CN102858325A - 包含非诺贝特酸和碱化剂的口服药物组合物 - Google Patents
包含非诺贝特酸和碱化剂的口服药物组合物 Download PDFInfo
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- CN102858325A CN102858325A CN2011800184071A CN201180018407A CN102858325A CN 102858325 A CN102858325 A CN 102858325A CN 2011800184071 A CN2011800184071 A CN 2011800184071A CN 201180018407 A CN201180018407 A CN 201180018407A CN 102858325 A CN102858325 A CN 102858325A
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- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000003795 chemical substances by application Substances 0.000 title abstract description 4
- 229960000701 fenofibric acid Drugs 0.000 title abstract description 4
- 239000008203 oral pharmaceutical composition Substances 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims description 105
- 229960002297 fenofibrate Drugs 0.000 claims description 104
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- -1 magnesium aluminate Chemical class 0.000 claims description 9
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Abstract
本发明的口服药物组合物包含非诺贝特酸或其可药用盐，以及基于按重量计1份非诺贝特酸的按重量计0.22至1份的碱化剂，其具有提高的生物利用度和在胃肠道中最小化的吸收偏差，可用于治疗高脂血症和高甘油三酯血症。
Description
技术领域
本发明涉及包含非诺贝特酸(fenofibric acid)或其可药用盐和碱化剂的口服药物组合物，其具有提高的生物利用度和在胃肠道中最小化的吸收偏差(deviation)。
背景技术
非诺贝特(fenofibrate)可用于治疗固有的高脂血症、高胆固醇血症和高甘油三酯血症。已知每日剂量为300至400mg的非诺贝特可使高胆固醇血症水平降低20～25％，使高甘油三酯血症水平降低40～50％。
非诺贝特在血浆中代谢为活性代谢物非诺贝特酸(化学名：2-[4-(4-氯苯甲酰基)苯氧基]-2-甲基-丙酸)。非诺贝特酸在血浆中以约20小时的半衰期消除，非诺贝特酸的峰值血浆水平出现在施用后约5小时。
已知非诺贝特酸降低所治疗患者中的总胆固醇(总-C)、低密度脂蛋白(LDL-C)、载脂蛋白B、总甘油三酯及富含甘油三酯的载脂蛋白(VLDL)、高密度脂蛋白(HDL)以及载脂蛋白AI和AII的水平。
因为非诺贝特和非诺贝特酸是疏水的且难溶于水，所以它们的生物利用度低，并且与在禁食状态下施用相比其在餐后不久施用时(饱食状态)在消化道中的吸收增加。一般来说，在饱食状态下在胃肠道中的停留时间变得长得多。因此，当药物生物利用度受胃肠道中食物存在的影响时，认为该药物表现出食物效应(food effect)。对非诺贝特来说，因为食物可提高非诺贝特的生物利用度，所以不与食物一起服用非诺贝特可导致吸收显著降低。与在空腹状态下施用相比，市售的含有非诺贝特的产品
(Abbot)在饱食状态下表现出提高(高达约35％)的吸收率。同时，非诺贝特酸在小肠中的较高pH下具有较高的溶解度。
由于这个原因，尝试了多种方法来提高非诺贝特的溶出度(dissolution rate)或使食物效应最小化(例如，使非诺贝特微粉化、添加表面活性剂、使非诺贝特与表面活性剂共微粉化)。
例如，欧洲专利No.256933描述了具有提高的非诺贝特生物利用度的微粉化非诺贝特颗粒。在所述颗粒中，晶体非诺贝特微颗粒的尺寸低于50μm并且使用聚乙烯吡咯烷酮作为粘合剂。该欧洲专利还提出不同类型的粘合剂，例如甲基丙烯酸聚合物、纤维素衍生物和聚乙二醇。或者，欧洲专利No.245933公开了使用有机溶剂的非诺贝特颗粒制剂。
欧洲专利No.330532公开了通过使非诺贝特与固体表面活性剂(例如，月桂基硫酸钠)共微粉化而提高非诺贝特生物利用度的方法。通过湿制粒法将共微粉化的产品配制成颗粒以增强粉末的流动性并且使其更容易配制成明胶胶囊。
国际公布No.WO 98/31361提出一种具有提高的生物利用度的非诺贝特组合物，其包含包被有含微粉化非诺贝特、亲水聚合物(例如，聚乙烯吡咯烷酮)以及任选地表面活性剂的膜的惰性水可分散性支持物。然而，因为该方法需要大量的聚乙烯吡咯烷酮和其它赋形剂，所以仅可获得含有少量(17.7wt％)非诺贝特的制剂。因此，最终剂型的体积变得太大，因而难以以单一或复合制剂施用期望剂量的非诺贝特。
同时，美国专利No.7259186公开了选自以下的非诺贝特酸的盐：胆碱盐、乙醇胺盐、二乙醇胺盐、哌嗪盐、钙盐和缓血酸胺(tromethamine)盐，以降低对生物利用度的食物效应。美国专利No.152714也在实施例中描述了非诺贝特之胆碱盐的制剂，并且表明通过盐的离子强度降低食物效应。
如上所述，持续需要开发含有非诺贝特酸的药物组合物，所述组合物具有提高的水溶性以及较低食物效应的高生物利用度，从而在胃肠道中具有最小化的吸收偏差。
发明的公开内容
本发明的一个目的是提供包含非诺贝特酸的口服药物组合物，其具有提高的生物利用度以及在胃肠道中最小化的吸收偏差。
根据本发明的一个方面，提供了一种包含非诺贝特酸或其可药用盐和碱化剂的口服药物组合物。
附图说明
结合以下附图，通过本发明的以下描述，本发明的上述和另一些目的和特征将变得明显，所述附图分别示出：
图1：非诺贝特、非诺贝特酸和非诺贝特胆碱(choline fenofibrate)的水溶解度(μg/ml)，如在测试实施例1中测得的那样；
图2：大鼠血液中非诺贝特、非诺贝特酸和非诺贝特胆碱的水平(μg/ml)，如在测试实施例2中测得的那样；
图3：通过改变碱化剂与非诺贝特酸的重量比而改变丸粒(pellet)长轴/短轴的长度比(纵横比(aspect ratio))，如在测试实施例4中观察到的那样；
图4：通过改变实施例13和14以及比较例10、12和13中所制备之非诺贝特酸丸粒和片剂的pH而获得的溶出度图，如在测试实施例5中观察到的那样；
图5和图6：通过分别改变实施例14和比较例12中制备的非诺贝特酸丸粒和片剂的桨旋转速度而获得的溶出度图，如测试实施例6中测得的那样；以及
图7：比较例10以及实施例13和14中制备的非诺贝特酸丸粒在比格犬(beagle)血液中的水平(μg/ml)，如测试实施例7中测得的那样。
实施本发明的最佳方式
根据本发明的口服药物组合物包含非诺贝特酸或其可药用盐，以及基于按重量计1份非诺贝特酸的按重量计0.22至1份的碱化剂。所述碱化剂与非诺贝特酸或其可药用盐直接接触，这可在暴露于体内环境之后提高非诺贝特酸周围微环境的pH，从而提高非诺贝特酸的水溶性并因此提高其生物利用度。
可将本发明的口服药物组合物配制可填充到胶囊中之丸粒的形式。所述丸粒可以相对容易地制备，并且最适合以通过用延迟释放包衣基质包衣的包衣制剂形式获得。此外，由于所述丸粒的含量便于控制，因此适于根据所需的药物含量而简单地配制。特别地，为了使药物的体内释放偏差最小化以及维持其恒定的释放速率，要求所述丸粒通过使其长轴长度与短轴长度相近而具有接近球形的形式。例如，所述丸粒可以是具有1.5或更低的长轴短轴长度比(即，长度比为1.0至1.5，优选1.0至1.2)的形式。因此，本发明的药物组合物还可包含滚圆添加剂(spheronizing additive)。
本发明的丸粒形式的药物组合物可通过包括以下步骤的方法来制备：
(i)将非诺贝特酸或其可药用盐与碱化剂进行第一湿混合；
(ii)向步骤(i)中获得的第一混合物中添加可药用赋形剂，并对它们进行第二湿混合；以及
(iii)使用挤出机和滚圆机(spheronizer)将步骤(ii)中获得的第二混合物制粒成球形。
任选地，在步骤(ii)中，所述方法还可包括向第一混合物中添加滚圆添加剂。此外，所述方法还可包括用延迟释放包衣基质对步骤(iii)中获得的颗粒进行包衣。
以下详细地描述本发明口服药物组合物的每种成分。
(1)非诺贝特酸或其可药用盐
本发明中用作活性成分的非诺贝特酸或其可药用盐是非诺贝特代谢物，其有助于显著降低患有高甘油三酯血症的患者中的血浆甘油三酯水平，以及显著降低患有高甘油三酯血症或混合型高血脂症的患者中的血浆胆固醇和LDL-C水平。
(2)碱化剂
本发明中使用的碱化剂是用于提高非诺贝特酸或其可药用盐之溶解度的添加剂。所述碱化剂与非诺贝特酸或其可药用盐直接接触，在暴露于体内环境后，所述碱化剂可提高非诺贝特酸周围微环境的pH，从而提高非诺贝特酸的水溶性并因此提高其生物利用度。另外，所述碱化剂还提高非诺贝特酸或其可药用盐在低pH环境中的溶解度。
本发明中使用的碱化剂的代表性实例包括碱金属盐，例如钙盐(碳酸钙、氢氧化钙、磷酸氢钙、磷酸钙)、镁盐(碳酸镁、氢氧化镁、硅酸镁、氧化镁、铝酸镁、镁铝水合物(magnesium aluminum hydrate))、钾盐(氢氧化钾)、磷酸钠(碳酸氢钠、硼酸钠、碳酸钠、氢氧化钠)等。另外，还可使用碱性添加剂，例如葡甲胺(meglumine)、精氨酸及其混合物。更优选地，所述碱化剂可以是碳酸钙、碳酸镁、葡甲胺或其混合物。
可以以基于按重量计1份非诺贝特酸或其可药用盐的按重量计0.22至1份的量使用所述碱化剂。当所述碱化剂的量按重量计低于0.22份时，非诺贝特酸的水溶解度不能达到所期望的至少1000ppm的水平；并且当按重量计多于1份时，丸粒长轴与短轴的长度比超过1.5，这导致丸粒难以滚圆(spheronization)，从而导致形成不适合包衣过程的丸粒。
(3)延迟释放的包衣基质
可用延迟释放包衣基质对根据本发明的含有碱化剂的非诺贝特酸丸粒进行包衣。用此类延迟释放包衣基质包衣有助于所述丸粒以恒定速度释放药物直至丸粒达到高pH区，这使得在胃肠道中的吸收偏差最小化。
本发明中使用的延迟释放包衣基质包括水溶性聚合物或疏水化合物。
所述水溶性聚合物可选自邻苯二甲酸羟丙基甲基纤维素(hydroxypropylmethylcellulose phthalate，HPMCP)、聚乙酸乙烯酯(例如，KOLLICOAT SR 30D)、水不溶性聚甲基丙烯酸酯共聚物[例如，聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物(例如，Eudragit NE30D)、聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸三甲氨基乙基酯氯化物)共聚物(例如，Eudragit RSPO)等]、乙基纤维素、纤维素酯、纤维素醚、丙烯酸纤维素、二丙烯酸纤维素、三丙烯酸纤维素、乙酸纤维素、二乙酸纤维素、三乙酸纤维素及其混合物；优选选自以下的至少一种：邻苯二甲酸羟丙基甲基纤维素(HPMCP)、聚乙酸乙烯酯、聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物、聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸三甲氨基乙基氯化物)共聚物、乙基纤维素和乙酸纤维素；更优选选自以下的至少一种：邻苯二甲酸羟丙基甲基纤维素(HPMCP)、聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物、乙基纤维素和乙酸纤维素。
所述疏水化合物可选自脂肪酸、脂肪酸酯、脂肪酸醇、蜡、无机材料及其混合物。所述脂肪酸和脂肪酸酯可以是选自以下的至少一种：棕榈酰硬脂酸甘油酯、硬脂酸甘油酯、山嵛酸甘油酯、棕榈酸鲸腊酯、单油酸甘油酯和硬脂酸；所述脂肪酸醇可以是选自以下的至少一种：鲸蜡硬脂醇、鲸蜡醇和硬脂酸醇；所述蜡可以是选自以下的至少一种：巴西棕榈蜡、蜂蜡和微晶蜡；并且所述无机材料可以是选自以下的至少一种：滑石、沉淀碳酸钙、磷酸二钙、氧化锌、氧化钛、高岭土、膨润土、蒙脱石和硅酸镁铝(veegum)。所述疏水化合物可优选地选自以下的至少一种：棕榈酰硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸、鲸蜡醇和巴西棕榈蜡，更优选地，选自以下的至少一种：山嵛酸甘油酯、硬脂酸和巴西棕榈蜡。
可以以基于按重量计1份丸粒(包衣之前的丸粒)的按重量计0.05至0.5份的量使用所述延迟释放包衣基质作为芯。当延迟释放包衣基质的量低于按重量计0.05份时，无法获得期望的延迟释放作用；并且当按重量计多于0.5份时，经包衣丸粒的尺寸变得太大，从而导致形成尺寸太大的胶囊。
(4)滚圆添加剂
本发明中使用的滚圆添加剂用于制备丸粒和给出对其恒定的机械粘附性，通过控制长轴长度与短轴长度相近，所述丸粒具有接近于球形的形式。所述滚圆添加剂包括天然大分子，例如角叉菜胶、瓜尔胶、黄原胶(xanthane gum)、槐豆胶(locust bean gum)、吉兰糖胶(gellan gum)、阿拉伯胶、琼脂、藻酸、藻酸丙二醇酯、藻酸钠及其混合物。
可以以基于与所述芯对应的所述丸粒(包衣之前的丸粒)总重量的按重量计0.05至0.5％的用量使用所述滚圆添加剂。当以按重量计低于0.05％的量使用所述滚圆添加剂时，难以获得期望的滚圆作用；当以按重量计多于0.5％的用量使用所述滚圆添加剂时，发生不期望的延迟释放，或者由于所述滚圆添加剂在挤出过程中的粘着性，所述丸粒可黏附于生产设备。
另外，本发明的药物组合物还可包含合适量的可药用赋形剂，例如常规的崩解剂、稀释剂、稳定剂、粘合剂、润滑剂等。
本发明的药物组合物可以以丸粒形式口服施用，其制备方法包括以下步骤：(i)将非诺贝特酸或其可药用盐与碱化剂进行第一湿混合；(ii)向步骤(i)中获得的第一混合物中添加可药用赋形剂，并对它们进行第二湿混合；以及(iii)使用挤出机和滚圆机将步骤(ii)中获得的第二混合物制粒成球形。
任选地，在步骤(ii)中，所述方法还可包括向所述第一混合物中添加滚圆添加剂。此外，所述方法还可包括用延迟释放包衣基质对步骤(iii)中获得的颗粒进行包衣。
本发明的包含非诺贝特酸的口服药物组合物表现出提高的生物利用度和在胃肠道中的最小化吸收偏差，因此，所述药物组合物可用于治疗高血脂症和高甘油三酯血症。
以下实施例旨在进一步说明本发明而不限制其范围。
测试实施例1：非诺贝特酸、非诺贝特和非诺贝特胆碱的溶解度测试
将非诺贝特(Harman，印度)、非诺贝特酸(Harman，印度)和非诺贝特胆碱中的每一种以相当于100mg非诺贝特酸的量置于100mL瓶中。向其中添加蒸馏水和人工肠液(pH 6.8；USP)中的每一种至100mL，将混合物剧烈混合1小时，并使其通过0.45μm滤器，随后进行HPLC分析。化合物的溶解度(ug/ml)示于表1和图1中(分析方法：参见USP中的“Fenofibrate”)。
<表1>
从表1和图1中可见，非诺贝特几乎不溶于水或其他溶剂，而非诺贝特酸在水中的溶解度高于非诺贝特的溶解度，但低于非诺贝特胆碱的溶解度，表明上述化合物水溶解度的顺序为：非诺贝特胆碱＞非诺贝特酸＞非诺贝特。同时，非诺贝特酸和非诺贝特胆碱在pH 6.8下完全溶解，如它们1000ppm的溶解度所证明的那样。
作为参考，根据韩国生物等效性研究的指导原则(Korean Guidelinefor Bioequivalence Studies)，推荐用200至300mL(更优选240mL)水服用药物。此外，鉴于空腹状态下的胃液体积为约45mL并且在饱食状态中胃膨胀至高达1000mL(Sherwood，Lauralee(1997).Humanphysiology：from cells to systems.Belmont，CA：Wadsworth Pub.Co)，当主要成分的水溶解度变得不低于1000ppm时，可预期非诺贝特的高体内生物利用度，从而当在空腹状态下用200mL水服用时，可使存在于含有非诺贝特之胶囊(例如，)中的200mg非诺贝特充分溶解。
测试实施例2：原料的药物代谢动力学评价
将非诺贝特(Harman，印度)、非诺贝特酸(Harman，印度)和非诺贝特胆碱中的每一种以相当于88mg非诺贝特酸的量置于微胶囊中。通过使用探头(Sonde)向7周龄的SD大鼠(Sprague Dawley，Samtako，每组4只大鼠，7天，自由喂饲)口服施用所述微胶囊。以预先确定的时间间隔从大鼠中采集血液样品，并评价了各自的药物代谢动力学谱。结果见表2和图2。
<表2>
如表2和图2所证明的那样，吸收速度的顺序表现为非诺贝特胆碱＞非诺贝特酸＞非诺贝特，该顺序与测试实施例1中获得的在水中的溶解度一致，表明药物的水溶解度与吸收速率之间的相关性。
实施例1至9和比较例1至9：制备包含碱化剂的非诺贝特酸丸粒
为了提高非诺贝特酸周围微环境的pH，以表3中列出的量向一定量的水中添加非诺贝特酸和碱化剂并将其充分混合(第一湿混合)。随后，向其中添加聚维酮(BASF，德国)并将其充分混合(第二湿混合)以获得组合的混合物。使用挤出器(MG-55，Dalton)将所述化合物通过0.8mm网筛挤出，并使用滚圆器(滚圆器Q-230T，Dalton)滚圆3分钟，随后在60℃下干燥以获得丸粒。
<表3>
(单位：mg)
比较例10和11：制备不含碱化剂的非诺贝特酸丸粒
根据以下表4中列出的条件重复实施例1的过程，只是不使用碱化剂。
<表4>
(单位：mg)
实施例10至12：制备含有滚圆添加剂的非诺贝特酸丸粒
根据表5中列出的条件重复实施例1的过程，只是在第二湿混合时添加角叉菜胶(FMC生物聚合物)、瓜尔胶(Haji dossa)或藻酸丙二醇酯(ISP)作为滚圆添加剂。
<表5>
(单位：mg)
实施例3：根据碱化剂的量比较非诺贝特酸的溶解度
根据测试实施例1的过程，通过以相当于100mg非诺贝特酸的量使用实施例1至9和比较例1至11中制备的丸粒测量了非诺贝特的水溶解度(μg/mL)。结果见表6。
<表6>
从表6中可见，非诺贝特酸的溶解度随碱化剂用量的增加而升高。当碱化剂/非诺贝特酸的重量比不低于0.22时，丸粒的水溶解度超过本发明的目标水平(即，1000ppm)。结果表明，本发明的丸粒具有相当于非诺贝特胆碱的非诺贝特酸水溶解度，并且可具有提高的体内吸收速度。测试实施例4：评价滚圆度
测量了实施例1至12和比较例1至9中制备的丸粒的长轴短轴长度比(纵横比)。测量结果见表7和图3。
<表7>
纵横比是用于评价滚圆度的指标。接近1的纵横比意味着近似球形的形状。一般来说，当丸粒的形状接近球形时，可重现地进行包衣(例如，延迟释放包衣)操作，并且填充胶囊时产生的质量偏差降低，从而导致生产率提高(参见[Chopra R.等，Pharm.Dev.Technol.2002年1月；7(1)：59-68]和[Chopra R等，Eur.J.Pharm.Biopharm.2002年5月；53(3)：327-33])。相反，差的滚圆使包衣效率变差。尤其是当进行功能性包衣(例如，延迟释放包衣)时，发生包衣偏差，这使得难以可重现地生产制剂。纵横比的范围最优选1.0至1.2，且纵横比超过1.5的丸粒应当重新形成。
从表7和图3中示出的结果中可见，纵横比随碱化剂的量成比例地增加。尤其是比较例3、6和9中获得的包含碱化剂(其量为非诺贝特酸量的1.48倍)的丸粒显示出1.5或更大的纵横比，因此，它们不适用于包衣。然而，实施例10至12的使用天然聚合物滚圆添加剂(例如，角叉菜胶、瓜尔胶和藻酸丙二醇)的丸粒显示出提高的滚圆度。
因此，证明了碱化剂最优选的量为基于按重量计1份非诺贝特酸的按重量计0.22至1份。
实施例13：制备包含碱化剂的非诺贝特酸丸粒
重复实施例10的过程，只是以50mg的量使用碱化剂(碳酸镁)，以获得丸粒。
<表8>
(单位：mg)
| 实施例13 | |
| 非诺贝特酸 | 135 |
| 角叉菜胶 | 35 |
| 碳酸镁 | 50 |
实施例14至16：制备具有延迟释放包衣的非诺贝特酸丸粒
用延迟释放包衣基质(即，邻苯二甲酸羟丙基甲基纤维素(HPMCP，Shinetsu)、乙基纤维素(EC，Aqualon)或聚乙酸乙烯酯(PVA，BASF)，如下表9中所示)对实施例13中获得的作为芯的丸粒进行包衣。为了进行常规包衣，将延迟释放包衣基质溶于水与乙醇的混合物中，并向其中添加羟丙基甲基纤维素(HPMC，Shinetsu，Japan)和丙二醇(PEG)作为包衣基质。使用常规的流化床包衣机进行包衣过程，以获得包衣的丸粒。
<表9>
(单位：mg)
比较例12和13：制备非诺贝特酸片剂
如下表10中所示，将作为赋形剂的MCC(微晶纤维素，FMCBiopolymer)、乳糖(DMV pharmaceutical)和/或硬脂酸镁与作为碱化剂的碳酸镁混合，并且对所产生的混合物进行压片以获得包含非诺贝特酸和碱化剂的片剂。使用片剂包衣机用具有相同组成的包衣溶液对所述片剂进行包衣，如实施例14中所使用的那样(但包含EC作为延迟释放包衣基质)。
<表10>
(单位：mg)
| 比较例12 | 比较例13 | |
| 非诺贝特酸 | 105 | 105 |
| 乳糖 | 100 | 235 |
| MCC | 135 | |
| 碳酸镁 | 50 | 50 |
| 硬脂酸镁 | 2 | 2 |
| EC | 32 | 32 |
| HPMC | 12 | 12 |
| PEG | 6 | 6 |
| EtOH | 350 | 350 |
| 蒸馏水 | 35 | 35 |
测试实施例5：溶出度试验-(1)
使用USP桨II法测试了实施例13和14以及比较例10、12和13中获得的非诺贝特酸丸粒或片剂的溶出度(转速：50rpm)。考虑胃中的停留时间(即，1至2小时)设计溶出度试验。首先，在700ml 0.1N HCl中对丸粒或片剂进行2小时的溶出度试验，随后向其中添加300ml磷酸缓冲液，以使所述测试在等于人工肠液(pH 6.8，USP)的pH下继续(参见USP中“delayed-release dosage form”的溶出)。结果示于表11和图4中。
<表11>
从表11和图4中所示的结果中可见，比较例10中获得的既没有碱化剂也没有延迟释放包衣的丸粒在低pH下表现出非常低的溶出度，但由于非诺贝特酸相对高的溶解度，其溶出度在pH 6.8下急剧升高。因此，由于药物的低溶解度，预计在停留于低pH的胃中期间洗脱的药物的仅一部分可被吸收，而由于药物在其中的高溶解度，药物的吸收在高pH的小肠中将急剧升高。对于包含碱化剂的实施例13的丸粒而言，观察到了类似的结果，而由于存在碱化剂，药物在低pH下的溶解度显著升高。此外，对于实施例14中获得的还包含延迟释放包衣的丸粒，药物以恒定的速度缓慢地释放，而不论pH如何变化。预期这种释放模式可使胃肠道中的体内吸收偏差最小化。
测试实施例6：溶出度测试-(2)
根据与测试实施例5中相同的过程(不同处仅在于改变桨的旋转速度)对实施例14和比较例12中获得的非诺贝特酸丸粒或片剂的溶出度进行了测试。结果示于表12以及图5和图6中。
<表12>
从表12以及图5和图6中所示的结果可见，实施例14中获得的丸粒的溶出度基本上不受桨旋转速度改变的影响，而比较例12中获得之片剂的溶出度则受到强烈的影响。一般来说，可从根据桨旋转速度的溶出度变化来预测根据内部器官之运动程度的药物释放程度。因此，预期片剂(例如，比较例12中所获得的那些)会表现出体内溶出度的较大偏差。相反，预期丸粒(例如，实施例14中所获得的那些)表现出体内溶出度的较小偏差，因此，丸粒被认为是优选的制剂。
测试实施例7：药物代谢动力学评价
在比格犬中对比较例10以及实施例13和14中获得的非诺贝特酸丸粒进行了药物代谢动力学评价。向各自具有四只比格犬的三个组施用所述丸粒，并以固定的时间间隔采集其血样，以测量药物代谢动力学(pK)谱，结果示于表13和图7中。
<表13>
| 实施例14 | 实施例13 | 比较例10 | |
| AUC 0-24(ng.hr/ml) | 74366.9±19893 | 64104.1±27882 | 42565.3±18192 |
| Cmax(ng/ml) | 15642.4±3894 | 13529.1±6998 | 9067.4±4453 |
| AUC(标准差/平均值) | 27％ | 43％ | 43％ |
| Cmax(标准差/平均值) | 25％ | 52％ | 49％ |
如表13和图7中所示，实施例13中获得的包含碱化剂的非诺贝特酸丸粒表现出比比较例10中获得的丸粒更高的吸收速率。同时，由于首先在胃中吸收并且随后在小肠中吸收，实施例13中获得的丸粒表现出双重pK谱。相反，实施例14中获得的还具有延迟释放包衣的丸粒表现出平衡且高的吸收速率。此外，应当理解，根据每个AUC和Cmax的标准差(S.D.)与平均值的比值，实施例14的具有延迟释放包衣的丸粒在胃和小肠中在pK方面具有小的偏差。该结果证明本发明的丸粒将在治疗高脂血症和高甘油三酯血症中极为有用。
虽然已针对上述具体实施方案描述了本发明，但应当承认，本领域技术人员可对本发明进行多种修改和改变，其也落入由所附权利要求所限定的本发明的范围之中。
Claims (16)
1.一种口服药物组合物，其包含非诺贝特酸或其可药用盐和碱化剂。
2.权利要求1的组合物，其中以基于按重量计1份非诺贝特酸的按重量计0.22至1份的量使用所述碱化剂。
3.权利要求2的组合物，其为丸粒的形式。
4.权利要求1的组合物，其中所述碱化剂选自：碳酸钙、氢氧化钙、磷酸氢钙、磷酸钙、碳酸镁、氢氧化镁、硅酸镁、氧化镁、铝酸镁、镁铝水合物、氢氧化锂、氢氧化钾、碳酸氢钠、硼酸钠、碳酸钠、氢氧化钠及其混合物。
5.权利要求1的组合物，其中所述碱化剂是碳酸钙、碳酸镁、葡甲胺或其混合物。
6.权利要求3的组合物，其还包含滚圆添加剂。
7.权利要求6的组合物，其中所述滚圆添加剂选自：角叉菜胶、瓜尔胶、黄原胶、槐豆胶、吉兰糖胶、阿拉伯胶、琼脂、藻酸、藻酸丙二醇酯、藻酸钠及其混合物。
8.权利要求6的组合物，其中以基于所述丸粒总重量的按重量计0.05至0.5％的量使用所述滚圆添加剂。
9.权利要求3的组合物，其中所述丸粒还用延迟释放包衣基质进行包衣。
10.权利要求9的组合物，其中所述延迟释放包衣基质是水不溶性聚合物或疏水化合物。
11.权利要求10的组合物，其中所述延迟释放包衣基质选自邻苯二甲酸羟丙基甲基纤维素(HPMCP)、乙基纤维素、聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物、乙酸纤维素及其混合物。
12.权利要求9的组合物，其中以基于按重量计1份包衣之前丸粒的按重量计0.05至0.5份的量使用所述延迟释放包衣基质。
13.权利要求3的组合物，其中所述丸粒具有1.0至1.5的长轴与短轴长度比。
14.一种制备权利要求3的组合物的方法，其包括以下步骤：
(i)将非诺贝特酸或其可药用盐与碱化剂进行第一湿混合；
(ii)向步骤(i)中获得的第一混合物中添加可药用赋形剂，并对它们进行第二湿混合；以及
(iii)使用挤出机和滚圆机将步骤(ii)中获得的第二混合物制粒成球形。
15.权利要求14的方法，其在步骤(ii)中还包括向所述第一混合物中添加滚圆添加剂。
16.权利要求14的方法，其还包括用延迟释放包衣基质对步骤(iii)中获得的颗粒进行包衣。
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020100033497A KR101202994B1 (ko) | 2010-04-12 | 2010-04-12 | 페노피브린산 및 알칼리화제를 포함하는 경구용 약학 조성물 |
| KR10-2010-0033497 | 2010-04-12 | ||
| PCT/KR2011/002560 WO2011129579A2 (en) | 2010-04-12 | 2011-04-12 | Oral pharmaceutical composition comprising fenofibric acid and an alkalifying agent |
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| EP (1) | EP2558077B1 (zh) |
| JP (1) | JP5685641B2 (zh) |
| KR (1) | KR101202994B1 (zh) |
| CN (1) | CN102858325A (zh) |
| ES (1) | ES2626181T3 (zh) |
| WO (1) | WO2011129579A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103877064A (zh) * | 2014-04-11 | 2014-06-25 | 白玲强 | 一种非诺贝特胶囊剂及其制备工艺 |
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| KR20150100826A (ko) * | 2012-12-21 | 2015-09-02 | 메르크 파텐트 게엠베하 | 활성 성분 방출이 개선된 약학 제제 중의 부형제로서의 수산화탄산마그네슘 |
| KR20160148385A (ko) | 2015-06-16 | 2016-12-26 | 삼성전기주식회사 | 웨이크업 검출 회로 및 그를 이용한 전자 가격 표시기 |
| KR102081095B1 (ko) * | 2018-04-24 | 2020-02-25 | 한국유나이티드제약 주식회사 | 페노피브릭산 또는 이의 약학적으로 허용 가능한 염을 포함하는 장용성 코팅 정제 |
| KR102216579B1 (ko) * | 2020-01-23 | 2021-02-17 | 한국유나이티드제약 주식회사 | 페노피브릭산 또는 이의 약학적으로 허용 가능한 염을 포함하는 장용성 코팅 정제 |
| KR102501636B1 (ko) * | 2021-12-07 | 2023-02-21 | 에이스바이오팜 주식회사 | 페노피브린산을 포함하는 경구용 정제 및 이의 제조방법 |
| KR20240084229A (ko) * | 2022-12-06 | 2024-06-13 | 유노비아 주식회사 | 안정성이 향상된 gpr40 효현제를 유효성분으로 포함하는 약제학적 조성물 |
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| CN103877064B (zh) * | 2014-04-11 | 2016-04-27 | 白玲强 | 一种非诺贝特胶囊剂及其制备工艺 |
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| WO2011129579A2 (en) | 2011-10-20 |
| US20130022684A1 (en) | 2013-01-24 |
| JP2013523878A (ja) | 2013-06-17 |
| WO2011129579A3 (en) | 2012-02-02 |
| ES2626181T3 (es) | 2017-07-24 |
| KR20110114073A (ko) | 2011-10-19 |
| EP2558077A4 (en) | 2014-01-01 |
| EP2558077B1 (en) | 2017-03-01 |
| KR101202994B1 (ko) | 2012-11-21 |
| JP5685641B2 (ja) | 2015-03-18 |
| EP2558077A2 (en) | 2013-02-20 |
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