CN104159576B - 在中性环境中具有良好抗性的药物保护性涂层的制备 - Google Patents
在中性环境中具有良好抗性的药物保护性涂层的制备 Download PDFInfo
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- CN104159576B CN104159576B CN201380013101.6A CN201380013101A CN104159576B CN 104159576 B CN104159576 B CN 104159576B CN 201380013101 A CN201380013101 A CN 201380013101A CN 104159576 B CN104159576 B CN 104159576B
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- A61K9/1605—Excipients; Inactive ingredients
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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Abstract
本发明涉及药物涂层,所述药物涂层由基于单体重量比为35:65‑55:45的甲基丙烯酸N,N‑二乙基氨基乙酯和甲基丙烯酸甲酯的成膜共聚物的涂料得到,其中共聚物以用C3‑C10二羧酸部分中和存在。
Description
本发明涉及在中性环境中具有良好抗性的药物保护性涂层,其中为了掩蔽气味或者保护以防湿气,药物剂型具有基于以部分中和形式存在的阳离子共聚物的膜涂层,所述阳离子共聚物通过包含甲基丙烯酸N,N-二乙基氨基乙酯的单体混合物自由基乳液聚合而得到。本发明还涉及相应涂层的制备和相应涂料组合物在制备在中性环境中具有良好抗性的保护性涂层中的用途。
当制备具有讨厌味道的活性成分的药物剂型时,存在向剂型提供涂层的基础问题,所述涂层一方面容许在口腔的中性环境中的良好味道掩蔽,但另一方面不具有过大的层厚度。该问题也出现在生产具有保护性涂层以保护湿气敏感性活性成分的包衣药物形式中。
过厚的涂层不仅是美学上不满意的,因为它们比美丽光滑的更粗糙,而且在经济上不满意,因为需要更多的涂料组合物产生更大的层厚度,此外,加工时间更长。此外的事实是过厚的涂层导致活性成分在胃的酸性环境中不想要的更慢释放,在那里它们应该尽可能快地释放活性成分。开发涂料组合物的目的因此总是制备尽可能最薄的膜涂层,但这些必须满足功能要求,如同在现在味道掩蔽的情况下。因此,理想的施涂量通常为1-20mg/cm2。
就味道掩蔽而言,涂层还必须稳定合适的时间。尤其是在口中快速分解的剂型(所谓的“口服分散片剂”)的情况下,其中具有味道掩蔽涂层的活性成分晶体或活性成分微丸嵌入在口腔环境中快速分解的基体中,通常出现包衣活性成分晶体或微丸暂时被捕获在牙齿间的空间中。如果涂层然后具有不适于在口腔的中性环境中分解的稠密性,则可因此出现不愉悦的味觉。关于合适涂层的要求因此是在中性pH值下至少1小时,优选甚至2小时的对活性成分释放的适当抗性。
另一要求是形成所用涂料组合物的基础的成膜聚合物在水中的良好再分散性。用于味道掩蔽的成膜聚合物通常为在中性环境中不溶于水,但在多种情况下快速溶于胃的酸性环境中以促进活性成分的快速释放的pH相关可溶性聚合物。
为提供用于具有低残余单体含量的药物涂层的基料,DE-B 2512238教导了通过将聚合物分散体喷雾干燥而得到的粉末在制备用于这些药物形式的涂渍溶液中的用途。关于用于喷雾干燥的分散体,参考DE 1090381、DE 1219175和DE 2135073。
DE 3049179 A1为DE 2512238的附加申请,并涉及通过根据最后提到的文件的教导以还包含增塑剂的含水悬浮液的形式喷雾干燥而得到的粉末在通过热胶凝制备涂层中的用途。
WO 00/05307研究了提供用于药物形式的涂层和基料,其包含具有具有叔氨基的单体基团的(甲基)丙烯酸酯共聚物,目的是可简单的干燥或含水进一步加工。
WO 02/067906涉及与WO 00/05307所述那些相比,具有改进的水蒸气渗透性的涂覆和粘合组合物。此处,涂覆和粘合组合物使用包含如下组分的混合物制备:(a)粉末形式且具有1-40μm的平均粒度的(甲基)丙烯酸的C1-C4酯和具有叔铵官能团的(甲基)丙烯酸酯单体的共聚物,(b)具有至少14的HLB值的乳化剂,和(c)C12-C18单羧酸或C12-C18羟基化合物。
WO 2004/019918描述了在其组成方面相当于WO 00/05307和WO02/067906所述那些的涂覆和粘合组合物。
EP88951 A2描述了使用基于乳液聚合物的水分散涂料组合物涂覆药物的方法,其中涂料组合物可以部分地以盐形式存在。涂料组合物也可由再分散的粉末得到。
WO 97/42255描述了可再分散于水溶液中且包含带有游离酸或碱的共聚物的聚合物粉末的喷雾干燥,其中在喷雾干燥以前,必须借助缓冲剂体系调整分散体的pH。
EP 262326 A2描述了制备可再分散塑料粉末的方法。
WO 2009/016258公开了如根据本发明所用基于甲基丙烯酸N,N-二乙基氨基乙酯的阳离子聚合物的聚合物水分散体的制备及其在涂覆药物中的用途。尽管描述了阳离子聚合物可以为部分中和的,非常一般性地列出了一系列无机和有机酸适于部分中和。
然而,用以部分中和形式存在的迄今所知的涂料组合物,存在用其涂覆的剂型对在口腔的中性环境中的过早分解具有不满意的抗性的问题。再分散性通常也不令人满意。
本发明的目的是提供赋予药物剂型对过早活性成分释放的良好抗性,同时在水中具有良好再分散性的涂料组合物。
因此,发现了由基于单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物的涂料组合物得到的药物成膜涂层,其中共聚物以用C3-C10二羧酸部分中和存在。
根据一个优选实施方案,涂料组合物以1-20mg/cm2的施涂量施涂,在4mg/cm2的施涂量的情况下,涂层具有在pH6.8的含水环境中在30分钟以后至少80%的对活性成分释放的抗性。
此外,发现了制备用于涂覆包含至少一种药物活性成分的剂型且对活性成分的过早释放具有抗性的涂料组合物的方法,其中涂料组合物包含单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物作为成膜聚合物,其中涂料组合物中的共聚物用C3-C10二羧酸部分中和。
根据一个优选实施方案,涂料组合物以粉末形式获得并在施涂于剂型上以前再分散于水中。
此外,发现药物剂型用成膜涂料组合物在保护含活性成分的药物剂型以防在pH6.8的含水环境中过早活性成分释放中的用途,所述组合物基于单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物,其中共聚物以用C3-C10二羧酸部分中和存在。
对药物活性成分在6.8范围内的pH值的含水环境中过早释放的抗性借助所谓的“平桨模型”测定。该测量方法描述于USP中。为此,根据USP在pH6.8+/-0.05的磷酸盐缓冲剂中借助所谓的“平桨设备”(设备2)测试涂覆的剂型。磷酸盐缓冲剂通过在校准的5升量瓶中将34.025g磷酸二氢钾溶于水中,加入112ml的1摩尔NaOH并加满至5升量瓶的校准标记而制备。
本发明涂层满足这一标准:对于4mg/cm2的施涂量,它们具有在pH6.8的含水环境中在30分钟以后至少80%的对活性成分释放的抗性。
测量在25℃下在大气压力下进行。活性成分的释放通过光度测定进行。释放以30分钟的间隔测定。
根据本发明,在30分钟以后80%的抗性意指在30分钟以后,不多于20%的活性成分释放。优选30分钟以后的抗性为100%,这意指在该期间内,没有可检测量(小于2%)的活性成分从剂型中释放。在60分钟以后在pH6.8下的抗性应为至少60%。
根据本发明合适的二羧酸具有3-10个碳原子的链长。合适的二羧酸特别是具有末端酸基团的非支化二羧酸。合适的二羧酸还有用一个或两个羟基取代的那些。
根据本发明,就部分中和而言,优选使用具有大于2的第一pKa值和大于4的第二pKa值的二羧酸。特别优选使用具有大于2.5的第一pKa值和大于5的第二pKa值的二羧酸。pKa值为酸常数的负底十对数,其中意指在25℃和大气压力下的酸常数。
除酸基团外,不带有其它取代基的合适二羧酸为饱和链烷烃二羧酸:丙二酸、琥珀酸、戊二酸、己二酸或癸二酸。用一个或两个羟基取代的合适链烷烃二羧酸为苹果酸(2-羟基琥珀酸)或酒石酸(2,3-二羟基琥珀酸)。合适的不饱和二羧酸主要是富马酸。
也可使用这类二羧酸的混合物。
因此,可推荐将产生特别好的涂层抗性的二羧酸与产生特别好的粉末再分散性的那些酸混合。合适的混合物为例如己二酸与硫酸或琥珀酸与草酸。
在本发明上下文内,部分中和意指2-15,优选4-10摩尔%的二乙基氨基乙基以盐形式存在。
关于通过乳液聚合制备在涂料中用作成膜剂的甲基丙烯酸甲酯和甲基丙烯酸N,N-二乙基氨基乙酯的共聚物,明确参考WO 2009/016258中的公开内容。
存在于分散体中的共聚物优选具有40-60的K值(根据Fikentscher在N-甲基吡咯烷酮(NMP)中的1%浓度溶液上测定)。
通过DSC“差示扫描量热法”测定的玻璃化转变温度TG优选为40-70℃,特别优选52-62℃。此处,首先将试样加热至150℃,然后从150℃快速冷却。玻璃化转变温度的测量以20°K/min的加热速率进行。
最小成膜温度根据DIN ISO 2115所述方法测定,且为40-70℃,优选50-65℃。该方法的测量精确度为+/-5℃范围内。
存在于分散体中的共聚物为基本无规共聚物。
存在于聚合物分散体中的聚合物颗粒的平均粒径(通过分析超速离心机测定)优选为70-200nm,特别优选80-150nm,特别是90-130nm。粒度分布优选为基本单峰的。
在0.01%浓度水分散体(2.5cm比色皿,白光)上测定的根据本发明使用的水分散体的LT值优选为至少70%,特别优选至少80%。光透射的测定描述于例如Dieter Distler,Polymerdispersionen[聚合物水分散体],Wiley-VCH(1999),第40页中。
特别优选甲基丙烯酸甲酯(MMA)与甲基丙烯酸二乙基氨基乙酯(DEAEMA)的重量比为55:45的共聚物。这类共聚物也作为Smartseal,BASF SE市售。
根据本发明,将开头所述C3-C10二羧酸加入共聚物粉末或相应水分散体中。优选加入的酸的量使得碱性基团部分以酸盐的形式存在。因此,1-20摩尔%的碱性基团可以以盐形式存在,优选2-15摩尔%,特别优选5-10摩尔%的碱性基团是中和的。
共聚物MMA/DEAMA的部分中和可以在含水初级分散体中或者在粉末上,或者在粉末的含水再分散期间或以后进行。粉末形式的共聚物可通过喷雾方法或冻干得到。
因此,例如可将二羧酸在喷雾干燥以前加入聚合物水分散体中。如果酸在喷雾干燥以前并入,则可使用常规方法将这搅入水分散体中。根据另一实施方案,部分中和的含水初级分散体可通过冻干转化成粉末形式。
根据另一实施方案,酸也可在预先由初级分散体制备的粉末再分散以前或期间加入。在加入粉末中的情况下,可进行酸并入聚合物粉末中使得首先通过简单的搅拌器将聚合物粉末粗略地预分散,然后加入酸,并通过另外搅拌实现完全的再分散。再分散通常是非常快的,在仅10分钟以后,存在细碎的分散质。在改进程序中,也可首先引入酸的水溶液作为初始进料,并将聚合物粉末随着搅拌加入其中。根据本发明另一实施方案,首先将聚合物粉末和酸混合并将该粉末混合物引入水中。根据该实施方案,也可首先制备完全中和的聚合物粉末,然后通过与未中和的聚合物粉末混合而将其调整至所需的部分中和度。
在各个情况下,待使用的酸的重量量受C3-C10二羧酸的特定分子量和所需中和度支配。
优选进行用酸处理使得水分散体、粉末或再分散于水中的粉末的pH为5-9。
特别优选加入酸或酸盐的加入使得水分散体、粉末或再分散于水中的粉末的pH为6-8。
如已提到的,本发明实施方案涉及粉末形式的MMA/DEAMA共聚物的部分中和。制备共聚物的粉末形式的优选程序为喷雾方法。
根据本发明用于喷雾方法的分散体的固体含量优选为10-50重量%,特别优选20-40重量%。在通过超滤将分散体预先提纯的情况下,根据本发明使用的分散体优选具有在超滤以前和以后的这些范围内的固体含量。当然也可使稀聚合物分散体在喷雾方法以前经受通过超滤浓缩。
优选用于制备本发明涂层的涂料组合物通过再分散于水中而得到,其中通过喷雾方法得到的粉末使用低剪切搅拌设备以至多1000rpm的转速再分散。令人惊讶的是,也可使用以>5000rpm的转速的高剪切分散设备。这可根据本发明进行而不存在再分散期间形成的细粒聚集和制剂凝结。
再分散于水中的聚合物粉末的平均粒度是下面初级分散体的至多5倍,优选至多3倍,特别优选至多2倍。
此处,平均粒度指Z-平均值,其通过光散射借助“Malvern Zetasizer nano S”作为Z平均值测定。
涂料组合物可例如通过精细混合或通过将根据本发明得到的聚合物粉末再分散以得到聚合物水分散体,向其中加入优选至少一种其它辅助剂而制备。
聚合物水分散体转化成粉末形式可通过喷雾方法进行。合适的喷雾方法原则上是喷雾干燥、凝聚喷雾干燥、喷雾制粒(喷雾流化床干燥)或喷雾附聚。
下文关于进行雾化和干燥所述的条件指原则上可进行的喷雾方法的所有实施方案,无论是正常喷雾干燥、喷雾制粒还是凝聚喷雾干燥。
雾化优选作为由于液体压力或空气压力的水力雾化借助喷嘴如单材质或多材质喷嘴或者借助雾化盘进行。
合适的喷雾设备为常规喷雾塔,待雾化的聚合物分散体从上面引入其中。所得聚合物粉末可在下端排出并在下游旋风器中与干燥气流分离。
可使用的干燥气体为空气或惰性气体如氮气、氩气或氦气。干燥气体可与通过喷雾设备雾化而产生的液滴逆流或并流引入。干燥气体优选并流使用。干燥气体的入口温度保持在玻璃化转变温度以上至少20℃,优选至少40℃,根据一个实施方案,也可以为在动态冷冻温度以上至少20℃,优选至少40℃和在聚合物的最小成膜温度以上至少20℃,优选至少40℃。干气体在喷雾设备中的入口温度特别优选保持在100-140℃,且干燥气体从喷雾设备中的出口温度保持在45-70℃。非常特别优选,干燥气体在喷雾设备中的入口温度保持在110-130℃且干燥气体从喷雾装置中的出口温度保持在50-60℃。干燥气体的出口温度非常特别优选在与最小成膜温度+/-5℃的相同温度范围内。
喷雾设备中水的蒸发可在0.06-0.12MPa的大气压力下进行。
在进行喷雾方法时,也可将聚合物喷雾辅助剂如聚乙烯醇、聚乙烯醇与聚乙二醇作为接枝基和聚乙烯醇侧链的接枝聚合物的混合物(作为Protect市售)、聚乙烯吡咯烷酮、烷基化和/或羟基烷基化纤维素、淀粉衍生物、木素磺酸盐、聚丙烯酸或聚丙烯酰胺加入聚合物水分散体中。这类喷雾辅助剂的合适量基于固体含量为0.1-30,优选1-10重量%。
此外,也可将防粘剂加入聚合物水分散体中。合适的防粘剂例如为硅酸铝如膨润土,以及硅藻土、胶态氧化锆、沉淀氧化硅、硅藻土、碳酸钙、二氧化钛、氧化锌、硅酸镁如滑石或磷酸三钙。这类防粘剂的合适量基于固体含量为0.1-15,优选0.5-5重量%。
原则上也可将常规涂覆辅助剂加入聚合物水分散体中。合适的辅助剂可以为:芳香物质、改进味道的物质、甜味剂(糖、糖醇、增甜剂如阿司帕坦(aspartame)、糖精钠、环氨酸钠)、助流剂、润湿剂、脱离剂、抗粘剂、稳定剂、抗氧化剂、成孔剂、中和剂、光泽剂、染料、颜料、消毒剂或防腐剂、增稠剂或增塑剂。合适辅助剂描述于例如Fiedler,H.P.Lexikonder Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete[Lexicon ofAuxiliaries for Pharmacy,Cosmetics and Related Fields],第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中。
此外,转化成粉末可通过喷雾制粒进行。为此,也将待干燥的聚合物水分散体雾化,然后使产生的液滴在流化床中与已作为初始进料引入的晶种颗粒接触。由于晶种颗粒与聚合物水分散体液滴的这一接触晶种颗粒生长以得到更大的颗粒,同时形成围绕用作晶种材料的颗粒的洋葱皮状结构。
转化成粉末形式也可借助凝聚喷雾干燥进行。此处,将聚合物分散体在如上所述喷雾塔中雾化,在那里同时将从干燥区中取出的细粉尘吹入雾化区中,其中聚合物水分散体以细滴的形式存在。细粉尘颗粒在此处粘合在以前以得到具有黑莓状结构的较大聚集体。另外,可连接流化床,其中形成的颗粒的水含量可进一步降低。所得聚集体可具有150-1000μm,优选200-500μm的粒度。在该实施方案中,也选择入口温度在玻璃化转变温度以上至少20℃,优选至少40℃,根据一个实施方案,也在动态冷冻温度以上至少20℃,优选至少40℃,以及在聚合物的最小成膜温度以上至少20℃,优选至少40℃,且干燥气体从喷雾设备中的出口温度为40-85℃,优选45-70℃。优选喷雾设备中的干燥气体的入口温度保持在100-140℃且干燥气体从喷雾设备中的出口温度保持在45-70℃。特别优选,喷雾设备中的干燥气体的入口温度保持在110-130℃且干燥气体从喷雾设备中的出口温度保持在50-60℃。通过喷雾凝聚得到的黑莓状结构是基本无粉尘的,且在再分散时显示出特别有利的行为。
在所有上述实施方案中,喷雾辅助剂,例如硅酸铝如膨润土、硅藻土、胶态氧化锆、沉淀氧化硅、硅藻土、碳酸钙、二氧化钛、氧化锌、硅酸镁如滑石或磷酸三钙可在喷雾方法期间以基于聚合物粉末0.1-15,优选0.5-5重量%的量吹入喷雾塔中。
总之,通过喷雾方法形成的粉末的粒度由特定变量支配。在正常喷雾干燥的情况下,可实现10-150μm的粒度。在喷雾制粒如喷雾流化床干燥的情况下,可实现150至1000μm的较大粒度。在凝聚喷雾干燥的情况下,可实现150-1000μm的粒度。
共聚物作为自由流动粉末得到,就本发明而言,这意指在根据DIN ISO4324使用Pfrengle设备而不用搅拌助剂测定流动性时,粉末自由且完全从漏斗中流出。
残余溶剂含量通常基于粉末的固体含量为不大于5重量%。
待根据本发明用于制备涂层的可再分散共聚物粉末具有在20重量%固体含量的水中优选小于300mPas,特别优选小于200mPas,特别是小于100mPas(通过布氏粘度计在20℃和100s-1下测定的值)的低粘度。这类粘度对许多应用而言是特别重要的。
就稳定化而言,可如所提到的将聚合物分散体在转化成粉末形式以前用微水溶性抗氧化剂处理。术语“抗氧化剂”本身是本领域技术人员已知的(参见例如-Lexikon der Chemie[Lexicon of Chemistry],第9版,1989,Georg-Thieme-Verlag,Stuttgart)并且指意欲抑制或防止通过氧气或其它氧化方法产生的不想要的改变的物质。根据本发明,用于使涂料组合物稳定化的合适抗氧化剂为微水溶性抗氧化剂,即在20℃下在水中的溶解度不大于1g/l的抗氧化剂。
就这点而言,合适的抗氧化剂主要是亲脂物质生育酚、生育酚乙酸酯、抗坏血酸棕榈酸酯、抗坏血酸硬脂酸酯、叔丁基氢醌、叔丁基羟基茴香醚、叔丁基羟基甲苯、没食子酸辛酯或没食子酸十二烷基酯或其组合。
所用抗氧化剂也可溶于有机溶剂中。合适的有机溶剂为一方面可与水溶混至可实现至少10重量%的浓度的足够程度,另一方面能够溶解微水溶性抗氧化剂的那些溶剂。合适的溶剂为醇类如乙醇或异丙醇,酮类如丙酮、甲乙酮,和酯类如乙酸甲酯。通常这些溶剂具有100℃以下的沸点。
抗氧化剂可以以本身常用的方式形成有机溶液。选择浓度使得每升溶剂使用10-1000g抗氧化剂。总之,选择有机溶剂的量使得使用基于水分散体的重量1-20重量%的溶剂。
根据另一实施方案,抗氧化剂可以以胶束水溶液的形式并入水分散体中。为此,使物质在增溶物质(“增溶剂”)的存在下形成溶液(关于术语“增溶”,参见-Chemielexikon,[Chemistry Lexicon],第9版)。合适的增溶剂为表面活性剂,例如多库酯钠(sodium docusate)或十二烷基硫酸钠、乙氧基化脂肪、乙氧基化脂肪酸、乙氧基化脂肪醇或聚合增溶剂。
合适的聚合增溶剂主要是两性共聚物。根据本发明,两性共聚物应当理解意指由亲水和疏水链段组成的共聚物。链段还可具有LCST(较低临界溶解温度)。链段就其部分而言是聚合物链,由于其组成和/或用于制备链段的单体,其为亲水或疏水的。两性共聚物可以为嵌段聚合物或接枝聚合物。除线性嵌段聚合物外,共聚物的结构也可以为梳型或星型的。在接枝聚合物的情况下,可存在疏水性侧链和亲水性接枝基,或者亲水性侧链和疏水性接枝基。侧链可接枝在其中或接枝在其上。合适的两性共聚物公开于例如WO 2007/017452、WO 2007/051743、WO 2007/065845和WO2007/0658462,此处参考其关于合适两性共聚物及其制备的描述。其它两性共聚物为例如泊洛沙姆(poloxamer)。
合适的亲水链段为N-乙烯基内酰胺均聚物或共聚物链,特别是含N-乙烯基吡咯烷酮的聚合物,以及聚乙烯醇链或聚醚。合适的疏水链段为例如乙酸乙烯酯的均聚物或共聚物。合适的共聚单体为例如N-乙烯基己内酰胺。优选的聚合增溶剂为以名称BASF SE市售的接枝聚合物,其具有PEG6000作为接枝基础以及由乙酸乙烯酯和N-乙烯基己内酰胺产生的共聚物侧链。适于制备胶束溶液的还有HLB大于12的所有表面活性剂。合适的表面活性剂描述于“Fiedler,Encyclopedia of Excipients”,Editio Cantor Verlag,第6版,2007,第112-119页中。含水抗氧化剂增溶物包含0.5-30重量%,优选1-20重量%抗氧化剂,和1-50重量%,优选1-30重量%增溶剂。总之,选择量使得使用基于水分散体的重量1-40重量%含水抗氧化剂增溶物。
此外,可将微水溶性抗氧化剂以细碎水分散体形式引入聚合涂料组合物的水分散体中。就这点而言,分散体使用于指可以为固体/液体(悬浮液)或液体/液体(乳液)的两相体系的术语。抗氧化剂的平均粒度(d4,3)在此处应为小于20μm,优选小于10μm,特别优选小于3μm。
因此,可将抗氧化剂溶于乳化剂中,然后分散于水中。然而,也可将抗氧化剂直接加入水中并借助乳化剂使用高剪切分散工具分散。此处特别优选将制剂加热至抗氧化剂的熔点以上的温度,因此形成乳液。可将该热乳液随着搅拌直接加入聚合物分散体中。作为选择,也可将它预先冷却,因此形成细碎悬浮液。特别优选将热乳液加入同样温度在抗氧化剂的熔点以上的聚合物分散体。
合适的乳化剂原则上是HLB值为>10的所有类别的界面活性物质(关于亲水亲脂平衡值,参见Fiedler,Encyclopedia of Excipients,Editio Cantor Verlag,第6版,2007,第112-119页)。合适的乳化剂原则上是具有相应HLB值的所有乙氧基化脂肪酸、乙氧基化脂肪醇、乙氧基化脂肪酸醚或乙氧基化脂肪酸酯。相应的乙氧基化脱水山梨糖醇、硬脂基、油基、月桂基或棕榈基衍生物,例如HS(Macrogol 15羟基硬脂酸酯),或者乙氧基化氢化蓖麻油,例如RH40(用40个氧化乙烯单元乙氧基化)或相应的品级例如是合适的。
其它合适的乳化剂为泊洛沙姆(poloxamer)(聚氧化乙烯-聚氧化丙烯嵌段共聚物)。
含水抗氧化剂/乳化剂分散体包含1-50重量%,优选2-30重量%,和0.1-30重量%,优选0.5-10重量%乳化剂。
总之,选择量使得基于聚合物水分散体的重量使用1-40重量%含水抗氧化剂/乳化剂分散体。
此外,抗氧化剂可以以所谓的“固溶体”使用。术语“固溶体”是本领域技术人员已知的且指已知固体在另一种固体中的分子分散分布。在本情况下,抗氧化剂可作为固溶体并入合适的固体增溶剂中或并入聚合保护胶体中。所得固溶体然后可以以固体形式直接并入含水涂料组合物分散体中,或者可预先转化成胶束水溶液或胶体溶液,然后并入含水涂料组合物分散体中。固溶体可例如通过将抗氧化剂与增溶剂或保护胶体一起溶于合适溶剂中,然后将溶剂蒸发而制备。
此外,抗氧化剂的固溶体可通过熔体挤出而制备,其中将抗氧化剂和增溶剂或聚合保护胶体一起熔融,然后挤出,模塑并固化。在挤出以后得到的颗粒固体熔融压出物可特别有利地并入聚合涂料组合物的水分散体中。用于固溶体的合适基体聚合物和保护胶体为已提到的两性共聚物,特别是或泊洛沙姆(poloxamer)如F86,而且还有非两性聚合物,例如聚乙烯吡咯烷酮、乙烯基吡咯烷酮-乙酸乙烯酯共聚物、聚乙二醇、聚乙烯醇、聚乙烯醇-聚乙二醇接枝共聚物或羟基烷基化纤维素。
涂料组合物可例如通过将根据本发明得到的聚合物粉末再分散以得到聚合物水分散体,向其中加入优选至少一种其它辅助剂密切混合而制备。
合适的其它辅助剂可以为:芳香物质、改进味道的物质、甜味剂(糖、糖醇、增甜剂如阿司帕坦(aspartame)、糖精钠、环氨酸钠)、助流剂、润湿剂、脱离剂、抗粘剂、稳定剂、抗氧化剂、成孔剂、中和剂、光泽剂、染料、颜料、消毒剂或防腐剂、增稠剂、增塑剂等。这类物质描述于例如Fiedler,H.P.Lexikon der Hilfsstoffe für Pharmazie,Kosmetik undangrenzende Gebiete[Lexicon of Auxiliaries for Pharmacy,Cosmetics and RelatedFields],第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中。
为制备涂料组合物,可在再分散于水中以前将MMA/DEAEMA聚合物粉末研磨。研磨也可在所述其它辅助剂的存在下进行。
辅助剂的常用量每种情况下基于涂料组合物的固体总重量为0-70重量%,优选0-60重量%,特别是1-50重量%。
根据本发明一个实施方案,涂层用含水形式的本发明涂料组合物制备。涂料组合物的施涂可以以含水形式通过制粒、倾倒、涂覆或借助喷涂进行。
根据本发明得到的涂料组合物也可以以粉末形式施涂于药物剂型上。
优选施涂作为通过使本发明粉状涂料组合物再分散得到的聚合物水分散体。原则上,任何分散设备适于再分散。此处,再分散优选随着低剪切力的施加,优选通过桨叶、螺旋桨、锚式搅拌器或相当的搅拌工具进行。由此将本发明聚合物粉末自发且快速地再分散。聚合物粉末在水中的再分散通常在10分钟内完成。
可将制备涂层所需的其它组分加入这些再分散制剂中。这类组分特别是增塑剂,例如柠檬酸三乙酯、柠檬酸三丁酯、癸二酸二乙酯、癸二酸二丁酯、柠檬酸乙酰三乙酯。
通过将分散体再分散而制备精细分散的分散体也可在非常高的剪切力下,例如在也称为Ultra-Turrax的转子-定子设备,或者胶体磨中进行。高剪切力的引入在转子-定子设备中借助设备的转数调整。优选,再分散借助以<5000rpm的分散设备进行。如果还必须将其它粗颗粒添加剂或聚集添加剂并入分散体中,使特殊的研磨成为必要的话,则该方法是特别有利的。因此省去了这些添加剂在水中和随后加入再分散的聚合物粉末中的分开研磨。
在一个特定实施方案中,将本发明可再分散聚合物粉末与上述其它常规涂覆组分和/或添加剂混合以制备包含最终涂层的所有所需组分的所谓即用制剂。这些以粉末或颗粒形式存在。使用者仅需要将它们搅入水中以产生即用喷雾型悬浮液。这些即用喷雾型悬浮液通过将组分与制粒液体混合、研磨、压缩或制粒,其后干燥步骤而产生。因此,例如根据本发明部分中和的聚合物粉末可用包含颜料和任选其它辅助剂的含水悬浮液制粒。然后可将这些颗粒再分散以得到喷雾悬浮液。
本发明涂料组合物还可包含至少一种其它聚合物组分。就这点而言,可使用至少两种分散体、至少一种分散体和至少一种溶液、至少一种分散体和至少一种粉末、至少两种粉末等的混合物。
不管本发明的单独实施方案,涂料组合物的施涂量优选为1-20mg/cm2,优选2-15mg/cm2,特别优选4-12mg/cm2。
根据本发明,涂料组合物用于制备意欲在胃的酸性环境中快速释放的药物剂型的涂层,即本发明涂层可溶于胃液中。就这点而言,快速释放意指至少80%的活性成分根据桨叶型号在大气压力下在25℃下在60分钟以后释放(介质:0.1N HCl)。根据本发明得到的涂层应在口腔和咽喉中不溶于唾液的中性或几乎中性环境中。
本发明涂层可用于味道掩蔽或保护以防湿气。涂层的水蒸气渗透性非常低,因此保护其对湿气敏感的活性成分。
具有本发明涂层的药物剂型是片剂、胶囊或丸剂。此外,活性成分晶体也可具有本发明涂层。
通过本发明方法得到的涂料组合物适于原则上具有任何所需药物活性成分且可优选以独立或保护形式给药的剂型,例如抗抑郁药、β受体阻断剂、抗糖尿病药、镇痛药、消炎药、抗风湿药、抗低血压药、抗高血压药、精神药物、安神药、止吐药、肌肉松弛药、糖皮质激素类、用于治疗溃疡性结肠炎或克罗恩氏病的药剂、抗过敏药、抗生素、镇癫痫药、抗凝血药、杀真菌药、镇咳药、动脉硬化药、利尿剂、酶、酶抑制剂、痛风药、激素及其抑制剂、强心苷、免疫治疗药和细胞活素、轻泻药、antilipanic agents、肠胃病治疗药、抗偏头痛药、矿物质制剂、耳科用药、治疗帕金森病的药剂、甲状腺治疗药、解痉挛药、抗血小板聚集药、维生素、细胞增殖抑制剂药和新陈代谢抑制药、植物药物、化学疗法用药、营养制品、维生素、类胡萝卜素和氨基酸。
合适活性成分的实例为:阿卡波糖(acarbose)、非类固醇抗风湿病药、强心苷(cardiac glycosides)、乙酰水杨酸、抗病毒药、阿柔比星(aclarubicin)、阿昔洛韦(aciclovir)、顺氯胺铂(cisplatin、放线菌素(actinomycin)、α-和β-拟交感神经药、别嘌呤醇(allopurinol)、阿洛司琼(alosetron)、前列地尔(alprostadil)、前列腺素(prostaglandins)、金刚烷胺(amantadine)、氨溴索(ambroxol)、氨氯地平(amlodipine)、氨甲喋呤(methotrexate)、5-氨基水杨酸、阿米替林(amitriptyline)、氨氯地平(amlodipine)、氢氨苄青霉素(amoxicillin)、阿那曲唑(anastrozole)、氨酰心安(atenolol)、阿托伐他汀(atorvastatin)、硫唑嘌呤(azathioprine)、巴柳氮(balsalazide)、倍氯米松(beclomethasone)、倍他司丁(betahistine)、苯扎贝特(bezafibrate)、比卡鲁胺(bicalutamide)、地西泮(diazepam)和地西泮衍生物、布地缩松(budesonide)、丁苯氰酸(bufexamac)、丁丙诺啡(buprenorphine)、美沙酮(methadone)、钙盐(calcium salts)、钾盐、镁盐、坎地沙坦(candesartan)、卡马西平(carbamazepine)、卡托普利(captopril)、头孢菌素(cephalosporins)、celetoxib、西替利嗪(cetirizine)、鹅去氧胆酸(chenodeoxycholic acid)、胆烷酸(ursodeoxycholic acid)、茶碱(theophylline)和茶碱衍生物、胰岛素(trypsin)、西咪替丁(cimetidine)、克拉霉素(clarithromycin)、克拉维酸(clavulanic acid)、克林霉素(clindamycin)、氯丁替诺(clobutinol)、可乐定(clonidine)、cotrimoxazole、可待因(codeine)、咖啡因(caffeine)、维生素D和维生素D衍生物、考来烯胺(colestyramine)、巴苷酸(cromoglycicacid)、香豆素(coumarin)和香豆素衍生物、半胱氨酸、阿糖胞苷(cytarabine)、环磷酰胺(cyclophosphamide)、环孢菌素(cyclosporin)、环丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、达哌唑(dapiprazole)、去氧孕烯(desogestrel)、地奈德(desonide)、双肼酞嗪(dihydralazine)、地尔硫卓(diltiazem)、麦角生物碱(ergot alkaloids)、茶苯海明(dimenhydrinate)、二甲亚砜、二甲硅油(dimeticone)、潘生丁(dipyridamole)、多潘立酮(domperidone)和多潘立酮衍生物、donepzil、多巴胺(dopamine)、多沙唑嗪(doxazosin)、阿霉素(doxorubicin)、多西拉敏(doxylamine)、达哌唑(dapiprazole)、苯并二氮(benzodiazepine)、双氯芬酸(diclofenac)、糖苷抗生素(glycoside antibiotics)、托架丙咪嗪(desipramine)、益康唑(econazole)、ACE抑制剂、依那普利(enalapril)、麻黄碱(ephedrine)、肾上腺素(epinephrin)、依泊艾汀(epoetin)和依泊艾汀衍生物、吗啡喃(morphinanes)、钙拮抗药(calcium antagonists)、伊立替康(irinotecan)、莫达非尼(modafinil)、奥利司他(orlistat)、肽类抗生素(peptideantibiotics)、苯妥英(phenytoin)、利鲁唑(riluzole)、利塞膦酸盐(risedronate)、西地那非(sildenafil)、托吡酯(topiramate)、大环内酯抗菌素(macrolide antibiotics)、伊美拉唑(esomeprazole)、雌激素(estrogen)和雌激素衍生物、促孕激素(gestagen)和促孕激素衍生物、睾丸激素(testosterone)和睾丸激素衍生物、雄激素(androgen)和雄激素衍生物、乙柳酰胺(ethenzamide)、依托非那酯(etofenamate)、依托贝特(etofibrate)、非诺贝特(fenofibrate)、乙羟茶碱(etofylline)、依托泊苷(etoposide)、泛昔洛韦(famciclovir)、法莫替丁(famotidine)、非洛地平(felodipine)、非诺贝特(fenofibrate)、芬太尼(fentanyl)、芬替康唑(fenticonazole)、促旋酶抑制剂(gyrase inhibitors)、氟康唑(fluconazole)、氟达拉滨(fludarabine)、氟桂嗪(flunarizine)、氟尿嘧啶(fluorouracil)、氟西汀(fluoxetine)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、氟他胺(flutamide)、氟伐他汀(fluvastatin)、促滤泡素(follitropin)、福莫特罗(formoterol)、磷霉素(fosfomycin)、呋塞米(furosemide)、夫西地酸(fusidic acid)、加兰他敏(galantamine)、加洛帕米(gallopamil)、更昔洛韦(ganciclovir)、吉非贝齐(gemfibrozil)、庆大霉素(gentamicin)、银杏(ginkgo)、金丝桃汁(St.John's wort)、格列本脲(glibenclamide)、作为口服抗糖尿病药的尿素衍生物、抗胰岛素(glucagon)、葡糖胺(glucosamine)和葡糖胺衍生物、谷胱甘肽(glutathione)、甘油和甘油衍生物、下丘脑激素(hypothalamus hormones)、性瑞林(goserelin)、胍乙啶(guanethidine)、卤泛曲林(halofantrine)、氟哌啶醇(haloperidol)、肝素(heparin)和肝素衍生物、透明质酸、肼苯哒嗪(hydralazine)、氢氯噻嗪(hydrochlorothiazide)和氢氯噻嗪衍生物、水杨盐酸(salicylates)、羟嗪(hydroxyzine)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、丙咪嗪(imipramine)、吲哚美辛(indometacin)、吲哚拉明(indoramin)、胰岛素(insulin)、干扰素(interferons)、碘和碘衍生物、益康唑(isoconazole)、喘息定(isoprenaline)、葡糖醇(glucitol)和葡糖醇衍生物、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、酮基布洛芬(ketoprofen)、酮替芬(ketotifen)、拉西地平(lacidipine)、兰索拉唑(lansoprazole)、左旋多巴(levodopa)、左美沙酮(levomethadone)、甲状腺激素类(thyroid hormones)、硫辛酸(lipoic acid)和硫辛酸衍生物、赖诺普利(lisinopril)、酰脲(lisuride)、洛菲帕明(lofepramine)、罗氮芥(lomustine)、洛哌丁胺(loperamide)、氯雷他定(loratadine)、马普替林(maprotiline)、甲苯达唑(mebendazole)、美贝维林(mebeverine)、美克洛嗪(meclozine)、甲灭酸(mefenamic acid)、甲氟喹(mefloquine)、美洛昔康(meloxicam)、吲哚洛尔(mepindolol)、甲丙氨酯(meprobamate)、美罗培南(meropenem)、美沙拉嗪(mesalazine)、甲琥胺(mesuximide)、metamizole、二甲双胍(metformin)、氨甲喋呤(methotrexate)、呱醋甲酯(methylphenidate)、甲泼尼龙(methylprednisolone)、美噻吨(metixene)、甲氧氯普胺(metoclopramide)、美托洛尔(metoprolol)、灭滴灵(metronidazole)、米安舍林(mianserin)、咪康唑(miconazole)、二甲胺四环素(minocycline)、米诺地尔(minoxidil)、米索前列醇(misoprostol)、丝裂霉素(mitomycin)、咪唑斯汀(mizolastine)、莫昔普利(moexipril)、吗啡(morphine)和吗啡衍生物;月牧草(evening primrose)、纳布啡(nalbuphine)、纳洛酮(naloxone)、替利定(tilidine)、萘普生(naproxen)、那可汀(narcotine)、多马霉素(natamycin)、新斯的明(neostigmine)、麦角溴烟酯(nicergoline)、尼可拉明(nicethamide)、硝苯地平(nifedipine)、尼氟灭酸(niflumic acid)、尼莫地平(nimodipine)、尼莫拉唑(nimorazole)、尼莫司汀(nimustine)、尼索地平(nisoldipine)、肾上腺素(adrenaline)和肾上腺素衍生物、诺氟沙星(norfloxacin)、novamine sulfone、那可汀(noscapine)、制霉菌素(nystatin)、氧氟沙星(ofloxacin)、奥氮平(olanzapine)、奥撒拉嗪(olsalazine)、奥美拉唑(omeprazole)、奥莫康唑(omoconazole)、昂丹司琼(ondansetron)、奥利司他(orlistat)、奥赛醚韦(oseltamivir)、奥沙西罗(oxaceprol)、苯甲异恶唑青霉素(oxacillin)、奥昔康唑(oxiconazole)、羟甲唑啉(oxymetazoline)、泮托拉唑(pantoprazole)、醋氨酚(paracetamol)、帕罗西汀(paroxetine)、喷昔洛韦(penciclovir)、口服青霉素(oral penicillin)、喷他佐辛(pentazocine)、己可可碱(pentifylline)、pentoxifylline、奋乃静(perphenazine)、哌替啶(pethidine)、植物提取物、安替比林(phenazone)、非尼拉敏(pheniramine)、巴比妥酸衍生物、苯基保泰松(phenylbutazone)、苯妥英(phenytoin)、匹莫齐特(pimozide)、吲哚洛尔(pindolol)、哌嗪、吡乙酰胺(piracetam)、哌仑西平(pirenzepine)、吡贝地尔(piribedil)、吡罗昔康(piroxicam)、普拉克索(pramipexole)、普伐他汀(pravastatin)、哌唑嗪(prazosin)、普鲁卡因(procaine)、丙嗪(promazine)、丙哌维林(propiverine)、普萘洛尔(propranolol)、异丙安替比林(propyphenazone)、前列腺素类(prostaglandins)、丙硫异烟胺(protionamide)、丙羟茶碱(proxyphylline)、喹噻平(quetiapine)、喹那普利(quinapril)、喹那普利(quinaprilat)、雷米普利(ramipril)、雷尼替丁(ranitidine)、茶丙特罗(reproterol)、利血平(reserpine)、利巴韦林(ribavirin)、利福平(rifampicin)、维思通(risperidone)、利托那韦(ritonavir)、ropinirole、罗格列酮(rosiglitazone)、罗沙替丁(roxatidine)、罗红霉素(roxithromycin)、ruscogenin、芦丁(rutoside)和芦丁衍生物、杀码草(sabadilla)、沙丁胺醇(salbutamol)、沙美特罗(salmeterol)、莨菪胺(scopolamine)、司立吉林(selegiline)、舍他康唑(sertaconazole)、舍吲哚(sertindole)、舍曲林(sertraline)、硅酸盐(silicates)、辛伐他汀(simvastatin)、谷甾醇(sitosterol)、甲磺胺心定(sotalol)、司谷氨酸(spaglumic acid)、司氟沙星(sparfloxacin)、大观霉素(spectinomycin)、螺旋霉素(spiramycin)、螺拉普利(spirapril)、螺内酯(spironolactone)、司他夫定(stavudine)、链霉素(streptomycin)、硫糖铝(sucralfate)、舒芬太尼(sufentanil)、sulbactam、硫酰胺类(sulfonamides)、柳氮磺吡啶(sulfasalazine)、舒必利(sulpiride)、磺内酰胺(sultamicillin)、噻嗪磺胺(sultiame)、舒马曲坦(sumatriptan)、氯琥珀胆碱(suxamethonium chloride)、他克林(tacrine、tacrolimus)、taliolol、他莫昔芬(tamoxifen)、taurolidine、他扎罗汀(tazarotene)、替加色罗(tegaserod)、替马西泮(temazepam)、替尼泊苷(teniposide)、替诺昔康(tenoxicam)、特拉唑嗪(terazosin)、特比萘芬(terbinafine)、特布他林(terbutaline)、特非那定(terfenadine)、特利加压素(terlipressin)、特他洛尔(tertatolol)、四环素(tetracyclines)、四氢唑林(tetryzoline)、可可碱(theobromine)、茶碱(theophylline)、butizine、甲硫咪唑(thiamazole)、吩噻嗪(phenothiazines)、噻替哌(thiotepa)、硫加宾(tiagabine)、硫必利(tiapride)、丙酸衍生物、噻氯匹定(ticlopidine)、噻吗咯尔(timolol)、替硝唑(tinidazole)、噻康唑(tioconazole)、硫鸟嘌呤(thioguanine)、噻克索酮(thioxolone)、苯酰胺桂胺(tiropramide)、替扎尼定(tizanidine)、妥拉苏林(tolazoline)、甲苯磺丁脲(tolbutamide)、tolcapone、托萘酯(tolnaftate)、托哌松(tolperisone)、拓扑替康(topotecan)、托拉塞米(torasemide)、抗雌激素(antiestrogens)、曲马多(tramadol)、曲马唑啉(tramazoline)、群多普利(trandolapril)、苯环丙胺(tranylcypromine)、曲匹地尔(trapidil)、曲拉唑酮(trazodone)、去炎松(triamcinolone)和去炎松衍生物、氨苯蝶啶(triamterene)、三氟哌丁苯(trifluperidol)、三氟尿苷(trifluridine)、三甲氧下二氨嘧啶(trimethoprim)、曲米帕明(trimipramine)、曲吡那敏(tripelennamine)、曲普立啶(triprolidine)、异环磷酰胺(trifosfamide)、托孟他定(tromantadine)、氨基丁三醇(trometamol)、tropalpine、三羟乙基芦丁(troxerutin)、妥布特罗(tulobuterol)、酪胺(tyramine)、短杆菌素(tyrothricin)、呱胺甲尿啶(urapidil)、胆烷酸(ursodeoxycholic acid)、鹅去氧胆酸(chenodeoxycholic acid)、缬昔洛韦(valaciclovir)、伐地考昔(valdecoxib)、丙戊酸、万古霉素(vancomycin)、维库溴铵氧化物(vecuronium chloride)、文拉法辛(venlafaxine)、维拉帕米(verapamil)、阿糖腺苷(vidarabine)、维加巴因(vigabatrin)、维洛沙嗪(viloxazine)、长春碱(vinblastine)、长春蔓胺(vincamine)、长春新碱(vincristine)、长春地辛(vindesine)、长春烯碱(vinorelbine)、长春西汀(vinpocetine)、维喹地尔(viquidil)、杀鼠灵(warfarin)、占替诺盐酸盐(xantinol nicotinate)、希帕胺(xipamide)、扎鲁司特(zafirlukast)、扎西他滨(zalcitabine)、扎那米韦(zanamivir)、齐多夫定(zidovudine)、佐米曲坦(zolmitriptan)、唑吡坦(zolpidem)、佐匹克隆(zopiclone)、佐替平(zotepine)等。
如果想要的话,活性成分也可以以其药物可接受盐或衍生物的形式使用,在手性活性成分的情况下,可使用旋光异构体以及外消旋物或非对映异构体混合物。如果想要的话,本发明组合物还可包含两种或更多种药物活性成分。
根据本发明,涂料组合物可用于涂覆压出物、迷你片剂、胶囊、软胶囊、颗粒、丸剂、微丸、微胶囊、纳米胶囊或晶体。
为制备剂型,可将包衣颗粒、丸剂、微丸、微胶囊、晶体与合适的辅助剂混合并压缩以得到片剂,所述片剂在口腔的含水环境中分解并再次释放涂覆的细型制品。就这点而言,特别重要的是所谓的口服分散物,即在口中在短时间内分解并释放味道掩蔽的小型物品的片剂。
此外,涂料组合物也可有利地用于涂覆片剂
通常可产生不愉悦的苦味并可有利地根据本发明配制的活性成分类和物质为例如:
镇痛药和抗风湿药,例如扑热息痛(paracetamol)、双氯芬酸(diclofenac)、醋氯芬酸(aceclofenac)、布洛芬(ibuprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、乙酰水杨酸、左醋美沙多(levacetylmethadol)和羟可待酮(oxycodone);
精神药物,例如异丙嗪(promethazines)、多奈哌齐(donepezil)、莫达非尼(modafinil)、奈法唑酮(nefazodone)、瑞波西汀(reboxetine)、舍吲哚(sertindole)和舍曲林(sertraline);
抗生素,例如红霉素(erythromycin)、罗红霉素(roxithromycin)、克拉霉素(clarithromycin)、格雷沙星(grepafloxacin)、环丙沙星(ciprofloxacin)、左氟沙星(levofloxacin)、司氟沙星(sparfloxacin)、曲氟沙星(trovafloxacin)和奈韦拉平(nevirapine);
β阻断剂,例如心得安(propranolol)、美托洛尔(metoprolol)、bisoprolol和nebivolol;
抗糖尿病药,例如二甲双胍(metformin)、米格列醇(miglitol)和瑞格列奈(repaglinide);
H1抗组胺,例如苯海拉明(diphenhydramine)、非索那定(fexofenadine)和咪唑斯汀(mizolastine);
H2抗组胺,例如西咪替丁(cimetidine)、法莫替丁(famotidine)、罗沙替丁(roxatidine)、尼扎替丁(nizatidine)、噻氯匹定(ticlopidine)、西替利嗪(cetirizine)和雷尼替丁(ranitidine);
维生素,例如硝酸硫胺素和硫酸奎尼丁、盐酸氨普立糖(amyloprilose HCl)、盐酸伪麻黄碱(pseudoephedrine HCl)、西地那非(sildenafil)、托吡酯(topiramate)、格拉司琼(granisetron)、雷巴米特(rebamipide)、盐酸奎宁(quinine HCl)等。
也可相应地配制这些活性成分的各种盐。
优越的味道掩蔽由本发明聚合物大于6的pH值下的不溶性和在6以下的pH值下的快速溶解性产生。即在唾液(pH:7.2)中,相应涂覆形式适于非常长时间且苦药与口腔粘膜之间不存在接触,但在pH值为1-5的胃中,存在活性成分的非常快速释放。此处溶解如此快以致与未涂覆的形式相比不存在作用开始的差别。通常,本发明聚合物的膜涂层在胃液中在5分钟内溶解,而在pH7.2的磷酸盐缓冲剂中,它们稳定2小时。令人惊讶的是,膜涂层还在pH值为4.5的介质中相对快地溶解,意味着由其制备的给药形式甚至在无酸病人或用抗酸药治疗的病人中发展快速效果。在转化成粉末和粉末的再分散或熔化以后也保持涂料组合物的这些优越施用性能。
实施例
所用缩写:
玻璃化转变温度:Tg
软化水:软化水
在所有实施例中,所用聚合物为称为聚合物A的聚合物。聚合物A的制备类似于WO2009/016258的实施例1进行。
聚合物A:甲基丙烯酸甲酯/甲基丙烯酸二乙基氨基乙酯,重量比55:45,K值49,Tg57℃
K值在NMP中以0.1重量%浓度测量。聚合物作为具有9+/-0.3的pH的水分散体使用或者作为喷雾干燥粉末使用。初级分散体的平均粒度为127nm。玻璃化转变温度通过DSC以20°K/min的加热速率测定。最小成膜温度相当于+/-5℃的测量精确度范围内的Tg。
当测定粉末的平均粒度时,D(4,3)值通过光散射使用Malvern Mastersizer2000测定。
当通过光散射测定再分散粉末的平均粒度时,该值使用“Malvern Zetasizernano S”作为Z平均值测定。
所用辅助剂:
包含94.4重量%乳糖、3.2重量%Kollidon30(USP)和3.4重量%Kollidon CL(USP)的自由流动颗粒
CL-F:交联聚维酮(Crospovidone)
PH102:微晶纤维素,平均粒径100μm
Simethicone:具有200-350个二甲基硅氧烷单元的平均链长的聚二甲基硅氧烷与硅胶的混合物的CTFA名
200:细碎二氧化硅
实施例1(对比例)
将1000ml的固体含量为30重量%的聚合物A水分散体随着搅拌与6.5g的85重量%浓度磷酸混合。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液在喷雾塔中喷雾干燥。雾化在此处借助1.4mm双材质喷嘴以3.0巴的雾化压力进行。使干燥气体切向进入喷雾干燥器的输入面积中并将干燥产物在旋风器中分离。入口空气温度为107℃且出口空气温度为56℃。粉末的平均粒度为30μm。
将100g喷雾干燥产物通过用桨式搅拌器搅拌60分钟而分散于水中以得到具有20%固体含量的喷雾悬浮液。通过光散射的粒度测量显示具有130nm和450nm的最大值的双峰分布。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时并通过喷雾施涂至片剂核心上。
表1:核心组成
组成 | [%] | [mg] |
咖啡因,颗粒0.2-0.5mm | 15.15 | 50 |
Ludipress | 72.43 | 239 |
Avicel PH 101 | 12.12 | 40 |
硬脂酸镁 | 0.3 | 1 |
100.00 | 330 |
为制备核心,在阶段1中将称重的组分咖啡因、Ludipress和Avicel PH101在Diosna混合机中混合3分钟。在加入硬脂酸镁以后,进行混合另外1分钟。将这样制备的粉末混合物在旋转式压机上压缩以得到具有330mg的重量和80N的断裂强度的片剂。
表2:喷雾条件
关于包衣片剂在缓冲剂pH6.8中的抗性的试验通过在释放设备(USP,设备2)中六次测定而进行。
片剂的抗性(活性成分释放<2%)在30、60、90和120分钟以后测定。
这样制备的片剂在缓冲剂pH6.8中没有显示出抗性。
实施例2(对比例)
将5.1g草酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度,将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为35μm。
将粉末类似于实施例1再分散并显示出具有180nm的最大值的单峰分布。
进一步加工以得到具有4mg/cm2的施涂量的膜片剂类似于实施例1进行。
这样制备的片剂没有显示出在缓冲剂pH6.8中的抗性,尽管具有非常好的再分散。
实施例3
将6.7g琥珀酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为34μm。
将粉末类似于实施例1再分散,显示出具有170nm的最大值的单峰分布。
进一步加工以得到具有4、8和12mg/cm2的施涂量的膜片剂类似于实施例1进行。
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
4mg/cm2 | 8mg/cm2 | 12mg/cm2 | |
30分钟 | 100% | 100% | 100% |
60分钟 | 72% | 95% | 100% |
实施例4(对比例)
将12.1g柠檬酸二氢钠溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约32μm。
将粉末类似于实施例1再分散,显示出具有197nm和520nm的最大值的粒度双峰分布。
表3:核心组成
为制备核心,将称重的组分盐酸普奈洛尔、Ludipress、Avicel PH102和KollidonVA64在阶段1中在Diosna混合机中混合3分钟。在加入硬脂酸镁以后,进行混合另外1分钟。将这样制备的粉末混合物在旋转式压机上压缩以得到具有300mg的重量和85N的断裂强度的片剂。
进一步加工以得到具有4mg/cm2的施涂量的膜片剂类似于实施例1进行。
这样制备的膜片剂没有显示出在缓冲剂pH6.8中的抗性。
实施例5(对比例)
将168.5ml的1摩尔硫酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约37μm。
将粉末类似于实施例1再分散,显示出具有192nm的最大值的单峰分布。
进一步加工以得到具有4mg/cm2的施涂量的膜片剂类似于实施例1进行。这样制备的片剂令人惊讶地没有显示出在缓冲剂pH6.8中的抗性,尽管具有非常好的再分散。
实施例6
将7.4g戊二酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约32μm。
将粉末类似于实施例1再分散,显示出具有178nm的最大值的单峰分布。
进一步加工以得到具有4、8和12mg/cm2的施涂量的膜片剂类似于实施例1进行。
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
4mg/cm2 | 8mg/cm2 | 12mg/cm2 | |
30分钟 | 100% | 100% | 100% |
60分钟 | 68% | 91% | 100% |
实施例7(对比例)
将15.9g硬脂酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约43μm。
将粉末类似于实施例1再分散。分布的测量没有显示出结果,因为再分散是完全不满意的。
进一步加工以得到膜片剂是不可能的。
实施例8(对比例)
将3.4ml乙酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约41μm。
将粉末类似于实施例1再分散,显示出具有191nm的最大值的单峰分布。
表4:核心组成
为制备核心,将称重的组分盐酸奎宁、Ludipress、Avicel PH102和Aerosil200在阶段1中在Diosna混合机中混合3分钟。在加入硬脂酸镁以后,进行混合另外1分钟。将这样制备的粉末混合物在旋转式压机上压缩以得到具有330mg的重量和80N的断裂强度的片剂。
进一步加工以得到具有4mg/cm2的施涂量的膜片剂类似于实施例1进行。这样制备的片剂令人惊讶地没有显示出在缓冲剂pH6.8中的抗性,尽管具有非常好的再分散。
实施例9
将6.5g富马酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为约39μm。
将粉末类似于实施例1再分散,显示出具有183nm的最大值的单峰分布。
进一步加工以得到具有4、8和12mg/cm2的施涂量的膜片剂类似于实施例1进行。
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
4mg/cm2 | 8mg/cm2 | 12mg/cm2 | |
30分钟 | 100% | 100% | 100% |
60分钟 | 65% | 87% | 100% |
实施例10
将6.5g富马酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体在FSD喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为110℃且出口空气温度为57℃。在喷雾干燥期间分离出细粒部分,并再次吹入喷嘴的正面中使得产生具有280μm的平均粒度的喷雾干燥颗粒。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。
通过光散射的粒度测量显示出175nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时并类似于实施例1通过喷雾到片剂核心(配制剂表1)上而施涂。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 71% |
实施例11
将6.7g琥珀酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体类似于实施例10在FSD喷雾塔中喷雾干燥。粉末的平均粒度为312μm。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示出172nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例4(表3)喷雾到片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 75% |
实施例12
将7.4g戊二酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体类似于实施例10在FSD喷雾塔中喷雾干燥。粉末的平均粒度为295μm。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示出188nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例8(表4)通过喷雾施涂于片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 72% |
实施例13
将1000ml的固体含量为30重量%的聚合物A水分散体在FSD喷雾塔中喷雾干燥,雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为127℃且出口空气温度为59℃.在喷雾干燥期间分离出细粒部分,并再次吹入喷嘴的正面中使得产生具有220μm的平均粒度的喷雾干燥颗粒。
将5.2g富马酸溶于1000ml软化水中,然后随着使用桨式搅拌器搅拌并入250g喷雾干燥粉末。这相当于8摩尔%的中和度。在60分钟的再分散时间以后,平均粒度为184nm。
将这样制备的制剂与35g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于片剂核心(配制剂表3)上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 68% |
实施例14
将5.3g琥珀酸溶于1000ml软化水中,然后随着使用桨式搅拌器搅拌而并入250g的来自实施例13的喷雾干燥粉末。这相当于8摩尔%的中和度。在60分钟的再分散时间以后,平均粒度为165nm。
将这样制备的制剂与35g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于片剂核心(配制剂表4)上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 79% |
实施例15
将5.9g戊二酸溶于1000ml软化水中,然后随着使用桨式搅拌器搅拌而并入250g的来自实施例13的喷雾干燥粉末。这相当于8摩尔%的中和度。在60分钟的再分散时间以后,平均粒度为174nm。
将这样制备的制剂与35g柠檬酸乙酰三乙酯混合,搅拌2小时并类似于实施例1通过喷雾到片剂核心(配制剂表1)上而施涂。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 69% |
实施例16
将6.5g富马酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体类似于实施例10在FSD喷雾塔中喷雾干燥。粉末的平均粒度为280μm。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示出175nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时并通过类似于实施例1喷雾而施涂于咖啡因丸剂上。
表5:丸剂的组成
将组分在Diosna混合器中混合3分钟,然后用水润湿。将该湿物质挤出,然后在成圆机器中团圆以得到具有0.7-1.4mm的直径的丸剂。
测试具有4mg/cm2的施涂量的丸剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 87% |
实施例17
将6.7g琥珀酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体类似于实施例10在FSD喷雾塔中喷雾干燥。粉末的平均粒度为312μm。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示出172nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于茶碱颗粒(粒度0.2-0.7mm)上。
测试具有4mg/cm2的施涂量的颗粒关于在缓冲剂pH6.8中的抗性以下结果:
30分钟 | 100% |
60分钟 | 91% |
实施例18
将7.4g戊二酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这相当于8摩尔%的中和度。将该部分中和的分散体类似于实施例10在FSD喷雾塔中喷雾干燥。粉末的平均粒度为295μm。
通过用桨式搅拌器搅拌60分钟而将喷雾干燥产物再分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示出188nm的值。
将这样制备的制剂与14g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于药物晶体(直径0.3mm)上。
测试具有4mg/cm2的施涂量得到颗粒关于在缓冲剂pH6.8中的抗性显示以下结果:
30分钟 | 100% |
60分钟 | 90% |
实施例19
将27.6g月桂基硫酸钠和14.7g富马酸溶于1500ml软化水中,然后随着搅拌并入3000ml的固体含量为30重量%的聚合物A水分散体中。这相当于6摩尔%的中和度。将该部分中和的喷雾悬浮液在喷雾塔中喷雾干燥。雾化在此处借助1.4mm双材质喷嘴以0.3MPa的雾化压力进行。使干燥气体切向进入喷雾干燥器的输入区中并在旋风器中分离出干燥产物。入口空气温度为112℃且出口空气温度为59℃。粉末的平均粒度为37μm。
通过使用螺旋桨搅拌器搅拌60分钟将750g喷雾干燥粉末再分散于软化水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示具有173nm的最大值的单峰分布。将喷雾悬浮液与基于固体聚合物13重量%柠檬酸三丁酯混合,并在搅拌2小时以后用表5中的参数进一步加工。
表5:喷雾条件
设备 | Manesty |
入口空气温度 | 60℃ |
入口空气量 | 450m3/h |
转鼓速度 | 14rpm |
批量 | 5kg |
核心 | 实施例1 |
喷雾速率 | 25g/min |
雾化压力 | 0.28MPa |
喷雾宽度 | 0.28MPa |
施涂量 | 4mg/cm2 |
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
30分钟 | 100% |
60分钟 | 69% |
实施例20
粉末A:
将1000ml的固体含量为30重量%的聚合物A水分散体在喷雾塔中喷雾干燥。此处,雾化借助1.4mm双材质喷嘴以0.3MPa雾化压力进行。干燥气体切向进入喷雾干燥器的入口面积中并在旋风器中分离出干燥产物。入口空气温度为109℃且出口空气温度为58℃。粉末的平均粒度为33μm。粉末B:
将105.1g酒石酸溶于500ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物水分散体。这相当于100摩尔%的中和度。将该喷雾悬浮液类似于粉末A在喷雾塔中喷雾干燥。
粉末的平均粒度为35μm。
将粉末A与粉末B在Turbula中混合式的建立7摩尔%的中和度,然后随着使用桨式搅拌器搅拌而再分散于软化水中以得到20重量%浓度分散体。
通过光散射的粒度测量显示具有168nm的最大值的单峰分布。在加入基于聚合物13重量%柠檬酸乙酰三乙酯以后,类似于实施例19将喷雾悬浮液喷雾于根据表1的咖啡因核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 72% |
实施例21
将14.2g癸二酸悬浮于500ml软化水中,然后随着搅拌并入100ml的固体含量为30重量%的聚合物A水分散体中。这相当于100摩尔%的中和度。
随着搅拌将该溶液并入1300ml的固体含量为30重量%的聚合物水分散体中使得建立7摩尔%的中和度。将这样制备的喷雾悬浮液在FSD喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为118℃且出口空气温度为63℃。在喷雾干燥期间分离出细粒部分,并再次吹入喷嘴的正面中使得产生平均粒度为263μm的喷雾干燥颗粒。通过用桨式搅拌器搅拌60分钟而将100g喷雾干燥产物分散于水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示具有178nm的最大值的单峰分布。
将这样制备的制剂与基于固体聚合物15重量%柠檬酸乙酰三乙酯混合,搅拌2小时,类似于实施例19通过喷雾施涂于根据表4的片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 78% |
实施例22
将50g PEG6000、200g滑石、9g二氧化钛和9g氧化铁红在Turbula混合器中混合并在销棒式磨机中研磨。将该混合物悬浮于250g软化水中并借助Diosna制粒施涂于500g的根据实施例10制备的聚合物粉末上使得产生平均粒度为187μm的颗粒。
表6:制粒条件
设备 | Diosna |
混合器转速 | 350rpm |
切碎器转速 | 2000rpm |
通过用桨式搅拌器搅拌60分钟而将100g的这些颗粒分散于水中以得到具有20重量%固体含量的喷雾悬浮液。借助光散射测量粒度显示具有177nm的最大值的单峰分布。
将这样制备的制剂与基于固体聚合物15重量%柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于根据表3的片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 82% |
实施例23
将500g的根据实施例11制备的聚合物粉末与3g卵磷脂、6g硬脂酸和150g滑石在Turbula混合器中混合,然后通过压片机进一步加工。将这样产生的片粉碎,然后再分散于软化水中。借助光散射测量粒度显示出具有181nm的最大值的单峰分布。
将2.5重量%BHT溶于15重量%柠檬酸乙酰三乙酯(基于固体聚合物)中,然后加入分散体中。
将这样制备的制剂与基于固体聚合物15重量%柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于根据表1的片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 84% |
实施例24
将200g滑石和8g靛蓝色淀悬浮于500g软化水中,然后在流化床方法中施涂于500g的根据实施例12制备的聚合物粉末上。
表7:制粒条件
设备 | Glatt GPC 1 |
入口空气温度 | 60℃ |
进入空气量 | 300m3/h |
批量 | 500g |
喷雾压力 | 0.15MPa |
颗粒的平均粒度为约312μm。
通过用螺旋桨搅拌器搅拌60分钟而将100g颗粒再分散于软化水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示具有193nm的最大值的单峰分布。将喷雾悬浮液与基于固体粉末13重量%柠檬酸三丁酯混合,在搅拌2小时以后类似于实施例19通过喷雾于根据表4的片剂核心上而进一步加工。
对于4mg/cm2的施涂量,74%的包衣片剂显示出在30分钟以后100%的抗性。
实施例25
将200g滑石、8g靛蓝色淀和11.9g戊二酸悬浮于500g软化水中,然后类似于实施例11在流化床方法中施涂于500g的根据实施例13制备的聚合物粉末上。这相当于8摩尔%的中和度。
颗粒的平均粒度为298μm。
通过使用螺旋桨搅拌器搅拌60分钟而将100g颗粒再分散于软化水中以得到具有20重量%固体含量的喷雾悬浮液。通过光散射的粒度测量显示具有184nm的最大值的单峰分布。将喷雾悬浮液与基于固体聚合物13重量%柠檬酸三丁酯混合,在搅拌2小时以后类似于实施例1通过喷雾到根据表3的片剂核心上而进一步加工。
对于4mg/cm2的施涂量,涂覆片剂显示出在60分钟以后83%的抗性。
实施例26
将100g滑石、20g氧化铁红和5.2g丙二酸悬浮于300g软化水中,然后通过Ultra-Turrax以10000rpm均化15分钟。随着搅拌将该颜料悬浮液并入1000ml的固体含量为30重量%的聚合物A水分散体中。然后将这样制备且具有7摩尔%的中和度的喷雾悬浮液在SBD喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.30MPa的雾化压力下进行。入口空气温度为135℃且出口空气温度为63℃。在喷雾干燥期间分离出细粒部分,并再次吹入喷嘴的正面中使得产生平均粒度为320μm的喷雾干燥颗粒。
通过使用桨式搅拌器搅拌而将喷雾干燥产物并入水中以得到具有20重量%固体含量的喷雾悬浮液。将这样制备的制剂与基于固体聚合物15%柠檬酸三乙酯混合,搅拌另外2小时,并通过喷雾施涂于类似于实施例1的片剂核心(表1)上。
具有4mg/cm2的施涂量的包衣片剂显示出在缓冲剂pH6.8中在60分钟以后100%的抗性。
实施例27
将100g根据实施例10制备的聚合物粉末与50g滑石和4g靛蓝色淀在Turbula混合器中混合。
使用桨式搅拌器将该制剂再分散于水中以得到20重量%浓度悬浮液产生182nm的粒度。将悬浮液与15重量%癸二酸二丁酯混合,在搅拌2小时以后,类似于实施例1喷雾于根据表4的片剂上。对于4mg/cm2的施涂量,包衣片剂显示出在30分钟以后100%的抗性和在60分钟以后78%的抗性。
实施例28
将100g的根据实施例13制备的聚合物粉末与50g非常细碎的滑石、4g靛蓝色淀和2.3g癸二酸在Turbula混合器中混合。
在借助桨式搅拌器将该制剂再分散于水中以得到具有5摩尔%的中和度的20重量%浓度悬浮液以后,粒度为175nm。将悬浮液与15重量%癸二酸二丁酯和0.5%混合,在搅拌2小时以后,类似于实施例1喷雾于根据表4的片剂上。对于4mg/cm2的施涂量,包衣片剂显示出在30分钟以后100%的抗性。
实施例29
将100g的根据实施例11制备的聚合物粉末与60g滑石、6g氧化铁红和0.5g卵磷脂在Turbula混合器中混合,然后在销棒式磨机中研磨。
借助桨式搅拌器将该制剂再分散于水中以得到20重量%浓度悬浮液产生176nm的粒度,对于该测定,预先将滑石和氧化铁离心分离出。
将悬浮液与15重量%癸二酸二丁酯混合,在搅拌2小时以后,类似于实施例19喷雾于根据表1的片剂上。对于4mg/cm2的施涂量,包衣片剂显示出在60分钟以后83%的抗性。
实施例30
将1000ml的固体含量为30重量%的聚合物A水分散体在SBD喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为110℃且出口空气温度为57℃。在喷雾干燥期间将细粒分离出并再次吹入喷嘴的正面中使得产生平均粒度为190μm的喷雾干燥颗粒。
将30g二氧化钛、200g滑石、8.4g己二酸和25g氧化铁在销棒式磨机中研磨,然后与喷雾干燥粉末混合并通过使用桨式搅拌器搅拌60分钟而再分散于软化水中以得到具有20重量%固体含量的喷雾悬浮液中。借助光散射的粒度测量产生170nm的值。
将这样制备的制剂与基于固体聚合物15重量%柠檬酸三乙酯混合,搅拌2小时,类似于实施例19通过喷雾施涂于根据表1的片剂核心上。
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
30分钟 | 100% |
60分钟 | 76% |
实施例31
将1000ml的固体含量为30重量%的聚合物A水分散体在喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为112℃且出口空气温度为58℃。
将该粉末与8.4g细粉己二酸、60g细滑石、2g细黄原胶、15g细氧化铁红混合,然后通过使用桨式搅拌器搅拌60分钟而随着搅拌再分散于水中以得到具有20%固体含量的喷雾悬浮液。借助光散射的粒度测量产生168nm的值,对于该测定,预先将滑石和氧化铁离心分离出。
将这样制备的制剂与基于固体聚合物15重量%柠檬酸三乙酯混合,搅拌2小时,类似于实施例19通过喷雾施涂于根据表1的片剂核心上。
测试片剂关于在缓冲剂pH6.8中的抗性显示出以下结果:
30分钟 | 100% |
60分钟 | 79% |
实施例32
将1000ml的固体含量为30重量%的聚合物A水分散体在FSD喷雾塔中喷雾干燥,其中雾化借助1.4mm双材质喷嘴在0.3MPa的雾化压力下进行。入口空气温度为123℃且出口空气温度为54℃。在喷雾干燥期间将细粒分离出并再次吹入喷嘴的正面中使得产生平均粒度为211μm的喷雾干燥颗粒。
每种情况下将15.1g/37.7g/75.5g苹果酸溶于1000ml软化水中并使用桨式搅拌器随着搅拌将250g喷雾干燥粉末并入各苹果酸溶液中。这相当于2、5或10摩尔%的中和度。在60分钟的再分散时间以后,各分散体的平均粒度为220/198/182nm。
将这样制备的制剂与35g柠檬酸乙酰三乙酯混合,搅拌2小时,并类似于实施例1通过喷雾施涂于根据表3的片剂核心上。
测试具有4mg/cm2的施涂量的片剂关于在缓冲剂pH6.8中的抗性显示出以下结果。
2摩尔% | 5摩尔% | 10摩尔% | |
30分钟 | 100% | 100% | 100% |
60分钟 | 37% | 65% | 89% |
实施例33
将1.3g琥珀酸、1.2g富马酸和1.6g酒石酸各自溶于150ml软化水中,然后随着搅拌并入1000ml的固体含量为30重量%的聚合物A水分散体中。这每种情况下相当于1.5摩尔%的中和度。将该部分中和的喷雾悬浮液类似于实施例1在喷雾塔中喷雾干燥。
粉末的平均粒度为37μm。
将粉末类似于实施例1再分散并显示出具有182nm的最大值的单峰分布。
进一步加工以得到具有4mg/cm2的施涂量的膜片剂类似于实施例1进行。
关于在缓冲剂pH6.8中的抗性测试片剂显示出以下结果:
30分钟 | 100% |
60分钟 | 72% |
Claims (34)
1.由成膜涂料组合物得到的药物涂层,所述成膜涂料组合物基于单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物,其中共聚物以用C3-C10二羧酸部分中和存在,其中所述共聚物以部分中和至4-15摩尔%存在。
2.根据权利要求1的涂层,其中涂料组合物以1-20mg/cm2的施涂量施涂,且对于4mg/cm2的施涂量,涂层具有在pH 6.8的含水环境中在30分钟以后至少80%的对活性成分释放的耐性。
3.根据权利要求1的涂层,其中涂料组合物的施涂量为2-15mg/cm2。
4.根据权利要求1的涂层,其中涂料组合物的施涂量为4-12mg/cm2。
5.根据权利要求1-4中任一项的涂层,其中共聚物以用非支化C3-C10二羧酸部分中和存在。
6.根据权利要求1-4中任一项的涂层,其中二羧酸为富马酸。
7.根据权利要求1-4中任一项的涂层,其中二羧酸为链烷烃二羧酸。
8.根据权利要求1-4中任一项的涂层,其中二羧酸选自丙二酸、琥珀酸、戊二酸、己二酸或癸二酸、苹果酸(2-羟基琥珀酸)和酒石酸(2,3-二羟基琥珀酸)。
9.根据权利要求1-4中任一项的涂层,其中共聚物以部分中和至4-10摩尔%存在。
10.根据权利要求5的涂层,其中共聚物以部分中和至4-10摩尔%存在。
11.根据权利要求6的涂层,其中共聚物以部分中和至4-10摩尔%存在。
12.根据权利要求7的涂层,其中共聚物以部分中和至4-10摩尔%存在。
13.根据权利要求8的涂层,其中共聚物以部分中和至4-10摩尔%存在。
14.根据权利要求1-4中任一项的涂层,其包含具有大于2的第一pKa值和大于4的第二pKa值的二羧酸。
15.根据权利要求8的涂层,其包含己二酸作为二羧酸。
16.根据权利要求1-4中任一项的涂层,其通过施涂通过将涂料组合物从粉末形式再分散而制备的含水涂料组合物而得到。
17.根据权利要求10-13中任一项的涂层,其通过施涂通过将涂料组合物从粉末形式再分散而制备的含水涂料组合物而得到。
18.制备用于涂覆包含至少一种药物活性成分的剂型且对活性成分的过早释放具有抗性的涂料组合物的方法,其中涂料组合物包含单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物作为聚合物,其中涂料组合物中的共聚物用C3-C10二羧酸部分中和,其中所述共聚物以部分中和至4-15摩尔%存在。
19.根据权利要求18的方法,其中所述共聚物在水分散体中用二羧酸部分中和。
20.根据权利要求18的方法,其中所述共聚物以粉末形式部分中和。
21.根据权利要求18-20中任一项的方法,其中所述共聚物以部分中和至4-10摩尔%存在。
22.根据权利要求18-20中任一项的方法,其中共聚物用非支化C3-C10二羧酸部分中和。
23.根据权利要求21的方法,其中共聚物用非支化C3-C10二羧酸部分中和。
24.根据权利要求18-20中任一项的方法,其中所用二羧酸为链烷烃二羧酸。
25.根据权利要求21的方法,其中所用二羧酸为链烷烃二羧酸。
26.根据权利要求18-20中任一项的方法,其中使用选自丙二酸、琥珀酸、戊二酸、己二酸或癸二酸、苹果酸(2-羟基琥珀酸)和酒石酸(2,3-二羟基琥珀酸)的二羧酸。
27.根据权利要求21的方法,其中使用选自丙二酸、琥珀酸、戊二酸、己二酸或癸二酸、苹果酸(2-羟基琥珀酸)和酒石酸(2,3-二羟基琥珀酸)的二羧酸。
28.根据权利要求18-20中任一项的方法,其中所用二羧酸为己二酸。
29.根据权利要求21的方法,其中所用二羧酸为己二酸。
30.根据权利要求18-20中任一项的方法,其中所用二羧酸为富马酸。
31.根据权利要求21的方法,其中所用二羧酸为富马酸。
32.根据权利要求18-20中任一项的方法,其中在施涂于剂型上以前将粉状涂料组合物再分散于水中。
33.根据权利要求23,25,27,29和31中任一项的方法,其中在施涂于剂型上以前将粉状涂料组合物再分散于水中。
34.根据权利要求18-33中任一项的涂料组合物在保护含活性成分的药物剂型以防在pH 6.8的含水环境中过早活性成分释放的用途,所述涂料组合物基于单体重量比为35:65-55:45的甲基丙烯酸N,N-二乙基氨基乙酯和甲基丙烯酸甲酯的共聚物,其中共聚物以用C3-C10二羧酸部分中和存在。
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PCT/EP2013/054549 WO2013131986A1 (de) | 2012-03-09 | 2013-03-07 | Herstellung von pharmazeutischen protektiven überzügen mit guter resistenz im neutralen milieu |
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