CN1146427C - 含有二甲双胍和格列本脲的固体口服剂型 - Google Patents
含有二甲双胍和格列本脲的固体口服剂型 Download PDFInfo
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Abstract
本发明涉及含有二甲双胍和格列本脲联合的固体口服剂型,其中格列本脲的颗粒大小是这样的,即能够使格列本脲的生物利用度相当于分开服用二甲双胍和格列本脲所获得的格列本脲生物利用度。
Description
本发明涉及治疗非胰岛素依赖型糖尿病的固体口服剂型。
非胰岛素依赖型糖尿病是一种特征为血糖过多的代谢性疾病,血糖过多的出现是由于胰岛素的缺乏、胰岛素的耐性和降低了的葡萄糖耐受性引起的。
目前可得到的口服抗糖尿病的药物有两大类:它们是磺酰脲类和双胍类。磺酰脲类是通过刺激胰岛素的释放起作用的并且这样只对一些残余的胰腺β-细胞的活性有效。可得到的磺酰脲类的例子有格列本脲、格列齐特、甲苯磺丁脲、格列吡嗪、甲磺氮卓脲、格列喹酮和氯磺丙脲。双胍类如二甲双胍是通过降低葡糖异生作用并且增加葡萄糖的外周利用率起作用的,当它们需要内源性胰岛素时,它们仅对一些残余的胰岛细胞活性有效。
最初对非胰岛素依赖性糖尿病的疗法包括饮食控制和锻炼。只有在这些疗法不够时使用口服抗糖尿病药物。用口服抗糖尿病药物的单一疗法能够有效治疗许多年。但是,随着时间疗效下降。由于磺酰脲类和双胍类具有互补的作用机理,现在联合疗法是一种已经建立起来治疗非胰岛素依赖性糖尿病的治疗形式。
为了改善患者的适应性,联合片剂将会是有益的。本发明涉及含有二甲双胍和格列本脲(又称优降糖)联合的固体口服剂型。
WO 97/17975中已经公开了以特定比例的二甲双胍和格列本脲联合使用治疗II型糖尿病,这种特定的比例为了获得理想的治疗作用是必需的。这篇现有技术把盐酸二甲双胍与格列本脲的理想疗效比例限定为100∶1,例如在单一剂量单位中有500mg的盐酸二甲双胍和5mg的格列本脲。这种比例考虑到了每日剂量的范围,以增加每天所服用的片数为基础,这样避免了当需要共同给药时任何一种组份服用不够的较差病情控制,并且也避免了当这样共同给药时过量服用任何一种组份引起的低血糖。对希望用联合制剂治疗患者的医生来说确保临床中的可操作性是主要的要求,而这种可操作性将来自于使产品具有格列本脲组份的适当生物利用度。适当的生物利用度意思是相对于相同强度的单一完整制剂把格列本脲给药时同时二甲双胍也以单一完整制剂给药时,与二甲双胍一起配制到联合片中的5mg的格列本脲会被吸收到可接受的相似程度,并且是以可比较的速率吸收的。
这篇现有技术没有教导怎样与格列本脲一起配制二甲双胍的联合产品以确保格列本脲组份的适当生物利用度。在盐酸二甲双胍高水溶性情况下而在这方面没有说明并因此也没有进一步讨论联合制剂的二甲双胍的生物利用度。但是,考虑到格列本脲是溶解性较差的药物(在25℃下水中的溶解度为0.1mg/ml-按USP定义是不溶的),所以这是非常重要的需考虑方面。
因此,在剂型给药后它的溶解速率将会影响整个药物进入血流中的速率和程度(生物利用度)。对适当的治疗作用来说,控制整个药剂进入血流中的速率和程度是重要的。
总之,文献公开了两种活性成分在单一剂型中的适当比例,目的是设计怎样使两种单个组份能理想地共同给药(基于按照与当前可得到的单一完整制剂相关的通常实践应当怎样把它们给药),它没有教导就格列本脲的生物利用度方面怎样确保这种联合制剂将会实现。这种生物利用度应当尽可能地与共同服用相当剂量的两种单一完整剂型时的相似。
此外,当用标准制剂步骤制备的联合片中用联合片剂中的常规一般格列本脲进行使用时,相对于共同处方的情况下降的生物利用度是显而易见的。
现通过体外和体内试验发现降低的生物利用度是与格列本脲的颗粒大小和颗粒大小的分布有关。现已发现太小的颗粒会导致格列本脲的高血液浓度,造成低血糖的危险并且太大的颗粒不能足够快速溶解从而给出与共同处方情况的相当生物利用度。所以,在联合形式中具有一个狭窄限定的颗粒大小分布是必需的。
选择特殊大小部分的格列本脲能够生产出含有二甲双胍和格列本脲的固体口服剂型,特别是片剂,当通过体内分析曲线下区域判断时,该剂型具有与分开服用二甲双胍和格列本脲所得到的生物利用度相当的格列本脲生物利用度。
本发明具体提供了含有二甲双胍和格列本脲联合的片剂,该片剂具有与一起服用片剂相当的格列本脲生物利用度。
在第一个实施例中,本发明的固体剂型如片剂含有联合的格列本脲和二甲双胍,其中格列本脲的大小是这样的,即至多10%的颗粒大小小于2μm并且至多10%的颗粒大于60μm。优选格列本脲的大小是这样的,即至多10%的颗粒大小小于3μm并且至多10%的颗粒大于40μm。这种特殊颗粒大小范围的格列本脲可以通过筛选或空气喷射磨得到。
在第二个实施例中,固体口服剂型含有联合的二甲双胍和格列本脲,其中格列本脲的大小是这样的,即至多25%的颗粒小于11μm并且至多25%的颗粒大于46μm。
优选的是,50%的颗粒小于23μm。
二甲双胍可以用其一种盐,如盐酸盐、延胡索酸盐、氢溴酸盐、对氯苯氧基乙酸盐或双羟萘酸盐。二甲双胍盐与格列本脲的重量比应当优选在50/1到250/1。
下列表中给出了优选的口服剂型组分,提供的是组份的范围:
组份用量 每片mg | |||
产品的一致性 | 500/5 | 500/2.5 | 250/1.25 |
组份 | |||
盐酸二甲双胍 | 500.0 | 500.0 | 250.0 |
格列本脲 | 5.00 | 2.50 | 1.25 |
交联羧甲基纤维素钠 | 6.0-30.0 | 6.0-30.0 | 3.0-15.0 |
微晶纤维素 | 30.0-120.0 | 30.0-120.0 | 15.0-60.0 |
聚乙烯吡咯烷酮 | 6.0-36.0 | 6.0-36.0 | 3.0-18.0 |
硬脂酸镁 | 0.6-15.0 | 0.6-15.0 | 0.3-7.5 |
包衣膜* | 9.0-24.0 | 9.0-24.0 | 4.5-12.0 |
*使用商业上可得到的包衣膜组合物,如Opadry(Colorcon,UK)。
下列是特别优选的组合物:
组份用量 每片mg | |||
产品的一致性 | 500/5 | 500/2.5 | 250/1.25 |
组份 | |||
盐酸二甲双胍 | 500.0 | 500.0 | 250.0 |
格列本脲 | 5.00 | 2.50 | 1.25 |
交联羧甲基纤维素钠 | 14.0 | 14.0 | 7.0 |
微晶纤维素 | 54.0 | 56.5 | 28.25 |
聚乙烯吡咯烷酮 | 20.0 | 20.0 | 10.0 |
硬脂酸镁 | 1.2-12.0 | 1.2-12.0 | 0.6-6.0 |
包衣膜* | 9.0-24.0 | 9.0-24.0 | 4.5-12.0 |
*使用商业上可得到的包衣膜组合物,如Opadry(Colorcon,UK)。
本发明的片剂可以通过下列步骤获得,其包括:
a)把二甲双胍和格列本脲混合物用湿制粒法制成颗粒;
b)用片剂助剂和稀释剂混合进颗粒中,并且
c)把这样得到的混合物压制成片。
有益的是用来形成颗粒的混合物含有颗粒粘合剂。这种颗粒粘合剂特别是聚乙烯吡咯烷酮如具有分子量为45,000的聚乙烯吡咯烷酮。可以使用最终片剂重量的2到4%的聚乙烯吡咯烷酮。
制粒步骤后,把颗粒筛分并干燥。
然后把颗粒与稀释剂和片剂助剂混合。稀释剂可以是制片中常用的任何物质如微晶纤维素。片剂助剂可以是制片常用的任何物质如硬脂酸镁。
然后把这样得到的片用亲水的纤维素聚合物和滑石粉包衣。亲水的纤维素聚合物可以是2-羟丙基甲基纤维素。
下列实施例和试验用来进一步说明本发明。
实施例1
现已按照下列方法制备了二甲双胍/格列本脲片:
用搅拌器把66.6g的聚乙烯吡咯烷酮与246g纯化水混合。在制粒机中混合1500g盐酸二甲双胍、7.5g格列本脲(10-90%的大小范围在2到60μm)、42g交联羧甲基纤维素钠和284.4g微晶纤维素。向制粒机中加入聚乙烯吡咯烷酮溶液并制成湿团块。挤压该颗粒通过1mm目。把该颗粒注入预热的流化床干燥器上并干燥颗粒。用转式混合机把97.5g微晶纤维素混合到颗粒中。把12g硬脂酸镁加入到转式混合机中混合。用适当的压片机压制颗粒混合物成片。在包衣机中用2%羟丙基甲基纤维素包衣剂给片包衣。
实施例2
现已按照下列方法制备二甲双胍/格列本脲片:
把5.83g格列本脲(10-90%的大小范围在2到60μm)与32.67g的交联羧甲基纤维素钠预混合。伴随搅拌把46.67g聚乙烯吡咯烷酮与93.33g纯化水混合。在制粒机中混合格列本脲-交联羧甲基纤维素钠混合物和1166.6g盐酸二甲双胍。向制粒机中加入聚乙烯吡咯烷酮溶液并制成湿颗粒。把颗粒倒入预热的流化床干燥器中干燥颗粒。通过让颗粒通过1mm目来降低颗粒的大小。在制粒机中把131.83g微晶纤维素混入颗粒中。向制粒机中加入16.3g硬脂酸镁并混合。用适当的压片机把颗粒混合物压制成片。在包衣机中用2%羟丙基甲基纤维素包衣剂包衣片。
试验1
用实施例2中制备的两批格列本脲片进行体内生物利用度试验。这两批具有下列10到90%颗粒大小的范围:
A批:3.47-38.08μm
B批:15.63-91.6μm。
图1中详细说明了A和B两批颗粒大小的分布。
把这两批片给健康患者服用并与共同服用格列本脲(市售商标Daonil)和盐酸二甲双胍(每组16名患者)比较。
图2和3分别显示了格列本脲在含有二甲双胍分别和A批和B批的格列本脲联合及共服用的片剂中的对照浓度。
下面是曲线(AUC)下区域:
AUC(ng/ml/h)
与A批联合 790.5
与B批联合 353.0
共同服用 869.3
这显示了使用与A批组合时,AUC实际上与共同服用时的相同,其中使用与B批组合时,AUC较明显地不同。
试验2
一系列的盐酸二甲双胍和格列本脲结合的片剂(用制剂Combo 1、2、3和4区分)除了所用的格列本脲的颗粒大小特征外制剂都是一样的。将它们给药后,仔细检测患者血液中格列本脲的浓度,与商业上可得到的一起给药的盐酸二甲双胍(GlucophageTM,Bristol-MyersSquibb)和格列本脲(MicronaseTM,Upjohn)参照制剂相比,可以确定确保联合制剂中格列本脲组份的适当生物利用度的格列本脲颗粒特征。这指的是在使用现有的单一药物之一治疗的医生知识基础上,当患者首次用这种联合制剂治疗时疾病的控制是可以预料的。
或者,如果患者已经通过如MicronaseTM的商品治疗加上用GlucophageTM的现存治疗(或者相反)稳定了它们的疾病的话,然后进行更方便的单一片剂的联合治疗(且确保优降糖组份的适当生物利用度)将会导致维持的疾病控制的理想水平。
来自用不同颗粒大小特征配置的盐酸二甲双胍/格列本脲片试验中的数据可以开发出药物颗粒大小和体内性能之间的关系。所用的一系列联合片剂中使用许多优降糖的特性显示在下表中:
格列本脲颗粒大小 (微米) | |||
片剂批量 | 25%下面大小的 | 50%下面大小的 | 75%下面大小的 |
Combo 1 | 15 | 33 | 62 |
Combo 2 | 28 | 58 | 88 |
Combo 3 | 10 | 25 | 52 |
Combo 4 | 6 | 11 | 19 |
当用这些多种格列本脲的每种制备四种组合-相同的单批盐酸二甲双胍/优降糖500/2.5mg的片并给人服用时,对格列本脲血浆浓度-时间曲线的分析发现了下列药物动力学参数:
格列本脲的药物动力学参数 | ||||
片剂批量 | Cmax(ng/ml,几何平均值) | AUC(ng/ml/hr,几何平均值) | Cmax(ng/ml,数学平均值) | AUC(ng/ml/hr,数学平均值) |
Combo 1 | 71 | 478 | 76 | 493 |
Combo 2 | 52 | 345 | 54 | 339 |
Combo 3 | 64 | 513 | 67 | 531 |
Combo 4 | 88 | 642 | 93 | 716 |
能够得出颗粒大小和所达到的格列本脲最大几何平均血浆浓度,Cmax之间的合理的相互关系以及颗粒大小与格列本脲血浆浓度-时间曲线AUC下几何平均值区域之间合理的相互关系。
从这些相互关系中,对用于体内试验研究中的参照格列本脲制剂MicronaseTM的批量来说可给出预期的Cmax和AUC值±25%的平均值的优降糖的颗粒大小可被界定:
25%颗粒大小的限
50%颗粒大小的限
75%颗粒大小的限
Cmax <0-18微米 <0-37微米 <0-63微米
AUC <0-11微米 <0-25微米 <0-46微米
适应Cmax和AUC的要求,设计的界限变为:
25%颗粒大小的限
50%颗粒大小的限
75%颗粒大小的限
<11微米 <23微米 <46微米
具有这些颗粒大小特征的格列本脲粉末的表面区数值在1.7到2.2m2g-1的范围,这正如用氮吸收法所测定的。所以,如试验中所述配制时这些特征的物质不同于US 3,979,520中所公开的物质,在US3,979,520中要求格列本脲的粉末表面区域数值大于3m2g-1(优选5到10m2g-1)以得到适当的格列本脲生物利用度。在试验中格列本脲颗粒大小特征已经详细描述,当按照这里所述的配制能够产生使人适当的格列本脲生物利用度,这正如在下列试验中所述的。
试验3
按照下列方法制备一批盐酸二甲双胍-格列本脲片500/5g。把上述所定义的大小的格列本脲(1.0kg)与2.8kg的交联羧甲基纤维素钠滚动混合,然后在高速剪切混合机中把该混合物与已经向其中加入0.5%(重量)硬脂酸镁的盐酸二甲双胍(100g)混合。
在高速剪切混合机中把该干燥混合物用12.1kg聚乙烯吡咯烷酮的水溶液(含有4kg聚乙烯吡咯烷酮)制成湿颗粒。在60℃的流化床干燥器中干燥该湿颗粒到规定的湿度含量。在振摇器(1.0mm筛孔)中把干燥(干燥损失2-3%w/w)颗粒大小减小,然后与10.8kg微晶纤维素滚动混合,接着与0.9kg片剂润滑剂硬脂酸镁混合。用16mm×8mm胶囊形状的工具把润滑过的颗粒压制并用专卖的膜包衣物质Opadry 32920给片芯包膜得到最终的黄色、胶囊状的片。在人的药物动力学研究中,给自愿者或者服用这些片中的一种或者用一种疗法,即共同服用500mg GlucophageTM片加5mg MicronaseTM片。给药后分析格列本脲的血浆浓度并发现该组份的下列药物动力学:
疗法 | 参数 | 平均值 | 调节的几何平均值 | 平均值之比(评估分) |
联合片500/5 | Cmax | 122 | 116 | 1.14 |
AUC(O-T) | 859 | 831 | 1.07 | |
Glucophage+Micronase | Cmax | 113 | 101 | - |
AUC(O-T) | 842 | 780 | - |
从联合片中得到的格列本脲的生物利用度相当于从参照的格列本脲制剂MicronaseTM中获得的。这将使得患者更方便地服用联合片剂来替代现在疗法中共用的两种片,并且不用担心将会造成较低的格列本脲血液浓度的结果,这种结果可能在现有制剂中出现并导致疾病控制的失败。
实施例3
把按照试验3所制备的颗粒填入大小为00号胶囊中来替代压制成片,从而提供盐酸二甲双胍/格列本脲500mg/5mg的产品或者提供500mg/2.5mg的产品。把颗粒填入大小为1号胶囊以提供250mg/2.5mg的产品。
这些胶囊具有可接受的生理特性并提供了片剂外的另一种选择。在WO 97/17975中所述的制剂中由于按照他们的描述,制剂使用了大量的赋型剂而不能填入对大多数患者可接受的大小的胶囊。
Claims (7)
1.含有二甲双胍和格列本脲联合的固体口服剂型,其中格列本脲的颗粒大小为至多10%的颗粒小于2μm并且至多10%的颗粒大于60μm。
2.权利要求1的固体口服剂型,其中格列本脲的颗粒大小为至多10%的颗粒小于3μm并且至多10%的颗粒大于40μm。
3.权利要求1的固体口服剂型,其中格列本脲的颗粒大小为至多25%的颗粒小于11μm并且至多25%的颗粒大于46μm。
4.权利要求1的固体口服剂型,其中50%的颗粒小于23μm。
5.权利要求1-4中任一项要求的固体口服剂型,其中二甲双胍是以二甲双胍盐存在的并且二甲双胍盐与格列本脲的重量比为50/1到250/1。
6.权利要求1的固体口服剂型,它是片剂。
7.制备权利要求6所要求的固体口服剂型的方法,其包括:
a)把二甲双胍和格列本脲混合物用湿制粒法制成颗粒;
b)压片助剂与颗粒混合;
c)把这样得到的混合物压制成片。
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