CN101132764A - 含重质碳酸镁的快速崩解剂型 - Google Patents
含重质碳酸镁的快速崩解剂型 Download PDFInfo
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- CN101132764A CN101132764A CNA2006800069782A CN200680006978A CN101132764A CN 101132764 A CN101132764 A CN 101132764A CN A2006800069782 A CNA2006800069782 A CN A2006800069782A CN 200680006978 A CN200680006978 A CN 200680006978A CN 101132764 A CN101132764 A CN 101132764A
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- microcrystalline cellulose
- magnesium carbonate
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Abstract
本发明描述了一种含有重质碳酸镁的快速崩解剂型,所述剂型在接触水分后崩解。该剂型可以为分散片也可以作为口腔分散片,并可以广泛适用于不同的活性物质。重质碳酸镁被发现是一种在碱性和中性环境下优良的崩解剂,并可以使片剂具有滑爽的口感。
Description
发明领域
本发明涉及固体药物剂型的组合物,在接触水分的条件下快速分散。
背景技术
对于那些吞咽困难并且需要服用大剂量有效成分才能达到治疗效果的病人来说,尤其是当制备容易吞咽的大小适宜的片剂发生困难时,吞咽前可快速崩解的剂型可以方便病人服用药物。
分散片和口腔分散片这两种剂型可以解决上述问题。分散片在服用前在水中崩解,而口腔分散片在接触口腔内壁的水分崩解。这两种剂型较传统的需要吞咽的片剂有显著的优势。将药片先溶于水,大量的药物就可以被病人服用,如若不然,病人将很难吞咽下相同剂量的药片形式的药物。很显然,吞咽前分散片在水介质中快速崩解,这就是分散片的优势。
同样,口腔分散片在缺水条件下必须服药时或者需要快速释放药物时更显优势。此外,非常年幼和年老的病人、依从性差以及有身体损伤者都有可能在给药时需要口腔分散片,在这样的情况下服用一大杯液体药物是不合适的。口腔分散片,也被认为是含化的片剂或快速口腔释放片剂,需要崩解迅速,例如至少在3分钟内崩解,但优选是在接触颊间隙内壁的数秒钟之内崩解。
分散片和口腔分散片这两种片剂通常必需做成不用咀嚼并且在接触水分后迅速崩解,这样的固有特性不可避免的带来一系列生产过程中的挑战。这些片剂优选以低压压制,从而保证片剂的多孔性,多孔性可以有助于片剂接触水分后的迅速崩解。同时该片剂必需具有低易碎性,以适合药品工业最常使用的制造方法的需要。组合物应该是足以通用的,可以通过制粒或者直接压制法的制备进行配制。组合物优选由不溶性成分组成,因为可溶性成分容易吸收水分,导致片剂高强度水化并且溶解缓慢,而不是使片剂迅速崩解。这些片剂优选与用于常规释放的,即在胃肠中释放的相同剂量的片剂有生物等效性。
本领域技术人员很清楚,目前存在若干生产分散片和口腔分散片的配制方法。为了配制口腔分散片,采用若干传统方法。比如,美国专利US 6,083,531叙述了快速口腔分散片的制作方法,其中各种组分混合在一起,在干燥和成型前分装到成品包装材料中。这与著名的Zydis***非常相似,Zydis***采用冷冻干燥方法干燥分装在包装材料的组分。由于片剂缺少水分以及多孔特性,可促进水分快速进入药片,这些片剂崩解非常迅速。然而,这两种方法受到在生产片剂的过程中需要特殊加工设备的限制,而特殊加工设备除了成本昂贵,通常在药品企业中并不广泛应用。
相反,生产口腔分散片的技术通常基于片剂的多孔特性崩解的剂型,其中除了发泡剂,诸如碳酸钠和弱酸,通常是柠檬酸外通常包括可溶性赋形剂,例如甘露醇或山梨醇,他们可以进一步加强片剂在颊间隙的崩解。例如,美国专利US 6,328,994描述了先用兰索拉唑包裹颗粒,然后再用肠溶包衣层包裹,随后颗粒与崩解剂混合再压制成片的形成的口腔分散片。颗粒中可以含有碱性无机盐,例如碳酸镁,来稳定有效成分,然后作为缓冲剂。欧洲专利EP 636,364描述了一种口腔崩解片,其中由水中可崩解的、可压制的碳水化合物以及粘合剂来进行崩解。
美国专利US 5,178,878描述了一种具有发泡剂的组合物,所述发泡剂帮助片剂在颊间隙中崩解。
美国专利US 5,464,632描述了一种赋形剂混合物使多粒径片剂在口腔中60秒内崩解。
发泡剂也广泛应用于分散片在水中溶解,水溶后给病人引用作为药物的一种给药方式。然而,泡腾片并不合适作为口腔分散片使用,因为泡腾剂在口中的泡腾作用(产生二氧化碳)经常让人感觉不愉快。
遗憾的是,上述发明没有提供一种通用的方法,即,利用湿法制粒和直接压制的工艺用于这两种片剂的配制,并且组合物可以同时用于口腔分散片和分散片。
发明概述
本发明所要解决的技术问题旨在寻找一种产生同时具有口腔分散片及分散片的所有基本特征的适宜剂型的方法,并且,除了满足目前所有对含有药物的固体剂型的要求,例如硬度和易碎性外,能够适应不同片剂的生产技术。
上述技术问题的解决通过本发明提供的具体实施例实现,权利要求中对其特征进行了限定并具体描述在下文。
通过非直觉的观察,令人惊奇的是,我们发现重质碳酸镁是解决上述技术问题的关键成分,可以使配制出具有上述所需特性的快速崩解剂型。碳酸镁通常被描述为两种存在形式,“重质碳酸镁”和“轻质碳酸镁”。通常,重质碳酸镁是指具有分子式[(MgCO3)3·Mg(OH)2·4H2O]的四水合物;而轻质碳酸镁为[(MgCO3)3·Mg(OH)2·3H2O]或者三水合物形式。碳酸镁不溶于水、95%乙醇等溶剂。但是,它在稀酸溶液中溶解并发泡,也溶于含有二氧化碳的水。碳酸镁在胃中遇到胃酸后有很好的分散能力,并且迅速溶解,形成氯化镁和二氧化碳。然而,本发明也惊奇的发现,即使在不溶的形式下,重质碳酸镁在接触中性水后或者在碱性环境中,例如口腔提供的环境中,都可以促进压制的剂型的快速分散。
此外,本发明提供了通用于在颊间隙中迅速崩解,并且具有令人愉快的口感的口腔分散片的配制方法。本发明的制剂与同等剂量的胃肠崩解剂型测试比较,发现具有生物等效性。本发明的教导也公开了一种配制分散剂型的方法,所述剂型在给药前在水中快速分散,并生物上可利用。本发明所述的片剂,虽然没有限制,通常重量范围为65~520mg,并能根据药物有效成分处于不包衣或包衣的颗粒状态进行调整。片剂的组合物可有含或不含水溶性赋形剂。使用重质碳酸镁后可以惊奇发现,可以同时获得感官良好的剂型,即同时获得分散片或口腔分散片并具有令人愉快的口感。
此外,本发明的组合物能够广泛适用于多种有效成分以及多种赋形剂的选择,诸如稀释剂、粘合剂、润滑剂、助流剂、掩味剂以及包衣剂。
发明详述
本发明涉及一种快速崩解的固体制剂。这些制剂在水中快速崩解,并且适于在给药前分散在水中。在给药前分散于水中的剂型通常是指分散片。在优选的实施方案中,配制所述剂型,可以在口腔中令人舒适地崩解,不需要预先在水中分散。那些适用于并旨在这种给药方式的片剂是指口腔分散片。通常口腔分散片也是“分散”的,即,通常能够在给药前分散于水中,例如,如果病人喜欢用这种给药方式的话。然而,可分散的剂型,并不需要都可口腔崩解,或者至少不需要适用于口腔崩解,因为例如有些有不良感官特点,不令人愉快口感等。
按照欧洲药典的标准,片剂剂型的优选易碎性应当小于1%。尽管这些片剂实际上具有低易碎性并且崩解迅速,这些片剂的硬度可以在15~170N范围内,比如最大的剂型在15~100N的范围内。
为了适合更广泛的多种药用成分,配制技术不能仅仅依赖单一的方法。本发明所公开的剂型和组合物适用于配制片剂,采用直接压制或者湿法制粒来生产口腔分散片或分散片。
本发明所公开的组合物不但可以使片剂与水分接触后迅速崩解,也优选产生具有令人愉快的口感和良好的感官特性的片剂。
适于例如因不愉快的口感或不稳定成分或其他原因需要包衣的成分也在本发明的范围内,前提为包衣不干扰进行的崩解。
本发明使用重质碳酸镁,为使制剂在接触水分后快速分散。片剂中可含有范围是重量百分比约为1~85%的重质碳酸镁,优选约4~75wt%的重质碳酸镁,例如重量百分比为4wt%和65wt%的重质碳酸镁用于快速口腔分散剂或者分散剂型,例如,范围约20~75wt%的重质碳酸镁,诸如范围约20~65wt%的重质碳酸镁,范围约30~65wt%的重质碳酸镁,或者范围约20~50wt%的重质碳酸镁,包括范围约25~45wt%的重质碳酸镁。在一些实施方案中,少量重质碳酸镁也被发现可以满足要求,例如重量百分比约为4~12%,包括重量百分比约为4~8%,例如重量百分比约为5%,6%,7%,或8%。
本发明所述的在分散剂型中掺入重质碳酸镁,可以有助于片剂在3分钟内在水中崩解,较优选在2分钟内崩解,或更优选在1分钟内崩解,或甚至更快的在30秒内崩解。
口腔分散剂型通常需要比分散制剂有更快的分散速度,并且本发明所述的口腔分散剂型,如下所述,可以在颊间隙中于2分钟内,较优选于1分钟内,更优选于30秒内或更短时间内,例如20秒内,较优选15秒内,更优选于10秒内崩解。这样快速的分散,如上所述是通过向片剂中掺入重质碳酸镁获得的。
本发明惊奇的发现重质碳酸镁的使用可以获得令人愉快的口感并且作为有效的分散剂发挥作用,而在碱性合中性环境下没有产生发泡的作用。
可用于本发明的其他赋形剂,可从下列辅料中选择,但不限于,通常使用的稀释剂、粘合剂、润滑剂、掩味剂和包衣剂。
稀释剂例如,但不限于:乳糖、喷雾干燥乳糖、木糖醇、山梨醇、二水硫酸钙、肌醇、淀粉、蔗糖、左旋糖、二水磷酸氢钙、甘露醇和微晶纤维素。尤其是,制粒用喷雾干燥甘露醇,比如Pearlitol SD200被发现对本发明所述的直接压制的片剂剂型特别有用。
可用的粘合剂例如,但不限于:蔗糖、葡萄糖、纤维素衍生物、聚乙烯吡咯烷酮(PVP)、羟甲基纤维素、乙基纤维素、西黄蓍胶、明胶、海藻酸钠、聚甲基丙烯酸酯、预糊化淀粉以及羟丙基纤维素。
可用的润滑剂例如,但不限于:硬脂酸钠、蜡、硬脂酸钙、硬脂酸、滑石粉、硬脂酸镁、氢化植物油、硼酸、氯化钠、卡波蜡4000和6000,油酸钠、乙酸钠、十二烷基硫酸钠、苯甲酸钠、DL-亮氨酸、苯甲酸钠和十二烷基硫酸钠。
部分实施方案中,低级取代的羟丙基纤维素尤其有用,用量范围约为2~10wt%,例如范围在3-6wt%,如约3wt%,约4wt%,约5wt%或约6wt%。
制剂中也可以掺入助流剂,例如,但不限于:滑石粉和玉米淀粉。
尤其是,本发明的剂型的优选组合物中,除重质碳酸镁外还含有AvicelCE-15(FMC BioPolymer,费城,美国),它是一种特殊的加工的颗粒成分,包括微晶纤维素和瓜尔胶,或者其他品牌的化学等价物。AvicelCE-15特别适用于咀嚼剂型,并且据我们所知的,还没有显示用于分散剂型。本发明所述的片剂剂型优选含有重量百分比范围约为3~15wt%的Avicel CE-15,较优选重量百分比范围约为3~10wt%的Avicel CE-15,例如10wt%;或者范围约为3~8wt%,例如约4wt%,约5wt%,约6wt%,约7wt%或约8wt%。
在随后的实施例中将会看到,使用细粒大小的微晶纤维素作为赋形剂被发现有助于本发明所述的剂型的直接压制和湿法制粒。例如,可以使用AvicelPH-102(FMC BioPolymer,美国费城),也可以使用其他具有相似材料特点的相似类型的纤维素,比如硅化微晶纤维素(如Prosolv SMCC-90(JRS Pharma,帕特森,美国纽约)),“UICEL”及其类似物。“UICEL”是一种用氢氧化钠处理过的纤维素粉末(参见Kumar,V等,Int J Pharm.2002Mar 20;235(1-2):129-40)。
本发明所述的片剂,优选包含这些细粒碎微晶纤维素,其用量的范围为约5-40wt%,优选范围为8-30wt%,比如范围约为10-20wt%,如约为8wt%,约10wt%,约15wt%,约20wt%,约25wt%或者约30wt%。
除了使用重质碳酸镁外,组合物中也可包括更多的崩解剂。崩解剂例如,但不限于:淀粉、预糊化淀粉、或其他修饰的淀粉、交联化羧甲基纤维素钠、硅酸镁铝、羟乙酸糖精钠、纤维素,尤其优选树胶和交联化聚乙烯吡咯烷酮(聚乙烯聚吡咯烷酮)。这些其他的崩解剂,若有用处,可以组成用量范围约为5-20wt%,优选用量范围约5-15wt%,例如范围约8-12wt%,诸如约8wt%,约10wt%,或者约15wt%。
本发明所述的制剂可包括其他本领域熟知的常规的改进制剂的成分。这些成分没有特别的限制,例如包括但不限于:天然和人工合成的芳香剂,比如甘露醇、山梨醇、麦芽糖醇、木糖醇、N-α-L-天冬氨酰-L-苯丙氨酸1-甲酯(阿斯巴甜)以及6-甲基-3,4-二氢-1,2,3-噁噻嗪-4(3氢)-酮-2,2-二氧,尤其是其钾盐(乙酰磺胺钾),天然的和合成的香精,比如酒石酸。本领域配制药品的技术人员将会认识到存在于组合物中的芳香剂以及甜味剂的量与那些需要掩盖的苦味成正比。
本发明可以广泛适用于多种药物有效成分。如实施例所阐述的,本发明的制剂和方法已经被证明可提供具有不同化学活性物质的分散制剂或口腔分散剂型,表明本发明通常适用于不同的化合物,所述化合物包括不同的化学性质,例如稳定性,疏水性,材料特性或者晶体形式。
可被制成口腔崩分散剂或者分散剂型,可单独使用或联合使用的药物有效成分的例子包括抗组胺药,抗运动呕吐药,止痛药,抗炎药(例如,吲哚美辛、阿司匹林、布洛芬、萘普生、酮咯酸、COX-1抑制剂、COX-2抑制剂等),抗生素,降脂药,抗焦虑药,抗高血压药,抗血管生成药(例如,风车子阻生素、contortrostatin、抗血管内皮生长因子等),抗癌药(例如,mechloretharine、环磷酰胺、氟尿嘧啶、硫鸟嘌呤、卡莫司汀、卢莫司汀、美法仑、苯丁酸氮芥、链脲霉素、甲氨蝶呤、长春新碱、博莱霉素、长春花碱、长春地辛、更生霉素、柔红霉素、多柔比星、他莫昔芬等),催眠药,***(例如,***、度冷丁、可待因等),局麻药(例如,含酰胺基或酰苯胺基型局麻药,诸如布比卡因、地布卡因、甲哌卡因、普鲁卡因、利多卡因、丁卡因等),抗溃疡药,冠脉扩张药,抗病毒药,抗精神***药,抗抑郁药,神经肌肉药,抗痢疾药,降血糖药,甲状腺抑制药,代谢药,抗痉挛药,抗偏头痛药,利尿药,***,解除充血药,子宫松弛剂,抗心律失常药,男性***功能障碍药包括昔多芬、他达拉非,Maxi-k通道开启剂或者治疗中风或者阿尔兹海默氏症的神经保护剂,以及治疗这些适应症的联合用药。
具体治疗剂的例子,包括5-羟色胺再摄取抑制剂,诸如依地普仑、西酞普兰、氟西汀、氟伏沙明、帕罗西汀、舍曲林和文拉法辛,非极性和弱极性的不同杂环的化合物包括硫苯氮二卓类化合物,诸如奥兰扎平和氯氮平;苯并咪唑类衍生物,诸如兰索拉唑、替莫拉唑、埃索美拉唑、奥美拉唑、潘妥拉唑、乐米诺拉唑、帕日拉唑;还有安非他酮、奈法唑酮;苯三嗪类衍生物包括拉莫三嗪、二氢吡啶钙通道阻断剂,例如硝苯地平、尼莫地平、尼索地平、尼卡地平、氨氯地平等;他汀类药物,例如阿托伐他汀、氟伐他汀、辛伐他汀、洛伐他汀等;抗惊厥药,例如苯妥英钠、酰胺咪嗪等;镇痛剂、甾体类,例如强的松、强的松龙、氢化可的松等;贝特类药物,例如吉非罗齐、非诺贝特、氯贝丁酯等,米氮平,和苯并异噁唑衍生物例如利司培酮。
如本发明所述,本发明适合于使用湿法制粒或直接压制法生产片剂。湿法制粒过程中,将成分混合,用制粒液体润湿,成团。持续润湿过程,直到获得所需的均匀度,随后干燥湿团。混合物随后过筛,任选添加其他成分,然后压制成片。相反的,对于直接压制,则将多种成分混合在一起直到均匀,过筛后便可压制成片剂型。直接压制法总体上优于其他大多数片剂的生产,因为它很经济。有效成分和/或片剂本身可以包衣也可以不包衣。
本发明所述的分散片旨在给药前在水里分散,形成均匀的分散体。但是,这些分散片通常也可以被咀嚼和/或吞咽。
本发明所述的口腔分散片,可理解为是指一种在吞咽前,在颊间隙内壁中接触到水分后才开始崩解的片剂。但是,这些口腔分散片也可以在给药前在水里分散然后被饮用,或者被咀嚼和/或吞咽。
在摄取药物前,或者在消化***内,或在皮下,或在体表,或者任何其他方式运用重质碳酸镁在中性或碱性条件下分散药物,以增加有效成分的递送为目的,也被认为包括在本发明当中。
崩解测试证明了片剂在放置于液体介质中是否能在规定时间内崩解。下列情况则认为片剂已经崩解:a)屏幕上无残渣残留,或b)如果有残留,它是由软团块组成,触摸不到坚硬物,未湿润的芯,或c)只有包衣的碎片在屏幕上可见。
为了确定片剂的表面在遭遇机械碰撞或磨损时是否损伤和/或出现层裂的迹象,或出现损坏,可以依据欧洲药典所述的基本规定进行易碎性测试实验。
在不背离本发明所述的范围和精神前提下,本发明所述的多种其他实施方案和修该对本领域技术人员而言也是显而易见的。因此,本发明所附的权利要求和实施例的范围不应该被认为是确切的描述,权利要求应该被理解为包括在本发明的范围内具有新颖性的所有特征,包括被本领域技术人员认为是等同的所有的特征和实施方案。本发明结合下列实施例进一步描述。
实施例
实施例1
用重质碳酸镁或甘露醇进行湿法制粒配制时,含有拉莫三嗪的分
散片的崩解时间的比较
拉莫三嗪的颗粒大小为:99.2%小于120μm并且5%小于10μm。
表1:含重质碳酸镁的片剂
成分 | mg/片 | |
1 | 拉莫三嗪 | 5 |
2 | 重质碳酸镁 | 122 |
3 | 微晶纤维素(Avicel PH-102) | 29 |
4 | 聚乙烯吡咯烷酮 | 4 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 8 |
6 | 糖精钠 | 2 |
7 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 8 |
8 | 纯净水 | 适量 |
9 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 8 |
10 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 10 |
11 | 黑醋栗香精Silarom | 2 |
12 | 非牛源的硬脂酸镁 | 2 |
200 |
制成的5mg片剂结果如下:
硬度:39.2N(35-49N)
崩解度:20秒(15℃水)
易碎性:0.06%
表2:含甘露醇的片剂
成分 | mg/片 | |
1 | 拉莫三嗪 | 5 |
2 | 甘露醇(Pearlitol SD 200) | 122 |
3 | 微晶纤维素(Avicel PH-102) | 29 |
4 | 聚乙烯吡咯烷酮 | 4 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 8 |
6 | 糖精钠 | 2 |
7 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 8 |
8 | 纯净水 | 适量 |
9 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 8 |
10 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 10 |
11 | 黑醋栗香精Silarom | 2 |
12 | 非牛源的硬脂酸镁 | 2 |
200 |
制成的5mg片剂结果如下:
硬度:43.5N(40-49N)
崩解度:40秒(15℃水)
易碎性:0.16%
成分1-7,Avicel PH-102、聚乙烯吡咯烷酮、Polyplasdone XL-10、拉莫三嗪、L-HPC、糖精钠及重质碳酸镁或者甘露醇按照上述顺序加入碗中;混合,过筛,再混合。混合物用成分8纯净水润湿,进一步混合后过筛。颗粒干燥,过筛。成分9-11,按照黑醋栗香精、PolyplasdoneXL-10、Avicel CE-15的顺序加入到混合物然后混合。最后,将成分12硬脂酸镁,加入混合物中并混合。然后将混合物压制成片剂。
分别加重质碳酸镁或甘露醇而其他组分相同的片剂的崩解时间比较结果清楚的显示使用前者获得显然更短的崩解时间。这是因为,似乎在片剂内形成多孔状结构或基质的重质碳酸镁被水破坏的事实。重质碳酸镁的一个重要因素是在碱性和中性条件下不会溶解。相反的,甘露醇通过吸收可获得的水分溶解,从而限制了有助于片剂崩解的水的进入。
实施例2
拉莫三嗪分散片的生物学研究
该生物学研究是可比较的、随机、单剂量、双向交叉生物利用度研究:(A)Actavis拉莫三嗪5mg分散片(根据实施例1a制作的),(B)Lamictal(葛兰素史克)5mg分散片在禁食条件下施用给24名健康受试者,。其结果如下:
表3:药物代谢动力学参数
AUCo-t 3 | AUCo-lnf | Cmax | |
比率190%几何置信区间2对象内CV | 103.79%100.98%-106.69%5.55% | 103.69%100.53%-106.95%6.25% | 103.57%97.39%-110.14%12.64% |
1根据公式用最小二乘均值计算:e(拉莫三嗪(A)-Lamictal(B)×100
2利用In-transformed数值的90%置信区间
3t为120小时
根据上述生物学研究,结论为两种片剂在禁食状态下是生物等效的。
实施例3到9描述了含有米氮平的剂型的不同配制方法以及生物利用度研究。
米氮平的颗粒大小为:90%小于60μm并且50%小于30μm。
实施例3
用湿法制粒配制含有米氮平的口腔分散片
表4:组合物
成分 | mg/片 | |
1 | 米氮平 | 45 |
2 | 重质碳酸镁 | 181.6 |
3 | 糖精钠 | 4 |
4 | 硅化微晶纤维素(Prosolv SMCC-90) | 43.5 |
5 | 甘露醇 | 65.25 |
6 | 聚乙烯吡咯烷酮 | 9 |
7 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 26.1 |
8 | 纯净水 | 适量 |
9 | 硅化微晶纤维素(Prosolv SMCC-90) | 21.75 |
10 | 黑醋栗香精Silarom | 8.7 |
11 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 26.1 |
12 | 非牛源的硬脂酸镁 | 4 |
435mg |
将成分1-7,米氮平,重质碳酸镁,糖精钠,Prosolv SMCC-90,甘露醇,聚乙烯吡咯烷酮和Polyplasdone XL-10混合,用纯净水润湿,制粒,过筛,干燥。然后将成分9-12,Prosolv SMCC-90,黑醋栗香精Silarom,Polyplasdone XL-10和硬脂酸镁加入到混合物,混合,然后将混合物准备压制成片。
结果如下:
崩解度:20秒(37℃水)
硬度:30-42N
实施例4
用湿法制粒配制含有米氮平的口腔分散片
表5:
成分 | mg/片 | |
1 | 米氮平 | 15 |
2 | 重质碳酸镁 | 67.875 |
3 | 阿斯巴甜 | 6 |
4 | 微晶纤维素(Avicel PH 102) | 15 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 6 |
6 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 9 |
7 | 纯净水 | 适量 |
8 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 15 |
9 | 柑橘香精Silesia | 6 |
10 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 9 |
11 | 非牛源的硬脂酸镁 | 1.125 |
150 |
将成分1-6,米氮平,重质碳酸镁,阿斯巴甜,Avicel PH 102,L-HPC和Polyplasdone XL-10混合,用纯净水润湿,制粒,过筛并干燥。然后将成分8-11,Avicel CE-15,柑橘香精Silesia,Polyplasdone XL-10和硬脂酸镁加入到混合物,混合,然后将混合物准备压制成片。
结果如下:
崩解度:15秒(37℃水)
硬度:15-23N
易碎性:0.67%
实施例5
用直接压制法配制含有米氮平的口腔分散片
表6:组合物
成分 | mg/片 | |
1 | 米氮平 | 15 |
2 | 甘露醇DC(Pearlitol SD 200) | 60.75 |
3 | 重质碳酸镁 | 7.5 |
4 | 微晶纤维素(Avicel PH-102) | 30.375 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 6 |
6 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 12 |
7 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 7.5 |
8 | 阿斯巴甜 | 6 |
9 | 柑橘香精Silesia | 3.75 |
10 | 非牛源的硬脂酸镁 | 1.125 |
150 |
将成分1-9,米氮平,Pearlitol,重质碳酸镁,Avicel PH 102,L-HPC,聚乙烯聚吡咯烷酮,Avicel CE-15,阿斯巴甜和柑橘香精混合,过筛,再混合。然后将成分10硬脂酸镁加入到混合物中,混合,混合物准备用于压制成片。用直接压制法压制成片。
结果如下:
崩解度:18秒(37℃水)
硬度:18-26N
易碎性:0.32%
实施例6
用直接压制法配制含有米氮平的口腔分散片
表7:组合物
成分 | mg/片 | |
1 | 米氮平 | 15 |
2 | 甘露醇DC(Pearlitol SD 200) | 60 |
3 | 重质碳酸镁 | 7.5 |
4 | 微晶纤维素(Avicel PH-102) | 30.375 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 6 |
6 | L-甲硫氨酸 | 0.75 |
7 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 12 |
8 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 7.5 |
9 | 阿斯巴甜 | 6 |
10 | 柑橘香精Silesia | 3.75 |
11 | 非牛源的硬脂酸镁 | 1.125 |
150 |
将成分1-10,米氮平,Pearlitol,重质碳酸镁,Avicel PH 102,L-HPC,L-甲硫氨酸,聚乙烯聚吡咯烷酮,Avicel CE-15,阿斯巴甜,柑橘香精混合,过筛,再混合。然后将成分11硬脂酸镁加入到混合物中,混合,混合物将准备用于压制成片。用直接压制法压制成片。
结果如下:
崩解度:19秒(37℃水)
硬度:21-29N
易碎性:0.27%
实施例7
用湿法制粒配制含有米氮平的口腔分散片
表8:组合物
成分 | mg/片 | |
1 | 米氮平 | 45 |
2 | 甘露醇DC(Pearlitol SD 200) | 33.75 |
3 | 微晶纤维素(Avicel PH 102) | 91.125 |
4 | 重质碳酸镁 | 22.5 |
5 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 9 |
6 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 18 |
7 | 无水硅胶(Aerosil 200) | 4.5 |
8 | L-甲硫氨酸 | 0.45 |
9 | 纯净水 | 适量 |
10 | 甘露醇DC(Pearlitol SD 200) | 14.0175 |
11 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 9 |
12 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 18 |
13 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 22.5 |
14 | 阿斯巴甜 | 18 |
15 | 柑橘香精Silesia | 11.25 |
16 | 非牛源的硬脂酸镁 | 6.75 |
450 |
将成分1-7,Avicel PH 102,米氮平,Pearlitol SD 200,Aerosil 200,Polyplasdone XL-10,L-HPC和重质碳酸镁混合。混合后的成分过筛再混合。成分8,L-甲硫氨酸用成分9纯净水溶解,并用这个溶液润湿上述混合物,制粒,过筛,干燥,再过筛。将成分10-15,柑橘香精Silesia,阿斯巴甜,Avicel CE-15,Polyplasdone XL-10,L-HPC和Pearlitol SD 200顺序加入到混合物,混合,然后将混合物准备压制成片。
结果如下:
崩解度:<25秒(37℃水)
硬度:35-55N
易碎性:<1%
实施例8
米氮平口腔分散片的生物学研究
该生物学研究是可比较的、随机、单剂量、三向交叉生物利用度研究:(A)Actavis 30mg米氮平口腔分散片(根据实施例7成比例放大制作的),(B)Organon Laboratories Limited公司(Zispin)30mg米氮平片和(C)Organon Laboratories Limited公司(RemergilSoltabTM)30mg米氮平口腔分散片,在禁食条件下施用健康成年男子受试者。其结果如下:
表9:血浆中的米氮平,LSM%比率(90%置信区间,来源于Intransformed参数)
参数 | Actavis(A)vs.Organon(Zispin)(B) | Actavis(A)vs.Organon(RemergilISoltabTM)(C) |
AUC 0-t | 103.1%(99.4%-107.0%) | 104.1%(100.3%-108.0%) |
AUCinf | 102.8%(99.1%-106.7%) | 103.8%(100.1%-107.6%) |
Cmax | 109.8%(102.2%-118.0%) | 115.1%(107.1%-123.7%) |
表10:血浆中的N-去甲基米氮平,LSM%比率(90%置信区间)
参数 | Actavis(A)vs.Organon(Zispin)(B) | Actavis(A)vs.Organon(RemergilISoltabTM)(C) |
AUC 0-t | 99.9%(97.9%-102.1%) | 99.4%(97.3%-101.5%) |
AUCinf | 99.6%(97.6%-101.6%) | 99.4%(97.4%-101.4%) |
Cmax | 100.6%(95.6%-105.8%) | 103.8%(98.7%-109.3%) |
根据上述结果,可以得出结论:片剂Actavis片剂(A)与Organon的常规片剂(B)及口腔分散片(C)是生物等效的。
实施例9
用湿法制粒配制含有奥兰扎平的口腔分散片
奥兰扎平是属于硫苯氮二卓类的神经药物。它对光和潮湿都很敏感,在水和中性PH值条件下不溶,酸性PH值条件下微溶。
由于奥兰扎平对光和湿的不稳定性,对奥兰扎平进行了增加其成粒性的实验。
奥兰扎平的颗粒大小必须小于100μm
表11:组合物
成分 | mg/片 | |
1 | 微晶纤维素(Avicel PH 102) | 21 |
2 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 2.1 |
3 | 无水硅胶(Aerosil 200) | 1.05 |
4 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 4.9 |
5 | 重质碳酸镁 | 21.53 |
6 | 纯净水 | 适量 |
7 | 奥兰扎平 | 5.0 |
8 | 低级取代的羟丙基纤维素(L-HPC,LH-11) | 1.4 |
9 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 2.1 |
10 | 微晶纤维素(Avicel PH 102) | 3.5 |
11 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 3.5 |
12 | 无水硅胶(Aerosil 200) | 0.175 |
13 | 天然薄荷油香精Silesia | 0.42 |
14 | 阿斯巴甜 | 2.8 |
15 | 非牛源的硬脂酸镁 | 0.525 |
70.0 |
将成分1-5,Avicel PH 102,L-HPC,Aerosil 200,PolyplasdoneXL-10和重质碳酸镁按上述顺序加入碗中混合。然后将他们过筛后再混合。混合物用成分6润湿,制粒,过筛,干燥,再过筛。将成分7-14,奥兰扎平,L-HPC,Polyplasdone XL-10,Avicel PH 102,Avicel CE-15,Aerosil 200,天然薄荷油香精和阿斯巴甜加入碗中混合。将成分7-14加入干燥颗粒中混合。最后,将成分15硬脂酸镁加入到混合物,混合,然后将混合物准备压制成片。
结果如下:
崩解度:9秒(37℃水)
口腔崩解时间:<15秒
硬度:38-60N
易碎性:0.0%
实施例10
用直接压制法配制含有利司培酮的口腔分散片
利司培酮是一种抗精神***药,属于苯尔氮卓类衍生物
表12:组合物
成分 | mg/片 | |
1 | 利司培酮 | 1 |
2 | 甘露醇DC(Pearlitol SD 200) | 20.98 |
3 | 重质碳酸镁 | 17.5 |
4 | 微晶纤维素(Avicel PH 102) | 14 |
5 | 低取代羟丙基纤维素(L-HPC,LH-11) | 2.8 |
6 | 聚乙烯聚吡咯烷酮(Polyplasdone XL-10) | 5.6 |
7 | 微晶纤维素+瓜尔胶(Avicel CE-15) | 3.5 |
8 | 阿斯巴甜 | 2.8 |
9 | 薄荷油香精 | 0.42 |
10 | 无水硅胶(Aerosil 200) | 0.7 |
11 | 非牛源的硬脂酸镁 | 0.7 |
12 | 70.0 |
将成分1-10,利司培酮,Pearlitol SD 200,重质碳酸镁,Avicel PH102,L-HPC,Polyplasdone XL-10,Avicel CE-15,阿斯巴甜,薄荷油香精和Aerosil 200加入箱中,混合,过筛,再混合。然后将成分11硬脂酸镁加入混合物中,混合,混合物准备压制成片。
结果如下:
崩解度:8秒
硬度:10-17N
易碎性:0.24%
Claims (30)
1.一种用于施用药物的分散剂型,所述剂型与水接触时崩解,含有作为分散剂的重质碳酸镁以及活性药学物质。
2.根据权利要求1所述的剂型,含有按重量计在1%~85%范围内的重质碳酸镁。
3.根据权利要求1所述的剂型,含有按重量计在4%~65wt%范围内的重质碳酸镁。
4.根据权利要求1所述的剂型,其是用于给药前于水中分散的分散片剂。
5.根据权利要求4所述的剂型,其中所述剂型在15℃少于3分钟的时间内在水中崩解。
6.根据权利要求5所述的剂型,其中所述剂型在15℃少于2分钟的时间内在水中崩解。
7.根据权利要求6所述的剂型,其中所述剂型在15℃少于1分钟的时间内在水中崩解。
8.根据权利要求1所述的剂型,是口腔分散片。
9.根据权利要求8所述的剂型,其在37℃在少于1分钟的时间内在水中崩解。
10.根据权利要求8所述的剂型,其在37℃少于30秒的时间内在水中崩解。
11.上述权利要求任一项所述的剂型,含有作为活性物质的米氮平或其药学上可接受的盐。
12.上述权利要求任一项所述的剂型,含有作为活性成分的奥兰扎平或者其药学上可接受的盐。
13.上述权利要求任一项所述的剂型,含有作为活性成分的利司培酮或者其药学可接受的盐。
14.上述权利要求任一项所述的剂型,含有作为活性成分的拉莫三嗪或者其药学可接受的盐。
15.上述权利要求任一项所述的剂型,其中所述剂型被压制成片剂。
16.根据权利要求15所述的剂型,其中所述片剂是直接压制的片剂。
17.根据权利要求15所述的剂型,其中所述片剂的配制是运用湿法制粒进行的。
18.根据权利要求15-17任一项所述的剂型,被压制成硬度范围为15~170N的片剂。
19.上述权利要求任一项所述的剂型,其中所述剂型为分散片和/或口腔分散片,其中片剂的易碎性小于1%。
20.上述权利要求任一项所述的剂型,含有微晶纤维素和瓜尔胶。
21.根据权利要求20所述的剂型,含有Avicel CE-15型的微晶纤维素和瓜尔胶。
22.一种药物分散剂型,含有作为活性成分的拉莫三嗪,并进一步含有:
-约50-65wt%范围内的重质碳酸镁;
-约10-30wt%范围内的细粒微晶纤维素;
-约3-10wt%范围内的低级取代的羟丙基纤维素;
-约5-15wt%范围内的聚乙烯聚吡咯烷酮;
-约4-20wt%范围内的微晶纤维素和瓜尔胶的Avicel CE-15混合物。
23.根据权利要求22所述的剂型,含有:
-约2,5wt%的拉莫三嗪;
-约61wt%的重质碳酸镁;
-约15wt%的细粒微晶纤维素;
-约4wt%的低级取代的羟丙基纤维素;
-约8wt%的聚乙烯聚吡咯烷酮;和
-约5wt%的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
24.一种药物分散剂型,含作为活性成分的米氮平,并进一步含有:
-约30-65wt%范围内的重质碳酸镁;
-约10-30wt%范围内的细粒微晶纤维素;
-约3-10wt%范围内的低级取代的羟丙基纤维素;
-约5-15wt%范围内的聚乙烯聚吡咯烷酮;
-约4-20wt%范围内的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
25.根据权利要求24所述的剂型,含有:
-约10wt%的米氮平;
-约5wt%的重质碳酸镁;
-约20wt%的细粒微晶纤维素;
-约4wt%的低级取代的羟丙基纤维素;
-约8wt%的聚乙烯聚吡咯烷酮;和
-约5wt%的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
26.根据权利要求24所述的剂型,含有:
-约10wt%的米氮平;
-约42wt%的重质碳酸镁;
-约15wt%的细粒微晶纤维素;
-约4wt%的低级取代的羟丙基纤维素;
-约8wt%的聚乙烯聚吡咯烷酮;和
-约5wt%的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
27.一种药物分散剂型,含作为活性成分的奥兰扎平,并进一步含有:
-约20-60wt%范围内的重质碳酸镁;
-约15-35wt%范围内的细粒微晶纤维素;
-约3-10wt%范围内的低级取代的羟丙基纤维素;
-约5-15wt%范围内的聚乙烯聚吡咯烷酮;
-约45-20wt%范围内的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
28.根据权利要求27所述的剂型,含有:
-约7wt%的奥兰扎平;
-约31wt%的重质碳酸镁;
-约30wt%的细粒微晶纤维素;
-约5wt%的低级取代的羟丙基纤维素;
-约10wt%的聚乙烯聚吡咯烷酮;和
-约5wt%的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
29.一种药物分散剂型,含作为活性成分的利司培酮,并进一步含有:
-约20-60wt%范围内的重质碳酸镁;
-约15-35wt%范围内的细粒微晶纤维素;
-约3-10wt%范围内的低级取代的羟丙基纤维素;
-约5-15wt%范围内的聚乙烯聚吡咯烷酮;
-约4-20wt%范围内的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
30.根据权利要求29所述的剂型,含有:
-约1,4wt%的利司培酮;
-约25wt%的重质碳酸镁;
-约20wt%的细粒微晶纤维素;
-约4wt%的低级取代的羟丙基纤维素;
-约8wt%的聚乙烯聚吡咯烷酮;和
-约5wt%的微晶纤维素和瓜尔胶的AvicelCE-15混合物。
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WO2013172805A1 (en) * | 2012-05-14 | 2013-11-21 | Mahmut Bilgic | New orodispersible tablet formulations of olanzapine |
JP6062693B2 (ja) * | 2012-09-14 | 2017-01-18 | 沢井製薬株式会社 | オランザピン含有製剤 |
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JP2017014119A (ja) * | 2015-06-26 | 2017-01-19 | 東和薬品株式会社 | 経口医薬組成物 |
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CN115252568A (zh) * | 2022-08-26 | 2022-11-01 | 苏州中化药品工业有限公司 | 一种盐酸西替利嗪片剂及其制备方法 |
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CA2552221A1 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Donepezil formulations |
-
2005
- 2005-03-02 IS IS7724A patent/IS7724A/is unknown
-
2006
- 2006-03-02 CA CA002599308A patent/CA2599308A1/en not_active Abandoned
- 2006-03-02 US US11/885,417 patent/US20080166406A1/en not_active Abandoned
- 2006-03-02 EP EP06711375A patent/EP1863443B1/en active Active
- 2006-03-02 AT AT06711375T patent/ATE446084T1/de not_active IP Right Cessation
- 2006-03-02 DE DE202006020222U patent/DE202006020222U1/de not_active Expired - Lifetime
- 2006-03-02 JP JP2007557680A patent/JP2008531681A/ja active Pending
- 2006-03-02 CN CNA2006800069782A patent/CN101132764A/zh active Pending
- 2006-03-02 DE DE602006009906T patent/DE602006009906D1/de active Active
- 2006-03-02 WO PCT/IS2006/000005 patent/WO2006092812A2/en active Application Filing
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104640569A (zh) * | 2012-09-18 | 2015-05-20 | 默克专利股份有限公司 | 在含活性成分的制剂中用作载体材料的碱式碳酸镁 |
CN104870018A (zh) * | 2012-12-21 | 2015-08-26 | 默克专利股份有限公司 | 具有改善的活性物质的释放作为药物制剂中载体的碱式碳酸镁 |
CN103520169A (zh) * | 2013-10-25 | 2014-01-22 | 山东鲁药制药有限公司 | 米氮平片及其制备方法 |
CN111714463A (zh) * | 2020-08-14 | 2020-09-29 | 华农(肇庆)生物产业技术研究院有限公司 | 米氮平口服剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
ATE446084T1 (de) | 2009-11-15 |
US20080166406A1 (en) | 2008-07-10 |
WO2006092812A2 (en) | 2006-09-08 |
IS7724A (is) | 2006-09-03 |
DE602006009906D1 (de) | 2009-12-03 |
DE202006020222U1 (de) | 2008-06-05 |
CA2599308A1 (en) | 2006-09-08 |
JP2008531681A (ja) | 2008-08-14 |
EP1863443A2 (en) | 2007-12-12 |
EP1863443B1 (en) | 2009-10-21 |
WO2006092812A3 (en) | 2006-12-21 |
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