CN1988891B - 包衣片制剂和方法 - Google Patents
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Abstract
本发明提供包衣片制剂,其包括易发生分子内环化的药物例如式(I)的DPP4-抑制剂saxaglipitin或其HCl盐,该制剂包括含有一种或多种填充剂的片芯和其他常规赋形剂,该片芯包括包被在其上的可包括两层或多层的包衣,其中至少一层为由一种或多种包衣聚合物形成的内密封包衣层,其中第二层由药物(DPP4-抑制剂)和一种或多种包衣聚合物形成,以及可选用可不选用但最好选用的由一种或多种包衣聚合物形成的第三外保护层。本发明也提供用于形成包衣片的方法。
Description
发明领域
本申请要求于2004年5月28日提出申请的美国专利临时申请第60/575,319号的优先权,其整体内容在此引作参考。
本发明涉及包括用药物例如DPP4-抑制剂,例如saxagliptin包衣片芯的包衣片制剂和用于制备这类包衣片制剂的方法。
发明背景
或其盐酸盐,
上面结构式的化合物或其盐酸盐(下文中为上述DPP4-抑制剂或saxaglipitin)为口服有效的可逆二肽基肽酶-4(DPP4)抑制剂,为公开于美国专利第6,395,767号中的用于治疗2型糖尿病的治疗剂。
在摄取食物后,释放促胰岛素激素GLP-1,进而诱导自胰腺释放胰岛素。某些GLP-1被存在于血浆和肠毛细管内皮中的DPP4所灭活。因此,若DPP4受到抑制,则可得到更多GLP-1以刺激自胰腺释放胰岛素。这种胰岛素释放机制的优点为胰岛素仅因响应进食而分泌。因此,与其他糖尿病药物有关的低血糖症问题对于DPP4抑制剂应该不成为问题。
上述DPP4抑制剂为不稳定化合物,其如下所示易于发生分子内环化。
DPP4抑制剂 环脒
形成环脒(CA)
得到的降解物环脒(主要为顺-环脒(CA))没有治疗活性,因此,其形成并非人们所想要的。这种环化反应可在固态和溶液状态两种情况下发生。当用常用加工行为例如湿法制粒、碾压或压片进行配制时,分子内环化速率加快。另外,大部分常用赋形剂当与该化合物混合时,可加速环化速率。此外,当药物与赋形剂比率增加时,顺-环脒水平增加,对低强度剂型造成更大挑战。考虑到分子的这些性质,制造DPP4-抑制剂的常规片剂剂型(为优选剂型)是一种不可行的选择。
目前,小规模地制造了含有DPP4-抑制剂与常用赋形剂干混的胶囊制剂,用于临床研究。含有DPP4-抑制剂的胶囊制剂的放大也有问题,因为其涉及为控制DPP4抑制剂粒径以便制造的低强度的胶囊摆脱含量均匀度的问题而碾磨的步骤。
另外,大部分用于糖尿病治疗的治疗剂作为单体或作为组合产品都是片剂剂型。既然用传统制造过程制造DPP4-抑制剂片剂剂型不可行,将其与其他治疗剂制造为组合片剂应该更成问题。
因此,可发现明显需要稳定的药物制剂,其含有易发生分子内环化的药物,分子内环化可导致无治疗活性的降解物例如环脒的形成。
Robl等的美国专利第6,395,767号(下文中的Robl等)公开了基于环丙基稠合的吡咯烷的二肽基肽酶IV抑制剂(DPP4抑制剂),其包括具有下列结构的化合物或其药物上可接受盐,
其中该药物上可接受盐可为盐酸盐或三氟乙酸盐。
Robl等公开了可将包括上面列出的那些DPP4抑制剂配制为片剂、胶囊剂、颗粒剂或粉剂。
发明简述
本发明提供可包括易发生分子内环化的药物的包衣片,其在正常贮存条件(即30℃和60%相对湿度)下惊人地稳定。
本发明包衣片包括片芯(也称作“芯”、“片芯”、“安慰剂”、“安慰剂芯片”、“片芯组合物”或“芯组合物”)和
a)包被在芯上面的包衣层,该包衣层为由至少一种包衣聚合物形成的内密封包衣;
b)第二包衣层,置于内密封包衣上,由药物和至少一种包衣聚合物(优选与内密封包衣聚合相同)形成;和任选
c)外保护包衣层,置于第二包衣层上,由至少一种包衣聚合物(优选与第二包衣层和内密封包衣聚合物相同,但不必包括同样量的这类聚合物)形成。
药物应优选下面结构式的DPP4-抑制剂或其药物上可接受盐,例如HCl盐,也称作化合物A。
在优选实施方案中,本发明包衣片应包括由一种或多种膨胀剂或填充剂、任选一种或多种粘合剂、任选一种或多种崩解剂、任选一种或多种压片润滑剂形成的片芯,
a)包括至少一种包衣聚合物,优选基于聚乙烯醇(PVA)的聚合物的内密封包衣层;
b)置于所述密封包衣层a)上的第二包衣层,包括至少一种药物和至少一种包衣聚合物,优选基于PVA的聚合物,优选与内密封包衣层相同的包衣聚合物。
优选通过喷雾包衣将上述包衣层涂到片芯上。
在本发明更优选实施方案中,外保护层或第三包衣层将包被在第二包衣层(含有药物)上,并且将起保护层的作用。第三层或保护包衣层除将不包括药物但可任选包括一种或多种着色剂外,可优选包括与第二包衣层相似的成分,可不必包括相同量的这类成分。也可任选涂覆含有着色剂与包衣聚合物的第四层(包括与第三层相似成分)以区分各种强度的片剂。第一、第二、第三和第四包衣层可由相同或不同包衣聚合物形成。
业已发现与用常规干法制粒或湿法制粒技术制造的传统片剂比较,本发明包衣片展示出优越的化学稳定性。
该包衣方法通过使用其他药物片作为起始片(代替上述片芯或安慰剂)并涂覆内密封包衣和含有该有问题的药物和包衣聚合物的第二包衣层,以及任选但优选包在该其他药物片上的外保护包衣层,也将有助于制备有问题的药物与另一药物的联合制剂。
本发明包衣片可优选使用多孔锅包衣机来制备。也可使用流化床包衣和喷雾包衣。
另外,根据本发明,提供了用于制备本发明包衣片的方法,该方法包括以下步骤:
a)提供片芯;
b)用包括至少一种包衣聚合物的内密封包衣层制剂包被片芯;
c)干燥包衣片以在其上形成内密封包衣;
d)用包括药物和至少一种包衣聚合物的第二包衣层制剂包被经这样包衣的片;
e)干燥经这样包衣的片以在其上形成第二包衣层(含有药物);
f)任选但优选用包括至少一种包衣聚合物的第三外保护包衣层制剂包被经这样包衣的片;和
g)任选用包括至少一种包衣聚合物和着色剂的第四外保护包衣层包被经这样包衣的片;和
h)干燥经这样包衣的片以形成本发明包衣片。
在本发明方法优选实施方案中,内密封包衣层制剂、第二包衣层制剂和外保护包衣层制剂的每一种将以包衣溶剂中的包衣聚合物悬浮液形式涂覆。
第三和第四外保护包衣层不必包括药物(尽管若需要也可以),它们可由第一包衣层和/或第二包衣层的其他成分形成。第二包衣层可由第一包衣层和/或第三和/或第四包衣层的成分形成,但不必与这类成分的量相同。
在制备本发明包衣片中,制备包括在水中的包衣聚合物的包衣悬浮液。可采用的其他包衣溶剂包括乙醇、甲醇和异丙醇,水为优选。用内密封包衣悬浮液包被形成片芯的安慰剂(不含药物)片,并且干燥。将含有药物和包衣聚合物的第二包衣层悬浮液涂覆在经这样包衣的片上,然后干燥。
若本发明包衣片包括外保护层,则包衣悬浮液的制备与内密封层悬浮液情况相同,只不过不含药物。然后将该包衣悬浮液包被在前述用于内密封包衣和第二包衣的包衣片上以在其上形成保护包衣层。
本发明包衣片用于治疗哺乳动物例如人类、狗和猫的II型糖尿病。
本发明详述
本发明包衣片中采用的片芯或安慰剂将包括常规药物赋形剂,从而形成药物可接受固体片芯。片芯可呈片、珠粒、微粒或丸形式,以上所有形式通称作片芯。
本发明包衣片将含有占片芯重量的约0.1-约70%范围内的量(优选片芯重量的约1-约50%)的药物,例如上述DPP4-抑制剂,saxaglipitin。
本发明包衣片采用的片芯将优选含有
a)至少一种膨胀剂或填充剂;
b)任选至少一种粘合剂;
c)任选至少一种崩解剂;和
d)优选但任选至少一种润滑剂。
其中
a)膨胀剂或填充剂以约1-约95%重量范围内的量存在,优选约10-约85%重量;
b)粘合剂以约0-约20%重量范围内的量存在,优选约1-约10%重量;
c)崩解剂以约0-约20%重量范围内的量存在,优选约0.25-约10%重量;和
d)润滑剂以约0-约5%重量范围内的量存在,优选约0.2-约2%重量,以上所有%重量都按片芯的重量计算。
优选膨胀剂为微晶纤维素和乳糖一水合物;
崩解剂为交联羧甲基纤维素钠;和
润滑剂为硬脂酸镁。
存在于本发明包衣片中的片芯可通过多种方法和赋形剂加入次序来制备。这些制剂的使用不限于特定剂型或制造方法。可通过湿法制粒、干法制粒、直接混合或任何其他药物可接受方法来制造片芯。
根据本发明,提供用于制备本发明包衣片采用的片芯的优选方法,包括混合一种或多种诸如膨胀剂、任选粘合剂和任选崩解剂等赋形剂的步骤。优选将润滑剂加入到混合物中以促进片剂形成。
存在于本发明片芯组合物中的膨胀剂或填充剂将以占芯组合物重量的约1-约95%范围内的量存在,优选占芯组合物重量的约10-约85%。适用于本文的膨胀剂或填充剂实例包括但不限于纤维素衍生物(例如微晶纤维素或木质纤维素)、乳糖、蔗糖、淀粉、预胶化淀粉、葡萄糖、甘露醇、果糖、木糖醇、山梨醇、玉米淀粉、改性玉米淀粉、无机盐(例如碳酸钙、磷酸钙、磷酸二钙、硫酸钙)、糊精/葡萄糖结合剂、麦芽糖糊精、可压糖(compressible suger)和其他已知膨胀剂或填充剂和/或其两种或多种混合物,优选微晶纤维素。
粘合剂将任选以占芯组合物重量的约0-约20%的量存在于本发明药物组合物中,优选占芯组合物重量的约1-约10%。适用于本文粘合剂的实例包括但不限于羟丙基纤维素、玉米淀粉、预胶化淀粉、改性玉米淀粉、聚乙烯吡咯烷酮(PVP)(分子量约5,000-约1,000,000,优选约40,000)、羟丙基甲基纤维素(HPMC)、乳糖、阿拉伯胶、乙基纤维素、醋酸纤维素以及蜡粘合剂(例如巴西棕榈蜡、石蜡、鲸油、聚乙烯或微晶蜡)以及其他常规粘合剂和/或其两种或多种混合物,优选羟丙基纤维素。
崩解剂任选以占芯组合物重量的约0-约20%范围内的量存在于本发明药物组合物中,优选占芯组合物重量的约0.25-约10%。适用于本文的崩解剂实例包括但不限于交联羧甲基纤维素钠、交联聚维酮、淀粉、土豆淀粉、预胶化淀粉、玉米淀粉、淀粉乙醇酸钠、微晶纤维素、低取代羟丙基纤维素或其他已知崩解剂,优选交联羧甲基纤维素钠。
润滑剂将以占芯组合物重量的约0.1-约5%的最佳范围内的量存在于本发明药物组合物中,优选占芯组合物重量的约0.2-约2%。适用于本文的压片润滑剂实例包括但不限于硬脂酸镁、硬脂酸锌、硬脂酸钙、滑石、巴西棕榈蜡、硬脂酸、棕榈酸、硬脂酰延胡索酸钠或氢化植物油和脂肪或其他已知压片润滑剂和/或其两个或多个混合物,优选硬脂酸镁。
内密封包衣层制剂(也称作第一包衣层)将包括占内密封包衣层重量最高达95%的聚合物,其可如前文所述制备。如上所述,该制剂应含有至少一种包衣层聚合物和包衣溶剂,优选水,其用于加工过程,通过干燥除去。包衣层聚合物可为羟丙基甲基纤维素、聚乙烯醇(PVA)、乙基纤维素、甲基丙酸烯聚合物或羟丙基纤维素,优选PVA。包衣层也可任选包括增塑剂,例如甘油三乙酸酯、酞酸二乙酯、癸二酸三丁酯或聚乙二醇(PEG),优选PEG;和抗粘剂或助流剂,例如滑石、热解硅石或硬脂酸镁;遮光剂,例如二氧化钛。包衣层也可包括基于铁氧化物的着色剂。包衣材料有市售,商品名为OpadryHP或OpadryII白。
虽然第二包衣层将优选与第一包衣层制剂的组成相似,但将包括药物,优选DPP4-抑制剂,药物的量为占第二包衣层重量的约0.5-约70%范围内,优选占第二包衣层层重量的约30-约50%。
第三外保护包衣层将优选与第一包衣层的组成相似。
若存在第四包衣层,则将优选与第三层外保护包衣层的组成相似,如需要将包括着色剂,例如占第四包衣层重量的约0.5-约5.0%范围内的量。
内密封包衣层将优选由占内密封包衣层重量的约10-约95%(优选约20-约90%)范围内的量的包衣层聚合物、任选占内密封包衣层重量的约10-约30%(优选约15-约20%)范围内的量的增塑剂、占内密封包衣层重量的约15-约30%(优选约10-约15%)范围内的量的抗粘剂或助流剂形成。
第二包衣层将优选由占第二包衣层重量的约30-约99.5%(优选约40-约60%)范围内的量的包衣层聚合物和占第二包衣层重量的约0.25%-约70%(优选约20-约50%)范围内的量的药物形成。
第二包衣层中的包衣层聚合物将为200mg片芯至少约5mg,而药物将为至少约0.5mg。
第三外保护包衣层将优选与第一包衣层的组成相似。
内密封包衣层将以已完成包衣片重量的约1-约5%(优选约1-约3%)范围内的量存在;第二包衣层(含有药物)将以已完成包衣片重量的约0.25-约70%(优选约1-约50%)范围内的量存在,其视药物规格(potency)而定;而若存在第三和第四外保护包衣层,则每层将以已完成包衣片重量的约1-约10%(优选约1-约5%)范围内的量存在。
根据本发明,优选包衣片制剂列于下。
下列工作实施例代表本发明优选实施方案。
实施例
500g的一批具有下列组成的2.5mg DPP4包衣片如下所述制备:
500g片芯如下制备。
将乳糖一水合物、交联羧甲基纤维素钠和微晶纤维素在行星(齿轮)式搅拌机中混合。然后用涡旋式搅拌机通过与预筛过的硬脂酸镁混合来润滑该混合物。用单冲压片机或用旋转式压片机将润滑混合物压为200mg安慰剂片。
内密封包衣层
内密封包衣悬浮液如下制备。
将0.1 N HCl(约226.7g)在金属容器中用减轻(lightening)搅拌机连续搅拌。将40g OpadryHP粉末快速加入到涡流中。粉末加完后,以低速继续混合直至见到明显的均一混合物。测量得到的悬浮液的pH,用浓HCl或NaOH将pH调整为2。
按下列参数设定Glatt包衣机。
Glatt包衣机参数
将片芯在包衣锅中预热约10到15分钟。将30片加热的片芯称重。继续干燥该片直至消除片中的水分,并使片恒重。30片片的最终重量定为A。
用采用Glatt包衣机如上制备的内密封包衣悬浮液包被30片药片。
将30片药片每10分钟称重一次(并且记录重量),直至片重达到目标重量(方程1)。通过加热干燥包衣片直至片恒重。将经这样包衣的片剂的最终重量标示为B。
方程1:
目标重量=A×1.02=B
中间(药物)包衣
含有药物的中间包衣层悬浮液如下制备。
在金属容器中,将12.5g DPP4-抑制剂(游离碱)加入到1000ml 0.1N HCl中。测量pH,调整到2。连续搅拌HCl,将100g OpadryHP快速加入到涡流中。然后以低速搅拌混合物直至见到明显的均一混合物。如必要用浓HCl或IN HCl将悬浮液pH保持为2。
用上面采用的Glatt包衣机制备的含有DPP4-抑制剂的包衣悬浮液包被上面制备的密封包衣片芯。将30片密封包衣片称重,开始每30分钟一次,然后每15分钟一次,记录重量,直至达到目标重量(方程2)。通过加热干燥经这样包衣的片剂直至片重恒定。将30片药片的最终重量标示为C。
方程2:
目标重量=B+30×(2.925(相当于2.5mg游离碱)+20mg)=B+687.75mg=C
用HPLC、光纤探头或NIR或其他合适手段测定包被在药片上的药物的量。当沉积了目标量的药物时停止包被。
外保护包衣层
将30片药片的最终重量标示为D。
方程3:
目标重量=C+30×4mg=C+120mg=D
将经这样包衣的片剂转移到合适容器中。
相对于常规片剂制剂(其中药物在芯中)和胶囊制剂,如此制备的本发明药片具有优良的稳定性。
将上面2.5mg药物规格的本发明包衣片贮存于不同贮存条件达到并包括41周,收集与降解物环脒(主要为顺-环脒(顺-CA))存在有关的稳定性数据。如下表1所示,在25℃/60%RH贮存条件下无顺-CA检出。在30℃/60%RH和40℃/75%RH贮存条件下顺-CA水平分别为0.22%和0.32%。这些水平显著低于示于表2的5mg和20mg药物规格的胶囊制剂所观察到的水平。
表2
胶囊制剂(DPP4苯甲酸盐4.8%、无水乳糖50.2%、含水乳糖40%、交联羧甲基纤维素钠2%和硬脂酰延胡索酸钠3%,5mg和20mg胶囊的填充重量分别为150mg和350mg)的稳定性数据。
Claims (6)
1.一种包衣片,所述包衣片包含:
a)片芯,
b)内密封包衣层,其包被在片芯上,其中所述内密封包衣层包含40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛;其中所述内密封包衣层占200mg片芯重量的2%;
c)第二包衣层,其中所述第二包衣层包含药物和包衣层聚合物,所述包衣层聚合物包含40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛,其中所述药物占200mg片芯重量的1.25%,以及所述包衣层聚合物占200mg片芯重量的10%;和
d)外保护包衣层,其包被在片芯第二包衣层上,其中所述外保护包衣层包含40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛,其中所述外保护包衣层占200mg片芯重量的2%;
其中包含于所述第二包衣层中的药物具有以下结构
或其药物上可接受盐。
2.权利要求1所定义的包衣片,其中所述片芯由一种或多种填充剂、任选一种或多种粘合剂、任选一种或多种崩解剂和任选一种或多种压片润滑剂组成。
3.权利要求2所定义的包衣片,其中所述片芯由微晶纤维素、乳糖一水合物、交联羧甲基纤维素钠和硬脂酸镁组成。
5.一种用于制备包衣片的方法,所述方法包括:
a)提供片芯;
b)用内密封包衣层包被该片,所述内密封包衣层由40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛组成;
c)干燥所述包衣片以在其上形成内密封包衣;
d)用第二包衣层制剂包被经这样包衣的片,所述第二包衣层制剂包括具有以下结构的药物和包衣层聚合物,所述包衣层聚合物包含40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛,其中所述药物占200mg片芯重量的1.25%,以及所述包衣层聚合物占200mg片芯重量的10%;
e)干燥经这样包衣的片以在其上形成第二包衣层;和
f)任选用第三外保护包衣层制剂包被经这样包衣的片,所述第三外保护包衣层制剂包括40%的聚乙烯醇、20%的聚乙二醇、15%的滑石和25%的二氧化钛;和
g)干燥经这样包衣的片以形成本发明包衣片。
6.权利要求5所定义的方法,其中所述包衣层以包衣聚合物悬浮液形式涂覆。
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- 2011-04-26 US US13/094,379 patent/US8628799B2/en active Active
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2012
- 2012-02-14 IL IL218117A patent/IL218117A/en active IP Right Grant
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2014
- 2014-01-08 US US14/150,331 patent/US9339472B2/en active Active
- 2014-05-22 US US14/284,840 patent/US20140255486A1/en not_active Abandoned
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2015
- 2015-02-24 AR ARP150100554A patent/AR099567A2/es unknown
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2016
- 2016-07-15 HR HRP20160880TT patent/HRP20160880T4/hr unknown
- 2016-07-19 CY CY20161100703T patent/CY1117813T1/el unknown
- 2016-09-21 HR HRP20161210TT patent/HRP20161210T4/hr unknown
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1400908A (zh) * | 2000-01-21 | 2003-03-05 | 诺瓦提斯公司 | 含有二肽基肽酶-iv抑制剂的联合形式 |
WO2003059330A1 (en) * | 2002-01-15 | 2003-07-24 | Ranbaxy Laboratories Limited | Stable pharmaceutical compositions comprising ace inhibitor(s) |
Non-Patent Citations (3)
Title |
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Edwin B. Villhauer,et al.1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:a potent,selective,and orally bioavailable dipeptidylpeptidase IV inhibitor with antihyperglycemic properties.J. Med.Chem46.2003,462774-2789. * |
表I-IV. |
说明书第2-6页 |
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