CN103347931B - 制备用于药物剂型的稳定保护性衣层的粉末包衣剂 - Google Patents
制备用于药物剂型的稳定保护性衣层的粉末包衣剂 Download PDFInfo
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- CN103347931B CN103347931B CN201280008040.XA CN201280008040A CN103347931B CN 103347931 B CN103347931 B CN 103347931B CN 201280008040 A CN201280008040 A CN 201280008040A CN 103347931 B CN103347931 B CN 103347931B
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Abstract
本发明涉及一种由含水聚合物分散体制备粉状、含抗氧化剂的包衣组合物的方法,其包含作为组分A的通过自由基聚合如下物质而获得的聚合物:a)甲基丙烯酸N,N-二乙基氨基乙酯,和b)至少一种选自α,β-烯属不饱和单-和二-羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物;其特征在于所述抗氧化剂以溶液或分散体的形式引入所述含水聚合物分散体中,并通过喷雾方法将所述含水分散体转化成粉末形式。
Description
本发明涉及制备用于药物剂型的稳定保护性衣层的包衣组合物,其出于遮盖味道或者防潮目的而具有基于阳离子聚合物的薄膜包衣,所述阳离子聚合物通过自由基乳液聚合包含甲基丙烯酸N,N-二乙基氨基乙酯的单体混合物而获得。本发明进一步涉及呈粉末形式的该包衣组合物的制备,包括借助喷雾方法将含水分散体转化成具有良好再分散性的自由流动粉末。
为了提供用于药物衣层的具有低残余单体含量的粘合剂,DE-B2512238教导了通过喷雾干燥聚合物分散体而获得的粉末在制备用于这些药物剂型的包衣溶液中的用途。就用于喷雾干燥的分散体而言,参见DE1090381、DE1219175和DE2135073。
DE3049179A1为DE2512238的附加申请,且涉及根据后一文献教导通过喷雾干燥含水悬浮液形式而获得的粉末在通过热胶凝化制备衣层中的用途,所述悬浮液额外保护增塑剂。
WO00/05307涉及提供用于药物剂型的包衣和粘合组合物,其包含具有含叔氨基的单体基团的(甲基)丙烯酸酯共聚物,其意图是使简单干燥或含水进一步加工成为可能。此外,该文献教导了一种方法,其中将(a)(甲基)丙烯酸的C1-C4酯和具有叔铵基的(甲基)丙烯酸酯单体的共聚物,(b)增塑剂和(c)HLB值为至少14的乳化剂彼此组合,并通过熔融、倾倒、铺展或喷雾而由其制备包衣或粘合组合物,其中共聚物(a)以平均粒度为1-40μm的粉末形式引入。此处,获得的加工性归因于提供具有极小粒度的粉末形式的共聚物(a)。
WO02/067906涉及与WO00/05307所述的那些相比具有改善的水蒸气渗透率的包衣和粘合组合物。此处,所述包衣和粘合组合物使用包含如下组分的混合物制备:(a)呈平均粒度为1-40μm的粉末形式的(甲基)丙烯酸的C1-C4酯与具有叔铵官能团的另一(甲基)丙烯酸酯单体的共聚物,(b)HLB值为至少14的乳化剂和(c)C12-C18单羧酸或C12-C18羟基化合物。
WO2004/019918描述了包衣和粘合组合物,就其组成而言对应于WO00/05307和WO02/067906中所述的那些。
根据US6,696,085B2,报道了将C型甲基丙烯酸共聚物作为崩解剂。所述C型甲基丙烯酸共聚物为包囊聚合物,其在酸性pH范围内是不溶的,而在pH为7下是水溶性的,正如在口腔中的那样。除低断裂强度(<20N)之外,所述片剂具有高脆性(>7%)且包含约15重量%的高比例粗颗粒状崩解剂。因此,其具有低机械强度且由于高比例的粗颗粒状崩解剂而在口中具有不愉悦的沙质感觉。
EP88951A2描述了一种使用基于乳液聚合物的水分散包衣组合物包衣药物的方法,其中所述包衣组合物可部分以盐形式存在。所述包衣组合物也可用描述为原则上合适的方法的喷雾干燥和冷冻干燥方法由再分散的粉末获得。然而,就此而言,还声称也可在合适玻璃化转变温度的下限使用冷冻干燥。具体描述了通过冷冻干燥或喷雾干燥而获得的30%甲基丙烯酸与70%甲基丙烯酸甲酯的粉末,其由于其组成而具有高玻璃化转变温度。
WO97/42255描述了借助喷雾干燥而喷雾干燥聚合物粉末,所述粉末可再分散于水溶液中且包含带有游离酸或碱的共聚物,其中在喷雾干燥之前,必须借助缓冲体系调节所述分散体的pH值。
EP262326A2描述了一种制备可再分散的塑料聚合物的方法,其中将最低成膜温度低于60℃且动态玻璃化转变温度低于150℃的(甲基)丙烯酸与(甲基)丙烯酸酯的共聚物的含水分散体以使得干燥气体的进入温度高于最低成膜温度且低于玻璃化转变温度的方式喷雾干燥。
EP901787A1描述了稳定化的药物制剂,其包含对由光和自由基所导致的分解敏感且用包衣组合物包衣的活性成分,所述包衣组合物除金属氧化物、碱性物质和增塑剂之外,还包含用于稳定所述活性成分的自由基清除剂。对所述包衣组合物提及的碱性物质为原则上可能的所有物质,如糖、纤维素衍生物、聚乙烯基吡咯烷酮或(甲基)丙烯酸酯聚合物。还提及所述包衣组合物可包含甲基丙烯酸氨基烷基酯作为缓释聚合物。
WO2009/016258公开了制备该发明所用的基于甲基丙烯酸N,N-二乙基氨基乙酯的阳离子聚合物的含水聚合物分散体,及其在药物包衣中的用途。仅以非常泛泛的方式提及了粉状包衣组合物。在特定情况下,由于其低玻璃化转变温度,所述聚合物显示出不希望的附聚倾向,因此就加工角度而言具有高要求。没有提及在储存时稳定化以(例如)防止褪色或者甚至在延长的储存或在逆境下获得释放稳定性的特定方法。
本发明的目的是寻找在水中具有良好再分散性且适合药物剂型的自由流动的粉状薄膜包衣组合物,所述药物剂型即使在延长的储存或热苛刻的储存下也不改变薄膜包衣的释放行为且不褪色。发现所述再分散包衣组合物的特定要求尤其为制备具有窄粒度分布的稳定小颗粒分散体且避免凝结。此外,其目的也为确保引入稳定性物质如抗氧化剂(由于该类稳定性物质通常所具有的不良水溶性),而不负面影响所述聚合物分散体或聚合物粉末的稳定性及其施加相关的性能。此处,待解决的另一问题不仅在于将在大多数情况下微溶于水中的抗氧化剂以均匀方式引入所述含水分散体中,而且在于使其与分散的聚合物颗粒充分接触,从而使得所述水不溶性抗氧化剂迁移至聚合物颗粒中,这是因为据推测其在其中发挥其作用。因此,已发现了一种方法,其将微溶于水中的物质经由该水相转移至另一相中。所述问题以特定方式由于如下事实而恶化:由于增塑剂在成膜开始时无法使该制剂转化成可再分散粉末,因此不可使用可起夹带剂作用的增塑剂。
因此,发现了一种制备粉状、含抗氧化剂的含水聚合物分散体的包衣组合物的方法,其包含作为组分A的通过自由基聚合如下物质而获得的聚合物:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种选自α,β-烯属不饱和单-和二-羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物;
其中所述抗氧化剂以溶液或细碎分散体的形式引入所述含水聚合物分散体中,并通过喷雾方法将所述含水分散体转化成粉末形式。
所述抗氧化剂以“细碎分散体”形式引入,其中根据本发明,“细碎”意指平均粒度小于20μm。
此外,发现了一种通过喷雾方法将用抗氧化剂稳定的含水聚合物分散体转化成自由流动粉末的方法,其中在干燥气体存在下通过喷雾方法将所述含水聚合物分散体转化成自由流动的粉末,其中所述干燥气体在进入喷雾装置中的进入温度比所述聚合物的玻璃化转变温度高至少20℃且比所述聚合物的最低成膜温度高至少20℃,且所述干燥气体离开喷雾装置的离开温度保持为40-85℃。
根据另一实施方案,干燥气体的进入温度比所述聚合物的玻璃化转变温度高至少20℃,比所述聚合物的动态玻璃化转变温度高至少20℃,且比所述聚合物的最低成膜温度高至少20℃,且其中所述干燥气体离开喷雾装置的离开温度为40-85℃。
优选地,所述干燥气体进入喷雾装置中的进入温度比所述聚合物的玻璃化转变温度高至少40℃且比所述聚合物的最低成膜温度高至少40℃。
根据另一实施方案,所述干燥气体的进入温度比所述聚合物的玻璃化转变温度高至少40℃,比所述聚合物的动态玻璃化转变温度高至少40℃,且比所述聚合物的最低成膜温度高至少40℃。
对上述所有实施方案而言,所述干燥气体的离开温度优选为45-70℃。
根据另一优选实施方案,转化至自由流动粉末通过团聚喷雾干燥进行。
根据另一优选实施方案,在喷雾方法之前或之后,用酸部分中和所述聚合物。
另一实施方案涉及在其他聚合物和/或其他助剂存在下实施喷雾干燥方法。
此外,发现以此方式获得的粉末作为药物包衣组合物的用途。优选地,所述包衣组合物通过将再分散于水中而获得,其中使用转速为至多1000rpm的低剪切搅拌装置将通过喷雾方法获得的粉末再分散。令人惊讶地,还可使用转速>5000rpm的高剪切分散装置。根据本发明,这可在在再分散团聚和制剂凝聚过程中不形成细颗粒的情况下进行。
本发明上下文中的自由流动粉末意指在使用Pfrengle设备且无搅拌辅助下根据DINISO4324测定流动性时,所述粉末自由且完全从漏斗中流出漏斗。
此外,本发明还涉及根据权利要求1-28中任一项获得的聚合物粉末,其由聚合物分散体和抗氧化剂构成,所述聚合物分散体包含通过自由基聚合如下物质而获得的聚合物作为组分A:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物,
其中所述聚合物粉末在再分散于水中时的平均粒度为初级母分散体粒度的至多5倍,优选至多3倍,特别优选至多2倍。
此处,平均粒度是指通过光散射法测定的强度平均值
用于所述喷雾方法的包衣组合物基于含水聚合物分散体,所述分散体通过在含水介质中于至少为8的pH值下自由基乳液聚合单体混合物M)而获得,所述混合物M)包含:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物。
所述呈含水聚合物分散体形式的包衣组合物优选在无额外有机溶剂下获得。
根据本发明,所述包衣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。即,本发明的衣层可溶于胃液中。就此而言,快速释放意指在60分钟后,释放至少80%的活性成分。根据本发明获得的衣层并非意欲在唾液的中性或几乎中性的环境中溶于口腔和喉咙中。
本发明包衣组合物可用于遮盖味道或者用于防潮。所述衣层的水蒸气渗透率非常低,由此保护湿气敏感性活性成分。
对通过自由基乳液聚合制备所述聚合物而言,此处明确引用WO2009/016258的公开内容,其中详细描述了制备以及与制备有关的优选实施方案以及组合物。
在本发明方法特别优选的实施方案中,使用通过由单体混合物M)获得的聚合物分散体,所述单体混合物M)由如下单体构成:
-43-47重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),基于用于所述聚合的单体总重量;和
-53-57重量%的至少一种化合物b),特别是甲基丙烯酸甲酯,基于用于所述聚合的单体总重量。
所述以分散体形式存在的聚合物的借助凝胶渗透色谱法测得的平均分子量Mw优选为30000-500000g/mol,特别优选为60000-140000g/mol,特别为80000-120000g/mol。
所述以分散体Pd)形式存在的聚合物优选具有40-60的K值(根据Fikentscher在1%浓度的N-甲基吡咯烷酮(NMP)溶液中测定)。
借助DSC“差示扫描量热法”测得的玻璃化转变温度TG优选为40-70℃,特别优选为52-62℃。此处,首先将试样加热至150℃,然后由150℃快速冷却。玻璃化转变温度的测量在20°K/分钟的加热速率下进行。
最低成膜温度根据DINISO2115所述的方法测定,且为40-70℃,优选为50-65℃。所述方法的测量精度为+/-5℃。
所述以分散体形式存在的聚合物为基本无规的共聚物。
所述以聚合物分散体形式存在的聚合物颗粒的平均粒径(借助分析超离心测定)优选为70-200nm,特别优选为80-150nm,特别为90-120nm。粒度分布优选为基本单峰的。
本发明分散体的LT值(在于水中为0.01%浓度的分散体中测定(2.5cm比色杯,白光))优选为至少70%,特别优选为至少80%。透射光的测定例如描述于DieterDistler,Polymerdispersionen[含水聚合物分散体],Wiley-VCH(1999),第40页中。
根据本发明用于所述喷雾方法的分散体的固含量优选为10-50重量%,特别优选为20-40重量%。在借助超滤对所述分散体事先进行纯化的情况下,本发明所用的分散体在该超滤之前和之后优选具有处于这些范围之内的固含量。当然,同样可在喷雾方法之前通过超滤将稀聚合物分散体浓缩。
根据本发明用于遮盖味道的再分散性聚合物粉末在水中具有20重量%的固含量,优选小于300mPas,特别优选小于200mPas,特别是小于100mPas的低粘度(借助布鲁克菲尔德粘度计在20℃和100s-1下测得的值)。该粘度对许多应用特别重要。
根据本发明,所述含水聚合物分散体转化成粉末借助喷雾方法进行。合适的喷雾方法原则上为喷雾干燥、团聚喷雾干燥、喷雾造粒(喷雾流化床干燥)或喷雾团聚。
下文对实施雾化和干燥所述的条件针对原则上可实施的喷雾方法的所有实施方案,不论是常规喷雾干燥、喷雾造粒还是团聚喷雾干燥。
所述雾化优选以水力雾化方式由于液压或气压经由喷嘴如单物料喷嘴或多物料喷嘴,或经由雾化盘进行。
合适的喷雾装置为常规喷雾塔,其中待雾化的聚合物分散体从上方引入。所得聚合物粉末可在下端排出并在下游旋风分离器中从干燥气流中分离出去。
可使用的干燥气体为空气或惰性气体,如氮气、氩气或氦气。所述干燥气体可反向或同向引入借助所述喷雾装置的雾化而产生的液滴中。所述干燥气体优选同向使用。所述干燥气体的进入温度保持比所述聚合物的玻璃化转变温度高至少20℃,优选高至少40℃;且根据一个实施方案,也比所述聚合物的动态玻璃化转变温度高至少20℃,优选高至少40℃,且比所述聚合物的最低成膜温度高至少20℃,优选高至少40℃。所述干燥气体进入喷雾装置中的进入温度特别优选保持为100-140℃,且所述干燥气体离开喷雾装置的离开温度保持为45-70℃。非常特别优选地,所述干燥气体进入喷雾装置中的进入温度保持为110-130℃,且所述干燥气体离开喷雾装置的离开温度保持为50-60℃。非常特别优选所述干燥气体的离开温度处于与最低成膜温度+/-5℃相同的范围内。
水在所述喷雾装置中的蒸发可在大气压下或在0.06-0.12MPa下进行。
在实施喷雾方法时,也可向所述含水聚合物分散体中添加聚合物喷雾助剂,如聚乙烯醇、聚乙烯醇与以聚乙二醇作为接枝基且具有聚乙烯醇侧链的聚合物的混合物(以Protect商购获得)、聚乙烯基吡咯烷酮、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、聚丙烯酰胺。该喷雾助剂的合适用量为0.1-30重量%,优选为1-10重量%,基于固含量。
此外,也可向所述含水聚合物分散体中添加抗粘连剂。合适的抗粘连剂例如为硅酸铝如膨润土,以及硅藻土(kieselguhr),胶态二氧化硅,沉淀二氧化硅,硅藻土(diatomaceousearth),碳酸钙、二氧化钛、氧化锌,硅酸镁如滑石,或磷酸三钙。该抗粘连剂的合适用量为0.1-15重量%,优选为0.5-5重量%,基于固含量。
原则上,也可向所述含水聚合物分散体中添加常规包衣助剂。合适的助剂可为:香料、口味改进物质、甜味剂(糖,糖醇,增甜剂如天冬甜素、糖精钠、环氨酸钠)、助流剂、润湿剂、脱模剂、抗粘剂、稳定剂、抗氧化剂、造孔剂、中和剂、光亮剂、染料、颜料、消毒剂或防腐剂、增稠剂或增塑剂。合适的助剂例如描述于Fiedler,H.P.,LexikonderHilfsstoffefürPharmazie,KosmetikundangrenzendeGebiete[药物、化妆品和相关领域用助剂手册],第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中。
正如已描述的那样,本发明的一个实施方案涉及常规喷雾干燥,在此期间使待干燥的含水聚合物分散体雾化并在干燥气体的气流中干燥且以此方式转化成粉末形式。
根据另一实施方案,转化成粉末可借助喷雾造粒进行。为此,同样将待干燥的含水聚合物分散体雾化,然后使产生的颗粒在流化床中与作为初始装料引入的种子颗粒接触。由于该使种子颗粒与含水聚合物分散体的液滴接触,所述种子颗粒生长,从而获得更大的粒状颗粒,其中形成包围用作种子材料的颗粒的洋葱皮状结构。
根据本发明的一个优选实施方案,转化成粉末借助团聚喷雾干燥进行。此处,如上所述使聚合物分散体在喷雾塔中雾化,同时将从干燥区域移除的细粉尘吹入雾化区域中,其中所述含水聚合物分散体以细液滴形式存在。所述细粉尘颗粒在其中粘合在一起,从而获得具有黑莓状结构的较大聚集体。此外,还可连接流化床,在其中可进一步降低所形成的颗粒的含水量。所得聚集体可具有150-1000μm,优选200-500μm的粒度。在该实施方案中,还将进入温度选择为比所述聚合物的玻璃化转变温度高至少20℃,优选高至少40℃,且根据一个实施方案,还比所述聚合物的动态玻璃化转变温度高至少20℃,优选高至少40℃,且比所述聚合物的最低成膜温度高至少20℃,优选高至少40℃;且所述干燥气体离开喷雾装置的离开温度选择为所述聚合物的40-85℃,优选45-70℃。优选地,所述干燥气体进入喷雾装置中的进入温度保持为100-140℃,且所述干燥气体离开喷雾装置的离开温度保持为45-70℃。特别优选地,所述干燥气体进入喷雾装置中的进入温度保持为110-130℃,且所述干燥气体离开喷雾装置的离开温度保持为50-60℃。通过喷雾团聚获得的黑莓状结构基本上无粉尘且在再分散时显示出特别有利的行为。
在上述所有实施方案中,可在喷雾方法期间,向喷雾塔中吹入基于聚合物粉末为0.1-15重量%,优选为0.5-5重量%量的喷雾助剂,例如硅酸铝如膨润土,硅藻土(kieselguhr),胶态二氧化硅,沉淀二氧化硅,硅藻土(diatomaceousearth),碳酸钙、二氧化钛、氧化锌,硅酸镁如滑石,或磷酸三钙。
残留溶剂的含量通常不超过5重量%,基于所述粉末的固含量。
总之,通过喷雾方法形成的粉末的粒度由特定变量决定。在常规喷雾干燥的情况下,可获得10-150μm的粒度。在喷雾造粒(例如喷雾流化床干燥)的情况下,可获得150-1000μm的更大粒度。在团聚喷雾干燥的情况下,可获得150-1000μm的粒度。
根据另一实施方案,可向所述聚合物中添加酸。优选地,添加的酸量使得碱性基团部分以酸式盐形式存在。优选地,1-20mol%,特别优选2-15mol%的碱性基团被中和。这可在喷雾干燥之前或之后进行。因此,例如可在喷雾干燥之前向所述含水聚合物分散体中添加酸。根据另一实施方案,也可在再分散之前或之中添加酸。如果酸的引入在喷雾干燥之前进行,则可借助常规方法将其搅入含水分散体中。在喷雾干燥之后添加的情况下,将酸引入聚合物粉末中以如下方式进行:首先借助简单搅拌器将所述聚合物粉末粗预分散于水中,然后添加酸,并通过进一步搅拌实现完全再分散。再分散非常快,因此甚至在10分钟之后,存在细碎分散质。在改进的程序中,也可首先将酸作为初始装料引入水中,并在搅拌下向其中添加聚合物粉末。也可首先将聚合物粉末与酸混合,并将该粉末混合物引入水中。
合适的酸为无机酸或酸式盐,如碳酸(注入二氧化碳)、碳酸氢铵、碳酸氢钠、盐酸、硫酸或磷酸,或磷酸盐如磷酸二氢钠。合适的还有有机酸,如酒石酸、柠檬酸、乳酸、乙醇酸、苹果酸、丙二酸、马来酸、琥珀酸、富马酸、天冬氨酸、谷氨酸、葡糖酸或其他生理相容性酸。当然,天然和/或合成基聚合物酸也是可能的。所述酸适于所述的所有实施方案。
根据本发明的另一实施方案,使用在所述喷雾方法条件下分解或蒸发的酸。根据该实施方案,在喷雾方法之前和之中,所述聚合物以中和或部分中和的形式存在,而在所得粉末中,再次以游离碱形式存在。
在各种情况下,酸的用量(重量)由具体分子量和上文所述的所需中和度决定。
优选地,用酸进行处理以使得所述粉末或水分散粉末的含水分散体的pH值为5-9。
特别优选地,酸或酸式盐的添加以使得所述粉末或水分散粉末的含水分散体的pH值为6-8的方式添加。
包衣组合物例如可通过将根据本发明获得的聚合物粉末再分散以获得含水聚合物分散体而充分混合而制备,其中优选在所述分散体中添加至少一种其他助剂。
为了进行稳定化,在转化成粉末形式之前,用微水溶性抗氧化剂对所述聚合物分散体进行处理。术语“抗氧化剂”本身是本领域技术人员所已知的(参见例如-LexikonderChemie[化学手册],第9版,1989,Georg-Thieme-Verlag,Stuttgart)且是指被认为抑制或防止由氧或其他氧化性过程所导致的不希望的变化的物质。根据本发明,用于稳定所述包衣组合物的合适抗氧化剂为微溶于水中的抗氧化剂,即在20℃下在水中的溶解度不超过1g/l的抗氧化剂。
根据本发明,合适的抗氧化剂主要为亲脂性物质生育酚、生育酚乙酸酯、棕榈酸抗坏血酸酯、硬脂酸抗坏血酸酯、叔丁基氢醌、叔丁基羟基苯甲醚、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。
抗氧化剂以在有机溶剂中的溶液形式引入。
根据本发明的一个实施方案,将所用的抗氧化剂溶于有机溶剂中。合适的有机溶剂为一方面与水充分溶混从而可获得在水中为至少10重量%浓度,而另一方面也能溶解所述微水溶性抗氧化剂的那些溶剂。合适的溶剂为醇,如乙醇或异丙醇,酮如丙酮、甲基乙基酮,以及酯如乙酸甲酯。这些溶剂通常具有低于100℃的沸点。
所述抗氧化剂可以以本身为常规的方式转化成有机溶液。对浓度加以选择以使得每升溶剂使用10-1000g抗氧化剂。总之,对有机溶剂的量加以选择以使得使用1-20重量%的溶剂,基于所述含水分散体的重量。
根据另一实施方案,所述抗氧化剂可以以含水胶束溶液的形式引入所述含水分散体中。为此,在加溶物质(“加溶剂”)存在下将所述物质转化成溶液(至于术语“加溶”参见-Chemielexikon[化学手册],第9版)。合适的加溶剂为表面活性剂,例如多库酯钠或十二烷基硫酸钠、乙氧基化脂肪、乙氧基化脂肪酸、乙氧基化脂肪醇或聚合物加溶剂。
合适的聚合物加溶剂尤其为两亲性共聚物。根据本发明,两亲性共聚物应理解为意指由亲水性和疏水性链段构成的共聚物。所述链段也可具有LCST(下部临界会溶温度)。所述链段就其本身而言为聚合物链,所述聚合物链由于其组成和/或用于制备所述链段的单体而为亲水性的或疏水性的。所述两亲性共聚物可为嵌段聚合物或接枝聚合物。除线性嵌段聚合物之外,所述共聚物的结构也可为梳状的或星形的。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。所述侧链可接枝至(angepfropft)或接枝上(aufgepfropft)。合适的两亲性共聚物例如公开于WO2007/017452、WO2007/051743、WO2007/065845和WO2007/065846中,由此参考其与合适两亲性共聚物及其制备有关的描述。其他两亲性共聚物例如为泊洛沙姆。
合适的亲水性链段为N-乙烯基内酰胺均聚物或共聚物链,尤其是含N-乙烯基吡咯烷酮的聚合物,以及聚乙烯醇链或聚醚。
合适的疏水性链段例如为乙酸N-乙烯酯的均聚物或共聚物。合适的共聚单体例如为N-乙烯基己内酰胺。
优选的聚合物加溶剂为以名称商购自BASFSE的接枝共聚物,其具有PEG6000作为接枝基以及由乙酸乙酯和N-乙烯基己内酰胺制备的共聚物侧链。
适于制备胶束溶液的还有HLB高于12的所有表面活性剂。该类表面活性剂描述于“Fiedler,EncyclopediaofExcipients”,EditioCantorVerlag,第6版,2007,第112-119页中。
所述含水抗氧化剂加溶物包含0.5-30重量%,优选1-20重量%的抗氧化剂和1-50重量%,优选1-30重量%的加溶剂。总之,对该量加以选择以使得使用1-40重量%的含水抗氧化剂加溶物,基于所述含水分散体的重量。
根据本发明的另一实施方案,将所述微水溶性抗氧化剂以细碎含水分散体形式引入聚合物包衣组合物的含水分散体中。就此而言,“分散体”为用于指代可为固/液(悬浮液)或液/液(乳液)的两相体系的术语。此时,所述抗氧化剂的平均粒度(d4,3)应小于20μm,优选小于10μm,特别优选小于3μm。
因此,可将所述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添加至水中,并使用高剪切分散工具借助乳化剂分散。此处,特别优选将所述制剂加热至高于抗氧化剂熔点的温度,由此形成乳液。可在搅拌下,将该热乳液直接添加至聚合物分散体中。或者,也可将其事先冷却,由此形成细碎的悬浮液。特别优选将热乳液添加至聚合物分散体中,其同样具有高于抗氧化剂熔点的温度。
合适的乳化剂原则上为HLB值>10的所有类别的界面活性物质(关于亲水-疏水平衡值,参见Fiedler,EncyclopediaofExcipients,EditioCantorVerlag,第6版,2007,第112-119页)。合适的乳化剂原则上为具有相应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。合适的有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(Macrogol15羟基硬脂酸酯)或乙氧基化氢化蓖麻油,如RH40(用40个氧化乙烯单元乙氧基化)或相应的等级。
其他合适的乳化剂为泊洛沙姆(聚氧化乙烯-聚氧化丙烯嵌段共聚物)。
所述含水抗氧化剂/乳化剂分散体包含1-50重量%,优选2-30重量%的抗氧化剂和0.1-30重量%,优选0.5-10重量%的乳化剂。总之,对该量加以选择以使得使用1-40重量%的含水抗氧化剂/乳化剂分散剂,基于所述含水聚合物分散体的重量。
根据本发明的一个优选实施方案,所述抗氧化剂以所谓的“固溶体”形式使用。术语“固溶体”是本领域技术人员所已知的,其是指将一种固体在另一种固体中的分子分散分布。在本发明的情况下,所述抗氧化剂可作为固溶体引入合适的固体加溶剂或聚合物保护性胶体中。然后,可将所得固溶体以固体形式直接引入所述含水包衣组合物分散体中,或者事先转化成胶束水溶液或胶态溶液,然后将其引入所述含水包衣组合物分散体中。所述固溶体例如可通过将抗氧化剂与加溶剂或保护性胶体一起溶于合适的溶剂中,然后蒸发溶剂而制备。
根据一个特别优选的实施方案,所述固溶体通过熔融挤出而制备,其中将抗氧化剂和加溶剂或聚合物保护性胶体一起熔融,然后挤出、模塑并固化。挤出后获得的粒状固体熔融挤出物可特别有利地引入所述聚合物包衣组合物的含水分散体中。此处,用于固溶体的合适基体聚合物和保护性胶体为已述的两亲性共聚物,特别是,或泊洛沙姆如F86,以及非两亲性聚合物如聚乙烯基吡咯烷酮、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的纤维素。
包衣组合物可例如通过将根据本发明获得的聚合物粉末再分散以获得含水聚合物分散体而充分混合,其中优选向所述分散体中添加至少一种其他助剂。
根据一个优选实施方案,在喷雾方法之中或之后,向所得聚合物粉末中添加二氧化硅。
合适的其他助剂可为:香料、口味改进物质、甜味剂(糖,糖醇,增甜剂如天冬甜素、糖精钠、环氨酸钠)、助流剂、润湿剂、脱模剂、抗粘剂、稳定剂、抗氧化剂、造孔剂、中和剂、光亮剂、染料、颜料、消毒剂或防腐剂、增稠剂、增塑剂等。合适的助剂例如描述于Fiedler,H.P.,LexikonderHilfsstoffefürPharmazie,KosmetikundangrenzendeGebiete[药物、化妆品和相关领域用助剂手册],第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中。
根据本发明的一个实施方案,在再分散于水中以制备所述包衣组合物之前,将所述甲基丙烯酸N,N-二乙基氨基乙酯基聚合物粉末研磨。研磨也可在所述的其他助剂存在下进行。
助剂的常规用量在每种情况下为0-70重量%,优选为0-60重量%,特别为1-50重量%,基于所述包衣组合物的固体总重量。
然而,由本发明粉末获得的包衣组合物也可以以粉末形式施加至药物剂型上。所述施加也可以以含水形式通过造粒、倾倒、铺展或借助喷雾施加而进行。
优选地,以通过再分散获得的含水聚合物分散体形式施加。原则上,任何分散装置都适于再分散。就此而言,再分散优选在施加低剪切力下,优选借助叶片、螺旋桨、桨式搅拌器或相当的搅拌工具进行。由此本发明的聚合物粉末自发且快速溶解。所述聚合物粉末在水中的再分散通常在10分钟内结束。
可向这些再分散的制剂中添加包衣应用所需的其他组分。该类其他组分尤其为增塑剂,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、柠檬酸乙酰基三乙酯。
令人惊讶地,所述细碎的分散体也经受非常高的剪切力,例如在转子-定子装置(也称为Ultra-turrax或胶体磨)中。通过所述装置的转速控制引入转子-定子装置中的高剪切力。优选地,借助<5000rpm的分散装置进行再分散。如果必须在分散体中额外引入其他粗颗粒的添加剂或团聚的添加剂从而必须进行特定粉碎时,该方法是特别有利的。因此,省去了这些添加剂在水中的单独粉碎并随后添加至再分散的聚合物粉末中。
在一个具体实施方案中,将本发明的再分散性聚合物粉末与上文所述的其他常规包衣成分和/或添加剂混合,从而制备包含包衣所需的所有成分的所谓即用型制剂。这些以粉末或颗粒形式存在。用户仅需将其搅入水中就可制备即喷型悬浮液。这些即用型制剂通过干混、研磨、压制或使用造粒液体将所述成分造粒,随后进行干燥步骤而制备。特别地,可以以此方式引入有助于再分散的酸或酸式盐。
除非另有说明,本发明上下文中的与微米尺度的粉末平均粒度有关的所有数据均为借助光散射测得的粒径的体积平均值(d4,3值)。
本发明包衣组合物可额外包含至少一种其他聚合物组分。就此而言,可使用至少两种分散体的混合物、至少一种分散体与至少一种溶液的混合物、至少一种分散体与至少一种粉末的混合物、至少两种粉末的混合物等。
本发明包衣组合物原则上适于可优选以分离或保护形式给药的任何所需药物活性成分的剂型,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、高血压药、精神活性药物、镇定剂、止吐药、肌肉松弛药、糖皮质激素、用于治疗溃疡性结肠炎或克罗恩氏病的药物、抗过敏药、抗生素、抗癫痫药、抗凝血药、抗霉菌剂、镇咳药、动脉硬化药、利尿药、酶、酶抑制剂、痛风药、激素及其抑制剂、强心苷、免疫治疗药和细胞因子、轻泻剂、降血脂药(antilipanicagent)、胃肠道治疗剂、抗偏头痛药(antimigraneagent)、矿物质制剂、耳科用药、治疗帕金森病的药物、甲状腺治疗用药、解痉药、血小板聚集抑制剂、维生素、细胞抑制剂和代谢抑制剂、植物药物、化学治疗药、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、非类固醇抗风湿药、强心苷、乙酰水杨酸、病毒抑制剂、阿柔比星、阿昔洛韦、顺铂、放射菌素、α-和β-拟交感神经药、别嘌呤醇、阿洛司琼、前列地尔、前列腺素、金刚烷胺、氨溴索、氨氯地平、甲氨蝶呤、5-氨基水杨酸、阿米替林、氨氯地平、阿莫西林、阿那曲唑、阿替洛尔、阿托伐他汀、硫唑嘌呤、巴柳氮、倍氯米松、倍他司汀、苯扎贝特、比卡鲁胺、地西泮和地西泮衍生物、布地奈德、丁苯羟酸、丁丙诺啡、美沙酮、钙盐、钾盐、镁盐、坎地沙坦、卡马西平、卡托普利、头孢菌素、塞来昔布、西替利嗪、鹅去氧胆酸、熊去氧胆酸、茶碱和茶碱衍生物、胰岛素、西咪替丁、克拉霉素、克拉维酸、克林霉素、氯丁替诺、可乐定、复方新诺明、可待因、咖啡因、维生素D和维生素D的衍生物、考来烯胺、色甘酸、香豆素和香豆素衍生物、半胱氨酸、阿糖胞苷、环磷酰胺、环孢菌素、环丙孕酮、阿糖胞苷、达哌唑、去氧孕烯、地奈德、双肼屈嗪、地尔硫卓、麦角生物碱、茶苯海明、二甲亚砜、二甲硅油、双嘧达莫、多潘立酮和多潘立酮衍生物、多奈哌齐、多巴胺、多沙唑嗪、多柔比星、多西拉敏、达哌唑、苯二氮杂双氯芬酸、苷抗生素、地昔帕明、益康唑、ACE抑制剂、依那普利、麻黄碱、肾上腺素、重组人肾红细胞生成素和重组人肾红细胞生成素衍生物、吗啡烷、钙拮抗剂、伊立替康、莫达非尼、奥利司他、肽抗生素、苯妥英、利芦噻唑、利塞膦酸盐、西地那非、托吡酯、大环内酯抗生素、埃索美拉唑、雌激素和雌激素衍生物、促孕素和促孕素衍生物、睾酮和睾酮衍生物、雄激素和雄激素衍生物、乙水杨胺、依托芬那酯、依托贝特、非诺贝特、乙羟茶碱、依托泊苷、泛昔洛韦、法莫替丁、非洛地平、非诺贝特、芬太尼、芬替康唑、促旋酶抑制剂、氟康唑、氟达拉滨、氟桂利嗪、氟尿嘧啶、氟西汀、氟比洛芬、布洛芬、氟他胺、氟伐他汀、促滤泡素、福莫特罗、磷霉素、呋塞米、夫西地酸、加兰他敏、戈洛帕米、更昔洛韦、吉非贝齐、庆大霉素、银杏、圣约翰草、优降糖、作为口服降血糖药的脲衍生物、胰高血糖素、葡糖胺和葡糖胺衍生物、谷胱苷肽、甘油和甘油衍生物、下丘脑激素、戈舍瑞林、胍乙啶、卤泛群、氟哌啶醇、肝素和肝素衍生物、透明质酸、肼苯哒嗪、氢氯噻嗪和氢氯噻嗪衍生物、水杨酸盐、羟嗪、伊达比星、异环磷酰胺、丙咪嗪、吲哚美辛、吲哚拉明、胰岛素、干扰素、碘和碘衍生物、异康唑、异丙肾上腺素、葡糖醇和葡糖醇衍生物、伊曲康唑、酮康唑、酮洛芬、酮替芬、拉西地平、兰索拉唑、左旋多巴、左美沙酮、甲状腺激素、硫辛酸和硫辛酸衍生物、赖诺普利、利舒脲、洛非帕明、洛莫司汀、洛哌丁胺、氯雷他定、马普替林、甲苯达唑、美贝维林、美克洛嗪、甲芬那酸、甲氟喹、美洛昔康、甲吲洛尔、甲丙氨酯、美罗培南、美沙拉嗪、甲琥胺、安乃近、二甲双胍、甲氨蝶呤、哌甲酯、甲泼尼龙、美噻吨、甲氧氯普胺、美托洛尔、甲硝唑、米安色林、咪康唑、米诺环素、米诺地尔、米索前列醇、丝裂霉素、咪唑斯汀、莫昔普利、吗啡和吗啡衍生物、月见草、纳布啡、纳洛酮、替利定、萘普生、那可汀、纳他霉素、新斯的明、尼麦角林、尼可刹米、硝苯地平、尼氟灭酸、尼莫地平、尼莫唑、尼莫司汀、尼索地平、肾上腺素和肾上腺素衍生物、诺氟沙星、novaminesulfone、那可丁、制霉菌素、氧氟沙星、奥氮平、奥沙拉嗪、奥美拉唑、奥莫康唑、昂丹司琼、奥利司他、奥司他韦、奥沙西罗、苯唑西林、奥昔康唑、羟甲唑啉、泮托拉唑、扑热息痛、帕罗西汀、喷昔洛韦、口服青霉素、喷他佐辛、喷替茶碱、己酮可可碱、奋乃静、杜冷丁、植物提取物、安替比林、非尼拉敏、巴比妥酸衍生物、保泰松、苯妥英、匹莫齐特、吲哚洛尔、哌嗪、吡拉西坦、哌仑西平、吡贝地尔、吡罗昔康、普拉克索、普伐他汀、哌唑嗪、普鲁卡因、丙嗪、丙哌维林、普萘洛尔、异丙安替比林、前列腺素、丙硫异烟胺、丙羟茶碱、喹硫平、喹那普利、喹普利拉、雷米普利、雷尼替丁、瑞普特罗、利血平、利巴韦林、利福平、利培酮、利托纳韦、罗匹尼罗、罗格列酮、罗沙替丁、罗红霉素、鲁斯可皂苷元、芦丁和芦丁衍生物、沙巴达、舒喘灵、沙美特罗、东莨菪碱、司立吉林、舍他康唑、舍吲哚、舍曲林、硅酸盐、辛伐他汀、谷甾醇、索他洛尔、司谷氨酸、司帕沙星、大观霉素、螺旋霉素、螺普利、螺内酯、司他夫定、链霉素、硫糖铝、舒芬太尼、舒巴坦、磺胺药、柳氮磺吡啶、舒必利、舒他西林、舒噻美、舒马普坦、氯化琥珀胆碱、他克林、他克莫司、他林洛尔、他莫昔芬、牛磺罗定、他扎罗汀、替加色罗、替马西泮、替尼泊苷、替诺昔康、特拉唑嗪、特比萘芬、特布他林、特非那定、特利加压素、特他洛尔、四环素、四氢唑林、可可碱、茶碱、butizine、甲硫咪唑、吩噻嗪、塞替派、噻加宾、泰必利、丙酸衍生物、噻氯匹定、噻吗洛尔、替硝唑、噻康唑、硫鸟嘌呤、噻克索酮、替罗拉胺、替扎尼定、妥拉唑啉、甲苯磺丁脲、托卡朋、托萘酯、托哌酮、托泊替坎、托拉塞米、抗雌激素、曲马多、曲马唑啉、群多普利、反苯环丙胺、曲匹地尔、曲唑酮、曲安西龙和曲安西龙衍生物、氨苯蝶啶、三氟哌多、曲氟尿苷、甲氧苄啶、曲米帕明、曲吡那敏、曲普利啶、曲磷胺、曲金刚胺、氨基丁三醇、曲帕替平、曲克芦丁、妥洛特罗、酪胺、短杆菌素、乌拉地尔、熊去氧胆酸、鹅去氧胆酸、伐昔洛韦、伐地考昔、丙戊酸、万古霉素、氯化维库铵(vecuroniumchloride)、文拉法辛、维拉帕米、阿糖腺苷、氨己烯酸、维洛沙嗪、长春碱、长春胺、长春新碱、长春地辛、长春瑞滨、长春西丁、维喹地尔、华法林、尼可占替诺、希帕胺、扎鲁司特、扎西他滨、扎那米韦、齐多夫定、佐米曲普坦、唑吡坦、佐匹克隆、佐替平等。
希望的话,活性成分也可以其可药用盐或衍生物形式使用,且在手性活性成分的情况下,可使用光学活性异构体以及外消旋或非对映异构体混合物。希望的话,本发明组合物也可包含两种或更多种药物活性成分。
根据本发明,所述包衣组合物可用于包衣挤出物、小片、胶囊、软胶囊、颗粒剂、丸剂、微丸剂、微胶囊、纳米胶囊或晶体。
为了制备剂型,可将包衣的颗粒剂、丸剂、微丸剂、微胶囊、晶体与合适的助剂混合并压实以获得片剂,所述片剂在口腔的含水环境中崩解并再次释放出所述经包衣的细制品。就此而言,特别重要的是所谓的口腔分散性,即在口腔中在短时间内崩解并释放出遮味小制品。
此外,所述包衣组合物也可有利地用于包衣片剂。
通常可导致令人不愉快的苦味且可有利地根据本发明配制的活性成分类别和物质例如为:
镇痛药和抗风湿药,如扑热息痛、双氯芬酸、醋氯芬酸、布洛芬、酮洛芬、氟比洛芬、乙酰水杨酸、左醋美沙朵和羟可酮;
精神活性药物,如普鲁米嗪、多奈哌齐、莫达非尼、奈法唑酮、瑞波西汀、舍吲哚和舍曲林;
抗生素,如红霉素、罗红霉素、克拉霉素、格帕沙星、环丙沙星、左氧氟沙星、司帕沙星、曲伐沙星和奈韦拉平;
β阻断剂,如普萘洛尔、美托洛尔、比索洛尔和奈必洛尔;
抗糖尿病药,如二甲双胍、米格列醇和瑞格列奈;
H1抗组胺药,如苯海拉明、非索非那定和咪唑斯汀;
H2抗组胺药,如西咪替丁、法莫替丁、罗沙替丁、尼扎替丁、噻氯匹定、西替利嗪和雷尼替丁;
维生素,如硝酸硫胺和硫酸奎尼丁、盐酸氨普立糖、盐酸伪麻黄碱、西地那非、托吡酯、格拉司琼、瑞巴派特、盐酸奎宁等;
也可相应配制这些活性成分的各种盐。
该优异的味道遮盖由本发明聚合物在高于6的pH值下的不溶性和在低于6的pH值下的快速溶解性所导致。即,在唾液(pH:7.2)中,相应的包衣剂型是长时间稳定的,且苦味药物不与口腔粘膜接触,但在pH值为1-5的胃中,活性成分快速释放。此时,溶解如此之快以至于与未包衣的剂型相比在作用开始方面没有区别。通常,本发明聚合物的薄膜包衣在胃液中在5分钟内溶解,而在pH7.2的磷酸盐缓冲液中,其在2小时内是稳定的。令人惊讶地,所述薄膜包衣在pH值为4.5的介质中也较快地溶解,这意味着由其制备的给药剂型即使在酸缺乏病人或用抗酸药治疗的病人中也导致快速作用。所述包衣组合物的这些优异施加性能在转化成粉末且将所述粉末再分散或熔融之后也得以保持。
令人惊讶地,借助本发明方法,微水溶性抗氧化剂引入聚合物分散体中以使得所述抗氧化剂迁移进聚合物颗粒中,且不再以颗粒形式存在于水相中的方式进行。仅仅由于该原因,可获得对所述聚合物的抗氧化效果和相应的保护作用。
此外,令人惊讶地,借助本发明方法,可将含水聚合物分散体转化成自由流动的粉末,而不在喷雾装置中导致较大的团聚和沉积物。考虑到现有技术关于干燥气体的干燥方法和温度控制的建议,这是本领域技术人员无法预料得到的。还令人惊讶的是高剪切力是有利的,因为本领域技术人员通常预期所述分散体会在剪切力下团聚。
因此,本发明方法导致具有良好粒度分布和良好施加性能,例如流动性的聚合物粉末。当用于制备包衣组合物时,所述粉末可非常有利地再分散以获得细碎分散体。
实施例
所用的缩写:
玻璃化转变温度:Tg
所有以%表示的数据均涉及重量%。
本发明聚合物的制备类似于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60:40,K值50,Tg62℃
聚合物B: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℃
聚合物C:甲基丙烯酸甲酯/甲基丙烯酸二乙基氨基乙酯,重量比53:47,K值52,Tg55℃
K值在NMP中的0.1重量%浓度下测定。所述聚合物以pH值为9+/-0.3的30重量%浓度的含水分散体形式使用。初级分散体的平均粒度为128、127和131nm。玻璃化转变温度借助DSC以20°K/分钟的加热速率测定。最低成膜温度对应于Tg,测量精度+/-5℃。
当测定所述粉末的平均粒度时,(d4,3值)借助光散射使用MalvernMastersizer2000测定。
当借助光散射测定再分散粉末的平均粒度时,使用“MalvernZetasizernano-s”以强度平均值测定该值。
实施例1
将3.0g丁基羟基甲苯溶于50g乙醇中,并在搅拌下引入1000ml固含量为30%的聚合物B的含水分散体中。然后,在搅拌下混入72.9ml的1M盐酸。这对应于10mol%的中和度。在搅拌0.5小时后,将该部分中和的分散体在FSD喷雾塔中喷雾干燥,经由1.2mm双物料喷嘴在2.5巴的喷雾压力下雾化。进入空气温度为115℃,且离开空气温度为58℃。在喷雾干燥期间分离出细级分,并在喷嘴前再次吹,从而获得平均粒度为170μm的喷雾干燥的颗粒。
通过使用桨式搅拌器搅拌15分钟,将所述喷雾干燥的产物再分散于水中以获得固含量为20%的喷雾悬浮液。借助光散射测定粒度获得135nm的值。
实施例2
将6.0g生育酚溶于20.0gCremophorRH40中,然后用80.0g水稀释该混合物。在搅拌下,将该加溶物添加至1000ml固含量为30%的聚合物A的含水分散体中,进一步搅拌1小时,并在喷雾塔中喷雾干燥。此时,经由1.2mm的双物料喷嘴在3.0巴的雾化压力下雾化。干燥气体以切线方式引入喷雾干燥器的进入区域中,并在旋风分离器中分离出干燥产物。进入温度为107℃,且离开空气温度为55℃。所述粉末的平均粒度为32μm。
将100g喷雾干燥的产物引入其中已事先溶解有2.30g琥珀酸的900ml水中。使用桨式搅拌器将所述制剂搅拌20分钟。借助光散射测定粒度获得139nm的值。
实施例3
将4.5g丁基羟基甲苯添加至30.0g水中,加热至80℃,使用Ultra-turrax在10000rpm下微乳化10分钟,然后在搅拌下缓慢添加至1000ml固含量为30%的聚合物A的75℃热的含水分散体中。将该制剂进一步搅拌1小时,并在喷雾塔中喷雾干燥。经由1.2mm的双物料喷嘴以3.0巴的雾化压力雾化。干燥气体切线方式引入喷雾干燥器的进入区域中,并在旋风分离器中分离出干燥产物。进入温度为108℃,且离开空气温度为55℃。所述粉末的平均粒度为34μm。
将150g喷雾干燥的产物引入850ml水中,并使用Ultra-turrax在12000rpm下将该制剂处理20分钟。借助光散射测定粒度获得230nm的值。
实施例4
将100g丁基羟基苯甲醚在挤出机中于140℃下与400gSoluplus加工以获得固溶体。将所得线材降至约2mm的尺寸。将20.0g的该固熔体添加至1000ml固含量为30%的聚合物B的含水分散体中,并将该混合物再搅拌1小时。然后,在搅拌下添加36.5ml的1M盐酸。这对应于5mol%的中和度。将该部分中和的分散体在FSD喷雾塔中喷雾干燥,经由1.2mm双物料喷嘴以3.0巴的雾化压力雾化。进入空气温度为125℃,且离开空气温度为56℃。在喷雾干燥期间分离出细级分,并在喷嘴前再次吹,从而获得平均粒度为180μm的喷雾干燥的颗粒。在喷雾方法期间,向所述塔中吹入其量基于聚合物粉末总质量为0.5%的BET表面积为200m2/g的胶态二氧化硅。
通过使用桨式搅拌器搅拌20分钟而将该喷雾干燥的产物再分散于水中以获得固含量为20%的喷雾悬浮液。借助光散射测定粒度获得140nm的值。实施例5
在搅拌下,将5.0g丁基羟基甲苯和10.0g多库酯钠添加至50.0g水中并加热至50℃。在所述丁基羟基甲苯溶解之后,在搅拌下将该制剂与1000ml固含量为30%的聚合物C的含水分散体混合。在添加1.31g丙二酸(这对应于5mol%的中和度)之后,将该部分中和的分散体与200ml40%浓度的滑石悬浮液混合,并在FSD喷雾塔中喷雾干燥,经由1.2mm双物料喷嘴以3.0巴的雾化压力雾化。进入空气温度为137℃,且离开空气温度为59℃。在喷雾干燥期间分离出细级分,并在喷嘴前再次吹,从而获得平均粒度为185μm的喷雾干燥的颗粒。
通过使用桨式搅拌器搅拌15分钟而将该喷雾干燥的产物再分散于水中以获得固含量为20%的喷雾悬浮液。借助光散射测定粒度获得145nm的值。实施例6
将100g实施例3中制备的聚合物粉末与50g极细研磨的滑石、4g靛蓝色淀和2g琥珀酸在Turbula混合器中混合。
在使用桨式搅拌器将该制剂再分散于水中之后获得15%浓度的悬浮液,获得160nm的聚合物颗粒的粒度。
实施例7
将在实施例6中制备的制剂与13.0g柠檬酸三乙酯混合,搅拌1小时并通过喷雾施加至片剂芯。
喷雾条件:
机器 | 卧式转鼓涂布机 |
进入空气温度 | 54℃ |
喷雾压力 | 0.2MPa |
成型空气压力 | 0.1MPa |
喷嘴 | Schlick930/1mm |
进入空气速率 | 200m3/h |
喷雾速率 | 30g/分钟 |
所得薄膜片剂具有光滑、有光泽的遮味衣层,其即使在低于40℃的逆境储存下也不发生变化。
Claims (39)
1.一种制备粉状、含抗氧化剂的含水聚合物分散体的包衣组合物的方法,其包含作为组分A的通过自由基聚合如下物质而获得的聚合物:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种选自α,β-烯属不饱和单-和二-羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物;
其中所述抗氧化剂以溶液或分散体形式引入所述含水聚合物分散体中,并通过喷雾方法将所述含水聚合物分散体转化成粉末形式。
2.根据权利要求1的方法,其中使用微水溶性抗氧化剂作为抗氧化剂。
3.根据权利要求1的方法,其中所述抗氧化剂以在有机溶剂中的溶液形式或者作为包含加溶剂的胶束水溶液形式引入。
4.根据权利要求2的方法,其中所述抗氧化剂以在有机溶剂中的溶液形式或者作为包含加溶剂的胶束水溶液形式引入。
5.根据权利要求1的方法,其中抗氧化剂的胶束溶液包含表面活性剂或两亲性共聚物作为加溶剂。
6.根据权利要求2的方法,其中抗氧化剂的胶束溶液包含表面活性剂或两亲性共聚物作为加溶剂。
7.根据权利要求3的方法,其中抗氧化剂的胶束溶液包含表面活性剂或两亲性共聚物作为加溶剂。
8.根据权利要求4的方法,其中抗氧化剂的胶束溶液包含表面活性剂或两亲性共聚物作为加溶剂。
9.根据权利要求1-8中任一项的方法,其中所述抗氧化剂以该抗氧化剂在表面活性剂或聚合物中的固溶体形式引入。
10.根据权利要求9的方法,其中所述抗氧化剂在表面活性剂或聚合物中的固溶体通过熔融挤出获得。
11.根据权利要求1-4中任一项的方法,其中所述抗氧化剂以包含亲水-亲油平衡值大于10的乳化剂的分散体形式引入所述含水聚合物分散体中。
12.根据权利要求1-8中任一项的方法,其中所述抗氧化剂以基于组分A为0.1-10.0重量%的量引入。
13.根据权利要求1-8中任一项的方法,其中所述含水聚合物分散体通过在干燥气体存在下的喷雾方法而转化成粉末,其中所述干燥气体进入喷雾装置中的进入温度比所述聚合物的玻璃化转变温度高至少20℃,且比所述聚合物的最低成膜温度高至少20℃,且所述干燥气体离开所述喷雾装置的离开温度保持为40-85℃。
14.根据权利要求1-8中任一项的方法,其中所述干燥气体进入喷雾装置中的进入温度比所述聚合物的玻璃化转变温度高至少40℃,且比所述聚合物的最低成膜温度高至少40℃。
15.根据权利要求1-8中任一项的方法,其中所述干燥气体进入喷雾装置中的进入温度比动态玻璃化转变温度高至少20℃。
16.根据权利要求1-8中任一项的方法,其中所述干燥气体进入喷雾装置中的进入温度比动态玻璃化转变温度高至少40℃。
17.根据权利要求1-8中任一项的方法,其中所述干燥气体离开喷雾装置的离开温度保持为45-70℃。
18.根据权利要求1-8中任一项的方法,其中所述干燥气体进入喷雾装置中的进入温度为100-140℃,且所述干燥气体离开所述喷雾装置的离开温度保持为45-70℃。
19.根据权利要求1-8中任一项的方法,其中所述干燥气体进入喷雾装置中的进入温度保持为110-130℃,且所述干燥气体离开所述喷雾装置的离开温度保持为50-60℃。
20.根据权利要求1-8中任一项的方法,其中所述干燥气体离开喷雾装置的离开温度保持为最低成膜温度+/-5℃。
21.根据权利要求1-8中任一项的方法,其中所述喷雾方法以喷雾干燥方式实施。
22.根据权利要求1-8中任一项的方法,其中所述喷雾方法以团聚喷雾干燥方式实施。
23.根据权利要求1-8中任一项的方法,其中在喷雾方法之前向所述含水聚合物分散体中添加酸或酸式盐。
24.根据权利要求1-8中任一项的方法,其中在喷雾方法之后向所得粉末中添加酸或酸式盐。
25.根据权利要求1-8中任一项的方法,其中在喷雾方法之后将所得聚合物再分散于水中并与酸或酸式盐混合。
26.根据权利要求1-8中任一项的方法,其中作为酸添加无机酸或其酸式盐。
27.根据权利要求1-8中任一项的方法,其中作为酸添加有机酸或其酸式盐。
28.根据权利要求1-8中任一项的方法,其中所添加的酸为在所述喷雾方法条件下分解或蒸发的酸或其酸式盐。
29.根据权利要求1-8中任一项的方法,其中由于添加所述酸或酸式盐,所述粉末或再水分散的粉末的含水分散体的pH值为5-9。
30.根据权利要求1-8中任一项的方法,其中由于添加所述酸或酸式盐,所述粉末或再水分散的粉末的含水分散体的pH值为6-8。
31.根据权利要求1-8中任一项的方法,其中在所述喷雾方法之前向所述含水聚合物分散体中添加其他助剂。
32.根据权利要求1-8中任一项的方法,其中将所述抗氧化剂以包含亲水-亲油平衡值大于10的乳化剂的乳液形式在高于该抗氧化剂熔点的温度下引入所述含水聚合物分散体中。
33.根据权利要求1-32中任一项的方法获得的聚合物粉末作为药物剂型的包衣组合物的用途。
34.根据权利要求33的用途,其中所述包衣组合物以再分散的含水分散体形式施加至所述剂型。
35.根据权利要求34的用途,其中所述再分散借助转速为<5000rpm的分散装置进行。
36.根据权利要求33或34的用途,其中所述再分散借助转速低于1000rpm的分散装置进行。
37.一种根据权利要求1-32中任一项的方法获得的聚合物粉末,其由聚合物分散体和抗氧化剂构成,所述聚合物分散体包含通过自由基聚合如下物质而获得的聚合物作为组分A:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的可自由基聚合的化合物,
其中再分散于水中的聚合物粉末的平均粒度为初级母分散体粒度的至多5倍。
38.根据权利要求37的聚合物粉末,其中再分散于水中的聚合物粉末的平均粒度为初级母分散体粒度的至多3倍。
39.根据权利要求37的聚合物粉末,其中再分散于水中的聚合物粉末的平均粒度为初级母分散体粒度的至多2倍。
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JP5623524B2 (ja) * | 2009-07-30 | 2014-11-12 | エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツングEvonik RoehmGmbH | コポリマー、脂肪モノカルボン酸の塩および脂肪モノカルボン酸および/または脂肪アルコールを含む粉末状または粒状組成物 |
WO2011051155A2 (en) * | 2009-10-28 | 2011-05-05 | Basf Se | Stable protective coatings for pharmaceutical dosage forms |
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CN1386776A (zh) * | 2001-05-17 | 2002-12-25 | 三菱丽阳株式会社 | 聚合物粒子的制造方法 |
CN101400705A (zh) * | 2006-03-16 | 2009-04-01 | 巴斯夫欧洲公司 | 包含效应物质的聚合物分散体及其用途 |
CN101778870A (zh) * | 2007-08-02 | 2010-07-14 | 巴斯夫欧洲公司 | 基于甲基丙烯酸n,n-二乙基氨基乙酯的聚合物水分散体,其制备及用途 |
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EP2681263A1 (de) | 2014-01-08 |
CN103347931A (zh) | 2013-10-09 |
BR112013020877B1 (pt) | 2020-06-02 |
BR112013020877A2 (pt) | 2016-09-27 |
JP2014508205A (ja) | 2014-04-03 |
WO2012116940A1 (de) | 2012-09-07 |
JP6027550B2 (ja) | 2016-11-16 |
EP2681263B1 (de) | 2018-09-12 |
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