CN101352421A - 一种制备基本上非结晶形式的替米沙坦的方法 - Google Patents
一种制备基本上非结晶形式的替米沙坦的方法 Download PDFInfo
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Abstract
本发明涉及一种制备基本上非结晶形式的替米沙坦的方法,包括a)制备包含替米沙坦以及至少一种碱性试剂的水溶液;b)喷雾干燥所述的含水溶液以得到喷雾干燥的颗粒。
Description
本申请是中国发明申请(发明名称:含有替米沙坦和利尿剂的双层药片及其制备方法;申请号:02827182.3;申请日:2002年01月16日)的分案申请。
发明领域
本发明涉及一种双层药片制剂,其含有血管紧张素II受体拮抗剂替米沙坦和利尿剂,如氢氯噻嗪(HCTZ)。本发明还提供了制备所述双层药片剂的方法。
背景技术:
EP-A-502314公开了INN替米沙坦是血管紧张素II受体拮抗剂,可开发用于治疗高血压和其它医学适应症。
替米沙坦的化学名称是4’-[2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基甲基]-联苯-2-羧酸,具有下式结构:
替米沙坦通常以游离酸的形式被制备和供给,其缺点是,在胃肠道的生理pH范围值1到7之间的水性系统中溶解性很差。如WO 00/43370所公开的,结晶态的替米沙坦存在两种具有不同熔点的多晶型。在热度和湿度的影响下,较低熔点的多晶型B不可逆的转变成高熔点的多晶型A。
氢氯噻嗪(HCTZ)是一种口服给药治疗水肿和高血压的噻嗪类利尿剂。
HCTZ的化学名是6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺酰胺-1,1-二氧化物,结构如下:
发明目的:
替米沙坦和利尿剂如HCTZ的联合治疗有望在治疗高血压中显示出协同治疗作用。
因此,本发明的一个目的就是提供一种包含替米沙坦和利尿剂如HCTZ的固定剂量的组合药物,所述的组合药物显示出所需的快速溶解、立即释放药物的特征以及足够的稳定性。
通常,需要立即释放的固定剂量的组合药物被制备成两种活性成分和必需的赋形剂的粉末混合物或者复合颗粒(co-granulate),一般保留相应的单一药物制剂的基本成分(basic formulation),再简单的加入第二种药物成分。
将替米沙坦和HCTZ组合的这种方法并不可行,因为HCTZ与碱性化合物如常规替米沙坦制剂中的成分葡甲胺(N-甲基-D-葡萄糖胺)是不相容的,并且与从崩解片的溶出相比,HCTZ从溶解片基质中溶出度降低。
一些有助于克服这种不相容性问题的植物制剂方法已经被研究。一种典型的方法是在流化床制粒机中用含有水溶性聚合物如羟丙基纤维素、羟丙基甲基纤维素或聚乙烯吡咯烷酮的聚合物溶液,将HCTZ颗粒包衣,从而减少HCTZ颗粒与替米沙坦制剂在混合和压缩过程中的表面接触面积。然而,这些方法并不能将HCTZ与替米沙坦制剂在压片过程中的接触面积充分降低到能获得想要的延长保存期的程度。
而且,由于聚合物的凝胶特性,HCTZ从含有包衣的HCTZ的替米沙坦制剂中的溶出速率更加慢。
另一种方法是分别制备能将其填充到胶囊中的大小和形状的替米沙坦和HCTZ的薄膜包衣片剂。通过将剂量分成两至四个单个的替米沙坦的小片和分成一或两个HCTZ的小片,可以使型号为1到0的胶囊填满。然而采用这种方法,由于较大的胶囊外壳的延迟效应,相对单个个体而言,替米沙坦的药物溶出度降低了。此外,考虑到病人的顺应性,认为零号长胶囊是不安全的。
发明简述
按照本发明,发现在制备含有替米沙坦和利尿剂的固定剂量组合药物中与常规方法有关的上述问题都可以通过双层药片来克服,该双层药片包括在溶解片基质中含有基本上非结晶形式存在的替米沙坦的第一层,以及在崩解片基质中含有利尿剂的第二层。
按照本发明的双层药片,能使水溶性差的替米沙坦获得在很大程度上不受pH影响的溶出,从而使药物在生理pH水平易于溶出,并且也能使利尿剂从快速崩解片基质中立即释放。同时,双层药片结构克服了由利尿剂如HCTZ和替米沙坦制剂中的碱性成分不相容所导致的稳定性问题。
另一方面,本发明涉及双层压片技术的一种改进,并提供一种生产双层药物片剂的方法,包括步骤:
(i)形成第一片层组合物,通过
a)制备替米沙坦、至少一种碱性试剂和任选的的增溶剂和/或结晶阻滞剂(retarder)的水溶液;
b)喷雾干燥所述的水溶液,得到喷雾干燥的颗粒;
c)混合所述的喷雾干燥的颗粒与水溶性的稀释剂,得到预混合料;
d)混合所述的预混合料和润滑剂,得到第一片层的最终混合物;
e)任选地,在步骤a)到d)中的任何步骤加入其它的赋形剂和/或佐剂;
(ii)形成第二片层组合物,通过
f)混合和/或粒化利尿剂和崩解片基质成分以及,任选的另外的赋形剂和/或佐剂;
g)再与润滑剂混合制得第二片层的最终混合物;
(iii)将第一或第二片层组合物置入压片机中;
(iv)压缩所述片层组合物,形成片层;
(v)将另一片层组合物置入压片机中;并
(vi)压缩两部分片层组合物,形成双层药片。
定义:
这里,术语“基本上非结晶”是指包含非结晶成分的比率至少90%,优选至少95%的产品,其是通过X-射线粉末衍射法测量的。
术语“溶解片基质”是指药物片剂基础制剂,其具有立即释放(快速溶出)特性,在生理水性介质中易于溶解。
术语“利尿剂”是指噻嗪和噻嗪类似物利尿剂,如氢氯噻嗪(HCTZ)、氯帕胺、希帕胺、或氯噻酮(chlorotalidone),以及任何其它的适于治疗高血压的利尿剂,如呋塞米、吡咯他尼及它们与阿米洛利和盐酸氨苯蝶啶的组合药物。
术语“崩解片基质”是指药物片剂基础制剂,其具有立即释放特性,在生理水性介质中易于膨胀和崩解。
优选实施方式的描述:
按照本发明的双层药片,其包含在溶解片基质中含有基本上非结晶形式的替米沙坦的第一层和在崩解片基质中含有利尿剂的第二层。
尽管活性成分替米沙坦的药用盐也可以使用,但它通常以其游离酸的形式被供给。因而在随后的制备过程中,替米沙坦一般被溶解并转变成基本上非结晶形式,它最初的结晶态和粒径对制得的双层药片制剂的物理和生物药剂学的性质并不重要。然而优选例如通过过筛从起始原料中除去团块,使得在进一步的制备过程中易于润湿和溶出。
基本上非结晶形式的替米沙坦可以采用本领域技术人员已知的合适方法制备,例如,采用冷冻干燥水溶液、在流化床中包衣载体颗粒以及糖衣片或其它载体上的溶剂附着。然而,优选地,基本上非结晶形式的替米沙坦可以采用下文描述的具体的喷雾干燥技术制备。
其它的活性成分,如利尿剂,通常采用的是细结晶粉末,任选为细碎的、压碎的(peg-milled)或微粉化形式。例如,在干燥的分散系统(Sympatec Helos/Rodos,焦距长100mm)中,采用激光散射法测量的氢氯噻嗪的粒径分布优选如下:
d10:≤20μm,优选2到10μm
d50:5到50μm,优选10到30μm
d90:20到100μm,优选40到80μm
按照本发明的双层药片,通常含有10到160mg,优选20到80mg的替米沙坦和6.25到50mg,优选12.5到25mg的利尿剂。目前优选的形式是分别含有40/12.5mg、80/12.5mg和80/25mg的替米沙坦和HCTZ双层药片。
第一片层含有分散在溶解片基质中以基本上非结晶形式存在的替米沙坦,其具有立即释放(快速溶出)性质。尽管碱性片基质是优选的,但溶解片基质可以具有酸性、中性或碱性性质。
在一些优选的实施例中,溶解片基质包括碱性试剂、水溶性稀释剂以及,任选的其它赋形剂或佐剂。
合适的碱性试剂的具体实例是,碱金属氢氧化物如NaOH和KOH;碱性氨基酸,如精氨酸和赖氨酸;和葡甲胺(N-甲基-D-葡萄糖胺),优选氢氧化钠和葡甲胺。
合适的水溶性稀释剂的具体实例是糖类,例如单糖如葡萄糖;寡聚糖如蔗糖、无水乳糖和乳糖一水合物;以及糖醇如山梨醇、甘露醇、半乳糖醇、核糖醇和木糖醇。优选稀释剂是山梨醇。
其它的赋形剂和/或佐剂是,例如选自粘合剂、载体、填充剂、润滑剂,流控剂、结晶阻滞剂、增溶剂、着色剂、pH调节剂、表面活性剂和乳化剂,其中与第二片层组合物有关的具体实例参见下文。第一片层的组合物中的赋形剂和/或佐剂优选是非酸性的,以便得到快速溶解片基质。
第一片层组合物通常包括3到50重量%,优选5到35重量%的活性成分;0.25到20重量%,优选0.40到15重量%的碱性试剂;和30到95重量%,优选60到80重量%的水溶性稀释剂。
其它(任选的)成分可以是,比如选自一种或多种下述含量的赋形剂和/或佐剂:
10到30重量%,优选15到25重量%的粘合剂、载体和/或填充剂,从而代替水溶性稀释剂;
0.1到5重量%,优选0.5到3重量%的润滑剂;
0.1到5重量%,优选0.3到2重量%的流控剂;
1到10重量%,优选2到8重量%的结晶阻滞剂;
1到10重量%,优选2到8重量%的增溶剂;
0.05到1.5重量%,优选0.1到0.8重量%的着色剂;
0.5到10重量%,优选2到8重量%的pH调节剂;
0.01到5重量%,优选0.05到1重量%的表面活性剂和乳化剂。
第二片层组合物在快速崩解片基质中含有利尿剂。在一个优选的实施例中,崩解片基质包含填充剂、粘合剂、崩解剂以及,任选的其它赋形剂和佐剂。
填充剂优选选自无水乳糖、喷雾干燥的乳糖和乳糖一水合物。
粘合剂选自干粘合剂组和/或湿制粒粘合剂组,具体根据第二片层的制备方法进行选择。适合的干粘合剂是,例如纤维素粉末和微晶纤维素。湿制粒粘合剂的具体实例是玉米淀粉、聚乙烯吡咯烷酮(聚维酮),乙烯基吡咯烷酮-乙酸乙烯酯共聚物(共聚维酮,Copovidone)、和纤维素衍生物,如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丙甲基纤维素。
适合的崩解剂是,例如淀粉羟乙酸钠、交联聚乙烯吡咯烷酮(crospovidon)、交联羧甲纤维素、羧甲基纤维素钠和干燥的玉米淀粉,优选淀粉羟乙酸钠。
其它的赋形剂和佐剂,如果需要,优选选自下列稀释剂和载体,如纤维素粉末,微晶纤维素,纤维素衍生物如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丙甲基纤维素,磷酸氢钙、玉米淀粉、预胶化淀粉、聚乙烯吡咯烷酮(聚维酮)等;润滑剂如硬脂酸、硬脂酸镁、硬脂基延胡索酸钠、甘油三山萮酸酯(glycerol tribehenate)等;流控剂如胶体二氧化硅、滑石粉等;结晶阻滞剂如聚维酮等;增溶剂如泊洛沙姆、聚维酮等;着色剂,包括染料和颜料如氧化铁红或氧化铁黄、二氧化钛、滑石粉等;pH调节剂如柠檬酸、酒石酸、富马酸、柠檬酸钠、磷酸氢钙、磷酸氢二钠等;表面活性剂和乳化剂如泊洛沙姆、聚乙二醇、羧甲基纤维素钠、聚乙氧基化和氢化蓖麻油等;以及这些赋形剂和/或佐剂中的两者或多种的混合物。
第二片层组合物通常包括1.5到35重量%,优选2到15重量%的活性成分;25到75重量%,优选35到65重量%的填充剂;10到40重量%,优选15到35重量%的干粘合剂;0.5到5重量%,优选1到4重量%的湿制粒粘合剂;以及1到10重量%,优选2到8重量%的崩解剂。其它的赋形剂和佐剂通常采用和在第一片层组合物中相同的量。
为了制备根据本发明的双层药片,可将第一和第二片层组合物在双层药片压片机中采用常规的方法压制,如双层压片模式的高速旋转压制。然而,应注意对第一片层不要采用过大的压力。优选在第一片层压缩过程中所施加的压力与在第一和第二片层压缩过程中所施加的压力的比例为1∶10到1∶2的范围。例如,可以采用4到8KN的中等压力压缩第一片层,然而对第一加上第二层采用的总压力为10到20KN。
在双层药片压制过程中,两层之间的充分连接结构是通过定距吸引力(分子间引力)和颗粒之间的机械结合作用实现的。
制得的双层药片释放活性成分迅速,且不受pH很大影响,完全释放不到60分钟,释放大部分不到15分钟。双层药片的溶出/崩解动力学可采用不同的方法加以控制。例如,双层可以同时溶出/崩解,然而优选含有利尿剂的第二片层首先崩解,而含有替米沙坦的第一片层同时或随后溶出。
按照本发明,实现了活性成分,具体是替米沙坦的溶解速度的实质性提高。一般情况下,30分钟后至少70%,典型的至少90%的药物负荷溶解。
本发明的双层药片有轻微的吸湿性倾向,因此优选采用防潮性包装材料包装,如铝箔泡罩包装、或聚丙烯软管,优选装有干燥剂的HDPE瓶。
为了获得适宜的溶出/崩解和药物释放特性,按照本发明的制备双层药片的具体的改进方法包括:
(i)形成第一片层组合物,通过
a)制备替米沙坦、至少一种碱性试剂和任选的增溶剂和/或结晶阻滞剂的水溶液;
b)喷雾干燥所述的水溶液,得到喷雾干燥的颗粒;
c)混合所述的喷雾干燥的颗粒与水溶性的稀释剂,得到预混合料;
d)混合所述的预混合料和润滑剂,得到第一层的最终混合物;
e)任选地,在步骤a)到d)中的任何步骤加入其它的赋形剂和/或佐剂;
(ii)形成第二片层组合物,通过
f)混合和/或粒化利尿剂和崩解片基质成分以及,任选的另外的赋形剂和/或佐剂;
g)再与润滑剂混合制得第二片层的最终混合物;
(iii)将第一或第二片层组合物置入压片机中;
(iv)压缩所述片层组合物,形成片层;
(v)将另一片层组合物置入压片机中;并
(vi)压缩两部分片层组合物,形成双层药片。
在本方法一个优选实施方案中,替米沙坦的碱性水溶液是通过将活性成分在一种或多种碱性试剂如氢氧化钠和葡甲胺的辅助下溶解在纯净水中制备得到的。任选地,可添加增溶剂和/或重结晶阻滞剂。起始水溶液中的干物质的含量通常为10到40重量%,优选20到30重量%。
然后将水溶剂在室温或优选在升高的温度,如50到100℃之间,在例如1到4bar的喷雾压力下,在并流(co-current)或对流(countercurrent)喷雾干燥机中进行喷雾干燥。通常来说,喷雾干燥的条件优选的方式是:在旋风分离器中获得具有≤5重量%,优选≤3.5重量%的残留湿度的喷雾干燥的颗粒。最终,喷雾干燥器的出口空气温度优选保持在80到90℃之间,并且其它的加工参数如喷雾压力、喷雾速度、入口空气温度等也作相应的调整。
制得的喷雾干燥的颗粒优选是具有下述粒径分布的细粒粉末:
d10:≤20μm,优选≤10μm
d50:≤80μm,优选20到55μm
d90:≤350μm,优选50到150μm
喷雾干燥后,喷雾干燥的颗粒中的活性成分(替米沙坦)与赋形剂都基本上以非晶形态存在,没有可测的结晶度。从物理的观点来看,喷雾干燥的颗粒是具有优选>50℃,更优选>80℃的玻璃转化温度Tg的固态溶液或玻璃态。
以100重量份的活性成分(替米沙坦)计,喷雾干燥的颗粒中优选含有5到200重量份的碱性试剂和任选的增溶剂和/或结晶阻滞剂。
以第一片层组合物的重量计,通常采用的水溶性的稀释剂的含量为30到95重量%,优选60到80重量%。
以第一片层组合物的重量计,通常加入到预混合料中的润滑剂的含量为0.1到5重量%,优选0.3到2重量%。
混合是分两阶段进行,即在第一混合步骤中,使用如高剪切混合机或自由降落混合机(free-fall blender),将喷雾干燥的颗粒和稀释剂混合;在第二混合步骤中,也优选在高速剪切的条件下将润滑剂与预混合料混合。然而本发明的方法并不限于这些混合方法,并且通常可供选择的混合方法也可应用于步骤c)、d)以及后续步骤f)和g)中,如用中等筛分(intermediate screen)混合的容器。
为便于直接压缩,第二片层组合物可以通过干燥-混合组合物的成分来制备,例如,采用高强度混合机(high-intensity mixer)或自由降落混合机。可供选择和优选的是,第二片层组合物采用湿制粒法技术来制备,其中将湿颗粒粘合剂的水溶液加入到预混合料中,接着例如在流化床干燥器或干燥室内干燥所得到的湿颗粒。过筛干燥的混合物,然后例如用滚筒拌合机或自由降落搅拌机,将润滑剂混合,接着对组合物准备压片。
为了制备本发明的双层药片,按照上面描述的方法,在双层药片压片机,例如采用双层压片模式的旋转压片机对第一和第二片层组合物进行压缩。为了避免第一和第二片层之间的交叉污染(可能导致HTCZ分解),在压片室内的压片过程中,任何粒状残渣都必须通过模具板(dietable)的强烈抽吸来小心的清除。
为了进一步阐述本发明,给出下面的非限定性的实施例:
实施例1
制备方法:
1.喷雾溶液
在20-40℃之间的温度下,将测量的225.000kg的纯净水置入一个合适的不锈钢容器中,接着在强烈搅拌下将3.780kg的氢氧化钠、45.000kg的替米沙坦(多晶型A和B的混合物)、13.500kg的聚维酮K 25和13.500kg的葡甲胺顺序溶解在纯净水中,直到完全澄清,有轻微淡黄色,制得碱性溶液。
2.喷雾干燥
将上述溶液喷入合适的喷雾干燥器中,如Niro P 6.3,其装有直径为1.0mm的Schlick雾化喷嘴,以及连接上游干燥器的流动通过加热螺旋管(flow-through heating coil),干燥得到白色至灰白色的细粒颗粒。喷雾模式是对流式,喷雾压力约3bar,进口空气的温度约125℃并且喷雾速度约11kg/h,这样可使出口空气温度为约85℃。流动通过加热螺旋管的水浴温度可设定在约80℃。
3.保护性筛选:
干颗粒粉末过0.5mm目径的筛,如采用Vibra Sieve机。
可将获得的非晶体形式的替米沙坦喷雾干燥的颗粒进一步制成替米沙坦单片或所述双层药片组合物的第一层。
实施例2
组分 | mg/第一层片 | mg/SD颗粒 | mg/第二层片 | |
(01) | 替米沙坦SD颗粒 | 67.360 | ||
由(02)到(06)组成: | ||||
(02) | 替米沙坦 | 40.000 | ||
(03) | 氢氧化钠 | 3.360 | ||
(04) | 聚维酮(聚乙烯吡咯酮25) | 12.000 | ||
(05) | 葡甲胺 | 12.000 | ||
(06) | 纯净水 | 264.000* | ||
(07) | 山梨醇P/6 | 168.640 | ||
(08) | 筛过的硬脂酸镁 | 4.000 | 1.000 | |
(09) | 氢氯噻嗪 | 12.500 | ||
(10) | 微晶纤维素(微晶纤维素pH 101) | 64.000 | ||
(11) | 氧化铁红 | 0.330 | ||
(12) | 淀粉羟乙酸钠 | 4.000 | ||
(13) | 过筛的精细的乳糖一水合物 | 112.170 | ||
(14) | 玉米淀粉,在45℃干燥 | 6.000 | ||
240.000 | 67.360 | 200.000 |
*其中200mg在SD颗粒中,64mg在HCTZ颗粒的粒化液体中。
制备方法:
1.最终混合物A
在适当的高剪切搅拌器如Diosna P 600中,将168.640kg的山梨醇与67.360kg替米沙坦喷雾干燥的颗粒,使用旋转混合器(impeller)和切碎机(chopper)混合4分钟。接着将4.0kg硬脂酸镁加入到获得的预混合物中,并在高剪切混合器中再次混合30秒。
2.最终混合物B
将9.000kg的约70℃的纯净水转入合适的混合容器中,然后将在45℃干燥的6.000kg玉米淀粉悬浮到水中。使用例如Ekato搅拌器,将该悬浮液搅拌到约90℃的55.000kg的纯净水中。
接下来,在适合的高剪切制粒机如Diosna P 600中,将112.170kg的乳糖一水合物、12.500kg氢氯噻嗪、64.000kg的微晶纤维素(微晶纤维素pH 101)、0.330kg的氧化铁红和4.000kg的淀粉羟乙酸钠混合直至均相,并用上述制备的70.000kg水性粒化液体使其润湿。
湿制粒法的制备参数:
制备步骤 | 延续时间(分钟) | 旋转混合器(装置) | 切碎机(装置) |
预混合 | 3 | 1 | 1 |
润湿化 | 2 | 1 | 1 |
湿式混合 | 4 | 2 | 2 |
排空 | 约0.5 | 1 | 0 |
润湿后,将制得的湿颗粒在合适的流化床干燥器,如Glatt WSG 120中干燥,进口空气温度为100℃,进口空气流速为2000-3000m3/h,直到获得产品温度为约55℃为止。
使用合适的筛选机如装有2mm目径锉磨滤网(rasp screen)的Comilscreen机来筛选干颗粒,以减小粒径。最后,将1.000kg的已筛过的硬脂酸镁与筛过的颗粒材料混合,并在适当的滚筒拌合机如Lermer旋转式钉齿混合机(rotating spike mixer)中混合,以8-10rpm的速度旋转100个循环。
3.双层药片的压制
使用合适的旋转压片机,将240kg的最终混合物(A)和200kg的最终混合物(B)压制成双层药片。第一层的目标重是240mg,第二层的目标重是200mg。
压片剂的工艺参数:
通常,片剂的硬度可根据第二层的主压缩压力的变化进行调整。制成的双层药片具有下述特征:
形态/直径 | 卵形,双面突起/14×6.8mm |
颜色 | 第一层:白色到灰白色第二层:红色 |
重量 | 440mg(全部)240mg(第一层:含替米沙坦)200mg(第二层:含氢氯噻嗪) |
厚度 | 约5.2mm |
硬度 | 约120N |
崩解时间 | NMT 15分钟(全部) |
实施例3
组分 | mg/第一片层 | mg/SD颗粒 | mg/第二片层 | |
(01) | 替米沙坦SD颗粒 | 67.360 | ||
由(02)到(06)组成: | ||||
(02) | 替米沙坦 | 40.000 | ||
(03) | 氢氧化钠 | 3.360 | ||
(04) | 聚维酮(聚乙烯吡咯酮25) | 12.000 | ||
(05) | 葡甲胺 | 12.000 | ||
(06) | 纯净水 | (200.000) | ||
(07) | 山梨醇P/6 | 168.640 | ||
(08) | 筛过的硬脂酸镁 | 4.000 | 1.000 | |
(09) | 氢氯噻嗪 | 25.000 | ||
(10) | 微晶纤维素(微晶纤维素pH 101) | 64.000 | ||
(11) | 氧化铁黄 | 0.330 | ||
(12) | 淀粉羟乙酸钠 | 4.000 | ||
(13) | 筛过的精细的乳糖一水合物 | 105.67 | ||
240.000 | 67.360 | 200.000 |
制备方法:
按照实施例2的方法制备。代替实施例2中描述的湿制法方法,第二层混合物是在合适的自由降落混合机中,如1m3容器混合机,以速度10rpm旋转200次,干法混合(09)到(13)制备的。然后,在容器混合机中将(08)和主混合物混合再次旋转50次。为了获得色料的均相分布,可应用另外的预混合料,其含有氧化铁黄和部分如2000kg微晶纤维素,手工过0.8mm筛后转入主混合物中。最终制得的双层药片与实施例2中描述的相比,除了颜色不同外,其余物理性质实质上相同。
实施例4
替米沙坦/氢氯噻嗪双层药片组合物(每片按mg计)
成分 | 40/12.5mg | 80/12.5mg |
替米沙坦层 | ||
替米沙坦 | 40.000 | 80.000 |
氢氧化钠 | 3.360 | 6.720 |
聚维酮 | 12.000 | 24.000 |
葡甲胺 | 12.000 | 24.000 |
纯净水* | (200.000) | (400.000) |
山梨醇 | 168.640 | 337.280 |
硬脂酸镁 | 4.000 | 8.000 |
总替米沙坦层 | 240.000 | 480.000 |
氢氯噻嗪层 | ||
氢氯噻嗪 | 12.500 | 12.500 |
乳糖一水合物 | 112.170 | 112.170 |
微晶纤维素 | 64.000 | 64.000 |
玉米淀粉 | 6.000 | 6.000 |
氧化铁红 | 0.330 | 0.330 |
淀粉羟乙酸钠 | 4.000 | 4.000 |
纯净水* | (64.000) | (64.000) |
硬脂酸镁 | 1.000 | 1.000 |
总HCTZ层 | 200.000 | 200.000 |
片总重 | 440.000 | 680.000 |
*在最终产物中不出现。
Claims (13)
1.一种制备基本上非结晶形式的替米沙坦的方法,包括
a)制备包含替米沙坦以及至少一种碱性试剂的水溶液;
b)喷雾干燥所述的含水溶液以得到喷雾干燥的颗粒。
2.如权利要求1所述的方法,其中以100重量份的替米沙坦计,喷雾干燥的颗粒中含有5到200重量份的碱性试剂。
3.如权利要求1的方法,其中替米沙坦借助于一种或者多种选自碱金属氢氧化物、碱性氨基酸和葡甲胺的碱性试剂溶解在水中。
4.权利要求2的方法,其中碱性试剂为氢氧化钠和/或葡甲胺。
5.权利要求1的方法,其中所述的替米沙坦水溶液另外包含增溶剂和/或结晶阻滞剂。
6.权利要求5的方法,其中起始水溶液中的干物质的含量通常为10%到40重量%。
7.权利要求1的方法,其中水溶液在室温或在50到100℃之间的升高的温度,在并流或对流喷雾干燥机中进行喷雾干燥。
8.权利要求1的方法,其中水溶液在1~4bar的喷雾压力下喷雾干燥。
9.权利要求1的方法,其中在旋风分离器中获得具有≤5重量%残留湿度的喷雾干燥的颗粒。
10.权利要求9的方法,其中喷雾干燥器的出口空气温度保持在约80到90℃之间。
11.权利要求1的方法,其中细粒粉末喷雾干燥的颗粒具有下述粒径分布的:
d10:≤20μm,
d50:≤80μm,
d90:≤350μm。
12.权利要求1的方法,其中喷雾干燥的颗粒是具有>50℃的玻璃转化温度Tg的固态溶液或玻璃态。
13.权利要求1的方法,其中喷雾干燥的颗粒中的替米沙坦与赋形剂以非晶形的形式存在,没有可测的结晶度。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103040817A (zh) * | 2013-01-08 | 2013-04-17 | 施慧达药业集团(吉林)有限公司 | 一种用于治疗高血压的复方制剂 |
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