CN102143737A - 制备西替利嗪片剂的方法 - Google Patents
制备西替利嗪片剂的方法 Download PDFInfo
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- CN102143737A CN102143737A CN2009801350955A CN200980135095A CN102143737A CN 102143737 A CN102143737 A CN 102143737A CN 2009801350955 A CN2009801350955 A CN 2009801350955A CN 200980135095 A CN200980135095 A CN 200980135095A CN 102143737 A CN102143737 A CN 102143737A
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- tablet
- cetirizine
- polyhydric alcohol
- weight
- solvent
- Prior art date
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- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 title claims abstract description 101
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- 238000000034 method Methods 0.000 title claims abstract description 59
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Abstract
在一个方面,本发明主要涉及一种制备包含西替利嗪的片剂的方法,其包括以下步骤:(i)将西替利嗪、多元醇和西替利嗪的溶剂混合以形成西替利嗪:多元醇复合物,其中溶剂包含水和碱化剂且pH值为约2至约7;(ii)将西替利嗪:多元醇复合物的颗粒与混合物分离;以及(iii)将颗粒形成为片剂。
Description
相关专利申请的交叉引用
本专利申请要求2008年9月5日提交的美国临时专利申请No.61/094,605的优先权的权益,其内容以引用方式并入。
背景技术
诸如环糊精、糖和其他碳水化合物之类的多元醇被用于包含药物活性剂的片剂中来达到各种目的,诸如对咀嚼片的掩味目的或对速溶片剂的体积充填目的。然而,药物活性剂西替利嗪具有苦味且极易通过与多元醇的酯化作用而降解。PCT专利申请WO 03/059328公开了可通过形成非常干燥的环境和/或物理地隔离片剂中的西替利嗪和多元醇来控制西替利嗪的酯化。然而,此方法不能形成用于掩味目的的有效环境,致使所得片剂的初始味道为苦味,因为西替利嗪须最初溶于口中,然后再引发片剂中多元醇的“原位”掩味作用。
然而,申请人意外地发现一种方法,通过该方法西替利嗪与多元醇可被物理结合以用于片剂中,而不导致西替利嗪显著酯化。具体地讲,意外地发现结合湿配法添加碱化剂可使得西替利嗪和多元醇共存于同一制剂中,并且还意外地发现其含量高于PCT专利申请WO 03/059328中指定的十摩尔当量。通过将西替利嗪和多元醇以湿配方组合,现有可能使西替利嗪-多元醇的复合发生在片剂制造过程中,从而避免了上述原位复合的缺点。
发明内容
在一个方面,本发明主要涉及一种制备包含西替利嗪的片剂的方法,其包括以下步骤:(i)将西替利嗪、多元醇和西替利嗪的溶剂混合以形成西替利嗪:多元醇复合物,其中溶剂包含水和碱化剂且pH值为约2至约7;(ii)将西替利嗪:多元醇复合物的颗粒从所述混合物分离;以及(iii)将颗粒形成为片剂。在另一方面,本发明主要涉及一种通过此方法制备的包含西替利嗪的片剂。
通过本发明的详细描述和权利要求书,本发明的其他特征和优点将变得显而易见。
具体实施方式
据信,本领域技术人员可以在此处描述的基础上,充分利用本发明。下面的具体实施例可理解为仅为示例性的,并且无论如何都不会以任何方式限制本公开内容的其余部分。
除非另有规定,本文使用的所有技术和科学术语,具有本发明所属技术领域公知的相同含义。另外,将本文提及的所有出版物、专利申请、专利和其他参考文献以引用方式并入本文中。本文所用的所有百分比均按重量计,除非另外指明。
西替利嗪
所谓西替利嗪是指化合物[2-[4-[(4-氯苯基)苯基甲基]-1-哌嗪基]乙氧基]乙酸,包括其异构体(例如称为左西替利嗪的2-[2-[4-[(R)-(4-氯苯基)-苯基-甲基]哌嗪-1-基]乙氧基]乙酸)及其药用盐(例如二盐酸西替利嗪和二盐酸左西替利嗪)。
在一个实施例中,颗粒包含约0.5至约20重量%的西替利嗪,例如约1至约10重量%的西替利嗪。在一个实施例中,该片剂包含约0.5mg至约20mg的西替利嗪,例如约1mg至约10mg的西替利嗪。
多元醇
所谓多元醇是指含有两个或更多个羟基的化合物。多元醇的例子包括(但不限于):诸如甘露糖醇、木糖醇、山梨醇和赤藓醇之类的糖醇;诸如蔗糖、果糖、甘露糖、右旋糖、乳糖(如一水乳糖)和异麦芽之类的糖;诸如β-环糊精和α-环糊精之类的环糊精。
在一个实施例中,这些颗粒包含约25至约95重量%的一种或多种多元醇,例如约40至约90重量%(约45至约70重量%)的一种或多种多元醇。在一个实施例中,该片剂包含约50至约98重量%的一种或多种多元醇,例如约80至约95重量%的一种或多种多元醇。
溶剂
本发明的方法涉及将西替利嗪溶解于含水溶剂中。该溶剂也可包含醇,诸如乙醇、甲醇和异丙醇以及它们的混合物。
在一个实施例中,溶剂的pH值为约2至约7,例如约2.4至约4。申请人已发现,过度增加pH可导致西替利嗪的叔胺基中和,使得其易于氧化或发生其他形式的可被质子化胺盐抑制的降解。因此,重要的是将pH(例如,所用碱化剂的量)以这样的方式平衡,即抑制酯化同时还保持叔胺官能团充分质子化,使它们的稳定性不受影响。此外,此方法使得西替利嗪对于向羰基碳的任何亲核加成(包括(但不限于):酰胺化反应)保持稳定。
在一个实施例中,碱化剂被添加到溶剂中。可用于增加溶剂pH的碱化剂的例子包括(但不限于):碳酸氢钠和柠檬酸钠、抗坏血酸钠、磷酸、硫酸、磺酸的钠盐和其他盐、碱性盐例如氢氧化铝、碱式碳酸镁、碳酸钙、氢氧化镁、碳酸镁、碱式碳酸铝镁、缓血酸胺、琥珀酸二钠、磷酸氢二钠、磷酸三钠、磷酸二钾以及左型精氨酸。
在一个实施例中,添加到西替利嗪和多元醇混合物中的碱化剂的量处于足以使酯降解和氧化降解成为最小的水平。通过将片剂在40℃和75%相对湿度的加速条件下储存3个月后分析得到的降解量来测定降解,该降解量取决于西替利嗪初始量的百分比。在一个实施例中,西替利嗪:多元醇的酯降解物含量小于0.5%,并且最大的西替利嗪氧化降解物含量小于0.5%,例如小于0.2%。在一个实施例中,以约0.25至约1.5摩尔当量的西替利嗪(例如约0.5至约1摩尔当量的西替利嗪)的量添加碱化剂。
包含西替利嗪:多元醇复合物的颗粒的制备
包含西替利嗪:多元醇复合物的颗粒可以用包括喷雾干燥和湿法制粒在内的多种方法制备和分离(例如,通过干燥除去溶剂)。喷雾干燥方法涉及将溶剂与西替利嗪、多元醇和碱化剂混合成浆料或悬浮液,其中将该浆料或悬浮液以一步法喷洒并干燥,该一步法得到包含这些材料的均匀的颗粒状物或颗粒。
湿法制粒涉及多种方法,这些方法包括低剪切搅拌器(例如行星式搅拌器)、高剪切制粒和流化床制粒。在这些方法中,将溶剂添加到多元醇和西替利嗪中,随后将结合成的复合物在盘式烘箱或流化床处理装置中干燥。在高剪切湿法制粒的一个实施例中,将碱化剂添加到包含溶剂的制粒液体中,并且喷洒或分配至包含西替利嗪和多元醇的流化床,随后干燥该混合物。在高剪切湿法制粒的另一个实施例中,将碱化剂和西替利嗪添加到包含溶剂的制粒液体中,随后分配到包含多元醇的流化床中,之后接着干燥该混合物。在高剪切湿法制粒的另一个实施例中,将多元醇、西替利嗪和碱化剂在高剪切制粒机中共混,将包含溶剂的制粒液体分配到该混合物中,随后干燥所得混合物。在另一个实施例中,将单独的粘合剂添加到制粒液体中或流化床中,以便于材料物理地粘合成颗粒状物。合适的湿粘合剂包括(但不限于):羟丙甲纤维素、聚乙烯吡咯烷酮、预胶凝淀粉、熟淀粉和羟丙基纤维素。
在流化床制粒的一个实施例中,将多元醇和西替利嗪添加至流化床,将碱化剂添加到包含溶剂的制粒液体中并喷洒到流化床上,之后接着干燥所得混合物。在流化床制粒的另一个实施例中,将多元醇和碱化剂添加至流化床,将西替利嗪添加到包含溶剂的制粒液体中并喷洒到流化床上,之后接着干燥所得混合物。在流化床制粒的另一个实施例中,将多元醇、碱化剂和西替利嗪添加至流化床,将包含溶剂的制粒液体喷洒到流化床上,之后接着干燥所得混合物。在流化床制粒的另一个实施例中,将多元醇添加至流化床,将西替利嗪和碱化剂添加到包含溶剂的制粒液体中并喷洒到流化床上,之后接着干燥所得混合物。在流化床制粒的这些实例中,将西替利嗪溶解于制粒液体中并喷洒到多元醇基材或多元醇和碱化剂基材上,此法在本文中也称为药物分层。在一个实施例中,多元醇也可与诸如微晶纤维素之类的惰性基材组合。
在一个实施例中,然后所得颗粒状材料可被干燥,并可选地与另外的成分(例如赋形剂,如润滑剂和着色剂)进行干混。最终的干混物即适用于压制。直接压制方法和湿法制粒方法是本领域已知的。在一个实施例中,片剂基质包含湿法制粒,其被配制成具有调释特性。如本文所用,术语“基质”被定义为不包括含有西替利嗪和多元醇的颗粒状物或层状颗粒的片剂部分。
在一个实施例中,包含西替利嗪和多元醇的复合物还包含第二活性成分。在一个实施例中,该第二活性成分用于治疗上呼吸道疾病,例如选自去氧肾上腺素、氯雷他定、非索非那定、苯海拉明、右美沙芬、氯苯那敏、氯苯达诺和伪麻黄碱的药物活性剂。
在一个实施例中,西替利嗪:多元醇复合物中或基质中的第二活性成分为止痛药、非甾体抗炎剂和退热剂。合适的止痛剂、抗炎剂和解热剂的例子包括(但不限于):非甾体抗炎药(NSAID),如丙酸衍生物(例如布洛芬、萘普生、酮洛芬、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、比丙芬、卡洛芬、丙嗪、普拉洛芬和舒洛芬)和COX抑制剂,如塞来考昔;对乙酰氨基酚;乙酰水杨酸;乙酸衍生物,如吲哚美辛、双氯芬酸、舒林酸和托美丁;芬那酸衍生物,如甲芬那酸、甲氯芬那酸和氟芬那酸;联苯羧酸衍生物,如二氟尼柳和氟苯柳;和昔康类,如吡罗昔康、舒多昔康、伊索昔康和美洛昔康;它们的异构体;以及它们的可药用盐和前药。
片剂的制备
在本发明的一个实施例中,将包含西替利嗪和多元醇的颗粒与片剂基质混合。在一个实施例中,载体的平均粒度为约50微米至约500微米,例如在50微米和300微米之间。在这个大小范围的颗粒尤其适用于直接压制方法。
在实施例中,载体组分与颗粒共混在一起(例如混合为干粉末)以形成片剂基质,并送入加压而形成片剂的设备的模腔中。可使用任何合适的压实设备,包括(但不限于):常规的单冲式或旋转式压片机。在一个实施例中,可通过用旋转式压片机(例如,诸如Fette America Inc.(Rockaway,N.J.)或Manesty Machines LTD(Liverpool,UK)市售的那些)进行压实来形成片剂。通常,将定量体积的片剂基质填充到旋转式压片机的模腔中,其中片剂基质以重力或者机械方式从送料器送入,并且模腔作为“模具台”的一部分从填充位置旋转至压实位置。在压实位置,片剂基质在上冲头和下冲头之间被压实,然后所得片剂通过下冲头从模腔被推出,接着通过静止的“引离棒(take-off bar)”引导至注射斜槽。有利地,当使用直接压制方法时,其可最小化或消除可能对溶解有负面影响的水溶性、非糖类聚合物粘合剂,如聚乙烯吡咯烷酮、海藻酸盐、羟丙基纤维素和羟丙基甲基纤维素、羟乙基纤维素。
在另一个实施例中,片剂可通过在美国专利申请公布No.20040156902中所描述的压制方法和设备来制备。具体地讲,可用单个设备中的包括填充区、插入区、压制区、顶出区和清除区的旋转压制模块来制备片剂,该单个设备具有双排压膜构造。然后可借助真空对压制模块的压膜进行填充,每个压膜之中或附近设置有过滤器。压制模块的清除区包括可选的片剂基质回收系统,用以将过量的片剂基质从过滤器回收并将片剂基质返回压膜。
在一个实施例中,该片剂通过公布的美国专利No.6,767,200中描述的压制方法和设备来制备,该专利的公开内容以引用方式并入本文中。具体地讲,片剂可用具有双排压膜构造的单个设备中的包括填充区、压制区、顶出区的旋转压制模块来制备,如本文图6所示。优选借助真空对压制模块的压膜进行填充,每个压膜之中或附近带有过滤器。
在本发明的一个实施例中,片剂可为从基本上不含水溶性聚合物粘合剂和水合聚合物的基质制成的直接压制片剂。本文所用的“基本上不含”是指小于5重量%,如小于1重量%,如小于0.1重量%,如完全不含(例如0重量%)。该组合物对于保持速释溶出特性(profile)、使加工和材料成本减至最低以及使片剂的物理和化学稳定性最佳是有利的。在一个实施例中,片剂的密度大于约0.9g/cc。
该片剂可具有多种不同形状中的其中一种。例如,片剂可成形为多面体,如立方体、棱椎、棱柱等;或者可具有带一些非平坦表面的空间外形的几何形状,如圆锥体、截头圆锥体、圆柱体、球体、圆环体等。在某些实施例中,片剂具有一个或多个主表面。例如,片剂表面通常具有通过与压制机器中的上冲头表面和下冲头表面接触而形成的相对的上表面和下表面。在这类实施例中,片剂表面通常还包括位于上表面和下表面之间的“腹带”,其通过与压制机器中的压膜壁接触而形成。片剂还可以是多层片剂。或者,如果相同组成的片剂要用于剂型中,则压制模块可装配有多头压制模具。例如,可将四头模具用于在一个压膜内制备四片片剂。片剂可具有单层或多层。
在一个实施例中,片剂基质含有第二活性成分。在一个实施例中,第二活性成分用于治疗上呼吸道疾病,其中药物活性剂选自去氧肾上腺素、氯雷他定、非索非那定、苯海拉明、右美沙芬、氯苯那敏、氯苯达诺和伪麻黄碱。
在某些实施例中,可用本文所述的发明制备多层片剂(例如可制备双层或三层片剂)。在一个实施例中,片剂模被填充第一部分片剂基质,并可选地首次推压片剂基质底座,然后加入第二部分片剂基质并压制片剂,然后将片剂从压膜顶出。在一个实施例中,第二部分片剂基质具有与第一部分片剂基质相同的共混物组成。在另一个实施例中,第二部分片剂基质具有与第一部分片剂基质不同的组成。在一个实施例中,第一部分片剂基质含有药物活性剂(例如,本发明的西替利嗪和多元醇颗粒状物),而第二部分片剂基质含有不同的药物活性剂。在一个实施例中,第一部分是为了即释,第二部分是为了调释。在一个实施例中,第一部分含有第一和第二药物活性剂的即释剂量,而第二部分含有一部分的包覆有本发明包衣的第一药物活性剂并含有含第二药物活性剂的调释片剂基质。
在另一个实施例中,片剂被制成口腔崩解片。在此类实施例中,本发明的西替利嗪-多元醇复合物与载体混合并形成为这种片剂。在一个实施例中,口腔崩解片符合2007年4月出版的《食品和药品管理指南草案》定义的口腔崩解片的标准,该草案以引用方式并入本文中。在一个实施例中,该口腔崩解片符合包括下述标准的适用于口腔崩解片的双重定义:1)该片剂为包含药用物质并且在置于舌头上时在几秒内快速崩解的片剂,和2)被视为固体口服剂型,其在根据美国药典(USP)用于一种或多种特定药用物质的崩解测试方法测试时,在口腔中在大约30秒或更短的体外崩解时间内快速崩解。
在制备口腔崩解片的实施例中,包含载体的片剂基质和西替利嗪:多元醇复合物在预成型模具或泡罩中成形。在一个实施例中,口腔崩解片通过冻干方法制备。用于通过冻干方法制备的片剂的合适载体包括(但不限于):诸如一水乳糖的乳糖和诸如一水右旋糖的右旋糖。还可将树胶或粘度调节剂(诸如黄原胶、羟丙甲纤维素、刺槐豆胶、藻酸钠和角叉菜胶)添加到基质中。还可将诸如粘合剂、甜味剂和酸化剂的其他材料添加到基质中。在采用冻干法制备这种片剂的一个实施例中,将西替利嗪:多元醇颗粒状物与基质载体材料和冻干溶剂混合,引入模具或泡罩中,冷冻干燥并包装或密封。
片剂基质
如上所述,在一个实施例中,通过将颗粒与片剂基质混合来制备片剂。载体可含有一种或多种适用于配制片剂的赋形剂。合适的赋形剂的例子包括(但不限于):填充剂、吸附剂、粘合剂、崩解剂、润滑剂、助流剂、调节释放的赋形剂、甜味剂、超级崩解剂、矫味剂和芳香剂、抗氧化剂、质构增强剂以及它们的混合物。
合适的填料包括(但不限于):水溶性可压制碳水化合物,如糖(例如右旋糖、蔗糖、麦芽糖和乳糖)、淀粉(例如玉米淀粉)、糖醇(例如甘露糖醇、山梨糖醇、麦芽糖醇、赤藓糖醇和木糖醇)、淀粉水解物(例如糊精和麦芽糊精)和水不溶性塑性变形材料(例如微晶纤维素或其他纤维素衍生物)以及它们的混合物。在一个实施例中,将包含多元醇、西替利嗪和碱化剂的预复合颗粒状物与不含西替利嗪的合适填料共混,随后压制成基质片剂。在一个实施例中,包含填料的基质基本上不含碱化剂。如本文所用,“基本上不含”定义为小于约0.5(例如0.1)重量%的基质。在一个采用多层片剂的实施例中,第二层不含西替利嗪且基本上不含碱化剂。
合适的吸附剂(例如吸附液态药物组合物)包括(但不限于):水不溶性吸附剂,如磷酸二钙、磷酸三钙、硅酸化微晶纤维素(例如,如以商品名PROSOLV(PenWest Pharmaceuticals,Patterson,NY)配销的)、偏硅酸铝镁(例如,如以商品名NEUSILINTM(Fuji Chemical Industries(USA)Inc.,Robbinsville,NJ)配销的)、黏土、二氧化硅、膨润土、沸石、硅酸镁、水滑石、veegum以及它们的混合物。
合适的粘合剂包括(但不限于):干粘合剂如聚乙烯吡咯烷酮和羟丙基甲基纤维素;湿粘合剂如水溶性聚合物,包括亲水胶体如阿拉伯胶、海藻酸盐、琼胶、瓜尔豆胶、刺槐豆胶、卡拉胶、羧甲基纤维素、他拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、明胶、麦芽糊精、半乳甘露聚糖、石耳素、海带多糖、小核菌葡聚糖、菊粉、威兰胶(whelan)、鼠李胶(rhamsan)、菌胶团(zooglan)、甲兰胶、几丁质、环糊精、壳聚糖、聚乙烯吡咯烷酮、纤维素、蔗糖和淀粉;以及它们的混合物。
合适的崩解剂包括(但不限于):羟基乙酸淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素、淀粉类、微晶纤维素,以及它们的混合物。
合适的润滑剂包括(但不限于):长链脂肪酸以及它们的盐(例如硬脂酸镁和硬脂酸)、滑石、甘油酯、蜡,以及它们的混合物。
合适的助流剂包括(但不限于):胶态二氧化硅。
合适的调节释放的赋形剂包括(但不限于):溶胀性可溶蚀亲水性材料、不溶性可食用材料、pH依赖性聚合物,以及它们的混合物。
适于用作调节释放的赋形剂的溶胀性可溶蚀亲水性材料包括(但不限于):水溶胀性纤维素衍生物、聚亚烷基二醇、热塑性聚环氧烷、丙烯酸类聚合物、亲水胶体、粘土、胶凝淀粉、溶胀交联聚合物,以及它们的混合物。合适的水可溶胀纤维素衍生物的例子包括(但不限于):羧甲基纤维素钠、交联羟丙基纤维素、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟基异丙基纤维素、羟丁基纤维素、羟苯基纤维素、羟乙基纤维素(HEC)、羟戊基纤维素、羟丙基乙基纤维素、羟丙基丁基纤维素和羟丙基乙基纤维素以及它们的混合物。合适的聚亚烷基二醇的例子包括(但不限于):聚乙二醇。合适的热塑性聚环氧烷的例子包括(但不限于):聚环氧乙烷。合适的丙烯酸类聚合物的例子包括(但不限于):甲基丙烯酸钾二乙烯基苯共聚物、聚甲基丙烯酸甲酯、高分子量交联丙烯酸均聚物和共聚物(可从Noveon Chemicals商购获得,商品名为CARBOPOLTM(例如当分散在碱性溶液中,采用布氏RVT型粘度计,用7号转子在25℃下测试时,具有大于50,000厘泊的粘度))。合适的亲水胶体的例子包括(但不限于):海藻酸盐、琼脂、瓜耳胶、刺槐豆胶、k卡拉胶、ι卡拉胶、塔拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、麦芽糊精、半乳甘露聚糖、石耳素、昆布多糖、小核菌葡聚糖、阿拉伯树胶、菊粉、果胶、明胶、威兰胶、鼠李胶、菌胶团、甲兰胶、几丁质、环糊精、壳聚糖,以及它们的混合物。合适的黏土的例子包括(但不限于):绿土如膨润土、高岭土和合成锂皂石(laponite);三硅酸镁;硅酸镁铝;以及它们的混合物。合适的胶化淀粉的例子包括(但不限于):酸水解淀粉、溶胀淀粉(例如羟基乙酸淀粉钠及其衍生物),以及它们的混合物。合适的溶胀交联聚合物的例子包括(但不限于):交联聚乙烯吡咯烷酮、交联琼脂和交联羧甲基纤维素钠,以及它们的混合物。
适于用作调节释放的赋形剂的不溶性可食用材料包括(但不限于):水不溶性聚合物和低熔点疏水性材料、它们的共聚物,以及它们的混合物。合适的水不溶性聚合物的例子包括(但不限于):乙基纤维素、聚乙烯醇、聚乙酸乙烯酯、聚己酸内酯、乙酸纤维素及其衍生物、丙烯酸酯、甲基丙烯酸酯、丙烯酸共聚物、它们的共聚物,以及它们的混合物。合适的低熔点疏水性材料包括(但不限于):脂肪、脂肪酸酯、磷脂、蜡,以及它们的混合物。合适的脂肪的例子包括(但不限于):氢化植物油(例如可可脂、氢化棕榈仁油、氢化棉籽油、氢化向日葵油和氢化大豆油)、游离脂肪酸和它们的盐,以及它们的混合物。合适的脂肪酸酯的例子包括(但不限于):蔗糖脂肪酸酯、甘油一酯、甘油二酯和甘油三酯、甘油基二十二烷酸酯、甘油基棕榈酰硬脂酸酯、甘油基单硬脂酸酯、甘油基三硬脂酸酯、甘油基三月桂酸酯、甘油基肉豆蔻酸酯、GlycoWax-932、月桂酰聚乙二醇-32甘油酯和硬脂酰聚乙二醇-32甘油酯,以及它们的混合物。合适的磷脂的例子包括磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸,以及它们的混合物。合适的蜡的例子包括(但不限于):巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、紫胶蜡、微晶蜡和石蜡;含脂肪的混合物如巧克力,以及它们的混合物。
供用作调释赋形剂的合适的pH依赖性聚合物包括(但不限于):肠溶纤维素衍生物,如羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯琥珀酸酯、乙酸纤维素邻苯二甲酸酯;天然树脂,如紫胶和玉米醇溶蛋白;肠溶乙酸酯衍生物,例如聚乙酸乙烯邻苯二甲酸酯、乙酸纤维素邻苯二甲酸酯、乙醛二甲基纤维素乙酸酯;及肠溶丙烯酸衍生物,如基于聚甲基丙烯酸的聚合物,如聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶2(其可以商品名EUDRAGIT STM市售获得)和聚(甲基丙烯酸,甲基丙烯酸甲酯)1∶1(其可以商品名EUDRAGIT LTM市售获得),以及它们的混合物。
合适的甜味剂的例子包括(但不限于):合成或天然糖类以及高强度甜味剂,例如三氯蔗糖、糖精、糖精钠、天冬甜素、丁磺氨K或丁磺氨、乙酰磺胺酸钾、非洲甜果素、甘草素、二氢查耳酮、阿力甜、奇异果素、应乐果甜蛋白、甜菊糖以及它们的混合物。在一个实施例中,高强度甜味剂被添加到包含西替利嗪、多元醇和碱化剂的预复合颗粒状物中。在一个实施例中,高强度甜味剂被添加到片剂基质中。
超级崩解剂的例子包括(但不限于):交联羧甲基纤维素钠、羟基乙酸淀粉钠和交联聚维酮(交联聚乙烯吡咯烷酮)。在一个实施例中,片剂含有最多约5重量%的这种超崩解剂。
合适的香料和芳香剂的例子包括(但不限于):精油,包括含有醇、酯、醛和内酯的混合物的切花、叶子、果皮或打浆全果的蒸馏物、溶剂萃取物或冷榨出物;香精,包括精油的稀释溶液,或者经共混以匹配水果(例如草莓、树莓和黑加仑)的天然香料的合成化学品的混合物;酿造酒和蒸馏酒(例如法国白兰地酒、威士忌酒、朗姆酒、杜松子酒、雪利酒、波尔多红葡萄酒和葡萄酒)的人造和天然香料;烟草、咖啡、茶叶、可可和薄荷;果汁,包括从洗擦过的水果如柠檬、橙和莱母酸橙榨出的果汁;薄荷;姜;肉桂;可可;香草;甘草;薄荷醇;桉树;大茴香;坚果(例如花生、椰子、榛子、栗子、胡桃和可乐果);杏仁;葡萄干;和粉末、面粉或植物材料部分,包括烟草植物部分(例如烟草属(Nicotiana),其数量不显著导致治疗性尼古丁的水平),以及它们的混合物。
抗氧化剂的例子包括(但不限于):生育酚、抗坏血酸、焦亚硫酸钠、丁基羟基甲苯、丁基化羟基苯甲醚、依地酸和依地酸盐,以及它们的混合物。防腐剂的例子包括(但不限于):柠檬酸、酒石酸、乳酸、苹果酸、乙酸、苯甲酸和山梨酸,以及它们的混合物。
质构增强剂的例子包括(但不限于):果胶、聚环氧乙烷和卡拉胶以及它们的混合物。在一个实施例中,质构增强剂的用量为约0.1重量%至约10重量%。
在一个实施例中,片剂基质基本上不含碱化剂。
片剂包衣
在一个实施例中,本发明方法还包括对片剂进行包覆(如用外包衣进行包覆)。在一个实施例中,该方法还包括给片剂包覆底包衣,然后再给片剂施加外包衣。
底包衣
在一个实施例中,片剂包括一个或多个底衣层。在一个实施例中,底包衣层基本上覆盖片剂的表面。底包衣的使用为本领域所熟知的,并且在(例如)美国专利No.3,185,626中公开,该专利以引用方式并入本文。适用的底包衣的例子公开于美国专利No.4,683,256、No 4,543,370、No 4,643,894、No 4,828,841、No 4,725,441、No 4,802,924、No.5,630,871和No 6,274,162,这些专利均以引用方式并入本文。合适的底包衣可包含以下成分中的一种或多种:纤维素醚如羟丙基甲基纤维素、羟丙基纤维素和羟乙基纤维素;聚碳水化合物如黄原胶、淀粉和麦芽糊精;增塑剂,包括例如甘油、聚乙二醇、丙二醇、癸二酸二丁酯、柠檬酸三乙酯,植物油如蓖麻油,表面活性剂如聚山梨醇酯-80、十二烷基硫酸钠和二辛基硫化琥珀酸钠;聚碳水化合物;色素;和遮光剂。
在一个实施例中,基于底包衣的总重量,底包衣包含约2重量%至约8重量%(例如约4重量%至约6重量%)的水溶性纤维素醚和约0.1重量%至约1重量%的蓖麻油,如美国专利No.5,658,589中详细公开,该专利以引用方式并入本文。在另一个实施例中,基于底包衣的总重量,底包衣包含约20重量%至约50重量%(如约25重量%至约40重量%)的HPMC;约45重量%至约75重量%(如约50重量%至约70重量%)的麦芽糖糊精;和约1重量%至约10重量%(如约5重量%至约10重量%)的PEG 400。
基于片剂的干重,底包衣的存在量通常为约0重量%至约5重量%。基于片剂和任选的底包衣的干重,干燥的浸涂层的存在量通常为约1.5重量%至约10重量%。在一个实施例中,片剂基本上无底包衣。
外包衣
所谓外包衣是指包衣片的外表面上的包衣。在一个实施例中,外包衣基本上覆盖片剂的表面(例如覆盖90重量%)。
干燥的浸涂层的平均厚度通常为约40至约400微米。然而,本领域技术人员将无需过多实验就会容易地认识到,浸涂包衣厚度可以变化,以提供更光滑、更容易吞咽的片剂,或者实现所需的溶出特性。此外,视基材的形状而定,浸膜包衣的厚度可在基材上的不同位置变化。例如,基材边缘或拐角处的包衣厚度可比基材主表面的中央处的包衣厚度小50重量%至70重量%。该差异可例如通过使用较厚的底包衣或者使用能导致在基材上的增重较高的浸渍组合物来减至最低。
在其中需要更厚的浸涂包衣的实施例中,可将有效量的增重提升剂(例如西甲硅油、聚山梨醇酯80和它们的混合物)加到含有成膜剂和任选的增稠剂(如亲水胶体)的成膜组合物。增重增强剂的用量要足以提升当干燥时基材上的包覆液体的增重例如达至少约10重量%、达至少约20重量%或达至少约30重量%。增重提升百分数是基于以下两个总重量之差测定的:用包含增重加强剂的包衣组合物涂覆的基材的总重量,和在相似处理条件下用不包含有效量的增重加强剂的包衣组合物涂覆的等同基材的总重量。
在一个实施例中,该方法还包括在片剂的未涂覆外包衣的部分的底包衣中形成一个或多个开口,以在包衣片剂的表面上使片剂暴露,如美国专利申请No.2005/0152970中所描述。
在一个实施例中,该方法还包括在外包衣中形成一个或多个开口以暴露片剂,但开口未穿透底包衣,这在美国专利申请No.2005/0152970所公开。由于明胶不适宜于激光钻孔,因此在具有这种明胶包衣的片剂中有必要先暴露底包衣再用激光钻开口。
在一个实施例中,外包衣仅覆盖片剂的一部分,如仅覆盖包衣片的一半。片剂的另一半可含有另一类型的外包衣例如明胶,或者专门暴露底包衣或片剂。
在某些其中需要药物活性剂的调释的实施例中,药物活性剂或片剂可以可选地使用已知的调释包衣包覆。这有利地提供对药物活性剂从片剂的释放进行调节的附加手段(例如除了颗粒上的调释包衣之外)。在一个实施例中,包衣含有pH依赖性成膜加合物,如肠溶聚合物。在一个实施例中,外包衣是调释包衣,而片剂中的活性颗粒具有不同的调释,以表现出可变的释放速度;包括片剂包衣所表现的脉冲式释放和包覆的药物活性剂所表现的一级释放。在另一个实施例中,将外调释包衣放在片剂上,以便以调释方式从片剂释放第二包覆的药物活性剂颗粒,而以另一调释方式释放第一颗粒包覆药物活性剂。
本文所用的“基本上包覆”应意指小于约20重量%、例如小于约15重量%或小于约1.0重量%的片剂表面积被暴露,例如不被所需的包衣覆盖。
在一个实施例中,片剂包衣含有热塑性水溶性成膜聚合物,如羟丙基甲基纤维素化合物。这种化合物的一个例子是“HPMC 291“,其是取代度为约1.9、羟丙基摩尔取代度为0.23,且基于化合物的总重量含有约29重量%至约30重量%的甲氧基基团和约7重量%至约12重量%的羟丙基基团的纤维素醚。HPMC 2910可从Dow Chemical公司市售获得,商品名为METHOCEL ETM。METHOCEL E5TM是适用于本发明的一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约4至6厘泊(4至6毫帕斯卡-秒)。类似地,METHOCEL E6TM是适用于本发明的另一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约5至7厘泊(5至7毫帕斯卡-秒)。METHOCEL E15TM是适用于本发明的另一种类别的HPMC-2910,其通过Ubbelohde粘度计在2重量%水溶液中在20C下测得的粘度为约15000厘泊(15毫帕斯卡-秒)。本文所用的术语“取代度”意指附接到脱水葡萄糖环上的取代基的平均数目,而术语“羟丙基摩尔取代”意指每摩尔脱水葡萄糖的羟丙基摩尔数。
在一个实施例中,包衣含有聚乙烯醇和聚乙二醇的共聚物。一种供用作片剂包衣的合适的聚乙烯醇和聚乙二醇共聚物可以商品名KOLLICOAT IRTM从BASF公司市售获得。
在一个实施例中,包衣含有改性淀粉。如本文所用,用于片剂包衣的“改性淀粉”包括已通过交联进行改性,化学改性(用于改善稳定性或优化性能)或物理改性(用于改善溶解特性或优化性能)的淀粉。化学改性淀粉的例子是本领域所熟知的,通常包括那些已通过化学处理以导致其某些羟基被酯基或醚基替代的淀粉。当相邻淀粉分子上的两个羟基基团发生化学连接时,会在改性淀粉中出现如本文所用的交联。本文所用的术语“预胶凝淀粉”或“速溶淀粉”指已经预先湿润然后干燥以提高其冷水溶解度的改性淀粉。
供用于片剂包衣的合适的改性淀粉可从若干个供应商商购获得,例如从A.E.Staley Manufacturing Company和National Starch & Chemical Company商购获得。一种合适的成膜改性淀粉包括预糊化的糯玉米衍生淀粉(它们可以商品名PURITY GUMTM和FILMSETTM从National Starch & Chemical公司市售获得)以及它们的混合物。基于淀粉的总重量,这种糯玉米淀粉通常含有约0重量%至约18重量%的直链淀粉和约100重量%至约88重量%的支链淀粉。
其他适用于片剂包衣的成膜改性淀粉包括羟丙基化淀粉,其中该淀粉的羟基基团中的一些已经用羟丙基基团醚化,通常是通过用环氧丙烷处理来醚化。具有成膜性质的合适的羟丙基淀粉的一个例子可以商品名PURE-COTE B790TM从Grain Processing公司市售获得。
在一个实施例中,片剂包衣含有木薯糊精。供作为成膜剂用作片剂包衣的合适的木薯糊精包括(但不限于):可以商品名CRYSTAL GUMTM或K-4484TM获自National Starch & Chemical公司的那些木薯糊精,以及它们的衍生物,如可以商品名PURITY GUM 40TM获自National Starch and Chemical的木薯衍生的改性食品级淀粉,以及它们的共聚物和混合物。
在一个实施例中,片剂包衣含有增稠剂。这类增稠剂的例子包括(但不限于):亲水胶体(在本文中也称为胶凝聚合物)、粘土、胶凝淀粉和可结晶碳水化合物,以及它们的混合物。
适于用作片剂包衣的亲水胶体(本文又称凝胶聚合物)的例子包括海藻酸盐、琼脂、瓜尔胶、刺槐豆胶、卡拉胶、塔拉胶、阿拉伯树胶、黄蓍胶、果胶、黄原胶、结冷胶、麦芽糊精、半乳甘露聚糖、石耳素、昆布多糖、小核菌葡聚糖、阿拉伯树胶、菊粉、果胶、威兰胶、鼠李胶、菌胶团、甲兰胶、几丁质、环糊精、壳聚糖。合适的黏土的例子包括绿土如膨润土、高岭土和合成锂皂石(laponite);三硅酸镁;硅酸镁铝;以及它们的混合物。合适的胶凝淀粉的例子包括酸水解淀粉以及它们的混合物。另外的合适增稠亲水胶体包括低水分的聚合物溶液,如明胶和其他亲水胶体的水分含量最多约30重量%的混合物,例如那些用于制备“gummi”糖果形式的混合物。另外的合适增稠剂包括(但不限于):可结晶碳水化合物。
在本发明的一个实施例中,片剂包衣含有明胶。明胶是天然的热胶凝聚合物。它是白蛋白类衍生蛋白质的无味无色混合物,通常可溶于温水中。通常使用两种类型的明胶-A型和B型。A型明胶是经酸处理的原材料的衍生物。B型明胶是经碱处理的原材料的衍生物。明胶的含水量以及其Bloom强度、组成和初始明胶加工条件决定其在液体和固体之间的转变温度。Bloom是明胶凝胶的强度的标准量度,与分子量大致相关。Bloom定义为将半英寸直径的塑料柱塞移动进入已在10C下保持17小时的6.67重量%明胶凝胶中4mm所需的重量,以克为单位。在一个优选的实施例中,可流动材料是含有20%275Bloom猪皮明胶、20%250Bloom骨明胶和60%水的水溶液。
片剂的用途
在一个实施例中,本发明主要涉及一种治疗疾病的方法,该方法包括口服上述片剂,其中该片剂包含一定量的对治疗该疾病有效的西替利嗪。这类疾病的例子包括(但不限于):
在该实施例中,“单位剂量”通常随附有给药说明,该说明指导患者根据(例如)该患者的年龄或体重服用一定量的药物活性剂,该量可以是多个该单位剂量。通常,单位剂量将含有对最小的患者治疗有效的量的药物活性剂。例如,合适的单位剂量体积可包括一个片剂。
实例
通过以下实例来举例说明本发明的具体实施例。本发明并不受限于在这些实例中所示出的具体限定。
实例1:包含西替利嗪的流化床制粒
A部分:包含西替利嗪的制粒溶液的制备
通过将5400g的25℃的纯化水加入合适的容器中来制备10%的聚乙烯吡咯烷酮(PVP)的制粒溶液。在实验室用旋转混合器中加入水,并一边以100RPM的速度搅拌一边加入600g的PVP。然后将搅拌速度降至50RPM,并且混合大约30分钟。
B部分:西替利嗪颗粒状物的制备
如表1所示,将二盐酸西替利嗪、β-环糊精、丁二酸钠和玉米淀粉装入流化床制粒机中。然后,用2巴的雾化空气压力将约3000g纯化水以约75至125克/分的速率喷入流化床中,入口空气温度为约55℃。然后,用2巴的雾化空气压力,将步骤A中制备的约5680g溶液以约75至125克/分的速率喷洒在颗粒状物上,入口空气温度约为55℃。喷洒后,将颗粒状物干燥至约30℃的产品最终温度或约7.5%的干燥失重分析(LOD)值。
表1:西替利嗪颗粒状物配方
材料 | 克/批 |
二盐酸西替利嗪 | 1000 |
β-环糊精(12.5%的水分) | 8428 |
丁二酸钠(无水) | 175.5 |
玉米淀粉 | 4214 |
PVP | 568 |
总计 | 14385.5 |
实例2:包含西替利嗪的喷雾干燥溶液的制备
A部分:喷雾干燥浆料的制备
通过将3000g水装入合适的不锈钢容器中来制备表2中所示材料的浆料。将二盐酸西替利嗪和丁二酸钠溶解于水中,同时用实验室用混合器以50RPM的转速搅拌。然后将β-环糊精添加到混合物中,并且在搅拌的同时散开而形成浆料。
表2:用于喷雾干燥的喷雾干燥浆料配方
材料 | 克/批 |
二盐酸西替利嗪 | 1000 |
丁二酸钠(无水) | 175.4 |
水 | 3000 |
β-环糊精 | 4214 |
B部分:喷雾干燥方法
将从A部分得到的浆料泵出,并在可从Niro Systems商购获得的实验室用喷雾干燥器(型号PSD-1)中进行喷雾干燥,其中喷雾速率为约100克/分钟,雾化压力为约1.0巴且出口气体温度为90℃。然后收集所得颗粒。
实例3:采用西替利嗪的高剪切制粒方法
配备有切碎机的A 65 L TK Fielder高剪切制粒机被用于高剪切制粒。将二盐酸西替利嗪、β-环糊精、PVP和丁二酸钠装入制粒机中并混合大约1分钟,同时运行切碎机。用2分钟时间缓慢添加1000g纯化水,同时搅拌并运行切碎机。然后添加玉米淀粉并让其被搅拌1分钟。然后在Glatt GCPG 15kg干燥设备中将颗粒状物干燥至约7%的最终LOD值。
表3:包含西替利嗪共混物的高剪切制粒
材料 | 克/批 |
盐酸西替利嗪 | 1000 |
β-环糊精(12.5%的水分) | 8428 |
丁二酸钠(无水) | 175.5 |
玉米淀粉 | 4214 |
PVP | 568 |
总计 | 14385.5 |
实例4:包含西替利嗪的单层压制咀嚼片
A部分:咀嚼片剂配方&共混
采用表4中列出的配方,将得自实例1、2和3的制成的或喷雾干燥的颗粒分别用于制备三种不同的咀嚼片混合物。将聚乙烯吡咯烷酮、三氯蔗糖、琥珀酸、矫味剂、染料和色淀通过60目筛网手动过滤,以形成矫味混合物。将甘露糖醇通过14目筛网手动过滤。将大约一半的甘露糖醇和全部矫味混合物添加到合适的V形混合器中。将甘露糖醇的剩余部分添加到V形混合器中并且翻滚共混大约7分钟。将硬脂酸镁和硬脂酸通过60目筛网手动过滤并且添加到V形混合器中。将共混物在V形混合器中翻滚共混2分钟。将3种共混物分别排放到3个不同的塑料袋中。
表4:咀嚼片剂配方
材料 | 量(g) |
得自实例1、2或3的颗粒 | 14386 |
甘露糖醇 | 29617 |
交联聚乙烯吡咯烷酮 | 500 |
三氯蔗糖 | 175 |
葡萄矫味剂 | 180 |
琥珀酸 | 90 |
甜味剂 | 45 |
胭脂红着色剂 | 54 |
蓝色着色剂 | 54 |
硬脂酸 | 450 |
硬脂酸镁 | 225 |
总计 | 45000 |
B部分:压制工序
在旋转式片剂压制模块(如美国专利No.6,767,20012第12栏第14至20行所述)上,用7/16英寸超深凹型片剂模具将得自此实例A部分的所得干混物压制成片剂。该压制模块是双排的旋转式装置,包括填充区、插入区、压制区、顶出区和清除区,如美国专利No.6,767,200的图6所示。压制模块的压模利用真空帮助来填充,在每个模具的模壁部分中设置有目筛网过滤器。所得片剂的平均重量为450mg,厚度为0.306英寸,硬度为3.2kp。
应当了解,虽然已结合本发明的具体实施方式描述了本发明,但是前述描述旨在说明而非限制由随附权利要求书所限定的本发明的范围。其他方面、优点和修改均在权利要求书范围内。
用通过实例1、2和3制备的西替利嗪-多元醇复合物样品压制的片剂分析西替利嗪在加速条件下的稳定性。西替利嗪降解的数据在表6和表8中示出。
实例5:使用β-环糊精在霍巴特搅拌器(Hobart Mixer)中进行高剪切制
粒
首先将下表5中列出的干料(除西替利嗪、柠檬酸钠、丁二酸钠和玉米淀粉外)在霍巴特搅拌器中以低速混合。还在样品B中将柠檬酸钠、在样品C中将丁二酸钠加到干成分中。然后,用纯化水以9.09%的固体重量比将二盐酸西替利嗪混合到水溶液中。在样品D和样品E中,将丁二酸钠加到该溶液中。
该溶液然后喷洒到干料中,同时搅拌约15分钟。然后,在持续搅拌下用2分钟时间加入玉米淀粉。颗粒状物在50℃下被盘式干燥约2小时。然后将颗粒状物回加到搅拌器中,再添加交联羧甲基纤维素钠并混合约2分钟。然后添加硬脂酸镁和硬脂酸,再混合1分钟。
表5:高剪切制粒配方
材料(重量) | 样品A | 样品B | 样品C | 样品D | 样品E |
盐酸西替利嗪 | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
β-环糊精 | 42.14g | 42.14g | 42.14g | 42.14g | 42.14g |
丁二酸钠 | 0.00g | 0.00g | 4.39g | 4.39g | 0.73g |
柠檬酸钠 | 0.00g | 12.75g | 0.00g | 0.00g | 0.00g |
聚乙烯吡咯烷酮(Kollidon 30-LPTM) | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
Avicel pH102(微晶纤维素) | 119.10g | 107.90g | 116.40g | 116.40g | 118.60g |
玉米淀粉 | 20.00g | 20.00g | 20.00g | 20.00g | 20.00g |
交联羧甲基纤维素钠 | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
硬脂酸镁 | 1.30g | 1.30g | 1.30g | 1.30g | 1.30g |
硬脂酸 | 2.50g | 2.50g | 2.50g | 2.50g | 2.50g |
然后将这些样品置于封闭的高密度聚乙烯瓶中并加以分析,以获知在40℃和75%的相对湿度下保持1个月时的β-环糊精酯和氧化降解物形式的降解。表6中所示的结果显示,当相对于西替利嗪盐含量在0.25和5摩尔当量之间时,酯的含量在0.36%和“未检测到”之间。当未添加盐时,酯的含量为0.60%。
表6:降解
样品A | 样品B | 样品C | 样品D | 样品E | |
样品类型 | 未添加盐 | 固体盐 | 固体盐 | 盐溶液 | 盐溶液 |
摩尔当量(%)盐 | 0.00 | 5.00 | 1.50 | 1.50 | 0.25 |
β-环糊精酯(%) | 0.60 | ND | ND | ND | 0.36 |
氧化降解物(%) | 0.02 | 0.04 | 0.05 | 0.04 | 0.02 |
ND-未检测到
实例6:使用乳糖在霍巴特搅拌器中进行的高剪切制粒
首先将下表7中列出的干料(除西替利嗪、柠檬酸钠、丁二酸钠和玉米淀粉外)在霍巴特搅拌器中以低速混合。还在样品B中将柠檬酸钠、在样品C中将丁二酸钠加到干成分中。然后,用纯化水以9.09%的固体重量比将二盐酸西替利嗪混合到水溶液中。在样品D和样品E中,将丁二酸钠加到该溶液中。
该溶液然后喷洒到干料中,同时搅拌约15分钟。然后,在持续搅拌下用2分钟时间加入玉米淀粉。颗粒状物在50℃下被盘式干燥约2小时。然后将颗粒状物回加到搅拌器中,再添加交联羧甲基纤维素钠并混合约2分钟。然后添加硬脂酸镁和硬脂酸,再混合1分钟。
表7:高剪切制粒配方
材料(重量) | 样品A | 样品B | 样品C | 样品D | 样品E |
二盐酸西替利嗪 | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
一水乳糖 | 41.05g | 41.05g | 41.05g | 41.05g | 41.05g |
丁二酸钠 | 0.00g | 0.00g | 4.39g | 4.39g | 0.73g |
柠檬酸钠 | 0.00g | 12.75g | 0.00g | 0.00g | 0.00g |
聚乙烯吡咯烷酮(Kollidon 30-LP) | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
Avicel pH102(微晶纤维素) | 120.10g | 108.90g | 117.50g | 117.50g | 119.70g |
玉米淀粉 | 20.00g | 20.00g | 20.00g | 20.00g | 20.00g |
交联羧甲基纤维素钠 | 5.00g | 5.00g | 5.00g | 5.00g | 5.00g |
硬脂酸镁 | 1.30g | 1.30g | 1.30g | 1.30g | 1.30g |
硬脂酸 | 2.50g | 2.50g | 2.50g | 2.50g | 2.50g |
将这些样品置于封闭的高密度聚乙烯瓶中并加以分析,以获知在40℃和75%的相对湿度下保持1个月时的乳糖酯和氧化降解物。结果显示,当相对于西替利嗪盐含量在0.25和5摩尔当量之间时,酯的含量在0.32%和0.06%之间。当未添加盐时,酯的含量为0.63%。当添加5摩尔当量的柠檬酸钠时,氧化降解物的含量为0.24%。当丁二酸钠的含量在0.25和1.5摩尔当量之间时,氧化降解物的含量在0.04和0.09%之间。
表8:降解
样品A | 样品B | 样品C | 样品D | 样品E | |
样品类型 | 未添加盐 | 固体盐 | 固体盐 | 盐溶液 | 盐溶液 |
摩尔当量(%)盐 | 0.00 | 5.00 | 1.50 | 1.50 | 0.25 |
乳糖酯(%) | 0.63 | 0.06 | 0.10 | 0.08 | 0.32 |
氧化降解物(%) | 0.02 | 0.24 | 0.09 | 0.09 | 0.04 |
Claims (20)
1.一种制备包含西替利嗪的片剂的方法,所述方法包括以下步骤:
(i)将西替利嗪、多元醇和所述西替利嗪的溶剂混合以形成西替利嗪:多元醇复合物,其中所述溶剂包含水和碱化剂并且具有约2.5至约4的pH值;
(ii)将所述西替利嗪:多元醇复合物的颗粒从所述混合物分离;以及
(iii)将所述颗粒形成为片剂。
2.根据权利要求1所述的方法,其中所述多元醇为β-环糊精。
3.根据权利要求1所述的方法,其中所述碱化剂选自碳酸氢钠和柠檬酸钠。
4.根据权利要求1所述的方法,其中所述西替利嗪为二盐酸西替利嗪。
5.根据权利要求1所述的方法,其中所述西替利嗪为二盐酸左西替利嗪。
6.根据权利要求1所述的方法,其中将所述多元醇和所述西替利嗪混合在一起,然后与所述溶剂混合。
7.根据权利要求1所述的方法,其中将所述多元醇、所述西替利嗪和所述碱化剂混合在一起,然后与所述溶剂混合。
8.根据权利要求1所述的方法,其中所述多元醇、所述西替利嗪和所述溶剂通过流化床方法混合。
9.根据权利要求1所述的方法,其中所述多元醇、所述西替利嗪和所述溶剂通过高剪切制粒方法混合。
10.根据权利要求1所述的方法,其中所述多元醇、所述西替利嗪和所述溶剂通过喷雾干燥方法混合。
11.根据权利要求1所述的方法,其中所述方法还包括在形成所述片剂之前将所述颗粒与片剂基质共混的步骤。
12.根据权利要求1所述的方法,其中所述片剂基质包含多元醇。
13.根据权利要求9所述的方法,其中所述片剂基质中包含的所述多元醇选自甘露糖醇、蔗糖、山梨醇、木糖醇、赤藓醇和右旋糖。
14.根据权利要求1所述的方法,其中所述片剂为口腔崩解片剂基质。
15.根据权利要求15所述的方法,其中所述片剂通过压制所述颗粒而形成。
16.根据权利要求15所述的方法,其中所述片剂通过冻干所述颗粒而形成。
17.一种包含西替利嗪的片剂,所述片剂通过权利要求1所述的方法制备。
18.根据权利要求17所述的片剂,其中所述多元醇为β-环糊精。
19.根据权利要求17所述的片剂,其中所述碱化剂选自碳酸氢钠和柠檬酸钠。
20.根据权利要求17所述的片剂,其中所述西替利嗪为二盐酸西替利嗪。
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EP (1) | EP2344137B1 (zh) |
CN (1) | CN102143737A (zh) |
AU (1) | AU2009288006B2 (zh) |
BR (1) | BRPI0918906A2 (zh) |
CA (1) | CA2734691C (zh) |
ES (1) | ES2564056T3 (zh) |
RU (1) | RU2011112926A (zh) |
WO (1) | WO2010028101A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102860986A (zh) * | 2012-09-28 | 2013-01-09 | 天津市聚星康华医药科技有限公司 | 一种稳定的掩味的左西替利嗪药物组合物及其制备方法 |
CN104546851A (zh) * | 2013-10-29 | 2015-04-29 | 北京韩美药品有限公司 | 一种颗粒组合物及其制备方法、制剂 |
CN106177973A (zh) * | 2014-06-11 | 2016-12-07 | 广东东阳光药业有限公司 | 一种盐酸西替利嗪固体制剂及其制备方法 |
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WO2011110939A2 (en) | 2010-03-11 | 2011-09-15 | Rubicon Research Private Limited | Pharmaceutical compositions of substituted benzhydrylpiperazines |
WO2011146032A2 (en) * | 2010-05-18 | 2011-11-24 | Mahmut Bilgic | Effervescent formulations |
WO2013058721A1 (en) * | 2011-10-13 | 2013-04-25 | Mahmut Bilgic | Pharmaceutical granules and production method |
CN102716099B (zh) * | 2012-07-05 | 2013-10-09 | 湖南千金湘江药业股份有限公司 | 盐酸左西替利嗪咀嚼片及其制备方法 |
KR102226833B1 (ko) * | 2013-06-28 | 2021-03-12 | 한미약품 주식회사 | 레보세티리진 및 몬테루카스트를 포함하는 안정성이 개선된 복합 과립 제형 |
JP2016094364A (ja) * | 2014-11-14 | 2016-05-26 | ニプロ株式会社 | 安定化および苦味抑制された口腔内崩壊製剤 |
KR20220137065A (ko) * | 2020-02-03 | 2022-10-11 | 존슨 앤드 존슨 컨수머 인코포레이티드 | 세티리진을 포함하는 단일층 츄어블 정제 |
JP2023549381A (ja) | 2020-11-18 | 2023-11-24 | バイオファーマ・シナジーズ,エス.エル. | 抗ヒスタミン活性化合物を含む口内分散性粉末組成物 |
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2009
- 2009-09-03 WO PCT/US2009/055809 patent/WO2010028101A1/en active Application Filing
- 2009-09-03 CN CN2009801350955A patent/CN102143737A/zh active Pending
- 2009-09-03 AU AU2009288006A patent/AU2009288006B2/en not_active Expired - Fee Related
- 2009-09-03 BR BRPI0918906A patent/BRPI0918906A2/pt not_active IP Right Cessation
- 2009-09-03 CA CA2734691A patent/CA2734691C/en active Active
- 2009-09-03 EP EP09792203.3A patent/EP2344137B1/en active Active
- 2009-09-03 US US12/553,157 patent/US8383632B2/en active Active
- 2009-09-03 ES ES09792203.3T patent/ES2564056T3/es active Active
- 2009-09-03 RU RU2011112926/15A patent/RU2011112926A/ru not_active Application Discontinuation
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102860986A (zh) * | 2012-09-28 | 2013-01-09 | 天津市聚星康华医药科技有限公司 | 一种稳定的掩味的左西替利嗪药物组合物及其制备方法 |
CN104546851A (zh) * | 2013-10-29 | 2015-04-29 | 北京韩美药品有限公司 | 一种颗粒组合物及其制备方法、制剂 |
CN104546851B (zh) * | 2013-10-29 | 2018-01-02 | 北京韩美药品有限公司 | 一种颗粒组合物及其制备方法、制剂 |
CN106177973A (zh) * | 2014-06-11 | 2016-12-07 | 广东东阳光药业有限公司 | 一种盐酸西替利嗪固体制剂及其制备方法 |
CN106177973B (zh) * | 2014-06-11 | 2019-10-18 | 广东东阳光药业有限公司 | 一种盐酸西替利嗪固体制剂及其制备方法 |
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US8383632B2 (en) | 2013-02-26 |
ES2564056T3 (es) | 2016-03-17 |
US20100062061A1 (en) | 2010-03-11 |
AU2009288006A1 (en) | 2010-03-11 |
CA2734691A1 (en) | 2010-03-11 |
EP2344137B1 (en) | 2015-12-02 |
EP2344137A1 (en) | 2011-07-20 |
CA2734691C (en) | 2017-05-16 |
BRPI0918906A2 (pt) | 2015-12-01 |
AU2009288006B2 (en) | 2014-07-17 |
WO2010028101A1 (en) | 2010-03-11 |
RU2011112926A (ru) | 2012-10-10 |
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