CN104739821B - 稳定性提高的(z)‑2‑氰基‑3‑羟基‑丁‑2‑烯酸‑(4’‑三氟甲基苯基)‑酰胺片剂制剂 - Google Patents
稳定性提高的(z)‑2‑氰基‑3‑羟基‑丁‑2‑烯酸‑(4’‑三氟甲基苯基)‑酰胺片剂制剂 Download PDFInfo
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及包含(Z)‑2‑氰基‑3‑羟基‑丁‑2‑烯酸‑(4’‑三氟甲基苯基)‑酰胺的固体药物组合物;涉及其制备方法;涉及使用所述组合物治疗罹患自身免疫疾病,特别是系统性红斑狼疮或慢性移植物抗宿主病、多发性硬化或类风湿性关节炎的受试者的方法。
Description
本申请是2010年9月14日提交的、申请号为201080041529.8、发明名称为“稳定性提高的(Z)-2-氰基-3-羟基-丁-2-烯酸-(4’-三氟甲基苯基)-酰胺片剂制剂”的中国发明专利申请的分案申请。
技术领域
本发明涉及包含(Z)-2-氰基-3-羟基-丁-2-烯酸-(4’-三氟甲基苯基)-酰胺(通常已知为特立氟胺(Teriflunomide))的药物组合物,涉及其制备方法,涉及使用所述组合物治疗罹患自身免疫疾病(特别是系统性红斑狼疮或慢性移植物抗宿主病或多发性硬化或类风湿性关节炎)的受试者的方法。
背景技术
(Z)-2-氰基-3-羟基-丁-2-烯酸-(4’-三氟甲基苯基)-酰胺(特立氟胺)具有如式I所示的结构:
(Z)-2-氰基-3-羟基-丁-2-烯酸-(4’-三氟甲基苯基)-酰胺(特立氟胺,式I)用于治疗慢性移植物抗宿主病已经公开于美国专利4,965,276(1990年10月23日)。美国专利5,459,163(1997年10月21日)和美国专利5,679,709(1997年10月21日)公开了用于治疗自身免疫疾病(特别是红斑狼疮)的组合物。特立氟胺已经显示对很多种免疫细胞和细胞系产生抗增殖作用(Cherwinski H.M.等人,J Pharmacol.Exp.Ther.1995;272:460-8;Prkash A.等人,Drugs 1999;58(6):1137-66;Bartlett R.R.等人,Agent Action 1991;32(1-2):10-21)。此外,其抑制双氢乳清酸酯脱氢酶,其为一种嘧啶合成所必需的酶(Bruneau J-M等人,Biochem.J.1998;36:299-303)。欧洲专利1381356B1公开了特立氟胺在制备用于治疗多发性硬化的药物中的用途,其中所述药物以口服给药。国际申请WO 2007/118684公开了含来氟米特的固体药物组合物,其包含有机酸或无机酸,特征在于稳定性提高。与市售片剂相比,所述组合物中来氟米特更少地分解为特立氟胺。公开了特立氟胺的量,在每片含10mg来氟米特的片剂中其范围为0.02mg至0.511mg。与片剂的总重(150mg)相比,特立氟胺的含量小于0.35%。
对临床研究中使用的特立氟胺的药物制剂进行了开发。稳定性研究中的一个发现是一种降解产物显著增加,该产物为2-氰基-N-(4-三氟甲基-苯基)-乙酰胺且具有如式II所示的结构:
在室温12个月[特立氟胺7mg片剂,Al/PVC包装,储存于25±2℃和60%相对湿度{RH}]后,在固体药物制剂中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的浓度水平达到0.2%。另一种降解产物是4-三氟甲基-苯胺。
本发明的目的在于发现一种特立氟胺的药物制剂,其不具有2-氰基-N-(4-三氟甲基-苯基)-乙酰胺或4-三氟甲基-苯胺(4-TFMA)浓度升高所带来的缺点。
目前已经发现一些不含胶体二氧化硅的特立氟胺固体药物制剂不具有所述缺点,即2-氰基-N-(4-三氟甲基-苯基)-乙酰胺形成增加受限以及4-TFMA形成受限。
目前还发现,将酸性反应化合物加入所述不含胶体二氧化硅的特立氟胺药物制剂中是有利的。
此外还发现,将酸性反应化合物加入含胶体二氧化硅的特立氟胺固体制剂中是有利的。
发明概述
本发明是一种固体药物组合物,其包含约1%至30%重量比(w:w)的特立氟胺或其药学上可接受的碱加成盐、约5%至20%重量比的崩解剂、约0%至40%重量比的粘合剂、约0.1%至2%重量比的润滑剂,且余下的百分比包含稀释剂,条件是所述固体药物组合物不包含胶体二氧化硅。
本发明的第二个方面是一种固体药物组合物,其包含约1%至20%重量比的特立氟胺或其药学上可接受的碱加成盐、约5%至20%重量比的崩解剂、约0%至30%重量比的粘合剂、约0.1%至2%重量比的润滑剂、约1%至20%重量比的酸性反应化合物,且余下的百分比包含稀释剂。
本发明的第三个方面是一种固体药物组合物,其包含约1%至20%重量比的特立氟胺或其药学上可接受的碱加成盐、约5%至20%重量比的崩解剂、约0%至30%重量比的粘合剂、约0.1%至2%重量比的润滑剂、约1%至20%重量比的酸性反应化合物、约0.1%至0.5%重量比的胶体二氧化硅,且余下的百分比包含稀释剂。
发明详述
因此,本发明的制剂提供了一种固体药物组合物,其包含
a)约1%至30%重量比的特立氟胺,或其药学上可接受的碱加成盐,
b)约5%至20%重量比的崩解剂,
c)约0%至40%重量比的粘合剂,
d)约0.1%至2%重量比的润滑剂,且
e)余下的百分比包含稀释剂,
条件是所述固体药物组合物不包含胶体二氧化硅。
此处所用的术语具有本说明书中限定的含义。
“胶体二氧化硅(colloidal silicon dioxide)”是亚显微的烟雾硅胶,也已知为热解硅胶。其为非晶状、细颗粒、低密度和高表面积的硅胶。主要粒径为5nm至50nm。其颗粒为无孔的,且具有50m2/g至600m2/g的表面积。其可(例如)以Evonik Industries[EvonikDegussa GmbH,Inorganic Materials,Weissfrauenstraβe 9,60287 Frankfurt,Germany]制备的商品名为Aeorsil 200Pharma的产品,或Cabot Corporation(总部位于Boston,Massachusetts,U.S.A)制备的商品名为CAB-O-SIL M-5P/5DP的产品获得。
“降解产物”是指在单位剂型制备之后产生的源于药物的物质。如本领域所公知地,使用反相HPLC技术对提取的样品进行杂质和降解产物的分析。
“药学上可接受的碱加成盐”是指化合物特立氟胺的任何无毒的有机碱加成盐或无机碱加成盐。形成合适盐的例示性无机碱包括氢氧化钾,氢氧化钠,L-赖氨酸或氢氧化钙。
“患者”是指恒温动物,例如大鼠、小鼠、狗、猫、豚鼠和灵长类(例如人)。
“治疗”是指任何包括但不限于以下的处理:减轻症状、暂时性或永久性消除症状的起因,或者防止或延缓症状的出现和所述疾病或病症的进展。
“治疗有效量”是指有效治疗所述疾病或病症的该化合物的量。
“立体异构体”是指仅仅原子空间方位不同的各个分子的所有异构体的通用术语。其包括镜像异构体(对映异构体)、几何异构体(顺式/反式异构体)和具有多于一个手性中心的化合物的非镜像异构体(非对映异构体)。
“特立氟胺”是指化合物(Z)-2-氰基-3-羟基-丁-2-烯酸-(4’-三氟甲基苯基)-酰胺的通用名。特立氟胺可以以其化学制备的形式使用,或可以接受改变其颗粒的物理性质的方法。例如,所述物质可经任何本领域已知的方法研磨。所述方法的非排他性实例包括机械研磨和喷射研磨。所制颗粒(或直接从制备特立氟胺的化学方法得到,或经研磨操作后得到)优选提供范围在1μm至100μm之间的平均颗粒直径。所述固体药物组合物的制备中有利地使用1μm至100μm之间特别是重量比为约1%至10%的的特立氟胺颗粒。
特立氟胺的合成已经被公开,并且可通过本领域技术人员公知的方法实现。例如,美国专利5,990.141(1999年11月23日)公开了合成方法。
在另一实施方案中,本发明涉及固体药物组合物,其包含约2%至15%重量比的特立氟胺和显示与上面的b)至e)所限定的相同含量的其他成分崩解剂、粘合剂、润滑剂和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约7%至15%重量比的崩解剂和显示与上面的a)和c)至e)所限定的相同含量的其他成分特立氟胺、粘合剂、润滑剂和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约15%至35%重量比的粘合剂和显示与上面的a)、b)、d)和e)所限定的相同含量的其他成分特立氟胺、崩解剂、润滑剂和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约0.1%至1.0%重量比的润滑剂和显示与上面的a)至c)和e)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂和稀释剂。
崩解剂的实例是羧甲基纤维素、低取代的羟丙基纤维素、微晶纤维素、粉状纤维素、交联羧甲基纤维素钠、甲基纤维素、波拉克林钾(polacrilin potassium)、海藻酸钠、淀粉羟乙酸钠,或一种或多种所述崩解剂的混合物。
粘合剂的实例是阿拉伯胶、羧甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、糊精、明胶、瓜儿胶、羟丙基甲基纤维素、麦芽糖糊精、甲基纤维素、海藻酸钠、预胶化淀粉、淀粉例如马铃薯淀粉、玉米淀粉或谷物淀粉和玉米蛋白,或一种或多种所述粘合剂的混合物。
润滑剂的实例是硬脂酸钙、棕榈酰硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、硬脂酰富马酸钠、硬脂酸、滑石、硬脂酸锌和硬脂酸镁,或一种或多种所述润滑剂的混合物。
稀释剂的实例是纤维素、乙酸纤维素、葡聚糖结合剂(dextrates)、糊精、葡萄糖、果糖、1-O-α-D-吡喃葡糖基-D-甘露醇、棕榈酰硬脂酸甘油酯、氢化植物油、高岭土、拉克替醇(lactitol)、乳糖、乳糖一水合物、麦芽糖醇、甘露醇、麦芽糖糊精、麦芽糖、预胶化淀粉、氯化钠、山梨糖醇、淀粉、蔗糖、滑石和木糖醇,或一种或多种所述稀释剂的混合物。
在另一实施方案中,本发明涉及固体药物组合物,其包含2%至15%重量比的特立氟胺,7%至15%重量比的选自微晶纤维素或淀粉羟乙酸钠中的一种或多种的崩解剂,15%至35%重量比的选自羟丙基纤维素或玉米淀粉中的一种或多种的粘合剂,0.1%至1.0%重量比的选自硬脂酸镁的润滑剂,且余下的百分比包含选自乳糖一水合物的稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含
A)约1%至20%重量比的特立氟胺或其药学上可接受的碱加成盐,
B)约5%至20%重量比的崩解剂,
C)约0%至30%重量比的粘合剂,
D)约0.1%至2%重量比的润滑剂,
E)约1%至20%重量比的酸性反应化合物,且
F)余下的百分比包含稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约2%至15%重量比的特立氟胺和显示与上面的B)至F)所限定的相同含量的其他成分崩解剂、粘合剂、润滑剂、酸性反应化合物和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约7%至15%重量比的崩解剂和显示与上面的A)和C)至F)所限定的相同含量的其他成分特立氟胺、粘合剂、润滑剂、酸性反应化合物和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约15%至30%重量比的粘合剂和显示与上面的A)、B)和D)至F)所限定的相同含量的其他成分特立氟胺,崩解剂,润滑剂,酸性反应化合物和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约0.1%至1.0%重量比的润滑剂和显示与上面的A)至C)、E和F)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、酸性反应化合物和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约3%至20%重量比的酸性反应化合物和显示与上面的A)至D)和F)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、润滑剂和稀释剂。
酸性反应化合物的实例是柠檬酸、乙酸、羟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯基乙酸、桂皮酸、水杨酸、2-苯氧基苯甲酸、对甲苯磺酸和磺酸(例如甲磺酸和2-羟基乙磺酸),或一种或多种所述酸性反应化合物的混合物。
特立氟胺与所述崩解剂、粘合剂、润滑剂和稀释剂成分混合,以使特立氟胺和所述其他成分在最终混合物中达到根据本发明的浓度,并且最终与酸性反应化合物混合。在本发明的另一实施方案中,当水被吸收至所述药物组合物中或将少量水加入所述药物组合物中时,包含如上定义的成分A)至F)的固体药物组合物显示pH值在4.5至2.0之间。在本发明的另一实施方案中,包含如上定义的成分A)至F)的固体药物组合物显示pH值在约3至约2之间。
pH值的测定,通过将一片片剂混悬于约1ml纯净水中进行。该上清液的pH用pH灵敏探针测定。
在另一实施方案中,本发明涉及固体药物组合物,其包含
A)约1%至20%重量比的特立氟胺或其药学上可接受的碱加成盐,
B)约5%至20%重量比的崩解剂,
C)约0%至30%重量比的粘合剂,
D)约0.1%至2%重量比的润滑剂,
E)约1%至20%重量比的酸性反应化合物,
F)约0.1%至0.5%重量比的胶体二氧化硅,且
G)余下的百分比包含稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约2%至15%重量比的特立氟胺和显示与上面的B)至G)所限定的相同含量的其他成分崩解剂、粘合剂、润滑剂、酸性反应化合物、胶体二氧化硅和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约7%至15%重量比的崩解剂和显示与上面的A)和C)至G)所限定的相同含量的其他成分特立氟胺、粘合剂、润滑剂、酸性反应化合物、胶体二氧化硅和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约15%至30%重量比的粘合剂和显示与上面的A)、B)和D)至G)所限定的相同含量的其他成分特立氟胺、崩解剂、润滑剂、酸性反应化合物、胶体二氧化硅和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约0.1%至1.0%重量比的润滑剂和显示与上面的A)至C)、E)和G)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、酸性反应化合物、胶体二氧化硅和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约3%至20%重量比的酸性反应化合物和显示与上面的A)至D)和F)和G)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、润滑剂、胶体二氧化硅和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约0.2%至0.4%重量比的胶体二氧化硅和显示与上面的A)至E)和G)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、润滑剂、酸性反应化合物和稀释剂。
在另一实施方案中,本发明涉及固体药物组合物,其包含约0.3%重量比的胶体二氧化硅和显示与上面的A)至E)和G)所限定的相同含量的其他成分特立氟胺、崩解剂、粘合剂、润滑剂、酸性反应化合物和稀释剂。
特立氟胺与所述崩解剂、粘合剂、润滑剂、胶体二氧化硅和稀释剂成分混合,以使特立氟胺和所述其他成分在最终混合物中达到根据本发明的浓度,并且最终与酸性反应化合物混合。在本发明的另一实施方案中,当水被吸收至所述药物组合物中或将少量水加入所述药物组合物中时,包含如上定义的成分A)至G)的固体药物组合物显示pH值在4.5至2.0之间。在本发明的另一实施方案中,包含如上定义的成分A)至G)的固体药物组合物显示pH值在约3至约2之间。
在适于单位剂量制剂形式的特立氟胺制剂的制备之中,本发明的固体药物组合物中特立氟胺和其他成分可以以粉末形式混合。所述混合可以使用本领域已知的任何混合技术进行。所述混合优选使用高剪切混合机、V-混合机(或其他双壳拌合器(twin-shellblender))、Bin型混合机或Turbula混合振摇机来进行。所述混合通常不加入润滑剂先进行一段确保完全混合的充分时间。然后,通常在加入润滑剂之后另外混合一小段时间(约1-10分钟)。一旦混合物制成,则通过本领域已知的操作来制备单位剂量形式。优选地,单位剂量形式用旋转式压片机或胶囊充填机制备。然后,如此制备的剂量形式可任选用薄膜来包衣,所述薄膜设计用于提供易吞咽性、专利或识别外观和/或保护所述剂量形式。
或者,固体药物组合物中特立氟胺和其他成分的湿法制粒的优选方法包括以下步骤:
(a)将特立氟胺与稀释剂和任选地一些或所有最终组合物所需的余下赋形剂混合。这些其他赋形剂可包括粘合剂、崩解剂、润滑剂、酸性反应化合物和胶体二氧化硅;
(b)在步骤(a)的物质剪切时加入制粒溶剂。优选的制粒溶剂包括水、乙醇、异丙醇及其组合。如本领域已知,其他成分可加入所述制粒溶剂中。这些添加剂的实例是粘合剂、酸性反应化合物、湿润剂、稳定剂和缓冲剂。所述溶剂可以以本领域已知的任何技术应用。应用溶剂同时兼顾剪切的优选方法包括高剪切制粒、低剪切制粒、流化床制粒和挤出制粒;
(c)任选地,步骤(b)中的物质可被研磨、磨碎或过筛。然后将所述湿物质干燥,优选使用空气干燥、流化床干燥、烘箱干燥或微波干燥。所述干燥优选在不超过约60℃的干燥温度进行;
(d)任选地,然后将所述物质研磨或过筛;
(e)然后将该物质与其他赋形剂混合;和
(f)任选地,将该组合物制成单位剂量形式,优选片剂或胶囊。
然后,如此制备的剂量形式可任选用薄膜来包衣,所述薄膜设计用于提供易吞咽性、专利或识别外观和/或保护所述剂量形式。
使用本领域已知的操作将最终剂量形式包装。对于本发明,所述包装优选以箔材-箔材冷成型泡罩(foil-foil cold form blisters)、塑料泡罩(plastic blisters)或者带有或不带有干燥剂的密封瓶。对于泡罩包装材料,其水蒸气渗透率优选低于0.25g/m2/天。
本发明的固体药物组合物可以以治疗有效量以任何使得化合物可生物利用的形式或方式给药,包括口服、舌下、含服、经皮、鼻内、经直肠、局部等。根据待治疗的具体特征性疾病、疾病所处阶段、患者的状况和其他相关情况,制剂领域的技术人员能够确定给药的合适形式和方式。例如,参见Remington's Pharmaceutical Sciences,18th Edition,MackPublishing Co.(1990)。
本发明的固体药物组合物可口服给药,例如以片剂、含片、胶囊、薄片(wafer)、咀嚼胶(chewing gum)等形式。
其他剂量单位形式可包含多种其他物质,其修饰了所述剂量单位的物理形式,例如作为包衣。因此片剂或丸剂可用非功能性包衣(如羟丙基甲基纤维素包衣)、糖、虫胶或其他肠溶包衣剂来包衣。
使特立氟胺显示出治疗作用的剂量范围可因严重程度、患者、所述患者患有的其他潜在疾病(underlying disease)状况、以及同时向所述患者给药的其他药物等很多因素而不同。通常,特立氟胺在以下剂量显示其治疗活性:约0.001mg/kg患者体重/天至约100mg/kg患者体重/天之间
本发明的固体药物组合物适于例如治疗急性免疫事件,例如败血病、变态反应、移植物抗宿主反应和宿主抗移植物反应、自身免疫疾病(例如类风湿性关节炎、系统性红斑狼疮或多发性硬化、牛皮癣、哮喘、荨麻疹、鼻炎和眼色素层炎)、癌性疾病(例如肺癌、白血病、卵巢癌、肉瘤、卡波西肉瘤、脑脊膜瘤、肠癌、淋巴结癌、脑瘤、乳腺癌、胰腺癌、前列腺癌或皮肤癌)。
下面的非限制性实施例示例性地说明了发明人制备和使用本发明的药物组合物的优选方法。
实施例
实施例1:制备方法
制粒液体:
将羟丙基纤维素7.5mPa*s(HPC)和柠檬酸一水合物溶解于219.3g纯净水中,并搅拌至少30分钟。相比于水的质量(不考虑所加入柠檬酸的量),最终溶液中HPC的浓度为6.4%。(表1)。
表1:制粒液体的组成
片剂:
1.将特立氟胺、乳糖或甘露醇(0C和0D)、玉米淀粉和(需要时的)柠檬酸一水合物(1D和1J)在流化床制粒机(UNI Glatt,拍打25%,进入空气温度~23℃,振摇间隔30秒,振摇5秒)中混合5分钟。
2.用HPC溶液和(需要时的)柠檬酸将所得混合物在流化床制粒机(UNI Glatt,拍打25-30%,进入空气温度60℃,振摇间隔60秒,振摇5秒,喷射速率~12.5g/分钟,雾化气压1巴,喷嘴直径0.8mm)中制粒。持续大约25分钟。
3.将该颗粒在流化床制粒机(UNI Glatt,拍打25-30%,进入空气温度60℃,振摇间隔60秒,振摇5秒)中干燥大约20分钟。
4.将该颗粒通过1mm筛校准,并用微晶纤维素、羟乙酸淀粉钠和(需要时的)胶体二氧化硅(实施例1F–1J)在Turbula混合机[2L玻璃容器]中润滑5分钟。
5.加入硬脂酸镁后,将该混合物在Turbula混合机[2L玻璃容器]中再混合一分钟。
用Korsch EK0单冲压片机将最终混合物压制成片剂。
所制备固体药物组合物的组成在表1、表2和表3中给出。
表1:
含胶体二氧化硅和不含胶体二氧化硅的特立氟胺片剂的组成(0A至0D)
上表中“xx”指未加入该成分
表2:
经柠檬酸酸化且不含胶体二氧化硅的特立氟胺片剂的组成
上表中“xx”指未加入该成分
表3:
经柠檬酸酸化且含有胶体二氧化硅的特立氟胺片剂的组成
上表中“xx”指未加入该成分
实施例2:2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的制剂
片剂的制备
根据实施例1给出的制备方法制备所述片剂。所述片剂的组成在表1、表2和表3中给出。
片剂的储存
样品在感应密封的HDPE瓶[广口瓶,45mL,白色,周围有感应密封和防止儿童开启的螺旋帽]中在25℃/60%RH、30℃/65%RH、40℃/75%RH的条件,和在开口玻璃瓶中在40℃/75%RH的条件储存长达6个月。瓶子直立地存放。
样品的分析
片剂通过HPLC检测含量。
片剂(经柠檬酸酸化,含有或不含有胶体二氧化硅)中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的含量在表4中给出。
表4:
在含有与不含胶体二氧化硅的片剂(0A和0B)中,和在不含胶体二氧化硅的酸化片剂制剂(1A至1D)中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的形成
“RSD”指相对标准偏差((数组X的标准偏差)×100/(数组X的平均值)=相对标准偏差)。
“RH”指相对湿度;空气-水混合物的相对湿度定义为该混合物中水蒸气的分压与指定温度下水的饱和蒸气压之比。
在开始时(0个月)和1个月、3个月、6个月之后,在每批次样品中测定4个样品的值。表中只给出所测试样品的平均值和RSD值。
经柠檬酸酸化的含有胶体二氧化硅的片剂中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的含量在表5中给出。
表5:
含有胶体二氧化硅的酸化片剂中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的形成
在开始时(0个月)和1个月、3个月、6个月之后,在每批次样品中测定4个样品的值。表中只给出所测试样品的平均值和RSD值。
在上述储存条件下在HDPE瓶中储存3或6个月后,与含有胶体二氧化硅的特立氟胺片剂(实施例0B)相比,含25mg柠檬酸、经或不经胶体二氧化硅润滑的特立氟胺片剂[实施例1C,D,I,J]和不含柠檬酸但不经胶体二氧化硅润滑的特立氟胺片剂(实施例0A)显示,2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的形成显著减少。在感应密封的HDPE瓶中,柠檬酸的稳定作用在胶体二氧化硅存在时变得更显著。
通过如下所示的梯度高效液相色谱系统(HPLC)进行特立氟胺、2-氰基-N-(4-三氟甲基-苯基)-乙酰胺和4-TFMA的测定:
流动相
通过向用于流动相的玻璃瓶中转移50mmol(4.2g)乙酸钠、50mmol(2.9g)氯化钠并加入1000mL水而制备缓冲液。利用pH计用冰乙酸将pH调节至6.5。
梯度:
操作:
保留时间:
特立氟胺 约15.0分钟
2-氰基-N-(4-三氟甲基-苯基)-乙酰胺 约19.3分钟
4-TFMA 约19.8分钟
实施例3:片剂的pH测定
通过将一片片剂混悬于约1ml纯净水中进行pH值的测定。在片剂崩解并且其固体内容物沉降之后,用pH敏感探针测定上清液的pH。将两片单独片剂的平均结果报告为片剂的pH(见表2和表3)。
实施例4:含有与不含胶体二氧化硅的特立氟胺片剂中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺和4-TFMA的形成
片剂的制备
根据实施例1给出的制备方法制备所述片剂。所述片剂的组成在表1中给出。
片剂的储存
在附加的稳定性研究中,样品在感应密封的HDPE瓶[广口瓶,60mL,白色,周围有感应密封和防止儿童开启的螺旋帽]中在40℃/75%RH的条件储存6个月。瓶子直立地存放。
样品的分析
片剂通过HPLC检测相关杂质(使用上述方法)。
在40℃/75%RH储存6个月后,在含有或不含胶体二氧化硅的片剂中,2-氰基-N-(4-三氟甲基-苯基)-乙酰胺和4-TFMA的含量在表6中给出。
表6:在含有和不含胶体二氧化硅的片剂(0A和0B)中2-氰基-N-(4-三氟甲基-苯基)-乙酰胺和4-TFMA的形成
在上述储存条件下在HDPE瓶中储存6个月后,与含胶体二氧化硅的特立氟胺片剂(实施例0B和0C)相比,不经胶体二氧化硅润滑的特立氟胺片剂(实施例0A和0D)显示,2-氰基-N-(4-三氟甲基-苯基)-乙酰胺的形成显著减少。此外,与经胶体二氧化硅润滑的片剂(实施例0B和0C)相比,不含胶体二氧化硅的片剂(实施例0A和0D)中4-TFMA的形成显著减少。
特立氟胺、2-氰基-N-(4-三氟甲基-苯基)-乙酰胺和4-TFMA的测定通过实施例2中所述的梯度高效液相色谱系统(HPLC)进行。
Claims (13)
1.一种固体药物组合物,其由以下成分组成:
a)1%至30%重量比的特立氟胺或其药学上可接受的碱加成盐,
b)5%至20%重量比的崩解剂,
c)0%至40%重量比的粘合剂,
d)0.1%至2%重量比的润滑剂,和
e)余下的百分比包含稀释剂,
条件是所述固体药物组合物不包含胶体二氧化硅。
2.一种固体药物组合物,其由以下成分组成:
a)2%至15%重量比的特立氟胺或其药学上可接受的碱加成盐,
b)7%至15%重量比的崩解剂,
c)15%至35%重量比的粘合剂,
d)0.1%至1.0%重量比的润滑剂,和
e)余下的百分比包含稀释剂,
条件是所述固体药物组合物不包含胶体二氧化硅。
3.根据权利要求1或2所述的固体药物组合物,其中所述崩解剂选自羧甲基纤维素、低取代的羟丙基纤维素、微晶纤维素、粉状纤维素、交联羧甲基纤维素钠、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠,或一种或多种所述崩解剂的混合物。
4.根据权利要求3所述的固体药物组合物,其中所述崩解剂选自低取代的羟丙基纤维素、微晶纤维素、粉状纤维素、交联羧甲基纤维素钠、淀粉羟乙酸钠,或一种或多种所述崩解剂的混合物。
5.根据权利要求1或2所述的固体药物组合物,其中所述粘合剂选自阿拉伯胶、羧甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、糊精、明胶、瓜儿胶、羟丙基甲基纤维素、麦芽糖糊精、甲基纤维素、海藻酸钠、预胶化淀粉、马铃薯淀粉、玉米淀粉或谷物淀粉和玉米蛋白或一种或多种所述粘合剂的混合物。
6.根据权利要求5所述的固体药物组合物,其中所述粘合剂选自羟基丙基纤维素、羟丙基甲基纤维素、预胶化淀粉、马铃薯淀粉、玉米淀粉或谷物淀粉,或一种或多种所述粘合剂的混合物。
7.根据权利要求1或2所述的固体药物组合物,其中所述润滑剂选自硬脂酸钙、棕榈酰硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、硬脂酰富马酸钠、硬脂酸、滑石、硬脂酸锌和硬脂酸镁,或一种或多种所述润滑剂的混合物。
8.根据权利要求7所述的固体药物组合物,其中所述润滑剂选自硬脂酰富马酸钠和硬脂酸镁,或一种或多种所述润滑剂的混合物。
9.根据权利要求1或2所述的固体药物组合物,其中所述稀释剂选自纤维素、乙酸纤维素、葡聚糖结合剂、糊精、葡萄糖、果糖、1-O-α-D-吡喃葡糖基-D-甘露醇、棕榈酰硬脂酸甘油酯、氢化植物油、高岭土、拉克替醇、乳糖、乳糖一水合物、麦芽糖醇、甘露醇、麦芽糖糊精、麦芽糖、预胶化淀粉、氯化钠、山梨糖醇、淀粉、蔗糖、滑石和木糖醇,或一种或多种所述稀释剂的混合物。
10.根据权利要求9所述的固体药物组合物,其中所述稀释剂选自乳糖、乳糖一水合物、甘露醇和淀粉,或一种或多种所述稀释剂的混合物。
11.根据权利要求1或2所述的固体药物组合物,其中所述组合物用羟丙基甲基纤维素包衣进行包衣。
12.一种固体药物组合物,其由以下成分组成:
A)1%至20%重量比的特立氟胺或其药学上可接受的碱加成盐,
B)5%至20%重量比的崩解剂,
C)0%至30%重量比的粘合剂,
D)0.1%至2%重量比的润滑剂,
E)1%至20%重量比的酸性反应化合物,其中所述酸性反应化合物选自柠檬酸、乙酸、羟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯基乙酸、桂皮酸、水杨酸、2-苯氧基苯甲酸和磺酸,或一种或多种所述酸性反应化合物的混合物,且
F)余下的百分比包含稀释剂。
13.权利要求1至12中任一项所述的固体药物组合物在制备用于治疗以下疾病的药物中的用途:败血病、变态反应、移植物抗宿主反应、宿主抗移植物反应、类风湿性关节炎、系统性红斑狼疮、多发性硬化、牛皮癣、荨麻疹、鼻炎、眼色素层炎、肺癌、白血病、卵巢癌、肉瘤、脑脊膜瘤、肠癌、淋巴结癌、脑瘤、乳腺癌、胰腺癌、前列腺癌或皮肤癌。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09290716.1 | 2009-09-18 | ||
EP09290716 | 2009-09-18 | ||
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UA (2) | UA115979C2 (zh) |
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JOP20190207A1 (ar) | 2017-03-14 | 2019-09-10 | Actelion Pharmaceuticals Ltd | تركيبة صيدلانية تشتمل على بونيسيمود |
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