CN1112929C - 含有咪唑拉汀的缓释药物制剂 - Google Patents

含有咪唑拉汀的缓释药物制剂 Download PDF

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CN1112929C
CN1112929C CN97192804A CN97192804A CN1112929C CN 1112929 C CN1112929 C CN 1112929C CN 97192804 A CN97192804 A CN 97192804A CN 97192804 A CN97192804 A CN 97192804A CN 1112929 C CN1112929 C CN 1112929C
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mizolastine
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M·查里奥特
G·勒维斯
J·蒙特尔
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Abstract

含有咪唑拉汀的缓释药物制剂，其特征在于该制剂包括由缓释药片构成的芯，该缓释药片含有与脂肪基料和有机酸配合的咪唑拉汀，所述的药片被涂敷。

Description

含有咪唑斯汀的缓释药物制剂
技术领域
本发明涉及含有2-[[1-[1-[(4-氟苯基)甲基]-1H-苯并咪唑-2-基]哌啶-4-基]甲基氨基]嘧啶-4-醇或2-[[1-[1-[(4-氟苯基)甲基]-1H-苯并咪唑-2-基]哌啶-4-基]甲基氨基]嘧啶-4(1H)-酮或咪唑斯汀作为活性组分的新的缓释药物制剂。
背景技术
咪唑斯汀(mizolastine)在欧洲专利EP 0217700中作过描述。
咪唑斯汀与组胺受体H1相结合，可在体外和体内抑制肥大细胞的去粒作用。因此，它可用来治疗呼吸、皮肤或眼的变态反应和各种变态反应症状。
当口服即刻释放的含有咪唑斯汀的制剂时，观察到不希望有的与存在高的血浆峰相关的镇静作用。
发明内容
因此，必须寻找口服制剂，这些制剂具有的活性组分释放曲线能够达到不高的血浆峰又不降低生物利用率。
本申请人根据咪唑斯汀溶解动力学研究结果寻找过这样一些制剂。事实上，咪唑斯汀是一种弱碱(pK5.6)，它在水中不太溶解(在中性pH，13毫克/升)而在酸性pH溶解高得多(在pH3时11克/升)；头等胶囊剂在pH2溶解介质中在30分钟内释放100％咪唑斯汀，而在pH6.8仅溶解40％。
另外，由本发明的缓释药物形式释放咪唑斯汀不应受到胃-肠道中pH不同的影响。
本发明的目的是提供含有咪唑斯汀的制剂，其溶解曲线如下：
-在1小时溶解约30-70％咪唑斯汀，
-在3-5小时溶解100％咪唑斯汀，
-曲线与pH无关。
本申请人指出，包含一种由缓释药片构成的芯的片剂特别满意，而所述缓释药片含有与脂肪基料和有机酸配合的咪唑斯汀，所述药片被包衣，以避免产品在光的作用下发生降解。
本发明的片剂含有1-25毫克咪唑斯汀。这些剂量相应于浓度为0.5-12％(重量)咪唑斯汀。
脂肪基料是用氢化蓖麻油或用氢化卵磷脂或长链脂肪酸(例如C12-C28脂肪酸，像山嵛酸)，或用如C8-C18脂肪酸之类的中等链的脂肪酸酯化的三甘油酯制备的。
有机酸的pK优选地等于或高于2，它可选自呈外消旋物或异构体状的马来酸、酒石酸、苹果酸、富马酸、乳酸、柠檬酸、己二酸、琥珀酸。根据本发明，特别优选的酸是L-酒石酸。
咪唑斯汀与有机酸的重量比应该是0.3-1。使用L-酒石酸时，这个比例优选地是等于0.5。
这些片剂可由活性组分、脂肪基料的组成剂、有机酸和其他赋形剂经制粒而制成，所述赋形剂例如像乳糖、甘露糖醇和蔗糖或类似的糖-醇、微晶纤维素、淀粉、磷酸钙和硫酸钙、聚乙烯吡咯烷酮、取代的纤维素，如羟丙基纤维素、羟丙基甲基纤维素或甲基纤维素。
可以例如在水或醇存在下以潮湿相进行制粒，或者采用熔融或采用压实制粒。制粒步骤可以任选地缩减，也可以采用直接压制咪唑斯汀和赋形剂的混合物制备片剂。
可以往所得到的颗粒中添加无水硅胶和硬脂酸镁，并压制该混合物。然后这些片在一种空气流化床设备中或者在涂敷涡轮机中通过喷洒涂层溶液而包一层涂层薄膜。
具体实施方式
下述实施例说明本发明而不限制其保护范围：
片剂                                 ％(重量)
咪唑斯汀                                4.8
氢化蓖麻油                              12.0
乳糖                                    60.0
微晶纤维素                              9.6
L-酒石酸                                9.6
聚乙烯吡咯烷酮                          2.9
无水硅胶                                0.2
硬脂酸镁                                0.9
已纯化的水                              适量
总量                             100.0
包衣液
甲基羟丙基纤维素                 74.0
二氧化钛(E171)                   18.5
丙二醇                           7.5
已纯化的水                       适量
总量                             100.0
用本发明制剂所得到的溶解曲线示于图1中。
该曲线给出在1小时约50％产品溶解，在3-5小时100％产品溶解，其产品溶解与pH无关。
与本发明相同制剂但不含有L-酒石酸的溶解曲线示于图2。
与含有10毫克即刻释放的标准胶囊剂相比，研究过健康志愿者一次口服含有10毫克本发明药剂后的血浆动力学。
表1列出了动力学参数，而图3给出了分别用每个制剂得到的血浆动力学曲线；用本发明药物形式得到的血浆动力学能够避免任何血浆峰又不损失生物利用率。
还研究了与没有L-酒石酸的同样制剂相比的本发明药物形式的血浆动力学。
研究了十二位健康志愿者在一次口服含有10毫克咪唑斯汀的本发明片剂或没有L-酒石酸的同样片剂后的情况。
表2表明不含有L-酒石酸制剂的生物利用率仅仅是用含有L-酒石酸的本发明制剂所观察到的生物利用率的43％。含有L-酒石酸制剂的Cmax和AUC值(0-∞)比不含有L-酒石酸的制剂分别高1.5与2倍。
另外，对于含有L-酒石酸的制剂，极小-极大可变性指数小得多，这可认为释放非常有规律。
全部结果表明本发明的制剂具有：
-溶解曲线与pH无关，
-体内释放避免任何血浆蜂，
-与即刻释放的制剂相比生物利用率没有降低，
-血浆动力学结果可变性比较低。

Claims (9)

1、包衣的缓释药片，该药片基本上由咪唑斯汀、脂肪基料、有机酸和包衣组成，该包衣的药片的溶解曲线与胃-肠道中的pH无关，所述脂肪基料选自氢化蓖麻油、氢化卵磷脂、C12-C28脂肪酸、用一种、两种或三种C8-C18脂肪酸酯化的三甘油酯，所述有机酸选自呈外消旋体或异构体状的马来酸、酒石酸、苹果酸、富马酸、乳酸、柠檬酸、己二酸和琥珀酸，其中咪唑斯汀与有机酸的重量比是0.3-1。
2、根据权利要求1所述的包衣的缓释药片，其中该药片含有0.5-12％重量的咪唑斯汀，以及咪唑斯汀与有机酸的重量比为0.3-1。
3、根据权利要求1所述的包衣的缓释药片，其中该药片进一步含有赋形剂，该赋形剂选自乳糖、甘露糖醇、微晶纤维素、淀粉、磷酸钙、硫酸钙、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素和甲基纤维素。
4、根据权利要求1所述的包衣的缓释药片，其中有机酸是L-酒石酸。
5、根据权利要求4所述的包衣的缓释药片，其中咪唑斯汀与L-酒石酸的重量比是0.5。
6、根据权利要求1所述的包衣的缓释药片，其中该药片含有1-25毫克咪唑斯汀。
7、根据权利要求1所述的包衣的缓释药片，其中该药片含有4.8％重量的咪唑斯汀、12％重量的氢化蓖麻油、60％重量的乳糖和9.6％重量的L-酒石酸。
8、根据权利要求7所述的包衣的缓释药片，其中该药片进一步含有9.6％重量的微晶纤维素。
9、根据权利要求1所述的包衣的缓释药片，其中该药片含有：
                                           重量％
咪唑斯汀                                   4.8
氢化蓖麻油                                 12.0
乳糖                                       60.0微晶纤维素                               9.6L-酒石酸                                 9.6聚乙烯吡咯烷酮                           2.9无水硅胶                                 0.2硬脂酸镁                                 0.9已纯化的水                               适量总量                                     100.0，该药片被以下物质包衣：
                                     重量％甲基羟丙基纤维素                         74.0二氧化钛                                 18.5丙二醇                                   7.5已纯化的水                               适量总量                                     100.0。
CN97192804A 1996-03-04 1997-02-28 含有咪唑拉汀的缓释药物制剂 Expired - Lifetime CN1112929C (zh)

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FR9602662A FR2745500B1 (fr) 1996-03-04 1996-03-04 Formulations pharmaceutiques a liberation prolongee contenant de la mizolastine
FR96/02662 1996-03-04

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CN1212624A (zh) 1999-03-31
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US20050202089A1 (en) 2005-09-15
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EP0906101B1 (fr) 2002-06-19
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HU227472B1 (en) 2011-07-28
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