CN105407875A - 包含异烟肼颗粒和利福喷汀颗粒的呈包衣片剂形式的抗结核病的稳定的药物组合物及其制备方法 - Google Patents
包含异烟肼颗粒和利福喷汀颗粒的呈包衣片剂形式的抗结核病的稳定的药物组合物及其制备方法 Download PDFInfo
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- CN105407875A CN105407875A CN201480041953.0A CN201480041953A CN105407875A CN 105407875 A CN105407875 A CN 105407875A CN 201480041953 A CN201480041953 A CN 201480041953A CN 105407875 A CN105407875 A CN 105407875A
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- Prior art keywords
- isoniazid
- granule
- rifapentine
- combination
- oral medication
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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Abstract
本发明涉及用于治疗结核病的口服药物固定剂量组合物及其制备方法，所述口服药物组合物包含：a)包含异烟肼和至少一种颗粒内赋形剂的颗粒；b)包含利福喷汀和至少一种颗粒内赋形剂的颗粒；及c)至少一种颗粒外赋形剂。
Description
技术领域
本发明涉及化学稳定的呈包衣片剂形式的抗结核病的药物固定剂量组合物，其包含在分开的颗粒中的两种活性成分即利福喷汀和异烟肼。本发明还提供了所述抗结核病的药物组合物的制备方法。
背景技术
感染性疾病结核病(TB)为由于单一人病原体导致的世界范围内死亡的主要原因，其相比于诸如获得性免疫缺陷综合征(AIDS)、疟疾、腹泻、麻风病和所有其它热带病的疾病总体而言使更多的成人死亡(ZumlaA,GrangeJ.BMJ(1998)316,1962-1964)。世界上约三分之一的人口目前感染有结核分枝杆菌(Mycobacteriumtuberculosis,Mtb)即引起疾病的原因；10％的感染人群将会发展成临床疾病。尽管人们发展成TB的比例已经有所下降，但是根据WHO的数据，病例的数目仍持续缓慢增加。最严重的感染区域为发展中国家，其中贫穷、其它疾病及不健全的健康护理为影响因素。TB每年使约160万人死亡，其为排在HIV/AIDS之后的世界范围内死亡的第二主要感染性原因。
目前就针对TB的有效治疗而言，至少以下药物即异烟肼、利福平和吡嗪酰胺的组合在持续8周的治疗初期给予患者，在此期间药物组合使用以杀死快速成倍增加的Mtb群落且防止药物耐受的出现。该治疗初期之后为持续24周的连续阶段，在此期间将至少以下药物即异烟肼和利福喷汀的组合给予患者。如此长的组合疗法并非总是成功的，尤其是对于发展出药物耐受菌株的患者而言。另外，对相对长的疗程的顺应性通常是差的。这样的非顺应性可导致治疗失败，从而导致发展出药物耐受。
为了控制药物耐受结核病的出现，WHO推荐使用呈片剂形式的固定剂量组合(FDC)，其在同一制剂中包含固定比例的两种不同的活性成分即异烟肼和利福喷汀。呈片剂形式的FDC先前被披露。
SUKAPHARMACEUTICALCO.,LTD的WO2007/43542披露了用于治疗结核病的药物组合物和试剂盒。所述药物组合物包含噁唑化合物即利福喷汀和异烟肼，其可呈片剂形式。
GUANXINCEN的CN1717912披露了包含利福喷汀和异烟肼的药物组合物，其可呈片剂形式。
SHUAIHUAMEDICINESCITECHCO的CN185728披露了包含利福喷汀和异烟肼的持续释放制剂(植入剂)，其可呈片剂形式。
然而，本领域技术人员熟知的是，使用这样的FDC可降低利福喷汀的生物利用度，这是因为与异烟肼发生不期望的化学反应，尤其是在酸性胃环境的催化条件下(PrasadB.etal.J.Pharm.Biomed.Anal.2006；41:1438-1441)。
因此，仍然需要以下包含利福喷汀和异烟肼的化学稳定的抗结核病的口服药物组合物，其可防止利福喷汀的生物利用度降低及与异烟肼的不期望的化学反应。
申请人已经发现可如下提供使两种活性成分都具有令人满意的生物利用度的口服药物组合物：将两种活性成分分开制粒且将它们引入到药物组合物中。
本发明的目的
本发明的第一个目的是用于治疗结核病的化学稳定的口服药物固定剂量组合物，所述口服药物组合物包含：
a)包含异烟肼和至少一种颗粒内赋形剂的颗粒，
b)包含利福喷汀和至少一种颗粒内赋形剂的颗粒，及
c)至少一种颗粒外赋形剂。
本发明的另一个目的是制备本发明口服药物组合物的方法，所述方法包括将异烟肼制粒和将利福喷汀制粒的不同步骤。
本发明
本发明的药物组合物是化学稳定的且适于通过口服给药来治疗结核病。
“化学稳定的”是指在60％RH至75％RH在保持恒温的25℃至30℃的涵盖通常且常规的工作环境的温度储存小于6个月后，由利福喷汀产生的杂质的总量相对于最初存在于片剂中的利福喷汀的重量而言小于8％w/w，且由异烟肼产生的杂质的总量相对于最初存在于片剂中的异烟肼的重量而言小于2％w/w。
在不结合任何理论的情况下，据信本发明的片剂使两种活性成分都具有良好的生物利用度，这是因为利福喷汀和异烟肼在胃条件下的反应由于所述口服药物组合物的特定构造而受到限制。
所述口服药物组合物为固定剂量组合物。“固定剂量组合物”是指两种药物或活性成分的组合存在于单一剂量单位即片剂中。
所述口服药物组合物包含两种活性成分即利福喷汀和异烟肼及药用赋形剂。
更确切地，所述口服药物组合物包含：包含异烟肼和至少一种颗粒内赋形剂的颗粒(异烟肼颗粒)；包含利福喷汀和至少一种颗粒内赋形剂的颗粒(利福喷汀颗粒)；及至少一种颗粒外赋形剂。
所述口服药物组合物呈包衣片剂形式。膜包衣为常规的膜包衣，其不会导致活性成分的控制释放，但是其有助于吞服和改善外观。
所述包衣片剂可为包衣单层片剂或包衣双层片剂。
根据其中所述口服药物组合物为包衣双层片剂的实施方案，所述口服药物组合物的一层包含异烟肼颗粒和至少一部分的颗粒外赋形剂。所述口服药物组合物的另一层包含利福喷汀颗粒和至少剩余的颗粒外赋形剂。
所述颗粒外赋形剂包括稳定剂。所述稳定剂选自抗坏血酸钠、焦亚硫酸钠、EDTA二钠盐、丁基羟基化甲苯、枸橼酸、生育酚、丁基羟基苯甲醚、抗坏血酸、酒石酸及其混合物。优选地，所述稳定剂选自抗坏血酸钠、焦亚硫酸钠、EDTA二钠盐及其混合物。
所述颗粒外赋形剂也可包括选自以下的化合物：稀释剂、崩解剂、润滑剂、增溶剂及其混合物。
可提及的稀释剂为微晶纤维素、预胶化淀粉、磷酸二钙、甘露醇及其混合物，优选微晶纤维素。
可提及的崩解剂为交聚维酮(交联聚乙烯吡咯烷酮)、交联羧甲基纤维素、淀粉羟乙酸钠、玉米淀粉、低取代的羟丙基纤维素、海藻酸及其混合物，优选淀粉羟乙酸钠。
可提及的润滑剂为粉状润滑剂例如硬脂酸镁、硬脂酰富马酸钠、硬脂酸钙、硬脂酸、硬脂酸锌、甘油二十二烷酸酯及其混合物，优选硬脂酸钙。
可提及的增溶剂为月桂基硫酸钠、吐温80、PEG4000及其混合物，优选月桂基硫酸钠。
根据具体的实施方案，存在于异烟肼颗粒中的颗粒内赋形剂不同于存在于利福喷汀颗粒中的颗粒内赋形剂。
所述颗粒内赋形剂选自稀释剂、崩解剂、增溶剂、稳定剂、制粒粘合剂及其混合物。
所述稀释剂、增溶剂、稳定剂和崩解剂如上所述。它们可与用作颗粒外赋形剂的稀释剂、增溶剂、稳定剂和崩解剂相同，或它们可以是不同的。
所述制粒粘合剂可选自聚维酮诸如聚维酮K30和聚维酮K90、羟丙基纤维素、聚乙烯醇、玉米淀粉、预胶化淀粉及其混合物，优选聚维酮或预胶化淀粉。
所述膜包衣可包含羟丙基甲基纤维素、抗坏血酸钠、EDTA二钠盐、聚乙酸乙烯酯、乳糖一水合物、聚乙二醇、甘油三乙酸酯和色素，优选聚乙酸乙烯酯、羟丙基甲基纤维素、EDTA二钠盐及其混合物。
本发明的口服药物组合物可借助于包装机而包装在任何适当的包装例如双层铝泡罩包装中。
根据一个实施方案，所述口服药物组合物包含100mg至400mg利福喷汀及50mg至400mg异烟肼。
对结核病的治疗为长期治疗，在此期间给药方案是变化的。例如，对于TB治疗的初期来说，通常开具的给药为600mg，每周两次，持续2个月，其中在各次给药之间的间隔不少于连续3天(72小时)，联用其它抗结核病的药物至多2个月。所述2个月阶段(600mg，每周一次)之后为通过使用异烟肼或其它适当的抗结核病的药物的直接观察疗法来进行的4个月阶段。针对异烟肼所通常开具的给药为每天单次给药的5mg/kg直至300mg及每周两次至三次给药的15mg/kg直至900mg/天。
由于所述类型的治疗，使用以下不同的片剂是非常有利的，所述片剂彼此的不同在于利福喷汀/异烟肼的比例。
根据一个实施方案，利福喷汀与异烟肼的比例包括5:1至1:0.5，利福喷汀与异烟肼的比例优选为1:1。
更具体地，本发明的片剂可含有300mg利福喷汀和300mg异烟肼、含有300mg利福喷汀和75mg异烟肼或含有225mg利福喷汀和75mg异烟肼。
根据其中所述稳定剂为抗坏血酸钠的优选实施方案，抗坏血酸钠与利福喷汀的比例包括1:100至1:0.1，优选1:70至1:50，更优选1:65至1:55，且甚至更优选1:60。
百分数以相对于片剂总重量的重量表示。
根据一个实施方案，所述口服药物组合物包含：
-10％至70％，优选20％至50％，且甚至更优选30％至43％的利福喷汀，及
-5％至70％，优选10％至45％，且甚至更优选11％至36％的异烟肼。
根据一个实施方案，所述口服药物组合物包含0.1％至50％，优选5％至45％，且更优选13％至42％的稀释剂。
根据一个实施方案，所述口服药物组合物包含0.1％至10％，优选1％至7％，且更优选2％至4％的崩解剂。
根据一个实施方案，所述口服药物组合物包含0.1％至10％，优选2％至7.5％，且更优选3％至7％的粘合剂。
根据一个实施方案，所述口服药物组合物包含0.1％至1％，优选0.2％至0.9％，且更优选0.25％至0.8％的润滑剂。
根据一个实施方案，所述口服药物组合物包含0.1％至1％，优选0.3％至0.80％，且更优选0.5％至0.7％的增溶剂。
根据一个实施方案，所述口服药物组合物包含0.1％至2％，优选0.25％至1.5％，且更优选0.5％至1％的稳定剂。
根据一个实施方案，所述口服药物组合物包含1％至10％，优选2.5％至7.5％，且更优选3.7％至5％的膜包衣。
根据另一个目的，本发明涉及制备所述口服药物组合物的方法，其包括将异烟肼制粒和将利福喷汀制粒的不同步骤。
根据具体的实施方案，用于制备单层片剂的方法包括以下步骤：
a)制备异烟肼颗粒，
b)制备利福喷汀颗粒，
c)使由步骤a)和b)获得的颗粒与颗粒外赋形剂混合，
d)压制步骤c)的混合物以获得片剂，及
e)通过本领域技术人员已知的方法对片剂进行膜包衣。
制粒的不同步骤通过湿法制粒来进行。
湿法制粒使用制粒组合物来进行，所述制粒组合物可为水性溶剂、液体粘合剂、有机溶剂诸如异丙醇、丙酮和氯仿，优选水性溶剂。所述制粒组合物也可包含粘合剂、稀释剂、崩解剂或其混合物。
在湿法制粒后，将颗粒干燥。可将它们过筛以改善和增强干燥性。
然后可将颗粒过筛以获得均匀的粒度并均匀地混合。优选地，异烟肼颗粒及利福喷汀颗粒的粒度包括1.3mm至0.1mm，优选1.25mm至0.25mm，更优选1.15mm至0.50mm，从而均匀地混合。
将所有颗粒外赋形剂混合在一起，除了将润滑剂在混合结束时掺入。
在压制前，可将混合物过筛以具有均匀的粒度且由此有助于压制。
当形成片剂时，通过本领域技术人员已知的方法对其进行包衣。包衣不意在调整活性物质的释放，而是意在改善其外观且有助于其吞服。
根据具体的实施方案，用于制备双层片剂的方法包括以下步骤：
a)制备包含异烟肼颗粒和至少一部分的颗粒外赋形剂的层，
b)制备包含利福喷汀颗粒和剩余部分的颗粒外赋形剂的层，
e)压制步骤a)的层和步骤b)的层以获得双层片剂，及
f)通过本领域技术人员已知的方法对片剂进行膜包衣。
以上就单层片剂所述的关于不同步骤的说明也适用于双层片剂。
制备层的步骤包括制备活性成分的颗粒，然后使它们与颗粒外赋形剂混合，任选之后进行过筛。本发明将在以下仅出于示例性目的而提供的实施例中得以更详细地描述。
实施例
实施例1：包衣双层片剂的组成
*在干燥过程中除去，在最终产品中仅以痕量存在。
包衣双层片剂的制备方法
将微晶纤维素、预胶化淀粉和淀粉羟乙酸钠各自过筛通过相应的0.425mm、0.250mm和0.180mm筛。然后将这些物质与利福喷汀共同过筛通过0.500mm筛。
然后将这些过筛的物质在快速混合制粒机中以100rpm干法混合20min。
然后将它们在快速混合制粒机中使用纯净水最初以125rpm且使用切碎器以1000rpm制粒3min。将该共混物进一步以175rpm并使用切碎器以1000rpm捏和6分20秒，得到具有所需一致性的颗粒。
然后将获得的湿颗粒在流化床干燥器中以55℃至60℃的入口温度干燥4小时。接下来将所得的干燥颗粒过筛通过0.850mm筛，得到过筛的干燥颗粒。
将抗坏血酸钠和淀粉羟乙酸钠过筛通过0.180mm筛并将月桂基硫酸钠过筛通过0.425mm筛。然后将这些过筛的物质与获得的过筛的干燥颗粒在双锥共混器中以18rpm的速度共混25min。
最后使用硬脂酸钙(过筛通过0.250mm筛)将该共混物在双锥共混器中以18rpm的速度润滑5min。
首先将异烟肼和微晶纤维素过筛通过0.425mm筛，然后在快速混合制粒机中以75rpm干法混合15min。将该所得的共混物使用聚维酮K30在纯净水中的溶液在快速混合制粒机中最初以100rpm且使用切碎器以280rpm制粒1.5min。将所述共混物进一步以125rpm并使用切碎器以500rpm捏和3min，得到具有所需一致性的颗粒。
然后将获得的湿颗粒在流化床干燥器中以45℃至50℃的入口温度干燥15min。然后将所得的干燥颗粒过筛通过0.600mm筛，选择粒度小于0.600mm的干燥颗粒。
将淀粉羟乙酸钠和微晶纤维素分别过筛通过相应的0.180mm和0.425mm筛。然后将这些过筛的物质与先前选择的干燥颗粒在双锥共混器中以18rpm的速度共混15min。
最后使用硬脂酸钙(过筛通过0.250mm筛)将该共混物在双锥共混器中以18rpm的速度润滑5min。
双层片剂如下获得：首先引入在第一层漏斗中的第一共混物，然后引入在第二层漏斗中的第二共混物，并使用20mm×10.5mm胶囊成型工具压制为双层片剂，获得厚度为5.8mm的双层片剂。
然后使用自动包衣机和以下参数将所得的双层片剂用由Colorcon商购的OpadryII(一种PVA聚合物与所需添加剂的预先制成的预混物)的水溶液包衣：盘转速为12rpm至14rpm，喷淋泵速为2rpm至3rpm，入口温度为55℃至65℃，床温度为36℃，且雾化气压为1巴。
最后将包衣双层片剂包装在Alu-Alu泡罩中。
包装的包衣双层片剂的稳定性数据研究
对包装的包衣双层片剂在加速[40℃/75％RH]及实时条件[25℃/60％RH和30℃/75％RH]下进行稳定性研究。在制备后即刻(最初)、在3个月及在6个月进行HPLC分析。通过HPLC方法进行的分析获得就利福喷汀相关物质和异烟肼相关物质而言的杂质总量。表1显示了利福喷汀和异烟肼在这些条件下的降解结果。结果表明就利福喷汀相关物质和异烟肼相关物质而言的杂质总量低于规定水平。
表1：来自利福喷汀和异烟肼的杂质量
实施例2：包衣单层片剂的组成
*在干燥过程中除去，在最终产品中仅以痕量存在。
包衣单层片剂的制备方法
颗粒如在实施例1中所述那样来制备，但是使用上表提及的组分。
首先将所选的利福喷汀干燥颗粒和异烟肼干燥颗粒与以下颗粒外赋形剂共混：抗坏血酸钠、淀粉羟乙酸钠和月桂基硫酸钠。然后使用硬脂酸钙将所得的共混物润滑。最后使用14mm圆形标准凹面工具在单层压片机中将润滑的共混物压制为圆形片剂。所得的单层片剂的直径和厚度分别为14mm和6.30mm。
然后使用自动包衣机和以下参数将单层片剂用溶解的EDTA二钠盐、抗坏血酸钠和商购的Opadry(Colorcon,IndiaLtd)(一种HPMC聚合物与所需添加剂的预先制成的预混物)的水溶液包衣：盘转速为4rpm至6rpm，喷淋泵速为1rpm至6rpm，入口温度为约70℃，床温度为约38℃，且雾化气压为1巴。
最后将包衣单层片剂包装在Alu-Alu泡罩中。
对包装的包衣单层片剂进行如在实施例1中的稳定性研究。表2显示了利福喷汀和异烟肼在这些条件下的降解。结果表明就利福喷汀相关物质和异烟肼相关物质而言的杂质总量低于规定水平。
表2：来自利福喷汀和异烟肼的杂质量
Claims (9)
1.用于治疗结核病的口服药物固定剂量组合物，所述口服药物组合物包含：
a)包含异烟肼和至少一种颗粒内赋形剂的颗粒，
b)包含利福喷汀和至少一种颗粒内赋形剂的颗粒，及
c)至少一种颗粒外赋形剂。
2.权利要求1的口服药物组合物，其中所述口服药物组合物是化学稳定的。
3.权利要求1或2的口服药物组合物，其中所述口服药物组合物呈包衣片剂形式。
4.权利要求1-3中任一项的口服药物组合物，其中所述口服药物组合物呈包衣双层片剂形式，其包含：
-包含异烟肼颗粒(a)和至少一种颗粒外赋形剂的层，
-包含利福喷汀颗粒(b)和至少一种颗粒外赋形剂的层，及
-膜包衣。
5.权利要求1-4中任一项的口服药物组合物，其中利福喷汀与异烟肼的比例包括5:1至1:0.5，优选所述比例为1:1。
6.制备权利要求1-5中任一项的口服药物组合物的方法，其特征在于其包括将异烟肼制粒和将利福喷汀制粒的不同步骤。
7.权利要求6的方法，其特征在于所述颗粒的制备通过湿法制粒来进行，优选在水性溶剂中进行。
8.权利要求6或7的方法，其特征在于其包括以下步骤：
a)制备异烟肼颗粒，
b)制备利福喷汀颗粒，
c)使由步骤a)和b)获得的颗粒与颗粒外赋形剂混合，
d)压制步骤c)的混合物以获得片剂，及
e)对片剂进行膜包衣。
9.权利要求6-8中任一项的方法，其特征在于其包括以下步骤：
a)制备异烟肼颗粒，
b)使由步骤a)获得的颗粒与至少一部分的颗粒外赋形剂混合，
c)制备利福喷汀颗粒，
d)使由步骤c)获得的颗粒与剩余部分的颗粒外赋形剂混合，
e)压制步骤b)和d)的混合物以获得双层片剂，及
f)对片剂进行膜包衣。
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| IN3341/CHE/2013 | 2013-07-26 | ||
| IN3341CH2013 | 2013-07-26 | ||
| PCT/EP2014/065761 WO2015011161A1 (en) | 2013-07-26 | 2014-07-22 | Anti-tuberculosis stable pharmaceutical composition in a form of a coated tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation |
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| CN115944638A (zh) * | 2022-12-26 | 2023-04-11 | 卓和药业集团股份有限公司 | 一种利福喷丁和左氧氟沙星的复方双层片 |
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| AU2014295099B2 (en) | 2013-07-26 | 2019-07-11 | Sanofi | Anti-tuberculosis stable pharmaceutical composition in a form of a dispersible tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation |
| MX2016001156A (es) | 2013-07-26 | 2016-04-29 | Sanofi Sa | Composicion antituberculosa que comprende rifampicina, isoniazid, etambutol y pirazinamida y su proceso de preparacion. |
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| Publication number | Publication date |
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| AU2014295098B2 (en) | 2019-07-11 |
| TWI651084B (zh) | 2019-02-21 |
| AU2014295098A1 (en) | 2016-02-11 |
| RU2016106384A (ru) | 2017-08-29 |
| HK1218862A1 (zh) | 2017-03-17 |
| PH12016500120A1 (en) | 2016-04-25 |
| RU2016106384A3 (zh) | 2018-05-31 |
| CL2016000182A1 (es) | 2016-06-24 |
| ECSP16005208A (es) | 2017-02-24 |
| RU2682178C2 (ru) | 2019-03-15 |
| WO2015011161A1 (en) | 2015-01-29 |
| TW201605442A (zh) | 2016-02-16 |
| EP3024443A1 (en) | 2016-06-01 |
| ZA201600109B (en) | 2017-04-26 |
| JP2016539109A (ja) | 2016-12-15 |
| MX2016001154A (es) | 2016-04-29 |
| PE20160520A1 (es) | 2016-05-31 |
| IL243368A0 (en) | 2016-02-29 |
| JP6461142B2 (ja) | 2019-01-30 |
| SG11201510730UA (en) | 2016-01-28 |
| SG10201800447UA (en) | 2018-02-27 |
| US20160158157A1 (en) | 2016-06-09 |
| CA2918827A1 (en) | 2015-01-29 |
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