溶性物质的组合，创造了一种能确保延长和控制的方式释放所含的活性成份，使得所含有的山楂叶提取物代表产物芦丁得到良好的预期的体外释放。
Description
技术领域 本发明涉及到可以缓慢、连续、控制的释放含有山楂叶提取物的口服给药系统，并且该系统采用口服途径给药后可达到降低血脂，降血压的作用。
背景技术 迄今含有山楂叶提取物的口服片剂已有上市，常规的服用方法为每日给药3次，每次2个剂量单位，临床用作治疗心血管系统疾病。本发明的一项目的是获得一种可每天1～2次给药的口服剂型。一方面，这对于病人使用方便，另一方面，它能更好地达到治疗效果；本发明的另一项目的是得到一种口服的缓释剂型，其中含有山楂叶的药理活性提取物，该提取物中的代表化合物的释放都是可控制的和可重现的。普通剂型能在病人血液中产生活性成份的短期高浓度，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。这样可以减少由血药浓度波动引起的不量反应和副作用。
发明内容 本发明研制了一种含有山楂叶提取物的缓释/控释给药系统，它可以通过口服途径给药，并且延长和控制释放活性成分在体内的释放，而且这种给药系统对活性成份的释放不受人体消化道内pH变化的影响。
用于高血压、高血脂症治疗的的含有山楂叶提取物的缓释给药系统，可提供更稳定的血药浓度和较小的体内血浆药物浓度的波动变化。释放速率是可再现的，并且可与给药后所测定到的血药浓度相关。
在控制山楂叶提取物中活性成分释放的机理之中，本发明所选择使用的机理如下：
1.在亲水性聚合物与释放介质(体外)或胃-肠液(体内)接触并溶胀之后形成凝胶水化层，活性成分通过水化层中的孔道的扩散释放。
2.将山楂叶提取物制备成颗粒、片剂或者胶囊，在颗粒、片剂、胶囊或者微丸的外部用适宜的包衣材料进行包衣，控制活性成分的释放。
3.将溶蚀性材料与山楂叶提取物混合后制备颗粒、胶囊、片剂或者微丸，通过逐渐溶蚀的作用控制药物的释放。
有许多适合制备这种缓释给药系统的聚合物。主要有羟丙基纤维素、羟乙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、醋酸纤维素、聚丙烯酸树脂、卡波姆、海藻酸钠、海藻酸钙、聚山榆酸甘油酯等聚合物。
本发明描述的口服给药后能延长释放的治疗高血压、高血脂症的含有山楂叶提取物的缓释给药系统以上述三种方法中的任意方法组合了至少一种纤维素化合物和可溶性物质，使得延长和控制活性成分的释放成为可能。
这种缓释释放使得活性成份在十二小时的期间内药物释放量都是可以控制的，以其中的活性物质代表总黄酮为例，在1至4小时之间释放药物总量的10～50％，4至6小时的时间内释放药物总量的30～70％，6至8小时的时间释放总量的60％以上。
申请人通过使用至少一种纤维素化合物和可溶性物质的特殊组合，创造了一种含有山楂叶提取物的口服缓释给药系统，它在组成和制备方法方面都是创新的。具体而言，它能以延长和控制的方式释放所含的活性成分，并且与释放介质的pH无关。
以下实例仅为本发明中的典型代表，但不是以任何方式限制本发明。
具体实施方式1
本发明第一步混合乙基纤维素、部分山楂叶提取物、乳糖，接着润湿混合物，进行湿法制粒。第一步的目的在于使用水不溶性物质包裹活性成分中活性物质，减缓它的释放；第二步，将以上得到的颗粒及剩余的山植叶提取物、羟丙基甲基纤维素混合，润湿制粒。这样做既可以获得活性物质的合理释放，也可以尽可能提供稳定的单位剂量。接着用硬脂酸镁润滑颗粒，然后将颗粒压制成片。口服给药后能延长释放的治疗高血压、高血脂症的含有山楂叶提取物的缓释给药系统制备按照以下生产工艺进行：
步骤A：
乙基纤维素、部分山楂叶提取物、乳糖混合物加适量乙醇制软材，所得到的软材接着制粒、干燥，得到具有良好物理特征的颗粒；
步骤B：
步骤A得到的颗粒与剩余的山楂叶提取物、羟丙基甲基纤维素混合，用适量的乙醇和水的混合溶液润湿制软材，将所得软材制粒、干燥，得到具有良好流动性、可良好填充的颗粒；
步骤C：
以硬脂酸镁润滑步骤B得到的颗粒；
步骤D：
使用旋转压片机对步骤C得到的润滑颗粒压片，以获得通过片剂硬度测量仪测量的具有大约6至10kg硬度的片子。
示例1：
示例1显示可溶性物质对活性成分中代表物质芦丁体外释放动力学的影响。可溶性物质分别选择了有机糖类的乳糖和无机盐类的氯化钠。羟丙基甲基纤维索和乙基纤维素的量保持稳定。乳糖和氯化钠的用量保持一致，以获得具有稳定片重的骨架片。具体片剂的处方见表1，按照步骤A至D描述程序进行制备。
表1：片剂的单位配制(mg/每片)和特征
| 用量 | 处方 | |
| Px1 | Px2 | |
| 100 | 山楂叶提取物 | 山楂叶提取物 |
| 70 | 羟丙基甲基纤维素 | 羟丙基甲基纤维素 |
| 50 | 乙基纤维素 | 乙基纤维素 |
| 150 | 乳糖 | 氯化钠 |
| 2 | 硬脂酸镁 | 硬脂酸镁 |
示例2：
示例2显示4000cp粘度的羟丙基甲基纤维素不同用量对活性成分中代表物质芦丁体外释放动力学的影响。可溶性物质选择为乳糖并且用量不变，乙基纤维素和50cp羟丙基甲基纤维素的用量也保持不变，4000cp羟丙基甲基纤维素的用量为10至35mg。具体片剂的处方见表2，按照步骤A至D描述的程序进行制备。
表2：片剂的单位配制(mg/每片)
| 处方 | 用量 | ||
| Px3 | Px4 | Px5 | |
| 山楂叶提取物 | 100 | 100 | 100 |
| 4000cp羟丙基甲基纤维素 | 10 | 20 | 35 |
| 50cp羟丙基甲级纤维素 | 50 | 50 | 50 |
| 乙基纤维素 | 30 | 30 | 30 |
| 乳糖 | 150 | 150 | 150 |
| 硬脂酸镁 | 2 | 2 | 2 |
示例3：
示例3显示乙基纤维素的不同用量对活性成分中代表物质芦丁体外释放动力学的影响。可溶性物质选择为乳糖并且用量不变，羟丙基甲级纤维素的用量也不变，乙基纤维素的用量从10至50mg。具体片剂的处方见表3，按照步骤A至D描述的程序进行制备。
表3：片剂的单位配制(mg/每片)
| 处方 | 用量 | ||
| Px6 | Px7 | Px8 | |
| 山楂叶提取物 | 100 | 100 | 100 |
| 羟丙基甲基纤维素 | 70 | 70 | 70 |
| 乙基纤维素 | 10 | 30 | 50 |
| 乳糖 | 150 | 150 | 150 |
| 硬脂酸镁 | 2 | 2 | 2 |
具体实施方式2
将山楂叶提取物与适宜的亲水溶性辅料混合，制成颗粒、微丸、片剂或者胶囊，采用水不溶解性的包衣材料对颗粒、微丸、片剂或者胶囊外进行包衣，在包衣材料中可以添加适当的水溶解性的物质，增加包衣膜对水份的通透能力。在包衣膜上也可以有一个或者多个直径在0.1mm～1.5mm的小孔，增加药物的释放作用。制备工艺按照以下进行，本工艺是本发明的代表，不对本发明做任何形式、任何方面的限制：
步骤A：
山楂叶提取物、乳糖、氯化钠混合物加适量乙醇制软材，所得到的软材接着制粒、干燥，得到具有良好物理特征的颗粒；
步骤B：
步骤A得到的颗粒与硬脂酸镁润滑，混合均匀。
步骤C：
采用乙醇为润湿剂，将聚氧乙烯制备成适当的颗粒，使用旋转压片机对步骤B、C得到的润滑颗粒压双层片，以获得通过片剂硬度测量仪测量的具有大约6至10kg硬度的片子。
步骤D：
将醋酸纤维素、PEG1500溶解在90％丙酮溶液中，制备成适宜浓度的包衣液，对步骤C所得到的片剂进行包衣。
步骤E：
在包衣片剂中含有山楂叶提取物一侧制备直径0.8mm的小孔，作为药物释放孔径。
示例4：
表4：片剂的单位配制(mg/每片)
| 处方 | 用量 |
| Px9 | |
| 山楂叶提取物 | 100 |
| 乳糖 | 40 |
| 氯化钠 | 10 |
| 聚氧乙烯 | 150 |
| 硬脂酸镁 | 2 |
| 醋酸纤维素 | 8.0 |
| PEG1500 | 1.0 |
采用上述方法制备的缓释制剂的主要有效物质芦丁体外释放度曲线见附图4。
附图说明
附图1采用Px1和Px2所制片剂中活性成分代表物质芦丁释放曲线。
附图2采用Px3、Px4、Px5所制片剂中活性成分代表物质芦丁释放曲线。
附图3采用Px6、Px7、Px8所制备片剂中活性成分代表物质芦丁释放曲线。
附图4采用Px9所制备片剂中活性成分代表物质芦丁释放曲线。
Claims (8)
1.一种含有山楂叶提取物的口服给药后能控制提取物中总黄酮释放速度的制剂，其特征在于该制剂包含阻滞剂和水溶性填充剂，其中所涉及的阻滞剂为羟丙基甲基纤维素，占片重百分比为2.9％～9.6％。
2.按照权利要求1的口服缓释给药制剂，其阻滞剂为粘度4000cp的羟丙基甲基纤维素。
3.按照权利要求1的口服缓释给药制剂，其特征在于山楂叶提取物占制剂重量的百分数范围为26.9％～30％。
4.按照权利要求1的口服缓释给药制剂，其特征在于含有粘度为4000cp的羟丙基甲基纤维素占制剂重量的2.9％、5.7％或9.6％。
5.按照权利要求1的口服缓释给药制剂，其特征在于水溶性填充剂是乳糖或氯化钠。
6.如前所述1～4任意一项权利要求的口服缓释给药制剂，还应含有乙基纤维素和硬脂酸镁。
7.按照权利要求1制备的口服缓释给药制剂，使得活性成份在12小时的期间内药物释放量都是可以控制的，其中的活性物质代表总黄酮，在1小时释放总量的10～35％，在4小时释放总量的40～75％，8小时的时间释放总量的60％以上。
8.如前面任意一项权利要求所述的制剂在制备治疗以高血压、高血脂为代表的心血管系统疾病的药物中的应用。
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| CN200310102297.4A CN1275597C (zh) | 2003-10-31 | 2003-10-31 | 含有山楂叶提取物的可延长释放的给药系统 |
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