CN102596183B - 迅速溶出/崩解的包衣组合物 - Google Patents
迅速溶出/崩解的包衣组合物 Download PDFInfo
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- CN102596183B CN102596183B CN201080049768.8A CN201080049768A CN102596183B CN 102596183 B CN102596183 B CN 102596183B CN 201080049768 A CN201080049768 A CN 201080049768A CN 102596183 B CN102596183 B CN 102596183B
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Abstract
本发明公开了一种表现出增强的崩解特性的口服药物组合物，所述药物组合物包含芯以及所述芯上的薄膜包衣。所述薄膜包衣包含成膜聚合物、有机溶剂、超级崩解剂和任选的酸不稳定性材料。
Description
技术领域
本发明涉及药物组合物，更具体地讲，涉及具有增强的崩解特性的薄膜包衣片剂组合物。该薄膜包衣片剂组合物由含有以下物质的溶剂基薄膜包衣组合物包覆：可溶于水和极性有机溶剂的聚合物、超级崩解剂和任选的酸不稳定性材料。
背景技术
许多疾病治疗中的标准疗法是以片剂剂型施用药物活性成分，其通常需要患者完整地吞服片剂。为了改善片剂的可吞服性，本领域已知的是用聚合物薄膜包覆片剂表面，从而为患者提供若干益处。首先，其可降低片剂与口腔内表面的粘附力，从而增强患者吞服片剂的能力。其次，其可有助于掩盖某些药物的不良味道。另外，其还可保护组分免于在大气中降解并且可改善外观。
通常用于此类薄膜包衣的聚合物薄膜包含(例如)：(1)乙烯基聚合物，如聚乙烯吡咯烷酮、聚乙烯醇和聚醋酸乙烯酯；(2)纤维素，如甲基纤维素和乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素和羟丙基纤维素；(3)丙烯酸酯和甲基丙烯酸酯；(4)共聚物，如乙烯基-马来酸共聚物和苯乙烯-马来酸共聚物；以及(5)天然树胶和树脂，如玉米蛋白、明胶、紫胶和阿拉伯树胶。参见“Remington′s Pharmaceutical Sciences”，第15版，Mack Publishers(1975)，第1613页。
虽然薄膜包衣可为片剂制剂增加某些优势，但有一个缺点是薄膜包衣可能会通过延迟片剂的崩解而减缓药物发挥作用。在某些情况下，这会延迟片剂在与液体介质接触的最初几分钟内的崩解。这会影响某些药物的性能，如需要快速发挥作用的抗酸剂。因此，需要表现出增强的崩解特性的薄膜包衣组合物，以便更快地递送活性物质以及更快地发挥作用。
在可吞服片制剂的片芯或制粒混合物中使用崩解剂(如干淀粉、藻酸钠、乳糖、碳酸氢钠、碳酸钙、聚乙烯吡咯烷酮、微晶纤维素等)是已知的。例如，美国专利No.4,965,072公开了使用七水硫酸镁和六偏磷酸钠的混合物与活性成分一起制备制粒组合物，当将其配制成可吞服片时，表现出快速崩解或分散特性。
近年来，已开发了多种更新的称为“超级崩解剂”的试剂。这些更新的物质在以较低浓度提供更高崩解效率和机械强度方面更有效。与水接触后，超级崩解剂即可溶胀、水合、改变体积或形成并产生片剂的破坏性变化。有效的超级崩解剂可提供改善的可压性、相容性，并且对含有高剂量药物的制剂的机械强度无负面影响。然而，以此类方式在片芯中使用崩解剂和/或超级崩解剂不能解决薄膜包衣片剂中与聚合物薄膜的溶出缓慢相关的问题。
授予R.P.Sheerer Corporation的美国专利No.6,413,549公开了快速崩解冻干剂型，其包含用聚合物或脂质材料包衣的活性物质的粗糙粒子。
授予SmithKline Beecham Corporation的美国专利No.7,125,562公开了崩解性甲基纤维素片。该专利公开说所述片剂具有第一相以及与第一相共混的第二相，并且每一相都可含有崩解剂和聚合物。
授予Hercules Incorporated的欧洲专利No.EP878189 B1公开了在个人护理产品中使用疏水改性的多糖，包括羟丙基纤维素。
授予Philip等人的美国专利申请No.20050255054公开了可溶性牙贴白，其包含可溶性物质，例如含乙酰化甘露聚糖的冻干水凝胶。
授予Wynn等人的美国专利申请No.20070077300 A1公开了这样的口服剂型，其包含可存在于剂型芯体中和/或包衣中的唾液诱生剂。
授予SmithKline Beecham Corporation的美国专利申请No.20080292669公开了适于透粘膜和/或透皮应用的发泡基质，其包含一种或多种聚合物以及一种或多种发泡剂，并且可包含一种或多种增塑剂、疏水性阻隔剂、牙齿增白剂、抗氧化剂、防腐剂、超级崩解剂或吸收剂、矫味剂、除臭剂、口气清新剂、着色剂、表面活性剂、薄膜改性剂、交联剂、抗微生物剂、控释剂、其他治疗剂或它们的任意组合。
授予Cambrex Charles City，Inc.的国际专利申请No.WO2008079963公开了含阴离子API(原料药)的离子络合物，其可用可药用包衣包覆。
授予Bangalore的美国专利申请No.20090047330 A1公开了基于水溶性聚合物的可食用薄膜，其使用该专利中所公开的制剂组合物及其他成分(包括增塑剂、填充剂、掩味剂、崩解剂和着色剂)而制备。
授予Bristol-Myers Squibb Co.的美国专利No.6,627,224公开了制备包含恩替卡韦的药物组合物的工艺，包括在溶剂中形成恩替卡韦和粘合剂的溶液，将该溶液沉积到基材粒子上，干燥包衣后的基质粒子并与其他成分(包括崩解剂)混合。
授予Ethypharm的美国专利No.6,660,382公开了制备能掩味并快速释放活性物质的包衣颗粒剂的工艺，包括：干混包含至少活性物质和崩解剂的粉末成分；在存在粘合剂的情况下对所得的粉末制粒以得到颗粒；通过喷洒包含至少一种包衣剂和一种崩解剂的悬浮液对颗粒进行包衣；以及干燥所得的包衣颗粒。
授予McNeil PPC，Inc.的美国专利No.5,807,580公开了包括表现出增强的崩解特性的薄膜包衣片的药物组合物，该片剂包含亲水性成膜聚合物和碱性剂(例如碱金属、碱土金属碳酸盐或碳酸氢盐，如碳酸氢钠或碳酸氢钾)，其中碱性剂可通过提高薄膜包衣聚合物的移除速率而缩短薄膜包衣的崩解时间。
仍然需要药物组合物，更具体地讲，需要具有增强崩解特性的薄膜包衣片剂组合物。
发明内容
片剂上的速释薄膜包衣本身具有限速步骤，因为聚合物必须水合到一定程度后才能溶解，即便它们为水溶性薄膜包衣也是如此。大部分薄膜无法支持添加可有助于此崩解过程的材料，因为这些材料可能不与水性包衣溶液相容，或者就薄膜条剂型(film strip dosage form)而言，不与包含活性成分的浇注溶液相容。
本发明的药物组合物显示具有增强的崩解特性，其包含芯以及在芯上的薄膜包衣，该薄膜包衣包含成膜聚合物、极性有机溶剂、超级崩解剂和任选的酸不稳定性材料。选择既可溶于极性有机溶剂又可溶于水的聚合物，以便使超级崩解剂在施加(例如喷雾、浸渍或浇注成膜)前完整地悬浮。典型的水性包衣体系会在处理过程中使超级崩解剂失活，或者会溶胀到因尺寸过大而无法施加的程度。有机溶剂体系则允许它们在成品包衣中保持其溶胀特性。所述新型包衣组合物可产生快速溶出/崩解的薄膜。在整个包衣过程中超级崩解剂基本上完整。
超级崩解剂可通过薄膜的溶胀和崩解，增加薄膜包衣聚合物的移除速率来缩短薄膜包衣的崩解时间。酸不稳定性材料将会提高薄膜崩解速率。当该薄膜包衣片接触液体介质时，其立即与该液体介质反应以使薄膜包衣崩解。
优选地，成膜聚合物为羟丙基纤维素。
优选地，极性有机溶剂选自乙醇、丙酮、甲醇和异丙醇。在一个实施例中，极性有机溶剂为两种或更多种有机溶剂的混合物。在一个实施例中，该有机溶剂为乙醇与选自丙酮、甲醇和异丙醇的辅助溶剂的混合物，其中乙醇与辅助溶剂的比率为约50∶50至约99∶1。
优选地，超级崩解剂选自低取代羟丙基纤维素(L-HPC)、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、大豆多糖、交联藻酸、结冷胶、黄原胶、硅酸钙和离子交换树脂。在一个优选的实施例中，超级崩解剂为交联羧甲基纤维素钠，因为其为离子型的。交联羧甲基纤维素钠的离子特性在制备和储存乙醇基包衣溶液或悬浮液时尤其有利，因为此特性可抑制溶液或悬浮液中超级崩解剂的反应或溶胀。在另一个优选的实施例中，超级崩解剂为L-HPC。
优选地，酸不稳定性材料选自碳酸氢钠、碳酸氢钾、碳酸钠和甘氨酸钠碳酸盐。
具体实施方式
根据本发明，在含有药物活性成分的芯的暴露表面的至少一部分上，优选整个表面上形成薄膜包衣。该薄膜包衣可任选含有：增塑剂，如蓖麻油、柠檬酸三乙酯、柠檬酸三丁酯、甘油三乙酸酯、矿物油、聚乙二醇、丙二醇或甘油；着色剂或遮光剂，如二氧化钛；调味剂；感觉剂，如凉爽剂、温热剂或麻刺剂；和/或改善适口性的甜味剂。薄膜包衣将通常含有约1重量％至约20重量％的成膜聚合物。
将薄膜包衣施加到含有活性成分的标准片剂或胶囊形片剂的芯上。芯根据标准药物制片技术制备，包括湿法制粒、干法制粒、直接压片、滚圆法等。使用常规的药物包衣设备将包衣材料施加到芯上，如使用得自Thomas Engineering，Inc.(Hoffman Estates，Ill)的Accela-CotaTM包衣锅或诸如Wurster包衣设备之类的流化床包衣装置。适用于本发明的其他薄膜包衣技术在“Remington′s Pharmaceutical Sciences”(A.L.Gennaro编辑)，MackPublishing Co.(Easton，Pa.)，第18版，第90章(1990)中有所描述，藉此将该文献以引用方式并入本文。施加本发明的薄膜包衣的优选方法是使用常规包衣设备进行喷雾包衣，但也可采用流化床包衣。
薄膜包衣(干燥的)通常占固体剂型总重量的约1至约10，优选约2至约6，更优选约2至约4重量％。在一个实施例中，干薄膜包衣的厚度为约30微米至约60微米。就咀嚼片剂而言，更优选地，薄膜包衣(干燥的)占固体剂型总重量的约0.2至约10重量％。同样就咀嚼片剂而言，更优选地，干薄膜包衣的厚度为约2微米至约40微米。
可采用本发明的薄膜包衣对多种需要快速发挥作用的活性物质进行包衣。与本发明的薄膜包衣一起使用的优选药物片剂含有抗酸剂，其中期望活性成分在胃中即刻释放以中和胃酸，并快速缓解酸过多性消化不良、胃灼热等。典型的抗酸剂由多种无机盐制成，如碳酸钙、碳酸氢钠、镁盐和铝盐。氢氧化镁和氢氧化铝是最有效的镁盐和铝盐，并且通常组合使用。此外，氧化镁、碳酸镁、磷酸铝、水化铝酸镁、三硅酸镁和蔗糖硫酸铝(硫糖铝)也可与本发明一起使用。在优选的实施例中，抗酸剂选自碳酸钙和碳酸镁或碳酸钙和氢氧化镁的组合。抗酸剂在制剂中的量可便利地在例如组合物的10％-90％w/v的范围内。有利的是，H2受体阻断剂如法莫替丁、雷尼替丁和/或西咪替丁也可与抗酸剂一起使用，或者可将薄膜包衣施加到H2受体阻断剂剂量中。本发明的包衣适用的其他活性成分包括抗胃肠气胀药、抗炎剂、止痛药、止泻药以及它们的组合。
如本文所用，术语“剂型”适用于设计为含有具体预定量(剂量)的某些成分(例如下文定义的活性成分)的任何固体物体、半固体或液体填充组合物。合适的剂型可以是给药体系，包括经口施用、颊面施用、直肠施用、局部或粘膜施用体系；皮下植入物或其他植入型药物递送体系；或递送矿物质、维生素和其他营养剂、口腔护理剂、香料等的组合物。优选地，将本发明的剂型考虑为固体，然而其可以含有液体组分或半固体组分。在特别优选的实施例中，剂型为用于将药物活性成分递送至人体胃肠道的经口施用体系。
适用于本发明的“活性成分”包括(例如)药物、矿物质、维生素和其他营养剂、口腔护理剂、香料以及它们的混合物。合适的药物包括：止痛药、抗炎剂、抗关节炎药、麻醉剂、抗组胺药、镇咳药、抗生素、抗感染剂、抗病毒剂、抗凝血剂、抗抑郁药、抗糖尿病剂、止吐药、抗胃肠气胀药、抗真菌剂、解痉药、食欲抑制剂、支气管扩张剂、心血管制剂、中枢神经系统制剂、中枢神经系统兴奋剂、减充血剂、口服避孕药、利尿剂、祛痰剂、胃肠制剂、偏头痛制剂、运动病产品、粘液溶解剂、肌肉松弛剂、骨质疏松症制剂、聚二甲基硅氧烷、呼吸制剂、助睡剂、尿道制剂以及它们的混合物。
合适的口腔护理剂包括口气清新剂、牙齿美白剂、抗微生物剂、牙齿矿化剂、牙齿防蛀剂、局部麻醉剂、粘膜保护剂等。
合适的矫味剂包括：薄荷醇、胡椒薄荷、薄荷风味剂、水果风味剂、巧克力、香草、泡泡糖风味剂、咖啡风味剂、利口酒风味剂以及它们的组合等。
合适的胃肠制剂的例子包括：诸如碳酸钙、氢氧化镁、氧化镁、碳酸镁、氢氧化铝、碳酸氢钠、二羟基铝碳酸钠之类的抗酸剂；诸如双醋苯啶、波希鼠李皮、二羟蒽醌、番泻叶、酚酞、芦荟、蓖麻油、蓖麻油酸、脱氢胆酸以及它们的混合物之类的刺激性缓泻剂；诸如法莫替丁、雷尼替丁、西咪替丁、尼扎替丁之类的H2受体拮抗剂；诸如奥美拉唑或兰索拉唑之类的质子泵抑制剂；诸如硫糖铝和米索前列醇之类的胃肠细胞保护剂；诸如普卢卡必利之类的胃肠促动药；针对幽门螺旋杆菌(H.pylori)的抗生素，如克拉霉素、阿莫西林、四环素和甲硝唑；诸如地芬诺酯和洛哌丁胺之类的止泻剂；甘罗溴铵；诸如昂丹司琼之类的止吐药；诸如美沙胺之类的止痛药。优选的胃肠制剂为奥美拉唑。
在本发明的一个实施例中，活性成分可选自双醋苯啶、法莫替丁、雷尼替丁、西咪替丁、普卢卡必利、地芬诺酯、洛哌丁胺、乳糖酶、美沙胺、铋、抗酸剂以及它们的可药用盐、酯、异构体和混合物。
在另一个实施例中，活性成分选自止痛药、抗炎剂和退热剂：例如非甾体抗炎药(NSAID)，包括丙酸衍生物，例如布洛芬、萘普生、酮洛芬等；乙酸衍生物，例如消炎痛、双氯芬酸、舒林酸、托美丁等；灭酸衍生物，例如甲灭酸、甲氯芬那酸、氟芬那酸等；联苯基甲酸衍生物，例如二氟苯水杨酸、氟苯沙酸等；和昔康类，例如吡罗昔康、舒多昔康、伊索昔康、美洛昔康等。在一个具体实施例中，活性成分选自丙酸衍生物NSAID，例如布洛芬、萘普生、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、吡洛芬、卡洛芬、噁丙嗪、普拉洛芬、舒洛芬以及它们的可药用盐、衍生物和组合。在本发明另一个具体实施例中，活性成分可选自：对乙酰氨基酚、乙酰水杨酸、布洛芬、萘普生、酮洛芬、氟比洛芬、双氯芬酸、环苯扎林、美洛昔康、罗非考昔、塞来考昔以及它们的可药用盐、酯、异构体和混合物。优选的(止痛药)为对乙酰氨基酚。
在本发明的另一个实施例中，活性成分可选自上呼吸道剂，如伪麻黄碱、去氧肾上腺素、愈创木酚甘油醚、去甲麻黄碱、扑尔敏、右美沙芬、苯海拉明、阿司咪唑、特非那定、非索非那定、氯雷他定、地氯雷他定、西替利嗪及其混合物，以及它们的可药用盐、酯、异构体和混合物。
所述一种或多种活性成分以治疗有效量存在于剂型中，治疗有效量为口服时产生所需治疗响应的量并易于由本领域的技术人员确定。在确定这种量时，必须考虑要给药的具体活性成分、活性成分的生物利用率特性、给药方案、患者的年龄和体重以及其他因素，如本领域所知的。通常，剂型包含至少约1重量％，例如剂型包含至少约5重量％(比方说至少约20重量％)的一种或多种活性成分的组合。在一个实施例中，芯总共包含至少约25重量％(以芯的重量计)的一种或多种活性成分。
活性成分可以按任何形式存在于剂型中。
每个芯可以是任何固体形式。如本文所用，“芯”指至少部分地被另一种材料包封或围绕并具有至少约2mm至约30mm厚度的材料。优选地，芯是整装的一体式物体，如片剂或胶囊。通常，芯包含固体，例如，芯可以是压制片或模制片或者为硬胶囊或软胶囊。
在一个实施例中，芯为能够咀嚼(即，咀嚼片剂)或能够在口腔中崩解的片剂。在一个实施例中，将片剂设计为当放置在舌头上时在短于约60秒(例如短于约45秒，例如短于约30秒，例如短于约15秒)内在口内崩解。本发明的薄膜包衣在用作咀嚼片剂或口腔崩解片剂的包衣时将尤其有利，因为它能足够快地崩解，从而允许片芯被嚼碎或类似地发生崩解。其他类型的包衣缓慢崩解，使得可能非有意地吞下剂型，或在口内留下不适口的薄膜或薄膜碎片。
在一个实施例中，片剂符合2007年4月出版的食品药品监督管理局指南草案(draft Food and Drug Administration guidance)所定义的口腔崩解片剂(ODT)的标准。在一个实施例中，片剂符合包括下述标准的适用于口腔崩解片剂的双重定义：1)该固体片剂为含有药用物质并且在置于舌头上时快速地，通常在几秒内崩解的片剂，和2)被视为在口腔中快速崩解的固体口服制剂，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，体外崩解时间为大约30秒或更短。
芯可通过任何合适的方法制备，包括(例如)压制和模制，并取决于其制备方法，通常包含活性成分和多种赋形剂。
在本发明的一个实施例中，将剂型用作底衣，并且进一步用凝胶包衣材料进行包衣或部分包衣。在一个实施例中，底衣包括暴露出芯的开口，并且进一步增强剂型的崩解。凝胶包衣可通过多种方法(包括浸渍、模制或包覆)施加，并可包含诸如明胶、结冷胶、淀粉、羟丙甲纤维素或改性淀粉之类的包衣材料以及诸如角叉菜胶和黄原胶之类的增稠剂。在一个实施例中，使用激光在底衣中产生开口。
在一个实施例中，包衣溶液或悬浮液基本上不含水。如本文所用，“基本上不含”定义为低于0.5％(如低于0.2％)的水。在一个实施例中，薄膜条溶液或悬浮液基本上不含水。如本文所用，“基本上不含”定义为低于0.5％(如低于0.2％)的水。
当将活性成分掺入薄膜中作为剂型时，其可以任何形式存在于剂型中。例如，可以分子水平(例如熔融或溶解)将活性成分分散在剂型内，或者活性成分可为粒子形式，继而又可对粒子进行包衣或不包衣。如果活性成分为粒子形式，则粒子(无论包衣还是未包衣)的平均粒度通常为约1微米至约2000微米。在一个实施例中，此类粒子为平均粒度为约1微米至约300微米的晶体。在另一个实施例中，粒子为平均粒度为约50微米至约2000微米，例如约50微米至约1000微米或约100微米至约800微米的颗粒或小丸。在另一个实施例中，本发明的包衣包含着色剂，其可以包括色淀、染料或遮光剂(如二氧化钛)或它们的混合物。
通过以下实例来举例说明本发明的具体实施例。本发明不受这些实例中提出的具体限制因素的限制，而是受限于所附权利要求的范围。除非另外指明，否则本文所公开的百分比和比率均按重量计。
实例
将聚合物(例如聚乙烯醇、聚乙烯吡咯烷酮、乙烯基吡咯烷酮与乙酸乙烯酯的共聚物、羟丙基纤维素和Eudragit E100)溶于有机溶剂(例如醇、酮、酯和卤化烃)中。然后，将超级崩解剂(例如低取代羟丙基纤维素(L-HPC)、羧甲淀粉钠、交联羧甲基纤维素钠)分散在所得的聚合物溶液中。在采用时，也将酸不稳定性材料(例如碳酸钠、碳酸氢钠、甘氨酸钠碳酸盐)分散在所得的聚合物溶液中。
可通过喷雾法或浸渍法将包衣组合物施加到片剂、胶囊剂或胶囊形片剂上。该包衣体系干燥成聚合物膜，并且提供在基材上形成截然不同的快速溶出/崩解的外壳所需的本体。
组合物：
A.在无水乙醇中包含约5-15％固形物的成膜组合物，具有：
-水溶性聚合物，如HPC(约2-8％的总溶液)
-超级崩解剂，如L-HPC(约3-10％的总溶液)
-任选的酸不稳定性材料，如碳酸氢钠(约0-5％的总溶液)
-任选的增塑剂，如PEG 400(约0-4％的总溶液)
B.具有快速崩解包衣的剂型，包含：
-水溶性聚合物(约15-40％)
-超级崩解剂，如交联羧甲基纤维素钠(约50-75％)
-任选的酸不稳定性材料，如碳酸钠(约0-30％)
-任选的增塑剂，如PEG-400(约0-25％)
(有利的是，包衣在暴露于胃肠液时立即崩解，从而避免活性成分溶出时间拖延)。
工艺选项：
包衣组合物适用于喷雾和浸渍施加。
实例
实例1：快速溶出HPC薄膜包衣
包含HPC和超级崩解剂的包衣溶液的制备
1)在室温下通过顶置式搅拌器将5.75g羟丙基纤维素(HPC，以商品名Klucel EF从Ashland Corporation(Covington，KY)商购获得)混合到207g无水乙醇中，得到2.7％固形物的HPC溶液。
2)然后在室温伴随搅拌下将17.25g交联羧甲基纤维素钠(以商品名Ac-Di-Sol从FMC Corporation(Philadelphia，PA)商购获得的超级崩解剂)添加到HPC溶液中，得到10％固形物的HPC/交联羧甲基纤维素钠悬浮液。
片芯的薄膜包衣
将市售的Tylenol超强度不带涂层的胶囊形片剂(900g)装到12英寸的通风包衣锅(可从O’Hara Technologies(Richmond Hill，ON，Canada)商购获得)中。按以下条件对该批胶囊形片剂进行喷雾包衣：大约10克/分钟的喷雾速率，约10RPM的包衣锅转速，约56℃的进气温度，约25psi的雾化气压。喷涂115g包衣悬浮液，其相当于23g干包衣或约2.5％增重。
将包衣片放入盛有900mL纯化水的容器中，其中包衣在短于15秒内崩解。许多市售包衣片上的包衣需要数分钟才能崩解。
实例2：基于快速溶解HPC薄膜的剂型
包含HPC和超级崩解剂的薄膜浇注溶液的制备
根据表1制备基于口腔溶解薄膜的剂型。
1)在室温下通过顶置式实验室搅拌器以20RPM的转速搅拌20分钟，将13.78g HPC混合到261.8g无水乙醇中，得到5％固形物的HPC溶液。
2)将三氯蔗糖、山梨酸钾、覆盆子风味剂和盐酸去氧肾上腺素添加至上述混合物。
3)然后在室温下以20RPM的转速搅拌将交联羧甲基纤维素钠和剩余的乙醇加到该HPC溶液中，得到15％固形物的悬浮液。
表1：口腔溶解薄膜配方
| 材料 | Mg/溶液 | mg/干薄膜 | ％/干薄膜 |
| 羟丙基纤维素 | 13.78 | 13.78 | 21.200 |
| 交联羧甲基纤维素钠 | 41.33 | 41.33 | 63.585 |
| 去氧肾上腺素 | 7.50 | 7.50 | 11.539 |
| 三氯蔗糖 | 1.50 | 1.50 | 2.308 |
| 覆盆子风味剂 | 0.80 | 0.80 | 1.231 |
| 山梨酸钾 | 0.09 | 0.09 | 0.139 |
| 乙醇 | 152.0 | NA* | NA* |
| 总计 | 217.0 | 65.00 | 100.00 |
*干燥移除
薄膜条制备
1)将大约217.0mg悬浮液倒入具有边缘的玻璃板上。
2)然后在室温下将该混合物干燥5-6小时，直到表面干燥。
3)将样品从玻璃板上取下。
实例3：无崩解剂的羟丙基纤维素薄膜比较例
1)在室温下通过顶置式搅拌器将6.00g羟丙基纤维素(HPC，以商品名Klucel EF从Ashland Corporation(Covington，KY)商购获得)混合到94g无水乙醇中，得到6％固形物的HPC溶液。
2)将(1)中的大约2g溶液浇注成大约1mm的薄膜，在40℃下干燥1小时。
3)将实例1中制得的大约2g溶液(包含超级崩解剂)浇注成大约6.5mm、5mm和3.5mm的薄膜，让其在40℃下干燥1小时。
4)将包含超级崩解剂和无超级崩解剂的薄膜安装到溶出仪上，并置于400ml烧杯的中央。将250mL 25℃的纯化水倒入烧杯中以接触薄膜表面。相应地记录崩解时间。对于6.5密耳、5密耳和3.5密耳的膜，包含超级崩解剂的HPC薄膜(根据实例1制备)分别在11秒、6秒和3秒内崩解。不使用超级崩解剂制备的HPC薄膜(1密耳)的崩解时间超过4分钟。这一结果出人意料，因为无超级崩解剂的薄膜比具有超级崩解剂的对应薄膜更薄，而更薄的膜通常会以更快的速率崩解。
尽管上面仅具体描述了本发明优选的实施例，但应该理解，本发明的修改形式和变化形式是可能的，只要不脱离本发明的精神和预期范围。
Claims (12)
1.一种包含芯和薄膜包衣的药物剂型，其具有改善的崩解特征，其中所述芯选自片剂，所述薄膜包衣包含羟丙基纤维素和交联羧甲基纤维素钠，其中，薄膜包衣通过将羟丙基纤维素和交联羧甲基纤维素钠悬浮在有机溶剂中进行制备，所述薄膜包衣增重2.5％，所述薄膜包衣在水中的崩解时间短于15秒。
2.根据权利要求1所述的药物剂型，其中所述片剂是胶囊形片剂。
3.根据权利要求1所述的药物剂型，还包括从所述薄膜包衣的表面延伸到所述芯的表面的开口。
4.根据权利要求1所述的药物剂型，其中所述片剂选自咀嚼片剂和口腔崩解片剂。
5.如权利要求1所述的药物剂型，其中所述芯包含对乙酰氨基酚。
6.一种制备包含芯和薄膜包衣的药物剂型的方法，包括制备薄膜包衣；以及将所述薄膜包衣施加到芯上，其中制备所述薄膜包衣包括将交联羧甲基纤维素钠悬浮在有机溶剂中的步骤以及将羟丙基纤维素溶解于所述有机溶剂中的步骤，其中所述薄膜包衣增重2.5％，所述薄膜包衣在水中的崩解时间短于15秒。
7.根据权利要求6所述的方法，其中所述有机溶剂选自乙醇、丙酮、甲醇和异丙醇。
8.根据权利要求6所述的方法，其中所述有机溶剂为两种或更多种有机溶剂的混合物。
9.根据权利要求8所述的方法，其中所述有机溶剂为乙醇与选自丙酮、甲醇和异丙醇的辅助溶剂的混合物。
10.根据权利要求9所述的方法，其中乙醇与辅助溶剂的比率为50:50至99:1。
11.根据权利要求6所述的方法，其中通过选自喷雾工艺、浸渍工艺以及浇注和包覆工艺的工艺将所述薄膜包衣施加到所述芯上。
12.根据权利要求6所述的方法，其中所述薄膜包衣包含活性成分。
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| CN102885798B (zh) * | 2011-07-21 | 2015-04-22 | 成都康弘药业集团股份有限公司 | 一种口腔崩解片 |
| EP2780001A4 (en) * | 2011-11-14 | 2015-10-28 | Hetero Research Foundation | SOLID ORAL ENTECAVIR COMPOSITIONS WITH FAST RELEASE |
| CA2880163A1 (en) * | 2012-08-01 | 2014-02-06 | Acura Pharmaceuticals, Inc. | Stabilization of one-pot methamphetamine synthesis systems |
| CN103006602B (zh) * | 2013-01-04 | 2015-06-10 | 青岛大学 | 一种快速溶出的阿托伐他汀钙片及其制备方法 |
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| FR2795962B1 (fr) | 1999-07-08 | 2003-05-09 | Prographarm Laboratoires | Procede de fabrication de granules enrobes a gout masque et liberation immediate du principe actif |
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| US20070077300A1 (en) | 2005-09-30 | 2007-04-05 | Wynn David W | Oral compositions containing a salivation inducing agent |
| BRPI0618828A2 (pt) | 2005-11-22 | 2011-09-13 | Smithkline Beecham Corp | substrato de espuma e método para sua preparação |
| WO2007103286A2 (en) | 2006-03-02 | 2007-09-13 | Spherics, Inc. | Rate-controlled bioadhesive oral dosage formulations |
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| US8367104B2 (en) | 2013-02-05 |
| US20110097399A1 (en) | 2011-04-28 |
| BR112012010170A2 (pt) | 2016-04-12 |
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