CN101778870A - 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 - Google Patents
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 Download PDFInfo
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- CN101778870A CN101778870A CN200880101625A CN200880101625A CN101778870A CN 101778870 A CN101778870 A CN 101778870A CN 200880101625 A CN200880101625 A CN 200880101625A CN 200880101625 A CN200880101625 A CN 200880101625A CN 101778870 A CN101778870 A CN 101778870A
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Abstract
本发明涉及一种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制备聚合物水分散体的方法,可通过该方法获得的聚合物分散体及其用途。
Description
本发明涉及一种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制备聚合物水分散体的方法,可通过该方法获得的聚合物分散体及其用途。
DE 1090381描述了一种用胃中可溶的包衣组合物对药物剂型包衣的方法。这些包含20-80%至少一种(甲基)丙烯酸氨基酯和80-20%形成作为均聚物的水不溶性聚合物的单体的共聚物。就合适的可聚合氨基酯所提及的具体实例是丙烯酸和(甲基)丙烯酸与N,N-二甲基氨基乙醇、N,N-二乙基氨基乙醇、N,N-二甲基氨基丙醇和N-(羟基乙基)吗啉的酯。提及的合适共聚单体是丙烯酸,优选(甲基)丙烯酸的低级酯如丙烯酸乙酯、(甲基)丙烯酸甲酯、(甲基)丙烯酸丁酯和(甲基)丙烯酸己酯。制备通过在合适溶剂中的溶液聚合进行;没有描述示例性实施方案。
DE 1219175描述了一种制备保护其免受反刍动物的瘤胃液影响的兽药活性成分制剂的方法。为此,用包含作为共聚单元的N,N-二烷基氨基烷基(甲基)丙烯酰胺和选自(甲基)丙烯酸酯、丙烯腈和乙烯基芳族化合物的共聚单体的共聚物对这些制剂包衣。根据该文献认为基于(甲基)丙烯酸N,N-二烷基氨基烷基酯的共聚物是不利的,因为酯基相比于酰胺基团在碱性介质中易于水解。
DE 2135073描述了包含聚合物水分散体的药物剂型用包衣组合物,其中聚合物由10-55重量%含羧基的单体和/或单烷基-或二烷基氨基烷基酯基团组成。除了许多其它单体外,甲基丙烯酸二乙基氨基乙酯(DEAEMA)也提及作为合适的单体。所提及的合适共聚单体为(甲基)丙烯酸的低级酯(优选甲基丙烯酸甲酯)、(甲基)丙烯腈、乙烯基芳族化合物、氯乙烯和乙酸乙烯酯。制备通过含水乳液聚合,优选通过乳液进料工艺进行。没有公开基于DEAEMA的特定乳液聚合物。
DE 2512238教导了使用通过喷雾干燥用于制备这些药物剂型用包衣溶液的聚合物分散体获得的粉末来提供具有低残余单体含量的药物包衣用粘合剂。关于用于喷雾干燥的分散体,参考DE 1090381、DE 1219175和DE 2135073。
DE 2838278描述了反刍动物的口服剂型用包衣,其由以下组分组成:
a)至少一种具有至少一个碱性氨基和3-14%氮含量的成膜聚合物,其在24小时内溶于pH超过5.5的瘤胃含水介质中,和
b)至少一种在聚合物中分散且选自C12-C32脂肪酸、这些脂肪酸的Al盐和/或聚羧酸的疏水性物质。
包衣通过使用有机溶剂中的溶液而制备。所提及的合适聚合物为许多含氮均聚物和共聚物,没有提及制备它们的合适方法。在该文献中,在示例性实施方案29中提及了40%甲基丙烯酸N,N-二乙基氨基乙酯的共聚物,但没有描述其制备方法。
GB 1324087描述了反刍动物的口服剂型用包衣聚合物,其包含作为共聚单元的以下组分:
a)至少一种(甲基)丙烯酸N,N-二烷基氨基烷基酯,和
b)至少一种选自乙烯基芳族化合物及其衍生物、乙烯基酯、(甲基)丙烯酸酯和丙烯腈的烯属不饱和化合物。
作为合适单体a)公开了甲基丙烯酸N,N-二甲基氨基乙酯(DMAEMA)和甲基丙烯酸叔丁基氨基乙酯(TBAEMA)。认为甲基丙烯酸甲酯尤其不适合作为共聚单体b),因为它易于形成太脆的包衣。描述的合适聚合工艺是本体、悬浮、溶液和乳液聚合。示例性实施方案的共聚物通过溶液聚合制备。
DE 3426587 A1描述了一种通过施加包含带有溶解的叔铵盐侧基的聚合物的液体成膜包衣剂对药物剂型包衣的方法。这些聚合物溶液尤其可通过用含水无机或有机酸将基于(甲基)丙烯酸N,N-二烷基氨基烷基酯的共聚物转化成铵盐水溶液而制备。
DE 3049179 A1为DE 2512238的分案申请并涉及根据后一文献的教导通过喷雾干燥获得的呈额外包含增塑剂的含水悬浮液形式的粉末在通过热胶凝化生产包衣中的用途。
EP 0058765 A2描述了可溶于或可溶胀于胃液的药物剂型用包衣组合物,其包含作为粘合剂的基于(甲基)丙烯酸N,N-二烷基氨基烷基酯的乳液聚合物,其中在直链中分布有至少三个碳原子的支化亚烷基或亚芳基位于氨基和(甲基)丙烯酸酯基团之间。
WO 2005/055986和WO 2005/056619描述了具有pH依赖的溶胀/溶解行为的聚合物及其在药物剂型中的用途。
WO 00/05307涉及提供包含(甲基)丙烯酸酯共聚物的药物剂型用包衣剂和粘合剂,所述(甲基)丙烯酸酯共聚物包含带有叔氨基的单体残余,其目的是可以简单干燥或可以进一步含水加工。为此,该文献教导了一种以下方法:其中将(a)(甲基)丙烯酸的C1-C4酯和包含叔铵基的(甲基)丙烯酸酯单体的共聚物、(b)增塑剂和(c)HLB至少为14的乳化剂一起混合并通过熔融、流延、铺展或喷雾而制备包衣剂或粘合剂,其中共聚物(a)以平均粒度为1-40μm的粉末形式引入。由此获得的加工性能归因于提供了呈粉末形式的粒度极小的共聚物(a)。
WO 02/067906涉及包衣剂和粘合剂,其相比于WO 00/05307中描述的那些具有改进的水蒸气渗透性。此时,所述包衣剂和粘合剂用包含(a)(甲基)丙烯酸的C1-C4酯和具有叔铵官能团的其它(甲基)丙烯酸酯单体的呈粉末形式的平均粒度为1-40μm的共聚物、(b)HLB至少为14的乳化剂和(c)C12-C18单羧酸或C12-C18羟基化合物的混合物制备。
WO 2004/019918描述了包衣剂和粘合剂,就其组成而言与WO 00/05307和WO 02/067906中描述的那些相对应。
本发明基于的目的是提供适合作为药物剂型用包衣剂且可以尽可能容易地制备和/或配制的聚合物及其制备方法。就此而言其目的在于所述聚合物具有尽可能多地符合以下条件的性能范围:基于这些聚合物膜的药物剂型用包衣应具有pH依赖的溶解性,其特征在于对水蒸气的良好阻隔性能,和/或适合于遮盖具有不愉悦味道的活性成分;制备应尽可能容易;应尽可能避免在配制过程中进行干燥和/或其它加工步骤。
现已惊人地发现包含作为共聚单元的甲基丙烯酸N,N-二乙基氨基乙酯(DEAEMA)的聚合物分散体的特征在于非常好的性能特征。基于该单体的分散体还尤其可以初级分散体的形式加工成聚合物膜,特别用于药物剂型。就此而言还惊人地是可以将极低粘度的初级分散体加工成聚合物膜。
因此,本发明的第一方面为一种通过在pH至少为8下在含水介质中自由基乳液聚合包含以下组分的单体混合物M)而制备聚合物水分散体Pd)的方法:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种能够自由基聚合的选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的化合物。
本发明的另一方面为可通过该方法获得的聚合物水分散体Pd)。
本发明的又一方面为包含该聚合物水分散体Pd)或可通过干燥由其获得的聚合物组合物的包衣组合物。
本发明的再一方面为包含以下组分的药物组合物:
A)可通过该聚合物分散体的干燥和/或成膜获得的聚合物组合物,
B)至少一种可药用活性成分,和
C)合适的话至少一种可药用赋形剂。
具体实施方案为呈包含基于该聚合物水分散体Pd)或可通过干燥由其获得的聚合物组合物的包衣的口服剂型形式的药物组合物。
乳液聚合根据本发明在pH至少为8下在含水介质中进行。这意味着聚合混合物的pH在单体加入过程中不会降至pH8以下。在单体加入之后,例如在任何后聚合过程中,含水介质的pH也可以为低于8的值,但不低于7.5。在聚合物分散体Pd)制备过程中含水介质的pH以及所得聚合物分散体Pd)的pH优选至少为8。含水介质的pH优选为8-10,更优选8.5-9.5。有利的是在聚合过程中将pH维持在上述范围内。pH可通过在聚合混合物中加入pH-调节物质如碱、酸或缓冲剂来调节。然而,对于特定应用领域,可能无需加入pH-调节物质。因此,盐或成盐组分的使用例如可导致由分散体产生的对本文所包括的活性成分而言具有不希望的高渗透性的膜。这还适用于其它盐或成盐组分如阴离子乳化剂、长链脂肪酸等。在许多情况下,也无需加入pH-调节物质,因为本发明所用单体a)(合适的话与其它阳离子单体c)结合)及合适的话带有离子基团的乳化剂导致所需范围内的pH。
适合于在聚合过程中或随后调节pH的原则上为所有无机或有机碱和酸,尤其是可溶于水的那些。合适碱的实例为碱金属和碱土金属氢氧化物,氨和伯胺,仲胺和叔胺如三乙胺,和氨基醇如三乙醇胺、甲基二乙醇胺、二甲基乙醇胺或2-氨基-2-甲基丙醇。合适酸的实例为羧酸如乳酸、乙酸、柠檬酸或酒石酸,或无机酸如磷酸、焦磷酸、硫酸或盐酸。聚合混合物的pH可在聚合之前或期间通过合适的测量装置,例如通过复合电极确定。
所用聚合介质优选仅为水。
就本发明而言,术语烷基包括直链和支化烷基。合适的短链烷基的实例为直链或支化C1-C8烷基,优选C1-C6烷基,特别优选C1-C4烷基。这些尤其包括甲基、乙基、丙基、异丙基、正丁基、2-丁基、仲丁基、叔丁基、正戊基、2-戊基、2-甲基丁基、3-甲基丁基、1,2-二甲基丙基、1,1-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、正己基、2-己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基丁基、2-乙基丁基、1-乙基-2-甲基丙基、正庚基、2-庚基、3-庚基、2-乙基戊基、1-丙基丁基、正辛基、2-辛基、3-辛基、2-乙基己基、1-丙基戊基等。
合适的长链C9-C30烷基或C9-C30链烯基为直链和支化烷基或链烯基。就此而言主要优选还存在于天然或合成脂肪酸和脂肪醇及羰基合成醇中的线性烷基,其合适的话可额外为单-、双-或多不饱和的。这些例如包括正壬基、正壬烯基、正癸基、正癸烯基、正十一烷基、正十一碳烯基、正十二烷基、正十二碳烯基、正十三烷基、正十三碳烯基、正十四烷基、正十四碳烯基、正十五烷基、正十五碳烯基、正十六烷基、正十六碳烯基、正十七烷基、正十七碳烯基、正十八烷基、正十八碳烯基、正十九烷基、正十九碳烯基等。
环烷基优选为C5-C8环烷基如环戊基、环己基、环庚基或环辛基。
在某些情况下,可由丙烯酸和甲基丙烯酸衍生的化合物在下文指通过将字节“(甲基)”插入由丙烯酸衍生的化合物中而呈部分缩写形式。
单体a)
根据本发明,甲基丙烯酸N,N-二乙基氨基乙酯用作单体a)。
本发明聚合物水分散体Pd)通过使用基于聚合用单体的总重量为优选25-65重量%,特别优选30-60重量%,特别是38-48重量%,尤其是43-47重量%的组分a)而制备。
单体b)
组分b)选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯。
合适的化合物b)为(甲基)丙烯酸甲酯、乙基丙烯酸甲酯、(甲基)丙烯酸乙酯、乙基丙烯酸乙酯、(甲基)丙烯酸正丙酯、(甲基)丙烯酸异丙酯、(甲基)丙烯酸正丁酯、(甲基)丙烯酸仲丁酯、(甲基)丙烯酸叔丁酯、乙基丙烯酸叔丁酯、(甲基)丙烯酸正己酯、(甲基)丙烯酸正庚酯、(甲基)丙烯酸正辛酯、(甲基)丙烯酸1,1,3,3-四甲基丁酯和(甲基)丙烯酸乙基己酯。
特别优选使用甲基丙烯酸甲酯或包含甲基丙烯酸甲酯的单体混合物作为组分b)。
本发明聚合物水分散体Pd)通过使用基于聚合用单体的总重量为优选35-75重量%,特别优选40-70重量%,特别是52-62重量%,尤其是53-57重量%的组分b)而制备。
单体c)
用于制备聚合物分散体Pd)的单体混合物M)可额外包含至少一种其它单体c)。额外单体c)优选选自α,β-烯属不饱和单-和二羧酸与C9-C30链烷醇和C2-C30链烷二醇的酯、α,β-烯属不饱和单-和二羧酸与带有伯氨基或仲氨基的C2-C30氨基醇的酰胺、α,β-烯属不饱和单羧酸的伯酰胺及其N烷基和N,N-二烷基衍生物、N-乙烯基内酰胺、开链N-乙烯基酰胺化合物、乙烯基醇和烯丙基醇与C1-C30单羧酸的酯、乙烯基醚、乙烯基芳族化合物、乙烯基卤、偏二卤乙烯、C2-C8单烯烃、不饱和腈、具有至少两个共轭双键的非芳族烃及其混合物。
合适的额外单体c)为α,β-烯属不饱和单-和二羧酸与C9-C30链烷醇的酯,例如(甲基)丙烯酸正壬酯、(甲基)丙烯酸正癸酯、(甲基)丙烯酸正十一烷基酯、(甲基)丙烯酸十三烷基酯、(甲基)丙烯酸肉豆蔻酯、(甲基)丙烯酸十五烷基酯、(甲基)丙烯酸棕榈酯、(甲基)丙烯酸十七烷基酯、(甲基)丙烯酸十九烷基酯、(甲基)丙烯酸二十烷基酯、(甲基)丙烯酸山萮酯、(甲基)丙烯酸二十四烷基酯、(甲基)丙烯酸二十六烷基酯、(甲基)丙烯酸三十烷基酯、(甲基)丙烯酸十六碳烯基酯、(甲基)丙烯酸油基酯、(甲基)丙烯酸亚油基酯、(甲基)丙烯酸亚麻基酯、(甲基)丙烯酸硬脂基酯、(甲基)丙烯酸月桂基酯及其混合物。
其它合适的额外单体c)为α,β-烯属不饱和单-和二羧酸与C2-C30链烷二醇的酯,例如丙烯酸2-羟基乙酯、甲基丙烯酸2-羟基乙酯、乙基丙烯酸2-羟基乙酯、丙烯酸2-羟基丙酯、甲基丙烯酸2-羟基丙酯、丙烯酸3-羟基丙酯、甲基丙烯酸3-羟基丙酯、丙烯酸3-羟基丁酯、甲基丙烯酸3-羟基丁酯、丙烯酸4-羟基丁酯、甲基丙烯酸4-羟基丁酯、丙烯酸6-羟基己酯、甲基丙烯酸6-羟基己酯、丙烯酸3-羟基-2-乙基己酯、甲基丙烯酸3-羟基-2-乙基己酯等。
其它合适的额外单体c)为α,β-烯属不饱和单羧酸的伯酰胺及其N烷基和N,N-二烷基衍生物,例如丙烯酰胺、甲基丙烯酰胺、N-甲基(甲基)丙烯酰胺、N-乙基(甲基)丙烯酰胺、N-丙基(甲基)丙烯酰胺、N-(正丁基)(甲基)丙烯酰胺、N-(叔丁基)(甲基)丙烯酰胺、N-(正辛基)(甲基)丙烯酰胺、N-(1,1,3,3-四甲基丁基)(甲基)丙烯酰胺、N-乙基己基(甲基)丙烯酰胺、N-(正壬基)(甲基)丙烯酰胺、N-(正癸基)(甲基)丙烯酰胺、N-(正十一烷基)(甲基)丙烯酰胺、N-十三烷基(甲基)丙烯酰胺、N-肉豆蔻基(甲基)丙烯酰胺、N-十五烷基(甲基)丙烯酰胺、N-棕榈基(甲基)丙烯酰胺、N-十七烷基(甲基)丙烯酰胺、N-十九烷基(甲基)丙烯酰胺、N-二十烷基(甲基)丙烯酰胺、N-山萮基(甲基)丙烯酰胺、N-二十四烷基(甲基)丙烯酰胺、N-二十六烷基(甲基)丙烯酰胺、N-三十烷基(甲基)丙烯酰胺、N-十六碳烯基(甲基)丙烯酰胺、N-油基(甲基)丙烯酰胺、N-亚油基(甲基)丙烯酰胺、N-亚麻基(甲基)丙烯酰胺、N-硬脂基(甲基)丙烯酰胺、N-月桂基(甲基)丙烯酰胺、N,N-二甲基(甲基)丙烯酰胺、N,N-二乙基(甲基)丙烯酰胺、吗啉基(甲基)丙烯酰胺。
其它合适的额外单体c)为N-乙烯基内酰胺及其衍生物,其可具有例如一个或多个C1-C6烷基取代基如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基等。这些例如包括N-乙烯基吡咯烷酮、N-乙烯基哌啶酮、N-乙烯基己内酰胺、N-乙烯基-5-甲基-2-吡咯烷酮、N-乙烯基-5-乙基-2-吡咯烷酮、N-乙烯基-6-甲基-2-哌啶酮、N-乙烯基-6-乙基-2-哌啶酮、N-乙烯基-7-甲基-2-己内酰胺、N-乙烯基-7-乙基-2-己内酰胺等。优选使用N-乙烯基吡咯烷酮和N-乙烯基己内酰胺。
适合作为单体c)的开链N-乙烯基酰胺化合物的实例为N-乙烯基甲酰胺、N-乙烯基-N-甲基甲酰胺、N-乙烯基乙酰胺、N-乙烯基-N-甲基乙酰胺、N-乙烯基-N-乙基乙酰胺、N-乙烯基丙酰胺、N-乙烯基-N-甲基丙酰胺和N-乙烯基丁酰胺。
其它合适的额外单体c)为乙酸乙烯酯、丙酸乙烯酯、丁酸乙烯酯及其混合物。
其它合适的额外单体c)为乙烯、丙烯、异丁烯、丁二烯、苯乙烯、α-甲基苯乙烯、丙烯腈、甲基丙烯腈、氯乙烯、偏二氯乙烯、氟乙烯、偏二氟乙烯及其混合物。
上述额外单体c)可单独或以任何混合物形式使用。
本发明聚合物水分散体Pd)通过使用基于聚合用单体的总重量优选为0-80重量%的组分c)制备。具体实施方案涉及不包含额外单体c)作为共聚单元的聚合物分散体Pd)。如果存在,组分c)以基于聚合用单体的总重量为优选0.1-70重量%,特别优选1-60重量%,尤其是5-50重量%的量使用。
优选不使用单体c)。
单体d)
用于制备聚合物分散体Pd)的单体混合物M)除了化合物a)外还包含至少一种与其不同且具有能够自由基聚合的α,β-烯属不饱和双键和每分子至少一个阳离子基团的其它化合物d)作为共聚单元。
组分d)的阳离子基团优选为含氮基团如伯氨基、仲氨基和叔氨基及季铵基。含氮基团优选叔氨基或季铵基。带电荷阳离子基团可通过质子化(例如用一元或多元羧酸如乳酸或酒石酸,或无机酸如磷酸、硫酸和盐酸)或通过季铵化(例如用烷基化剂如C1-C4烷基卤或硫酸C1-C4烷基酯)由胺氮产生。该类烷基化剂的实例是乙基氯、乙基溴、甲基氯、甲基溴、硫酸二甲酯和硫酸二乙酯。
合适的化合物d)的实例是与α,β-烯属不饱和单-和二羧酸与氨基醇的DEAEMA不同的酯。优选的氨基醇为C2-C12氨基醇,其为胺氮上C1-C8单-或二烷基化的。这些酯的合适酸组分的实例为丙烯酸、甲基丙烯酸、富马酸、马来酸、衣康酸、巴豆酸、马来酸酐、马来酸单丁酯及其混合物。优选丙烯酸、甲基丙烯酸及其混合物用作这些酯的酸组分。
合适的额外化合物d)为(甲基)丙烯酸N,N-二甲基氨基甲酯、(甲基)丙烯酸N,N-二甲基氨基乙酯、丙烯酸N,N-二乙基氨基乙酯、(甲基)丙烯酸N,N-二甲基氨基丙酯、(甲基)丙烯酸N,N-二乙基氨基丙酯和(甲基)丙烯酸N,N-二甲基氨基环己酯。
其它合适的单体d)为上述α,β-烯属不饱和单-和二羧酸与具有至少一个伯氨基或仲氨基的二胺的酰胺。优选具有一个叔氨基和一个伯氨基或仲氨基的二胺。
这些包括N-[2-(二甲基氨基)乙基]丙烯酰胺、N-[2-(二甲基氨基)乙基]甲基丙烯酰胺、N-[3-(二甲基氨基)丙基]丙烯酰胺、N-[3-(二甲基氨基)丙基]甲基丙烯酰胺、N-[4-(二甲基氨基)丁基]丙烯酰胺、N-[4-(二甲基氨基)-丁基]甲基丙烯酰胺、N-[2-(二乙基氨基)乙基]丙烯酰胺、N-[4-(二甲基氨基)环己基]丙烯酰胺、N-[4-(二甲基氨基)环己基]甲基丙烯酰胺等。
其它合适的单体d)为N,N-二烯丙基胺和N,N-二烯丙基-N-烷基胺及其酸加成盐和季铵化产物。就此而言,烷基优选为C1-C24烷基。优选N,N-二烯丙基-N-甲基胺和N,N-二烯丙基-N,N-二甲基铵化合物如氯化物和溴化物。
其它合适的单体d)为乙烯基-和烯丙基取代的氮杂环如N-乙烯基咪唑、N-乙烯基-2-甲基咪唑,乙烯基-和烯丙基取代的杂芳族化合物如2-和4-乙烯基吡啶、2-和4-烯丙基吡啶及其盐。
本发明聚合物水分散体Pd)通过使用组分d)制备,如果存在,优选其用量应使得组分a)和组分d)的总量基于聚合用单体的总重量为25-65重量%,特别优选30-60重量%。
本发明聚合物水分散体Pd)通过使用基于聚合用单体的总重量优选为0-50重量%的组分d)制备。
如上所述,已惊人地发现本发明基于DEAEMA(组分a))且根据本发明使用的聚合物分散体Pd)具有特别好的性能特征。该性能特征通常可不使用具有阳离子基团的其它单体而获得。因此,具体实施方案涉及不包含额外单体d)作为共聚单元的聚合物分散体Pd)。
如果存在,组分d)优选以基于聚合用单体的总重量为0.1-40重量%,特别优选1-30重量%,尤其是2-25重量%的量使用。
在本发明方法特别优选的实施方案中,使用由以下组分组成的单体混合物M):
-基于聚合用单体的总重量为43-47重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),和
-基于聚合用单体的总重量为53-57重量%的至少一种化合物b),尤其是甲基丙烯酸甲酯。
调节剂
单体混合物M)的自由基聚合可在至少一种调节剂存在下进行。调节剂优选以基于聚合用单体的总重量为0.0005-5重量%,特别优选0.001-2.5重量%,尤其是0.01-1.5重量%的量使用。
调节剂(聚合调节剂)通常指具有高转移常数的化合物。调节剂加速了链转移反应且由此导致所得聚合物的聚合度降低而不影响总反应速率。就调节剂而言,可以依赖能够导致一种或多种链转移反应的分子中官能团的数量来区分单-、双-或多官能调节剂。合适的调节剂例如详细描述于K.C.Berger和G.Brandrup,J.Brandrup,E.H.Immergut,PolymerHandbook,第3版,John Wiley & Sons,New York,1989,第II/81-II/141页中。
优选用作调节剂的化合物包含呈结合形式的硫。
此外,合适的聚合调节剂为硫醇(包含呈SH基团形式的硫的化合物,也称为硫醇)。优选的调节剂为单-、双-和多官能硫醇、巯基醇和/或巯基羧酸。这些化合物的实例为硫基乙醇酸烷基酯,硫基乙醇酸乙基己酯,巯基丙氨酸,2-巯基乙醇,3-巯基-1-丙醇,3-巯基丙烷-1,2-二醇,4-巯基-1-丁醇,巯基乙酸,3-巯基丙酸,巯基琥珀酸,硫甘油,硫代乙酸,硫脲和烷基硫醇如正丁基硫醇、正己基硫醇、正十二烷基硫醇和叔十二烷基硫醇。
所有所述调节剂可单独或相互结合使用。
聚合物可通过借助形成自由基的引发剂聚合单体而制备。
可用于自由基聚合的引发剂为常用于此的过氧化物和/或偶氮化合物,例如碱金属过二硫酸盐或过二硫酸铵、过氧化二乙酰、过氧化二苯甲酰、过氧化二琥珀酰、过氧化二叔丁基、过苯甲酸叔丁酯、过戊酸叔丁酯、过-2-乙基己酸叔丁酯、过马来酸叔丁酯、氢过氧化枯烯、过二氨基甲酸二异丙酯、过氧化二(邻甲苯甲酰)、过氧化二癸酰、过氧化二辛酰、过氧化二月桂酰、过异丁酸叔丁酯、过乙酸叔丁酯、过氧化二叔戊基、氢过氧化叔丁基、偶氮二异丁腈、偶氮二(2-脒基丙烷)二盐酸盐或2,2′-偶氮二(2-甲基丁腈)。还合适的为引发剂混合物或氧化还原引发剂体系如抗坏血酸/硫酸铁(II)/过二硫酸钠、氢过氧化叔丁基/焦亚硫酸钠、氢过氧化叔丁基/羟基甲烷亚磺酸钠、H2O2/CuI。
本发明及根据本发明使用的聚合物水分散体Pd)优选通过使用至少一种无机过氧化物作为引发剂而制备。引发剂特别优选选自过二硫酸铵和碱金属过二硫酸盐。非常特别优选过二硫酸钠或过二硫酸钾。这些过二硫酸盐优选以过二硫酸盐浓度为0.5-20重量%,特别优选2-10重量%的水溶液形式使用。
如上所述,聚合在碱性pH下进行。就此而言特别有利的是不仅使聚合介质在聚合过程中尽可能维持在所需pH范围内,而且调节引发剂进料的pH至不太呈酸性的pH。如果使用至少一种无机过氧化物的水溶液作为聚合引发剂,则其pH优选大于2,特别优选大于3,尤其是大于4。优选的过二硫酸盐浓度为上述那些。原则上适合于调节pH的为所有无机或有机碱,尤其是除了可能成盐外不与单体反应的那些。合适碱的实例为碱金属和碱土金属氢氧化物,叔胺如三乙胺和氨基醇如三乙醇胺、甲基二乙醇胺或二甲基乙醇胺。NaOH或KOH优选用于调节pH。或者,过二硫酸钠水溶液或过二硫酸钾水溶液用作自由基乳液聚合用引发剂且在紧临用于聚合之前制备并由此具有有利范围内的pH。在紧临用于聚合之前制备指的是制备进行不超过24小时,优选不超过12小时,尤其是不超过6小时后,用于聚合。
本发明和根据本发明使用的聚合物水分散体Pd)通常在至少一种表面活性化合物存在下制备。
合适的表面活性化合物为保护性胶体和通常在乳液聚合中用作分散剂的乳化剂,其例如描述于Houben-Weyl,Methoden der organischenChemie,第XIV/1卷,Makromolekulare Stoffe,Georg-Thieme-Verlag,Stuttgart,1961,第411-420页中。合适的乳化剂为阴离子和非离子乳化剂。优选使用的表面活性物质为相对分子量通常低于2500g/mol的乳化剂。
有用的非离子乳化剂为芳脂族或脂族非离子乳化剂,例如乙氧基化单-、二-和三烷基酚(乙氧基化程度:3-50,烷基:C4-C10),长链醇乙氧基化物(乙氧基化程度:3-100,烷基:C8-C36)和聚氧乙烯/聚氧丙烯均聚物和共聚物。这些可包含无规分布或以嵌段形式聚合的氧化烯单元。非常合适的实例是EO/PO嵌段共聚物。优选使用长链链烷醇乙氧基化物(烷基:C1-C30,平均乙氧基化程度:5-100),并且其中优选使用特别优选具有线性C12-C20烷基和平均乙氧基化程度为10-50的那些,和乙氧基化单烷基酚。
特别优选的非离子乳化剂为具有12-30个碳原子的醇的脂肪醇烷氧基化物。这些优选具有10-30个氧化乙烯单元。在具体实施方案中,非离子乳化剂选自每种情况下具有10-30个氧化乙烯单元(例如20个氧化乙烯单元)的鲸蜡醇和/或硬脂醇乙氧基化物。
合适的阴离子型乳化剂的实例是以下物质的碱金属盐及铵盐:硫酸烷基酯(烷基:C8-C22)、乙氧基化链烷醇的硫酸单酯(乙氧基化程度:2-50,烷基:C12-C18)、乙氧基化烷基酚的硫酸单酯(乙氧基化程度:3-50,烷基:C4-C9)、烷基磺酸(烷基:C12-C18)和烷基芳基磺酸(烷基:C9-C18)。其它合适的乳化剂将在Houben-Weyl,Methoden der organischen Chemie,第XIV/1卷,Makromolekulare Stoffe,Georg-Thieme-Verlag,Stuttgart,1961,第192-208页中找到。合适的阴离子乳化剂同样为二(苯基磺酸)醚及其碱金属或铵盐,其在一个或两个芳族环上具有C4-C24烷基。这些化合物通常由例如US-A-4,269,749已知且以例如2A1(DoW ChemicalCompany)市售。
特别合适的阴离子乳化剂为月桂基硫酸钠、(鲸蜡基/硬脂基)硫酸钠等。
自由基乳液聚合优选在至少一种非离子乳化剂或包含至少一种阴离子乳化剂和至少一种非离子乳化剂的乳化剂混合物存在下进行。这些包括例如月桂基硫酸钠和具有12-30个碳原子的醇且每种情况下具有10-30个氧化乙烯单元的上述脂肪醇烷氧基化物的混合物。
乳化剂总量基于待聚合单体的量通常为约0.05-6重量%,优选1-5重量%。阴离子乳化剂与非离子乳化剂的重量比优选为1∶2-2∶1,特别优选为约1∶1(例如1.3∶1-1∶1.3)。在具体实施方案中,非离子乳化剂含量基于待聚合单体的量不超过4重量%。聚合物分散体Pd)的乳化剂含量还可以在聚合之后改变。因此,如果分散体进行超滤,则例如乳化剂含量可降低。此时,则可以获得乳化剂总含量基于单体的量为小于5重量%,特别小于4重量%,甚至更特别小于3重量%的分散体。
聚合物分散体Pd)可进一步通过使用与上述乳化剂不同的分散剂D)制备。这些包括例如聚合物分散剂,如果存在,其用量基于待聚合单体的量通常为0-10重量%,优选0.01-5重量%。优选不使用与上述乳化剂不同的分散剂。
还可以在聚合物分散体Pd)中加入常规赋形剂和添加剂。
这些包括例如pH-调节物质、还原剂和漂白剂如羟基甲烷亚磺酸的碱金属盐(例如C,来自BASF Aktiengesellschaft)、络合剂、芳香剂、调味剂、增味剂、消毒剂、防腐剂和粘度改进剂,例如醇类如甘油、甲醇、乙醇、叔丁醇、乙二醇、丙二醇或2-吡咯烷酮、N-甲基-2-吡咯烷酮、聚乙二醇400等。
合适的防腐剂原则上为在超过7的pH范围下有效的所有物质。该类物质例如列于″Praxis der Sterilisation,Desinfektion-Konservierung″,Karl Heinz第5修订版,Georg Thieme Verlag Stuttgart,1995,第465-652页中。特别合适的物质为苄醇,2,4-二氯苄醇,苯乙醇,2-苯氧基乙醇,2-苯氧基-1-丙醇,氯苯甘醚,丙二醇,甲醛,乙醛,丙烯醛,乙二醛,戊二醛,对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,对羟基苯甲酸丙酯,对羟基苯甲酸丁酯,对羟基苯甲酸苄酯,苯酚,氯苯酚,季铵化合物如苯扎氯铵和十六烷基氯化吡啶鎓、季铵盐-15,甲酚,氯甲酚,银和银盐,有机汞化合物如乙酸苯汞、乙基汞硫代水杨酸钠、磺基硫柳汞(sulfomerthiolate),氯,二氧化氯,次氯酸盐,碘,次碘酸盐,过氧化氢,过氧化苯甲酰,1,3-二羟甲基-5,5-二甲基乙内酰脲及其混合物。
这些赋形剂和添加剂可在初始进料中以进料之一或在聚合完成之后加入聚合物分散体中。
聚合通常在0-150℃,优选20-100℃,特别优选55-95℃的温度下进行。聚合优选在大气压力下进行,但聚合也可以在升高压力,例如聚合用组分的自生压力下进行。优选压力范围为1-5巴。在优选实施方案中,聚合在至少一种惰性气体如氮气或氩气存在下进行。就此而言,所用惰性气体优选为无水的。
聚合以进料工艺形式进行。就此而言各进料可连续或以分步或梯度程序引入聚合区中。在一个可能实施方案中,聚合以如下的进料工艺进行:其中首先加入部分聚合混合物(但优选不含单体)并且其它组分全部或部分以分批或连续、一起或以分开进料加入初始进料中。
在优选实施方案中,各组分从下方(浸入)加入聚合反应器中。
在本发明方法中,优选在用于反应的聚合区中首先不加入单体。此外,自由基乳液聚合优选不在种子胶乳存在下进行。
优选在聚合区中首先加入部分所用乳化剂和至少部分含水介质并将其加热到聚合温度,然后将剩余聚合混合物经由一股或多股空间分开的进料引入聚合区中。就此而言单体和/或引发剂的引入适当地以其消耗速率进行,即维持聚合。此时,聚合引发剂和单体通常以分开进料加入。单体原则上可单独或以混合物形式引入。
优选在基本无水条件下操作甲基丙烯酸N,N-二乙基氨基乙酯(组分a))直到其用于聚合。为此,例如组分a)的贮存和/或引入聚合区中基本在排除水情况下进行。同样适用于包含甲基丙烯酸N,N-二乙基氨基乙酯的单体混合物。排除、贮存和输送水分敏感物质的合适方法对本领域熟练技术人员已知。这些包括例如在操作组分a)时排除水,以及预先干燥与组分a)接触的装置表面。术语“在基本无水条件下”指就本发明而言例如当输送时通过与水分接触而发生与少量水的接触通常不重要。
在本发明方法的具体实施方案中,甲基丙烯酸N,N-二乙基氨基乙酯a)与水在混合装置中在其紧临用于聚合之前混合。术语“在其紧临用于聚合之前”在本文指与水混合进行不超过1小时,优选不超过10分钟,特别优选不超过1分钟之后,用于聚合。为此,混合还优选在紧临进入反应区之前在空间进行。甲基丙烯酸N,N-二乙基氨基乙酯a)优选在混合装置中与水、至少一种乳化剂及合适的话至少一种其它单体混合而得到单体乳液。
本发明方法用于制备共聚物,其中每种情况下各共聚单体可单独或以任何混合物形式在至少一个混合装置中混合而得到乳液。聚合用共聚单体优选在混合装置中混合而得到乳液。多种单体可分开或以混合物引入混合装置中,所述混合物例如可通过将各进料合并到共有管道中而产生。优选将在进入混合装置之前加入了至少一种表面活性物质(乳化剂)的无水进料引入混合装置中。
引发剂的加入在分开进料中,通常在水相中进行,但单体进料和引发剂进料可在进入混合装置之前合并。或者,引发剂也可直接加入与单体进料无关的反应器中。
合适的话,可以将其它组分(在下文更详细定义)取决于与上述进料之一的相容性,或以纯净形式分开,以水溶液或在合适溶剂中溶液加入反应区中。
在本发明方法中,可以使用一种或多种混合器作为混合装置,其中混合器可以具有相同或不同设计,并且它们以任何顺序、设置和组合使用,例如所有混合器串联设置、平行和串联设置组合或所有混合器平行设置。如果使用多个混合器,则优选串联设置。合适的混合器为其混合单元包括移动部件的动态混合器和静态混合器,即混合单元在内部没有移动部件。优选尤其是根据管道原理操作的混合器。合适的混合器例如描述于A.Echte,Handbuch der technischen Polymerchemie,VCHVerlagsgesellschaft Weinheim,第104页及后续页(1993)中。
在本发明方法的优选实施方案中,使用包括至少一个动态混合器的混合装置。
合适的动态管道混合器例如为ZFL-Zeitschrift fürLebensmitteltechnologie und-Verfahrenstechnik(1982)33(3),第139页及后续页中描述的Kratz换热器、通过转子-定子原理操作的粉碎机如齿轮分散器(例如类型,来自Kinematica)、胶体磨和刚玉圆盘式粉碎机以及高压和超声均化器。
合适的静态管道混合器例如为ZFL-Zeitschrift fürLebensmitteltechnologie und-Verfahrenstechnik(1982)33(3)第139页及后续页中描述的那些,例如其中流体流动通过具有穿孔的内件引导的RossISG混合器,穿孔将流体流动分成部分料流,然后侧向排出并以不同顺序再合并一起。还合适的是包括多个相同或不同固定混合单元的静态混合器,所述混合单元例如每种情况下交错排列,依次并入一个管道或通道中。这些包括例如Kenics、Sulzer SMV和Sulzer SMX混合器。
其它合适的静态管道混合器为剪切混合器如EP-B-101 007中描述的喷射分散器。
其它合适的混合器还为用于管道乳化的装置,例如膜和喷射混合器。
在合适的实施方案中使用的混合装置为至少一个管道混合器,其适当地正好固定在反应容器前面。
特别优选混合装置包括动态混合器及合适的话静态混合器。如果使用两个混合器,则它们串联设置。本文优选使用的动态混合器为连续管式混合器或齿轮分散器。
适合用于乳液聚合的反应区为通常用于此的反应器类型。这些包括例如搅拌容器。合适搅拌器类型的实例包括螺旋桨搅拌器、叶轮搅拌器、盘式搅拌器、桨式搅拌器、锚式搅拌器、斜桨式搅拌器、横梁搅拌器、螺旋带搅拌器、螺旋式搅拌器等。
优选与聚合物水分散体Pd)接触的所有系统部件与碱在开始自由基乳液聚合之前接触。为此合适的为开头所述碱的水溶液,优选含水NaOH和KOH。优选使用稀水溶液(例如2-4重量%)。为此,反应器,包括任何反应器内件、搅拌装置、加热/冷却装置等,和与反应器出料接触的所有表面均用含水碱冲洗。
在聚合工艺之后,聚合所得分散体可进行物理或化学后处理。该类工艺的实例为降低残余单体的已知工艺,例如通过在合适温度下加入聚合引发剂或多种聚合引发剂混合物的后处理、聚合物溶液用水蒸气的后处理或用惰性气体的汽提或反应混合器用氧化剂或还原剂的处理、吸附工艺如杂质在所选介质如活性炭上的吸附或超滤。在优选的实施方案中,所得聚合物分散体Pd)进行超滤。因此可以得到具有低残余单体含量的分散体,如在药物应用中尤其需要的那样。就此而言尤其可以通过超滤得到具有非常低的可聚合单体含量的分散体Pd)。
为了通过超滤纯化分散体,即除去在分散介质中溶解的低分子量化合物,使分散体与膜在压力下接触并在比进料侧低的压力下在膜的反面排出包含溶解化合物的不含聚合物的渗透液(滤液)。可通过超滤除去的低分子量化合物选自前体、前体的分解产物、低聚物、盐、表面活性剂等及其混合物。在溶解化合物中贫含的浓缩聚合物分散体作为保留物得到。为了防止聚合物浓度太高,可通过分散剂(水)在保留物中连续或间歇地置换去除量的渗透液。未进行干燥,但其中置换去除量的渗透液的超滤也称为渗滤(diafiltration)。分散体通常可以导致合成的浓度(例如20-40%浓度,在水中)用于超滤。当然同样可以在超滤之前用水稀释分散体,然后使其在较低聚合物浓度下进行超滤(优选进行渗滤,此时除去的渗透液在保留物中通过加入水而置换使得聚合物浓度维持恒定)及合适的话随后将其浓缩到所需聚合物浓度。
例如通过泵循环、机械移动膜或膜之间的搅拌单元,可以防止或最小化聚合物颗粒在膜表面沉积(覆盖层结构),所述沉积导致渗透液流量显著降低。此时,优选在膜和分散体之间产生0.1-20m/s(线圈几何结构:0.1-5m/s,管状几何结构:1-6m/s,旋转几何结构:2-20m/s)的相对速率。本发明聚合物分散体惊人地显示出足以用于该目的的剪切稳定性。
除了膜内径为1-25mm,优选2-15mm的管状膜几何结构外,优选的几何结构为定型几何结构,其可用来彼此独立地调节剪切力和可透性膜压,因为此时可获得比用管状膜大的渗透液流量。
使用适当的模件,一方面通过机械移动膜或通过膜之间的搅拌单元而在膜和悬浮液之间产生2-20m/s的相对速率,另一方面通过控制进料、保留物或渗透液的量而手工控制可透性膜压。
渗滤和浓缩可在间歇程序中通过使悬浮液多次通过膜模件或连续地一次通过一个或多个串联连接的进料和渗料段而进行。
对于膜工艺,可以使用孔径为1nm(截留分子量(molecular cut-off)为约1kD)至1μm,优选10nm(截留分子量为约20kD)至400nm(截留分子量为约500kD)的膜分离层。所述分离层可由有机聚合物、陶瓷、金属、碳及其组合组成并必须在过滤温度下在进料介质中稳定。出于力学原因,分离层通常施加至由相同或多种不同材料制成的单层或多层多孔亚结构上作为分离层。可能材料组合的实例详述于下表中:
特别优选的分离层由亲水性材料如金属、陶瓷、再生纤维素、丙烯腈和亲水化丙烯腈、聚砜和亲水化聚砜、聚醚砜和亲水化聚醚砜、聚醚醚酮和亲水化聚醚醚酮及亲水化PVDF组成。实施例已经用再生纤维素(30kD)、亲水化PVDF(30nm)和亲水化聚醚砜(20kD)操作。
膜原则上可以平坦、管状、多通道单元、毛细或线圈几何结构使用,为此可以获得适当的压力箱,其允许保留物和渗透液之间的分离。
保留物和渗透液之间的最佳可透性膜压基本取决于膜孔径、影响覆盖层结构的流体压力和膜在过滤温度下的机械稳定性,其取决于膜类型优选为0.2-20巴,特别优选0.3-6巴。更高的可透性膜压通常导致更高的渗透液流量。此外可能的情况是其中多个模件串联设置以降低可透性膜压及由此通过提高渗透液压力适合于每个模件。操作温度取决于膜稳定性和分散体热稳定性。超滤的合适温度范围为20-80℃。更高的温度通常导致更高的渗透液流量。可获得的渗透液流量大大取决于膜类型和所用膜几何结构、工艺条件、进料组成(基本上聚合物浓度)。流量通常为5-500kg/m2/h。因此,例如在具有30%聚合物含量,40℃和截留分子量为30kD的再生纤维素膜上1巴可透性膜压的旋转系统中,取决于旋转速率而达到15-70kg/m2/h的渗透液流量。此时,渗透液流量从超滤开始至结束通常以约2的倍数增加。所需的水溶性组分消耗通常通过渗滤步骤以至多5,优选至多3的溶剂交换系数实现。就此而言,溶剂交换系数表示分散体溶剂在渗滤过程中多久交换一次。这意味着在溶剂交换系数为X情况下,对于每m3分散体除去Xm3渗透液并且同时在分散体中引入Xm3溶剂(水)。
例如可使用以下膜:
本发明聚合物分散体Pd)进行超滤之后,其特征在于分散介质中溶解的低分子量化合物的残余含量非常低。这尤其适用于来自单体a)和b)的不希望水解产物。因此可以提供尤其适合作为药物剂型用包衣组合物的分散体。
本发明聚合物分散体Pd)包含优选不超过2500重量ppm,特别优选不超过1000重量ppm,尤其是不超过500重量ppm的N,N-二乙基氨基乙醇。
本发明聚合物分散体Pd)包含优选不超过100重量ppm,特别优选不超过50重量ppm的甲基丙烯酸。
本发明聚合物分散体Pd)包含优选不超过500重量ppm,特别优选不超过250重量ppm,尤其是不超过50重量ppm的甲醇。
原则上可以在超滤期间或之后在本发明聚合物分散体Pd)中加入至少一种上述添加剂或赋形剂。这些包括例如缓冲物质、防腐剂或抗氧化剂。
还可以进行进一步加工步骤,例如合适的干燥工艺。聚合物分散体Pd)可通过各种干燥工艺如喷雾干燥、硫化喷雾干燥、转鼓干燥或冷冻干燥而转化成粉末形式。优选使用喷雾干燥。以此方式获得的干燥聚合物粉末可有利地通过再分散于合适pH下的水中而再次转化成水分散体。然而,通过本发明方法获得的分散体优选出售和/或作为初级分散体直接进一步加工。
本发明分散体惊人地具有优异的物理和化学稳定性。因此,分散体在室温下贮存几年而没有沉降或絮凝。技术应用性能在贮存后没有改变。与所有预期相反,尽管碱性pH和存在通常催化水解的氨基,但聚合物酯基仅发生少量水解。
在本发明分散体Pd)中存在的聚合物通过凝胶渗透色谱法测定的平均分子量Mw优选为30000-500000g/mol,特别优选60000-140000g/mol,尤其是80000-120000g/mol。
GPC通过以下方法进行:
洗脱剂:THF+0.02mol/l三乙胺
柱温:35℃
流速:1ml/min
注射:100μl 2[g/l]的溶液
样品溶液通过Sartorius Minisart SRP 25(孔宽0.2[μm])过滤。
分离柱组件:
编号 | 柱内径[mm] | 长度[cm] | 分离材料 | 截留分子量 |
775 | 7.5 | 30 | PL Gel Mixed B | 8000000 |
776 | 7.5 | 30 | PL Gel Mixed B | 8000000 |
在所述流速下组件的塔板数:40000
检测器:HP-1100差示折光计
校准:校准用来自Polymer Laboratories的具有窄分布的分子量M=580-7500000的聚苯乙烯标样和己基苯(M=162)进行。位于该范围之外的洗脱区通过外推法估测。
本发明分散体Pd)中存在的聚合物优选具有的K值(通过Fikentscher方法以N-甲基吡咯烷酮(NMP)中1%浓度溶液测定)为40-60。
用于测定K值的1%浓度溶液通过称出其固体含量为约0.7g的样品量并加入计算的溶剂体积。溶剂比例通过以下方程计算:
其中含义为:
VL=计算的溶剂体积[ml]
mS=样品重量[g]
SC=固体含量[g/100g]
c=预期浓度[g/100ml]
在该计算中样品密度假定为1g/ml。总体积为约70ml。溶液在室温下溶解并通过0.40μm金属筛过滤。粘度测量则通过在25℃(±0.05℃)下测定过滤溶液和纯溶剂流过毛细管粘度计的时间而进行。
玻璃化转变温度TG(通过DSC测定)优选为40-70℃,特别优选52-62℃。
本发明分散体Pd)中存在的聚合物基本为无规共聚物。
聚合物分散体Pd)中存在的聚合物颗粒的平均粒径(使用分析超速离心机测定)优选为70-200nm,特别优选80-150nm,尤其是90-120nm。粒度分布优选基本为单峰的。
本发明分散体Pd)的光透射优选为至少70%,特别优选至少80%,其以水中0.01%浓度分散体测定(2.5cm比色杯,白光)。光透射的测量例如描述于Dieter Distler,Polymerdispersionen,Wiley-VCH(1999),第40页中。
本发明分散体Pd)的固体含量优选为10-50重量%,特别优选20-40重量%。当通过超滤纯化分散体时,本发明分散体在超滤之前和之后优选具有上述范围内的固体含量。当然同样可以通过超滤使稀聚合物分散体进行浓缩。
本发明分散体例如甚至在30重量%固体含量下显示出极低粘度,优选小于50mPas,特别优选小于25mPas,尤其小于10mPas(使用B型粘度计在20℃和100s-1下测定的值)。该低粘度对许多应用尤其重要。
本发明分散体Pd)中存在的聚合物的电荷取决于分散体的pH。等电点优选为约7.5-8.5的pH范围。最终分散体具有的pH优选为8-10,特别优选8.5-9.5(固体含量为30重量%)。有利的是选择最终分散体的pH以高于其等电点(更具碱性),只要不需要分散体中存在的聚合物颗粒溶解或溶胀。本发明分散体因此优选为碱性分散体。
本发明聚合物分散体Pd)特征在于其pH依赖的溶解性。其中分散体在酸化时溶解的pH范围例如通过聚合物中甲基丙烯酸N,N-二乙基氨基乙酯(单体a)的量及合适的话通过使用具有阳离子基团的其它单体(单体d)调节。本发明聚合物分散体Pd)中存在的聚合物优选在不超过6.8,特别优选不超过5.5的pH下溶解。
因此,本发明另一方面为通过降低pH而可溶且包含以下组分的聚合物水分散体Pd):
-至少一种包含作为共聚单元的以下组分的聚合物:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种能够自由基聚合且选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的化合物,
-至少一种选自阴离子和非离子乳化剂的乳化剂,和
-水。
优选实施方案包括包含聚合物的分散体,所述聚合物包含作为共聚物中仅有单体的以下组分:
-基于聚合用单体的总重量为43-47重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),和
-基于聚合用单体的总重量为53-57重量%的至少一种化合物b)。
上述聚合物分散体Pd)特别适合于生产药物组合物。首先,提供含碱性氨基的聚合物的水分散体,该分散体适合于药物应用,具有合适纯度和足够稳定性。此外,它们例如用作聚合物成膜剂,尤其用于生产药物剂型用包衣组合物。
本发明药物剂型用包衣组合物的配制剂基体可包含至少一种其它可药用赋形剂。可药用赋形剂为已知可用于药物、食品技术和相邻领域的那些,尤其是在相关药典(例如Ph.Eur.,USP,JP)中列出的那些,及其它性能不妨碍生理应用的赋形剂。
可能的合适赋形剂为:调味剂、味道改善物质、增甜剂(糖,糖醇,增甜剂如天冬甜素、糖精钠、环氨酸钠)、润滑剂、润湿剂、脱模剂、增塑剂、抗粘剂、脱氧剂、稳定剂、造孔剂、中和剂、光泽剂、着色剂、颜料、消毒剂或防腐剂、增稠剂等。该类物质例如描述于Fiedler,H.P.Lexikon derHilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete,第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中。
赋形剂的常用量每种情况下基于包衣组合物的总重量为0-50重量%,优选0-20重量%,尤其是0.01-10重量%。
包衣组合物例如可通过均质混合本发明聚合物分散体或可通过干燥工艺由其获得的聚合物与至少一种赋形剂而制备。在特别优选的实施方案中,本发明聚合物分散体不经预先干燥而直接用于生产包衣组合物。然而,还可以首先使本发明聚合物分散体干燥并使以此方式获得的聚合物组合物用于生产包衣组合物。聚合物组合物可随后例如以粉末形式、熔体、溶液或二次分散体用于生产包衣组合物。
本发明又一方面为包含该聚合物水分散体Pd)或可通过干燥由其获得的聚合物组合物的包衣组合物。
本发明再一方面为包含以下组分的药物组合物:
A)可通过该聚合物分散体的干燥和/或成膜获得的聚合物组合物,
B)至少一种可药用活性成分,和
C)合适的话至少一种可药用赋形剂。
本发明聚合物分散体可以药物组合物例如用于生产粘合剂或包衣组合物。此时作用效果通常通过包衣组合物或粘合剂的干燥和/或成膜而产生。该干燥和/或成膜可独立于应用工艺而通过输入能量进行。这可通过对流(加热)、辐射(红外或微波)或传导进行。在应用中用作分散剂的水在该过程中蒸发并且合适的话还可通过使用真空促进蒸发。
本发明包衣组合物例如可以粉末形式、熔体或水乳液通过成粒、流延、铺展或通过喷雾应用而使用。优选以聚合物分散体,尤其是初级分散体使用。本发明包衣组合物可额外包含至少一种其它聚合物组分。此外可以使用至少两种分散体的混合物、至少一种分散体和至少一种溶液的混合物、至少一种分散体和至少一种粉末的混合物、至少两种粉末的混合物等。
本发明配制剂原则上适合于任何活性药物成分的给药,其可优选以密封或保护形式给药,例如抗抑郁药、β-受体阻断剂、抗糖尿病药、镇痛药、抗炎药、抗风湿药、抗低血压药、抗高血压药、精神活性药物、安定药、止吐药、肌肉松弛药、糖皮质激素、溃疡性结肠炎或克罗恩病处理药、抗过敏药、抗生素、抗癫痫药、抗凝血药、抗真菌药、止咳药、动脉硬化治疗药、利尿药、酶、酶抑制剂、痛风治疗药、激素及其抑制剂、强心苷、免疫治疗药和细胞因子治疗药、缓泻药、降脂药、胃肠治疗药、偏头痛治疗药、矿产、耳科药(otologicals)、帕金森治疗药、甲状腺治疗药、解痉药、血小板聚集抑制剂、维生素、细胞生长抑制剂和转移抑制剂、植物药、化疗药、营养制品、维生素、类胡萝卜素和氨基酸。
合适的活性成分的实例为:阿卡波糖、非甾类抗风湿药、强心苷、乙酰水杨酸、抑制病毒药、阿柔比星、阿昔洛韦、顺铂、放线菌素、α-和β-拟交感神经药、别嘌醇、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、贝可乐、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(cefalosporins)、塞来考昔、西替利嗪、鹅去氧胆酸、熊去氧胆酸、茶碱和茶碱衍生物、胰蛋白酶、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、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、多萘哌齐、多巴胺、多沙唑嗪、多柔比星、多西拉敏、达哌唑、苯二氮、双氯芬、苷类抗生素、地昔帕明、益康唑、ACE抑制剂、依那普利、麻黄碱、肾上腺素、依泊汀和依泊汀衍生物、吗啡喃、钙拮抗剂、伊立替康、莫达非尼、奥利司他、肽类抗菌素、苯妥英、利鲁唑、利塞膦酸盐、西地那非、托吡酯、大环内酯类抗生素、艾美拉唑、雌激素和雌激素衍生物、孕激素和孕激素衍生物、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、呋噻米、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、格列本脲、作为口服抗糖尿病药的尿素衍生物、高血糖素、葡糖胺和葡糖胺衍生物、谷胱甘肽、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、肼屈嗪、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、丙米嗪、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、山梨糖醇和山梨糖醇衍生物、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、美沙拉秦、甲琥胺、安乃近、二甲双胍、甲氨蝶呤、哌甲酯、甲泼尼松、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、莫西普利、吗啡和吗啡衍生物、月见草、纳布啡、纳洛酮、替利定、萘普生、那可丁、那他霉素、新斯的明、尼麦角林、尼可刹米、硝苯地平、尼氟酸、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、novaminsulfone、那可丁、制霉菌素、氧氟沙星、奥氮平、奥沙拉秦、奥美拉唑、奥莫康唑、昂丹司琼、奥利司他、奥塞米韦、奥沙西罗、苯唑西林、奥昔康唑、羟甲唑啉、泮托拉唑、对乙酰氨基酚、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、哌替啶、植物提取物、安替比林、非尼拉敏、巴比土酸衍生物、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、利托那韦、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、沙巴草、沙丁胺醇、沙美特罗、东莨菪碱、司来吉兰、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、磺胺类药、柳氮磺吡啶、舒必利、舒他西林、舒噻美、舒马曲坦、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、甲巯咪唑、吩噻嗪、塞替派、噻加宾、硫必利、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、妥拉唑林、甲苯磺丁脲、托卡朋、托萘酯、托哌酮、托泊替康、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、氨丁三醇、tropalpin、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、维库氯铵、文拉法辛、维拉帕米、阿糖腺苷、氨己烯酸、维洛沙秦、长春碱、长春胺、长春新碱、长春地辛、长春瑞滨、长春西汀、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、佐米曲坦、唑吡旦、佐匹克隆、佐替平等。
需要的话,活性成分还可以其可药用盐或衍生物形式使用,并且在手性活性成分情况下可以使用光学活性异构体和外消旋体或非对映体混合物。需要的话,本发明组合物还可包含两种或更多种活性药物成分。
本发明分散体优选用于对片剂、挤出物、小片剂、胶囊、软胶囊、颗粒、丸剂、微丸剂、微胶囊、晶体包衣。包衣的颗粒、丸剂、微丸剂、微胶囊、晶体可与合适的赋形剂混合并压制成片剂,其在水中快速分解并再释放出精细包衣成型物。可以此方式生产所谓的MUPS剂型,多单元颗粒体系。这些为在摄取之后分解且释放出用本发明包衣组合物包衣的亚单元。就此而言尤其重要的是所谓的口服分散体,即在口中短时间内分解且释放出遮味的小成型物。
在特定变型中,本发明分散体用于使活性成分合适的话与合适赋形剂一起成粒,然后将颗粒压制成片剂。
本发明分散体还可以用于生产经皮活性成分贴剂或喷雾。
同样适合掺入聚乙二醇或脂质附聚物以生产栓剂或阴道药物剂型。
通常可发出苦味且可有利地用本发明包衣组合物和粘合剂配制的活性成分组和物质例如为:
镇痛药和抗风湿药如对乙酰氨基酚、双氯芬、醋氯芬酸、布洛芬、酮洛芬、氟比洛芬、乙酰水杨酸、左醋美沙朵和羟考酮;
精神活性药物如异丙嗪、多萘哌齐、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(amyloprilose HCl)、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。
遮味显著适用性来自本发明聚合物在超过6的pH值下不溶且在低于6的pH值下快速溶解。这意味着相应包衣剂型在唾液(pH 7.2)中稳定很长时间,并且苦味药物不与口腔黏膜接触,但活性成分在pH值为1-5的胃中极快释放。此外,溶解如此快使得作用开始与未包衣剂型相比没有区别。本发明聚合物薄膜包衣通常在胃液中在5分钟内溶解,而它们在pH 7.2的磷酸盐缓冲剂中稳定超过2小时。惊人的是,薄膜包衣还较快溶解于pH值为4.5的介质中,从而使得由其生产的剂型甚至在酸缺乏病人或用解酸药治疗的病人中快速作用。
本发明包衣组合物显示出对水蒸气和氧气的低渗透性并由此使得可以配制和稳定对水蒸气和氧气特别敏感的药物如乙酰水杨酸、依那普利、醋酸可的松、奥美拉唑、类胡萝卜素。在这些情况下包衣具有保护特性。
本发明包衣组合物可额外用于通过包封一种或多种成分并由此防止相互接触而使剂型中不相容的活性成分或赋形剂隔开。
本发明薄膜包衣的极优异技术应用性能可通过聚合物分散体的优异均匀成膜、膜的低粘性和包衣的良好柔韧性或弹性获得,从而使得即使片剂或丸剂芯溶胀,薄膜包衣也不断裂。就此而言特别惊人的是高柔韧性与极低粘性结合,因为聚合物通常是刚性的,即具有低柔韧性且不粘,或是柔性的,即柔韧但发粘。
聚合物分散体具有低粘度,从而可获得喷雾悬浮液中的高固体浓度和极短的喷雾过程。喷雾悬浮液中固体浓度通常为10-60重量%,优选20-50重量%,尤其是25-40重量%。基于本发明所用固体含氨基聚合物的浓度通常为5-50重量%,优选10-40重量%,尤其是20-35重量%。低粘度确保喷嘴中非常精细和均匀的雾化、片剂或丸剂表面上非常好的铺展及快速均匀成膜。着色剂和颜料的掺入以通常方式进行,但极简单且快速及不含溶剂。简单处理导致的事实是本发明所用含氨基聚合物分散体使颜料在喷雾悬浮液中稳定。喷雾即用悬浮液可以此方式在约10分钟内制备。
本发明药物组合物的配制剂基体优选包含可药用赋形剂。可药用赋形剂为已知可用于药物、食品技术和相邻领域的那些,尤其是在相关药典(例如DAB,Ph.Eur.,BP,USP,JP)中列出的那些,及其它性能不妨碍生理应用的赋形剂。
合适赋形剂可以为:润滑剂、润湿剂、乳化和悬浮剂、防腐剂、抗氧化剂、抗刺激剂、螯合剂、乳化稳定剂、成膜剂、胶凝剂、遮味剂、树脂、水胶体、溶剂、增溶剂、中和剂、渗透促进剂、颜料、着色剂、稳定剂、分解剂、干燥剂、遮光剂、增稠剂、蜡、增塑剂、调味剂、增甜剂、降低渗透的赋形剂等。与此有关的排列基于如描述于例如Fiedler,H.P.Lexikonder Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete,第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996中的专业知识。
特别合适的增塑剂的实例为:柠檬酸三乙酯、柠檬酸三丁酯、三醋精、乙酰柠檬酸三乙酯、Labrasol、三缩四乙二醇、聚丙二醇400。
薄膜包衣渗透性可进一步通过掺入无机固体(颜料如滑石、高岭土、二氧化钛)或亲脂有机固体,例如脂肪、蜡、甘油酯、脂肪酸如硬脂酸、脂肪醇如硬脂醇而降低。
本发明药物组合物可通过用合适赋形剂混合或稀释活性成分而生产。赋形剂可为固体或半固体材料,其可用作活性成分的载色剂、载体或介质。需要的话,其它赋形剂的混合以熟练技术人员已知的方式进行。
还可以相同方式生产兽用药剂型,尤其是瘤胃稳定剂型,和具有维生素、类胡萝卜素、痕量元素、保健食品、氨基酸和营养强化剂的剂型。后者还可以认为是食品或强化剂。
本发明另一方面为如上文所定义的聚合物水分散体Pd)在膜生产、化妆品、作物保护、种子包衣、食品、动物营养、作为粘合原料、造纸、作为皮革和织物中粘合剂或助剂、作为杀微生物表面包衣、非织造物领域、洗涤剂和清洁剂、油漆生产、建筑领域中的用途。
本发明又一方面为如上文所定义的聚合物水分散体Pd)作为或在化妆品、食品、动物营养、织物、纸张、印刷、皮革和粘合剂工业用包衣组合物中的用途。
借助以下非限制性实施例更详细地说明本发明。
实施例1
初始进料:
481.75kg的去离子水
5.59kg的具有约20个氧化乙烯单元的C16/C18烷基聚乙二醇醚,医药级,10%浓度水溶液,
4.58kg的月桂基硫酸钠GMP,15%浓度水溶液
加料1:
14.60kg的去离子水
0.38kg的过二硫酸钠
进料1:
248.52kg的去离子水
86.43kg的具有约20个氧化乙烯单元的C16/C18烷基聚乙二醇醚,医药级,10%浓度水溶液
71.38kg的月桂基硫酸钠GMP,15%浓度水溶液
进料2:
172.00kg的甲基丙烯酸二乙基氨基乙酯
258.00kg的甲基丙烯酸甲酯
进料3:
153.09kg的去离子水
3.92kg的过二硫酸钠
通过合适的技术措施(用丙酮冲洗和/或吹干)确保进料容器(进料2)基本不含水。加料1和进料3是直接新制的,即在开始聚合之前1小时制得(溶解于去离子水中的固体过二硫酸钠)。动态混合器(Megatron MT 3-61,Kinematica AG)在开始试验之前装入水。
聚合反应器(容器体积约2050l)和与聚合物分散体接触的所有管路在开始试验之前用3%浓度氢氧化钠水溶液冲洗。聚合反应器然后装入初始进料。在开始反应之前,将初始进料抽真空,用5巴氮气充气一次,再抽真空并用氮气使其达到大气压力。然后将初始进料加热到75℃的反应温度,同时搅拌。当内部温度达到70℃时,在2分钟内加入加料1。
将进料1和2经由动态混合器(转数设定为5000rpm)计量加入反应器中,将进料3经由位于动态混合器和聚合反应器之间延长管路中的静态混合器计量加入反应器中。
进料1紧临进料2和3之前开始。进料1在1.75小时内加入,进料2在1.50小时内加入,并且进料3在3.75小时内加入。
在进料3完成之后,后聚合在75℃下进行,同时搅拌2小时。然后将反应混合物冷却到室温并测定固体含量和pH。聚合过程中(更确切为在单体加入过程中)pH在实施例1和以下实施例2-6中总是高于8.0。对于所有实施例,K值以NMP中1%浓度溶液测定。
分散体然后进行超滤并测定以下特性:
实施例2
程序如实施例1中那样,但在进料3中仅使用2.2kg过二硫酸钠并且进料2中包含0.4kg硫基乙醇酸乙基己酯。
实施例3
程序如实施例1中那样,但在进料2中使用193.5kg甲基丙烯酸二乙基氨基乙酯和236.5kg甲基丙烯酸甲酯。
分散体然后进行超滤并测定以下特性:
实施例4
初始进料:
378.24kg的去离子水
5.59kg的具有约20个氧化乙烯单元的C16/C18烷基聚乙二醇醚,医药级,10%浓度水溶液,
4.58kg的月桂基硫酸钠GMP,15%浓度水溶液
加料1:
14.60kg的去离子水
0.38kg的过二硫酸钠
进料1:
352.03kg的去离子水
86.43kg的具有约20个氧化乙烯单元的C16/C18烷基聚乙二醇醚,医药级,10%浓度水溶液
71.38kg的月桂基硫酸钠GMP,15%浓度水溶液
进料2:
172.00kg的甲基丙烯酸二乙基氨基乙酯
258.00kg的甲基丙烯酸甲酯
进料3:
153.09kg的去离子水
3.92kg的过二硫酸钠
聚合反应器(容器体积约2050l)和与聚合物分散体接触的所有管路在开始试验之前用3%浓度氢氧化钠水溶液冲洗。聚合反应器然后装入初始进料。
在开始反应之前,将初始进料抽真空,用5巴氮气充气一次,再抽真空并用氮气使其达到大气压力。然后将初始进料加热到75℃的反应温度,同时搅拌。当内部温度达到70℃时,在2分钟内加入加料1。
将进料1和2经由动态混合器(转数设定为5000rpm)计量加入反应器中,将进料3经由位于动态混合器和聚合反应器之间延长管路中的静态混合器计量加入反应器中。
进料1紧临进料2和3之前开始。进料1在1.75小时内加入,进料2在1.50小时内加入,并且进料3在3.75小时内加入。
在进料3完成之后,后聚合在75℃下进行,同时搅拌2小时。然后将反应混合物冷却到室温并测定固体含量和pH。
分散体然后进行超滤并测定以下特性:
实施例5
程序如实施例4中那样,但在加料1和进料3中使用过二硫酸钾而不是过二硫酸钠。
分散体然后进行超滤并测定以下特性:
实施例6
程序如实施例4中那样,但在加料1和进料3中使用过二硫酸铵而不是过二硫酸钠,并且每种情况下用含水NaOH将pH调节至pH 9。
分散体然后进行超滤并测定以下特性:
在上述实施例变型中,当然还可以制备固体含量相差30重量%的分散体。为此例如可以在以下组分中加入去离子水(目的在于降低固体含量)或除去去离子水(目的在于提高固体含量):
a)初始进料,和/或
b)进料1,和/或
c)进料3。
在另一实施方案中,例如可以将来自初始进料的水投入进料1和/或进料3中,此时固体含量没有改变。然而,还可以以下方式进行再分布:将从初始进料和/或进料1和/或进料3中取出的水全部或部分投入新进料(″进料4″)中,此时进料4可平行加入聚合中,可延后或在聚合之后连续或立即全部加入聚合中。这例如用于使配制适合所用容器的尺寸,例如以避免进料1的过满或补充。
当然可能有利的是实施例中公开的初始进料和进料1的乳化剂分布以将来自初始进料的阴离子和/或非离子乳化剂投入进料1(或反之亦然)的方式改变。当然还可以将来自初始进料和/或进料1的阴离子和/或非离子乳化剂投入额外的进料4中(参见上文)。在所有这些测量的情况下,优选乳化剂总量维持恒定。
当然还可能有利的是进料1和/或进料2和/或进料3不以恒定速率计量加入,而以非恒定速率引入。例如,引发剂进料可以比进料2完成之后高的速率在聚合阶段过程中(即在进料2加入过程中)计量加入。
膜生产实施例
将来自实施例1的30%浓度的甲基丙烯酸二乙基氨基乙酯-甲基丙烯酸甲酯共聚物分散体在搅拌下与15%柠檬酸三乙酯(以固体计)混合,并将其铺展在涂布器(Erichsen Coatmaster)上,在45℃的板温度下干燥成膜。
膜厚度为100μm。
发现以下性能:
断裂伸长率: 93%
拉伸强度: 9.8N/mm2
根据DIN 53122在93%r.h.下的水蒸气渗透性: 58g/(m2/d)/100μm膜
在0.1N HCl中溶解时间: 2分钟50秒
在pH 6.8磷酸盐缓冲剂中溶解时间: >120分钟
通过Hoessel方法的粘性,
在20℃/80%r.h.下为0.25(用三醋精代替柠檬酸三乙酯作为增塑剂)
在30℃/75%r.h.下为0.25(用三醋精代替柠檬酸三乙酯作为增塑剂)
Cosmetics and Toiletries,111(8),第73页及后续页(1996)中描述的方法;
标度从0(不粘)至5(粘),r.h.=相对湿度
剂型包衣实施例
包衣实施例1:普萘洛尔盐酸40mg薄膜包衣片剂
片剂组成
物质 | 每片组成[mg] |
普萘洛尔盐酸 | 40 |
Ludipress | 97.5 |
Avicel PH 105 | 97.5 |
Kollidon VA 64 | 12.5 |
硬脂酸镁 | 2.5 |
全部 | 250 |
规格:9mm,包衣片剂
喷雾配制剂组成
物质 | 膜中比例[%] | 悬浮液中比例[%] |
来自实施例2的30%水分散体 | 67.83 | 45.22 |
柠檬酸三乙酯 | 10.17 | 2.03 |
铁红 | 2 | 0.4 |
滑石 | 20 | 4 |
软水 | - | 48.35 |
全部 | 100 | 100 |
将柠檬酸三乙酯增塑剂加入聚合物分散体中并继续搅拌。使滑石和铁红在水中淤浆化并使用高剪切混合器均化。然后通过将颜料悬浮液加入聚合物分散体中而混合两相。
包衣参数:
Manesty″Accela Cota 24″水平转鼓式涂漆机用于包衣。
设定以下条件或以下条件设定产生:
喷嘴 | 具有1mm液体插入物的Schlick 937 |
喷嘴数量 | 1 |
进料 | 10kg的普萘洛尔盐酸芯 |
芯床-喷嘴距离 | 20cm |
喷雾压力 | 1.5巴 |
模型空气压力(Patternair pressure) | 0.5巴 |
入口空气温度 | 60℃ |
出口空气温度 | 36℃ |
转鼓转速 | 15rpm |
喷雾速率 | 40g/min. |
喷雾时间 | 55分钟 |
干燥 | 约5分钟 |
施用率 | 6mg/cm2 |
薄膜包衣片剂性能
释放
桨,50rpm,37℃,1000ml
0.08N HCl | 磷酸盐缓冲剂pH 6.8 | |
45分钟之后 | >90% | <5% |
分解时间
Erweka型ZT 74分解测试器,37℃,800ml
0.08N HCl(min:s) | 磷酸盐缓冲剂pH 6.8(min:s) |
4:30 | >45分钟 |
包衣实施例2:依那普利10mg薄膜包衣片剂
片剂组成
物质 | 每片组成[mg] |
依那普利 | 10 |
Avicel PH 102 | 120 |
Di-Tab | 60 |
Kollidon CL | 8 |
硬脂酸镁 | 2 |
全部 | 200 |
规格:7mm,包衣片剂
喷雾配制剂组成
物质 | 膜中比例[%] | 悬浮液中比例[%] |
来自实施例3的30%水分散体 | 62.4 | 41.60 |
柠檬酸三丁酯 | 9.36 | 1.87 |
聚乙烯醇5-88 | 6.24 | 1.25 |
软水 | - | 30.88 |
二氧化钛 | 2.00 | 0.40 |
滑石 | 20.00 | 4.00 |
软水 | - | 20.00 |
全部 | 100.00 | 100.00 |
将柠檬酸三丁酯增塑剂加入聚合物分散体中并继续搅拌。使滑石和二氧化钛在水中淤浆化并使用高剪切混合器均化。在水中将聚乙烯醇加热至85℃并溶解。将冷却溶液搅拌加入聚合物分散体中。然后在搅拌下加入颜料悬浮液。
包衣参数:
Manesty″Accela Cota 24″水平转鼓式涂漆机用于包衣。
设定以下条件或以下条件设定产生:
喷嘴 | 具有1mm液体插入物的Schlick 937 |
喷嘴数量 | 1 |
进料 | 12kg的依那普利芯 |
芯床-喷嘴距离 | 20cm |
喷雾压力 | 1.5巴 |
模型空气压力 | 0.5巴 |
入口空气温度 | 65℃ |
出口空气温度 | 38℃ |
转鼓转速 | 15rpm |
喷雾速率 | 45g/min. |
喷雾时间 | 50分钟 |
干燥 | 约5分钟 |
施用率 | 5mg/cm2 |
结果
释放:桨,50rpm,37℃,1000ml
0.08N HCl | 磷酸盐缓冲剂pH 6.8 | |
45分钟之后 | >90% | <10% |
分解时间:Erweka型ZT 74分解测试器,37℃
0.08N HCl(min:s) | 磷酸盐缓冲剂pH 6.8(min:s) |
3:59 | >45 |
稳定性:在30℃/70%r.h.下贮存1年
依那普利含量(%)0个月 | 依那普利含量(%)12个月 | |
芯 | 100.2 | 92.3 |
薄膜包衣片剂 | 100.7 | 100.1 |
包衣实施例3:包衣布洛芬小丸剂
丸剂组成
物质 | 每丸组成[%] |
布洛芬 | 100 |
丸剂尺寸200-400μm
喷雾配制剂组成
物质 | 膜中比例[%] | 悬浮液中比例[%] |
来自实施例4的30%水分散体 | 65.42 | 43.61 |
三醋精 | 13.08 | 2.62 |
滑石 | 21.5 | 4.3 |
软水 | - | 49.47 |
全部 | 100 | 100 |
将三醋精增塑剂加入聚合物分散体中并继续搅拌。使滑石在水中淤浆化并使用高剪切混合器均化。然后混合两种制剂。
包衣参数
来自Glatt的″Glatt GPCG 3.1″流化床成粒机用于包衣。
设定以下条件或以下条件设定产生:
喷嘴 | 1mm直径 |
喷嘴数量 | 1 |
进料 | 2.5kg的布洛芬丸剂200-400μm |
喷嘴 | 1mm直径 |
工艺 | 底部喷雾(Wurster) |
喷雾压力 | 1.0巴 |
入口空气温度 | 60℃ |
出口空气温度 | 46℃ |
喷雾速率 | 12g/min. |
喷雾时间 | 4小时 |
干燥 | 约5分钟 |
所得施用率/重量 | 20% |
MUPS片剂的压片
可以通过混合及压制上文用102型微晶纤维素生产的包衣丸剂而生产片剂,其在分解时再分解成丸剂。
物质 | 每片组成[mg] |
包衣布洛芬小丸剂 | 120 |
微晶纤维素,102型 | 258 |
Kollidon CL | 20 |
硬脂酸镁 | 2 |
全部 | 400 |
规格:11mm,平坦,斜切
片剂和丸剂性能:
释放,丸剂,桨,50rpm,37℃,1000ml,重量250mg
乙酸盐缓冲剂pH 4.5 | 乙酸盐缓冲剂pH 6.8 | |
45分钟之后 | >90% | <10% |
片剂:
桨,50rpm,37℃,1000ml
乙酸盐缓冲剂pH 4.5 | 乙酸盐缓冲剂pH 6.8 | |
45分钟之后 | >90% | <15% |
片剂分解:
Erweka type ZT 74分解测试器,37℃
乙酸盐缓冲剂pH 4.5 | 乙酸盐缓冲剂pH 6.8 |
2:29 | 2:45 |
包衣实施例4:包衣咖啡因丸剂
丸剂组成
喷雾配制剂组成
物质 | 膜中比例[%] | 悬浮液中比例[%] |
来自实施例5的30%水分散体 | 62.61 | 41.74 |
乙酰柠檬酸三乙酯 | 9.39 | 1.88 |
铁黄 | 3 | 0.6 |
高岭土 | 25 | 5 |
软水 | - | 50.78 |
全部 | 100 | 100 |
将乙酰柠檬酸三乙酯增塑剂直接加入阳离子聚合物分散体中并继续搅拌。使滑石和铁黄在水中淤浆化并使用Ultraturrax均化。然后通过将颜料悬浮液加入聚合物分散体中而混合两相。
包衣参数:
来自Glatt的″Glatt GPCG 3.1″流化床成粒机用于包衣。
设定以下条件或以下条件设定产生:
喷嘴 | 1mm直径 |
喷嘴数量 | 1 |
进料 | 2.5kg咖啡因丸剂0.7-1.4mm |
工艺 | 顶部喷雾 |
喷雾压力 | 1.0巴 |
入口空气温度 | 60℃ |
出口空气温度 | 43℃ |
喷雾速率 | 14g/min. |
喷雾时间 | 135分钟 |
干燥 | 约5分钟 |
所得施用率/重量 | 15% |
释放:
桨,50rpm,37℃,1000ml,重量300mg
0.08N HCl | 磷酸盐缓冲剂pH 6.8 | |
45分钟之后 | >95% | <10% |
包衣实施例5:包衣硫酸奎宁小丸剂
丸剂组成
喷雾配制剂组成
物质 | 膜中比例[%] | 悬浮液中比例[%] |
来自实施例6的30%水分散体 | 68.26 | 45.51 |
三醋精 | 10.24 | 2.05 |
靛蓝色淀 | 1.5 | 0.3 |
滑石 | 20 | 4 |
软水 | - | 48.14 |
全部 | 100 | 100 |
将三醋精增塑剂直接加入阳离子聚合物分散体中并继续搅拌。将滑石和靛蓝色淀在水中淤浆化并使用Ultraturrax均化。然后通过将颜料悬浮液加入聚合物分散体中而混合两种制剂。
包衣参数:
来自Glatt的″Glatt GPCG 3.1″流化床成粒机用于包衣。
设定以下条件或以下条件设定产生:
喷嘴 | 1mm直径 |
喷嘴数量 | 1 |
进料 | 1.5kg硫酸奎宁丸剂125-300μm |
工艺 | 底部喷雾(Wurster) |
喷雾压力 | 1.0巴 |
喷嘴 | 1mm直径 |
入口空气温度 | 60℃ |
出口空气温度 | 47℃ |
喷雾速率 | 10g/min. |
喷雾时间 | 225分钟 |
干燥 | 约5分钟 |
所得施用率/重量 | 30% |
释放:
桨,50rpm,37℃,1000ml,重量300mg
0.08N HCl | 磷酸盐缓冲剂pH 6.8 | |
45分钟之后 | >90% | <10% |
Claims (32)
1.一种通过在pH至少为8下在含水介质中自由基乳液聚合包含以下组分的单体混合物M)而制备聚合物水分散体Pd)的方法:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种能够自由基聚合的选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的化合物。
2.根据权利要求1的方法,其中甲基丙烯酸甲酯用作组分b)。
3.根据权利要求1或2的方法,其中使用包含以下组分的单体混合物M):
-基于聚合用单体的总重量为25-65重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),和
-基于聚合用单体的总重量为35-75重量%的至少一种化合物b)。
4.根据上述权利要求中任一项的方法,其中使用由以下组分组成的单体混合物M):
-基于聚合用单体的总重量为43-47重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),和
-基于聚合用单体的总重量为53-57重量%的至少一种化合物b)。
5.根据上述权利要求中任一项的方法,其中所述自由基乳液聚合在至少一种非离子乳化剂或包含至少一种阴离子乳化剂和至少一种非离子乳化剂的乳化剂混合物存在下进行。
6.根据权利要求5的方法,其中所述非离子乳化剂包含至少一种具有12-30个碳原子的醇的脂肪醇烷氧基化物。
7.根据权利要求6的方法,其中所述非离子乳化剂选自每种情况下具有10-30个氧化乙烯单元的鲸蜡醇和/或硬脂醇乙氧基化物。
8.根据上述权利要求中任一项的方法,其中至少一种无机过氧化物用作自由基乳液聚合用引发剂。
9.根据权利要求8的方法,其中所述引发剂选自过二硫酸铵和碱金属过二硫酸盐。
10.根据权利要求8或9的方法,其中pH大于2,优选大于3,尤其是大于4的至少一种无机过氧化物水溶液用作自由基乳液聚合用引发剂。
11.根据权利要求8-10中任一项的方法,其中在其紧临用于聚合之前制备的或在其用于聚合之前pH值通过加入至少一种碱而调节到大于2,优选大于3,尤其是大于4的过二硫酸钠水溶液或过二硫酸钾水溶液用作自由基乳液聚合用引发剂。
12.根据权利要求8-11中任一项的方法,其中过二硫酸盐浓度为0.5-20重量%,特别优选2-10重量%的过二硫酸盐水溶液用作自由基乳液聚合用引发剂。
13.根据上述权利要求中任一项的方法,其中在开始自由基乳液聚合之前在聚合区中不引入单体。
14.根据上述权利要求中任一项的方法,其中所述自由基乳液聚合不在种子胶乳存在下进行。
15.根据上述权利要求中任一项的方法,其中甲基丙烯酸N,N-二乙基氨基乙酯a)与水在混合装置中在其紧临用于聚合之前混合。
16.根据权利要求15的方法,其中甲基丙烯酸N,N-二乙基氨基乙酯a)与水、至少一种乳化剂及合适的话至少一种其它单体在混合装置中混合而得到单体乳液。
17.根据权利要求15或16的方法,其中使用包括至少一个动态混合器的混合装置。
18.根据上述权利要求中任一项的方法,其中与聚合物水分散体Pd)接触的所有系统部件与碱在开始自由基乳液聚合之前接触。
19.根据上述权利要求中任一项的方法,其中将所得聚合物分散体Pd)进行超滤。
20.可通过根据权利要求1-19中任一项定义的方法获得的聚合物水分散体Pd)。
21.一种通过降低pH而可溶且包含以下组分的聚合物水分散体Pd):-至少一种包含作为共聚单元的以下组分的聚合物:
a)甲基丙烯酸N,N-二乙基氨基乙酯,和
b)至少一种能够自由基聚合且选自α,β-烯属不饱和单-和二羧酸与C1-C8链烷醇的酯的化合物,
-至少一种选自阴离子和非离子乳化剂的乳化剂,和
-水。
22.根据权利要求20的聚合物分散体,其包含聚合物,所述聚合物包含作为共聚物中仅有单体的以下组分:
-基于聚合用单体的总重量为43-47重量%的甲基丙烯酸N,N-二乙基氨基乙酯a),和
-基于聚合用单体的总重量为53-57重量%的至少一种化合物b)。
23.根据权利要求20-22中任一项的聚合物分散体,其包含不超过2500重量ppm,特别优选不超过1000重量ppm,尤其是不超过500重量ppm的N,N-二乙基氨基乙醇。
24.根据权利要求20-23中任一项的聚合物分散体,其包含不超过100重量ppm,特别优选不超过50重量ppm的甲基丙烯酸。
25.根据权利要求20-24中任一项的聚合物分散体,其包含不超过500重量ppm,特别优选不超过250重量ppm,尤其是不超过50重量ppm的甲醇。
26.一种包含根据权利要求20-25中任一项定义的聚合物水分散体Pd)或可通过干燥由其获得的聚合物组合物的包衣组合物。
27.根据权利要求26的包衣组合物,其额外包含至少一种其它聚合物组分。
28.一种包含以下组分的药物组合物或食品:
A)可通过根据权利要求20-25中任一项定义的聚合物分散体的干燥和/或成膜获得的聚合物组合物,
B)至少一种可药用活性成分或营养强化剂,和
C)合适的话至少一种可药用赋形剂或食品领域中可用助剂。
29.根据权利要求28的药物组合物或食品,其呈包含基于根据权利要求1-18中任一项定义的聚合物水分散体Pd)或可通过干燥由其获得的聚合物组合物的包衣的口服剂型形式。
30.根据权利要求28的药物组合物或食品,其呈包衣的片剂、丸剂、微胶囊、颗粒或晶体形式。
31.根据权利要求20-25中任一项定义的聚合物水分散体Pd)在膜生产、化妆品、作物保护、种子包衣、食品、兽药、动物营养、作为粘合原料、造纸、作为皮革和织物用粘合剂或助剂、作为杀微生物表面包衣、非织造物领域、洗涤剂和清洁剂、油漆生产、建筑领域中的用途。
32.根据权利要求20-25中任一项定义的聚合物水分散体Pd)作为或在化妆品、食品、兽药、动物营养、种子以及织物、纸张、印刷、皮革和粘合剂工业用包衣组合物中的用途。
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- 2008-08-01 CN CN200880101625XA patent/CN101778870B/zh active Active
- 2008-08-01 EP EP08786773.5A patent/EP2176301B1/de active Active
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CN103347931A (zh) * | 2011-02-28 | 2013-10-09 | 巴斯夫欧洲公司 | 制备用于药物剂型的稳定保护性衣层的粉末包衣剂 |
CN103403069A (zh) * | 2011-02-28 | 2013-11-20 | 巴斯夫欧洲公司 | 制备用于药物剂型的稳定保护涂层的粉末涂覆剂的方法 |
CN103347931B (zh) * | 2011-02-28 | 2016-02-17 | 巴斯夫欧洲公司 | 制备用于药物剂型的稳定保护性衣层的粉末包衣剂 |
CN103403069B (zh) * | 2011-02-28 | 2017-06-13 | 巴斯夫欧洲公司 | 制备用于药物剂型的稳定保护涂层的粉末涂覆剂的方法 |
CN104159576A (zh) * | 2012-03-09 | 2014-11-19 | 巴斯夫欧洲公司 | 在中性环境中具有良好抗性的药物保护性涂层的制备 |
CN104159576B (zh) * | 2012-03-09 | 2017-09-22 | 巴斯夫欧洲公司 | 在中性环境中具有良好抗性的药物保护性涂层的制备 |
CN109851696A (zh) * | 2019-01-14 | 2019-06-07 | 英德茂丰药业有限公司 | 一种降低含叔氨基(甲基)丙烯酸酯共聚物残留单体和溶剂的方法 |
CN109851696B (zh) * | 2019-01-14 | 2021-07-02 | 英德茂丰药业有限公司 | 一种降低含叔氨基(甲基)丙烯酸酯共聚物残留单体和溶剂的方法 |
CN114196234A (zh) * | 2021-12-23 | 2022-03-18 | 江苏圣天新材料有限公司 | 一种软性硅微粉及其制备方法 |
Also Published As
Publication number | Publication date |
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EP2176301A1 (de) | 2010-04-21 |
US9732200B2 (en) | 2017-08-15 |
JP5632282B2 (ja) | 2014-11-26 |
US20140335182A1 (en) | 2014-11-13 |
WO2009016258A1 (de) | 2009-02-05 |
US20110033532A1 (en) | 2011-02-10 |
JP2010535261A (ja) | 2010-11-18 |
EP2176301B1 (de) | 2013-05-15 |
US8790693B2 (en) | 2014-07-29 |
CN101778870B (zh) | 2012-11-07 |
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