CN117615751A - 包含(甲基)丙烯酸酯共聚物、饱和脂族单羧酸的碱金属盐或铵盐以及特定助流剂的组合物 - Google Patents
包含(甲基)丙烯酸酯共聚物、饱和脂族单羧酸的碱金属盐或铵盐以及特定助流剂的组合物 Download PDFInfo
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- CN117615751A CN117615751A CN202280048285.9A CN202280048285A CN117615751A CN 117615751 A CN117615751 A CN 117615751A CN 202280048285 A CN202280048285 A CN 202280048285A CN 117615751 A CN117615751 A CN 117615751A
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Abstract
本发明涉及一种适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的组合物,其包含以下组分:a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,以及c)或d)或者c)和d)二者:c)基于a)的总重量计2至25重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山
Description
技术领域
本发明涉及一种适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的组合物,其包含以下组分:
a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和
b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,
以及c)或d)或者c)和d)二者
c)基于a)的总重量计2至25重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯的化合物,和/或
d)基于a)的总重量计25至90重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素的化合物。
另外,本发明还涉及一种水性分散体,其包含水和5至50重量%的根据本发明的组合物,以及剂型,其包含药物、营养制品或化妆品活性成分和聚合物包衣或聚合物基体,其中所述聚合物包衣或所述聚合物基体包含根据本发明的组合物。最后,本发明涉及根据本发明的组合物作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的用途。
背景技术
一些保健成分和活性药物成分(API)需要保护以免受胃中酸性环境的影响,或者应当在小肠中释放以避免刺激粘膜或打嗝效应。因此,需要肠溶包衣以确保在小肠中的保留释放(save release)。有一些市场上可得的聚合物显示出对于补充剂和药物的延迟释放。
对于补充剂,现有的方案可包含聚合物的组合,例如纤维素和藻酸盐或者虫胶和藻酸盐,但没有可得的单一的聚合物可以提供所需的性能。
L 100和/>L 100-55是公知的可商购获得的用于药物应用的(甲基)丙烯酸酯共聚物产品。/>L 100是由50重量%的甲基丙烯酸甲酯和50重量%的甲基丙烯酸聚合而成的共聚物。特定的活性成分在肠液或模拟肠液中开始释放的pH为约pH 6.0。/>L 100-55是由50重量%的丙烯酸乙酯和50重量%的甲基丙烯酸聚合而成的共聚物。特定的活性成分在肠液或模拟肠液中开始释放的pH为约pH 5.5。
然而,L 100和/>L 100-55未经监管机构批准用于补充剂。另外,对于药物而言,在pH 6.8下释放的情况下,还存在减少在包衣配制剂中或者在聚合物基体形成剂(formation)中的羧酸基团总量的倾向。
FS是由10重量%的甲基丙烯酸、65重量%的丙烯酸甲酯和25重量%的甲基丙烯酸甲酯聚合而成的共聚物,它的甲基丙烯酸基团的含量比在L 100或/>L 100-55中的甲基丙烯酸基团的含量低五倍。然而,/>FS聚合物的特定活性成分开始释放时的pH为高于pH 7.0。
US 5644011公开了一种包含丙烯酸系共聚物的包衣剂。实施例4公开了用丙烯酸酯聚合物和甘油单硬脂酸酯的混合物将比沙可啶丸粒进行包衣。然而,所述包衣在pH 6.8下以非常快的速率从所述丸粒中释放比沙可啶(在45分钟内100%释放)。
类似地,WO 2020/114714 A1公开了用Eudragit FS 30D聚合物将二羟丙茶碱丸粒进行包衣。然而,在pH达到6.8的20分钟内,活性成分就被释放出来。Eudragit FS是由甲基丙烯酸甲酯、丙烯酸甲酯和甲基丙烯酸聚合而成的共聚物。
因此,需要肠溶包衣或粘结组合物,其易于分散在水中以形成分散体,该分散体适合于在含有活性成分的芯或含有活性成分的基体组合物上产生肠溶包衣。进一步地,还需要以下组合物和衍生剂型,其具有相对降低含量的酸基团,但同时其具有以下特征:约在pH7.0以下,例如在pH 6.8,活性组分在肠液中开始释放。
发明内容
因此,本发明的目的是提供一种包衣,其在肠中有效释放活性成分,在目标pH水平6.8下在180分钟,优选90分钟后释放至少70%,优选80%,更优选90%的活性成分。
本发明的发明人已经惊奇地发现,这些目的可通过特定的根据本发明的组合物得以解决,所述组合物需要至少一种特定的(甲基)丙烯酸酯共聚物,特定量的至少一种特定的饱和脂族单羧酸的碱金属盐或铵盐,以及特定量的特定的助流剂。特别地,只有确定量的这三种组分的确定组合才能在pH值6.8下产生所需的释放。
发明概述
在第一方面,本发明涉及一种组合物,其适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂,该组合物包含以下组分:
a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和
b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%,优选5至18重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,
以及c)或d)或者c)和d)二者
c)基于a)的总重量计2至25重量%,优选2至20重量%,更优选5至15重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯的化合物,和/或
d)基于a)的总重量计25至90重量%,优选25至75重量%,更优选40至60重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素的化合物。
另外,在第二方面,本发明还涉及一种水性分散体,其包含水和5至50重量%的根据本发明的组合物。
在第三方面,本发明涉及一种剂型,其包含药物、营养制品或化妆品活性成分和聚合物包衣或聚合物基体,其中所述聚合物包衣或所述聚合物基体包含根据本发明的组合物。
在第四方面,本发明涉及根据本发明的组合物作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的用途。
本发明公开了一种通过梯度乳液聚合利用如下的总单体组合物制备聚合物粒子形式的(甲基)丙烯酸酯共聚物a)的方法,所述(甲基)丙烯酸酯共聚物a)包含由甲基丙烯酸和其它单体形成的聚合单元,所述总单体组合物包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的其它单体,其中所述其它单体选自甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,其中由甲基丙烯酸形成的聚合单元与由其它单体形成的聚合单元的重量比例从所述粒子的中心到表面以梯度方式增加,和其中所述聚合物粒子以水性分散体的形式获得。
术语“从所述粒子的中心到表面”的意思应当指,假设粒子是圆形或球形的,从所述聚合物粒子内部的中点(中心)到(朝向)所述粒子的外部(表面)的直接路径。由甲基丙烯酸形成的聚合单元的含量从所述聚合物粒子的中心到表面增加。
本发明的发明人认为,由所公开的方法得到的(甲基)丙烯酸酯共聚物a)聚合物的粒子显示出,与它们总体上低的甲基丙烯酸含量相比,在它们表面上的由甲基丙烯酸形成的聚合单元的羧酸基团的浓度是增加的。尽管所述总体甲基丙烯酸含量相对较低,但看起来所公开的聚合物粒子,当在包含活性成分的剂型中被用作包衣或粘结材料时,其作用类似于具有高得多的甲基丙烯酸含量的共聚物或共聚物粒子。因此,提供一种制备聚合物粒子的方法,所述聚合物粒子具有相对较低的总体甲基丙烯酸含量,并且同时具有预料不到的低溶出和活性成分释放行为。
本发明的发明人已经惊奇地发现,包含所述(甲基)丙烯酸酯共聚物a)与具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐以及特定组分c)和/或d)的组合的组合物显示出甚至在比单独包含所述(甲基)丙烯酸酯共聚物a)的组合物更低的pH下释放活性成分。根据本发明的组合物适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂。
发明详述
本发明涉及一种组合物,其适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂,该组合物包含以下组分:
a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和
b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%,优选5至18重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,
以及c)或d)或者c)和d)二者
c)基于a)的总重量计2至25重量%,优选2至20重量%,更优选5至15重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯的化合物,和/或
d)基于a)的总重量计25至90重量%,优选25至75重量%,更优选40至60重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素的化合物。
优选地,在所述组合物中的(甲基)丙烯酸酯共聚物a)的固体含量为至少10重量%,优选20至90重量%。
组分a):(甲基)丙烯酸酯共聚物
所述组合物包含至少一种(甲基)丙烯酸酯共聚物a)。
所述(甲基)丙烯酸酯共聚物a)包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯。所述(甲基)丙烯酸酯共聚物a)可以聚合物粒子的形式存在。优选地,所述单体可总计达100%。
丙烯酸或甲基丙烯酸的C1至C4烷基酯特别是甲基丙烯酸甲酯、甲基丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸甲酯、丙烯酸乙酯和丙烯酸丁酯。
所述(甲基)丙烯酸酯共聚物a)可源自乳液聚合法,其中将全部量的总单体加料并且在一个步骤中同时聚合成聚合物粒子。该方法的结果是,所述聚合物粒子显示出所述单体的唯一分布,尤其是由甲基丙烯酸形成的聚合单元,可以被认为从所述粒子的中心(内部)和表面(外部)来看是恒定的。
所述聚合物粒子可以水性分散的形式存在或者以通过干燥由包含所述聚合物粒子的水性分散体获得的可再分散粉末的形式存在。
优选地,所述(甲基)丙烯酸酯共聚物a)包含以下单体组合物,该单体组合物包含由以下物质形成的聚合单元:10至30重量%的甲基丙烯酸甲酯、50至70重量%的丙烯酸甲酯和5至15重量%的甲基丙烯酸。优选地,所述单体优选总计达100%。
合适的(甲基)丙烯酸酯共聚物a)是以商品名FS 30D或biotic销售的以30重量%水性分散体的形式的可商购获得的(甲基)丙烯酸酯共聚物。所述共聚物是由10重量%的甲基丙烯酸、65重量%的丙烯酸甲酯和25重量%的甲基丙烯酸甲酯聚合而成的。
所述(甲基)丙烯酸酯共聚物a)的特定溶出pH值,尤其是FS 30 D聚合物的特定溶出pH值,为约pH 7.0至pH 7.2。在低于pH 7.0,例如在pH 6.8的情况下,不会有明显的溶出。
制备(甲基)丙烯酸酯共聚物a)的方法
所述(甲基)丙烯酸酯共聚物a)可以本领域中已知的方式通过单体的自由基聚合来制备,如例如在EP 0 704 207 A2和EP 0 704 208 A2中所描述的。所述(甲基)丙烯酸酯共聚物a)可通过间歇法由自由基聚合的常规方法连续制备,例如在自由基形成引发剂和,如果合适,未稀释的用于调节分子量的调节剂的存在下,通过乳液聚合制备,在溶液中,通过珠状聚合,或者在乳液中制备。平均分子量Mw(重均,例如通过测量溶液粘度测定的)可例如在80 000g/mol至1 000 000g/mol范围内。
在水溶性引发剂和优选阴离子乳化剂的存在下在水相中的乳液聚合是优选的。所得的聚合物粒子的重均尺寸(半径)通常在50至500,优选80至300nm范围内,因此确保了粘度低于1000mPa·s,这有利于加工技术。所述粒子尺寸可通过激光衍射来测定,例如,使用Mastersizer 2000(得自Malvern Inc.)。
在本体聚合的情况下,所述共聚物可通过破碎、挤出、造粒或热切割以固体形式获得。
所述(甲基)丙烯酸酯共聚物a)可以本领域中已知的方式通过自由基本体聚合、溶液聚合、珠状聚合或乳液聚合获得。在加工之前,可以通过适当的研磨、干燥或喷射方法将其调整到适当的粒子尺寸范围。这可通过简单地破碎已挤出和冷却的丸粒或热切割来实现。使用聚合物粉末可能是有利的,尤其是对于与其它粉末或液体混合而言。适合于制备粉末的典型设备是本领域技术人员公知的,例如:空气喷射磨机、钉盘磨机(pinned discmill)、多室式磨机。如果合适,可以包括适当的筛分步骤。用于工业大批量的合适的研磨机例如是在约6巴表压下操作的对撞式喷射磨机(Multi No.4200)。
乳液聚合法可有利地在聚合反应器中分别通过单体乳液进料法或单体进料法进行。为此,将水在聚合反应器中加热到反应温度。可以在此阶段添加表面活性剂和/或引发剂。可以在添加所述引发剂之前将全部量的所有单体加料到所述反应器中。这种方法经常被称为“间歇乳液法”。
可以使用的乳化剂尤其是阴离子和非离子表面活性剂。基于所述单体的总重量计,乳化剂的用量通常不超过5重量%,优选为0.1至3重量%。典型的乳化剂例如是烷基硫酸盐(例如十二烷基硫酸钠)、烷基醚硫酸盐、二辛基磺基琥珀酸钠、聚山梨酯(例如聚氧乙烯(20)脱水山梨醇单油酸酯)、壬基酚乙氧基化物(壬苯醇醚-9)等。
除了在乳液聚合中常规使用的那些聚合引发剂(例如过氧化合物,例如过氧二硫酸铵(APS))之外,还可以应用氧化还原体系,例如亚硫酸氢钠-APS-铁。另外,可以应用水溶性偶氮引发剂和/或可以使用引发剂的混合物。基于所述单体的重量计,引发剂的量通常在0.005至0.5重量%,优选0.01至0.3重量%之间。
可以添加链转移剂以改进工艺稳定性和重均分子量(Mw)的再现性。链转移剂的典型的量可以是基于单体重量计的0.05至1重量%。典型的链转移剂可以是例如巯基乙酸2-乙基己酯(TGEH)或正十二烷基硫醇(nDDM)。然而,在一些情况下,可以省略所述链转移剂,而不影响根据本发明的性能。
典型的乳液聚合液可包含典型重量比为约3至7的所述单体和水作为主要组分,以及0.005至0.5重量%的一种或多种聚合引发剂、0.05至1重量%的一种或多种链转移剂、小于5重量%或0.1至3.0重量%的乳化剂和0至0.5重量%的消泡剂,其中所有组分优选总计达100%。
聚合温度在一定限度内取决于所述引发剂。例如,如果使用APS,则在60至90℃范围内进行操作是有利的;如果使用氧化还原体系,则还可以在更低温度下进行聚合,例如在30℃下。
在所述方法结束时,通常使反应器内容物冷却,例如冷却到20至25℃,并且可以例如通过250μm gaze过滤所得的分散体。
在所述乳液聚合中产生的聚合物粒子的平均粒子尺寸(D50)的范围可以为50至500nm,优选80至300nm。所述聚合物粒子的平均粒子尺寸可通过本领域技术人员公知的方法测定,例如通过激光衍射的方法。所述粒子尺寸可通过激光衍射,使用Mastersizer 2000(Malvern)来测定。这些值可以表示为粒子半径rMS[nm],它是基于体积的粒子尺寸分布d(v,50)的中值的一半。
还可以优选通过喷雾干燥、喷雾造粒、冷冻干燥、凝结或挤出将所述分散体干燥成粉末或颗粒。因此,可以获得固体粉末或颗粒,其在处理和物流方面提供了某些优点。干燥的粉末或颗粒可被用作基体剂型的聚合物粘结剂。
然后可以通过将所述固体再分散在水中,例如(如果需要)通过使用高剪切混合器,将经干燥的聚合产物转移到包衣悬浮液中。
所述(甲基)丙烯酸酯共聚物a)的水性分散体
所述(甲基)丙烯酸酯共聚物a)通常以水性分散体的形式得自乳液聚合法,或者可作为这种分散体商购获得(FS 30 D),例如以约30重量%的聚合物浓度。然后可将组分b)以及c)和/或d))和任选将药物、营养制品或化妆品辅料添加到所述水性分散体中以在作为包衣剂或粘结剂的应用中进行进一步加工。
粉末或颗粒
通过将所述水性分散体喷雾干燥、喷雾造粒、喷雾附聚、冷冻干燥、凝结或挤出,可以将所述(甲基)丙烯酸酯共聚物a)由所述水性分散体转化为干燥形式,优选转化为粉末或颗粒。所得的颗粒或粉末可具有在约0.01至5mm范围内的粒子尺寸D50。粉末可具有在约0.01直至小于0.5mm范围内的粒子尺寸D50。颗粒可具有在约0.5mm至5mm范围内的粒子尺寸D50。颗粒的平均粒子尺寸优选通过公知的筛分方法确定。粉末的粒子尺寸D50优选通过激光衍射确定。(甲基)丙烯酸酯共聚物a)的干燥形式可用于再分散成水性分散体,或者可替代地,用于与组分b)以及c)和/或d)干混合,从而以如所公开的干燥形式获得(即用型)组合物。所述干燥形式可被再转化为水性分散体,然后可以任选添加药物辅料、营养制品辅料或化妆品辅料以在作为包衣剂或粘结剂的应用中进行进一步加工。
组分b):单羧酸
所述组合物包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%,优选5至15重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐。
所述具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐可选自由以下单羧酸形成的碱金属盐或铵盐:癸酸(羊蜡酸,C10)、十一烷酸、十二烷酸(月桂酸,C12)、十三烷酸、十四烷酸、十五烷酸、十六烷酸(hexadecenoic acid)(棕榈酸,C16)、十七烷酸、十八烷酸(硬脂酸,C18)、十九烷酸、二十烷酸(花生酸,C20)、二十一烷酸(山萮酸,C22)、二十二烷酸、二十三烷酸、二十五烷酸、二十六烷酸(蜡酸(ceratic acid))、二十七烷酸、二十八烷酸、二十九烷酸和三十烷酸(蜂花酸,C30)。
优选地,所述具有10至30个碳原子的饱和脂族单羧酸的碱金属盐是硬脂酸钠。
组分c)和d)
除了所述组分a)和b)之外,所述组合物还包含组分c)或d)或者c)和d)(两者)。
组分c):甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯
所述组合物可包含基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计2至25重量%,优选2至20重量%,更优选5至15重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯或它们的混合物的化合物。在一个实施方案中,所述化合物是甘油三硬脂酸酯。在一个实施方案中,所述化合物是羟丙基甲基纤维素。在一个实施方案中,所述化合物是甘油山萮酸酯。在一个实施方案中,所述化合物是甘油单硬脂酸酯。
组分d):滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素
所述组合物可包含基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计25至90重量%,优选25至75重量%,更优选40至60重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素或它们的混合物的化合物。在一个实施方案中,所述化合物是滑石。在一个实施方案中,所述化合物是粉末形式的稻壳,其例如可以商品名商购自RIBUS Inc,或以/>商购自RIBUS Inc。在一个实施方案中,所述化合物是硬脂酸镁。在一个实施方案中,所述化合物是玉米淀粉。在一个实施方案中,所述化合物是微晶纤维素。
所述组合物的制备
所公开的组合物可以通过混合所述组分a)、b)以及c)和/或d)以多种方式制备。以下实例可给出指导:可将预期量的所述具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐b),例如硬脂酸钠,通过加热到约50至80℃以约1至10重量%的浓度溶解或分散在水中。然后例如通过使用FS 30 D,将所得的溶液或分散体添加到大致相同体积的聚合物含量为约30重量%的所述至少一种(甲基)丙烯酸酯共聚物a)的分散体中,从而得到中间分散体。所述中间分散体可显示出约12至18重量%的(甲基)丙烯酸酯共聚物a)含量。然后可以在剧烈搅拌下,例如在10,000至15,000rpm下搅拌2至20分钟,将组分c)和/或d)添加到所得的分散体中。所得的最终分散体可以在喷雾干燥过程中进行干燥,例如在约75至85℃的入口温度和约45至50℃的出口温度下干燥。所得的粉末产物包含所公开的组合物并且可被直接加工或者可另选地以再分散形式用作用于含有活性成分的剂型的包衣剂或粘结剂。或者,所得的最终分散体无需预先干燥即被直接使用。
剂型
根据本发明的剂型包含根据本发明的组合物,药物、营养制品或化妆品活性成分和聚合物包衣或聚合物基体,其中所述聚合物包衣或所述聚合物基体包含根据本发明的组合物。
聚合物包衣可例如通过将包含所述至少一种(甲基)丙烯酸酯共聚物a)聚合物粒子与所述至少一种组分b)以及c)和/或d)和任选添加的药物、营养制品或化妆品辅料的水性分散体进行喷涂而施加到包含药物、营养制品或化妆品活性成分的芯上。基于所述芯的重量计,所述包衣层的量可以在约3至50重量%,优选4至30重量%的范围内。所述包衣层的厚度可以在约10至100μm,优选15至80μm范围内。
聚合物基体可以例如通过诸如湿法或干法造粒、挤出造粒或粉末粘结的方法,衍生自包含本发明的组合物和任选添加的药物辅料、营养制品辅料或化妆品辅料的水性分散体,或衍生自这种水性分散体的经喷雾干燥的粉末,其中添加了药物活性成分、营养制品活性成分或化妆品活性成分和任选额外的药物辅料、营养制品辅料或化妆品辅料,例如抗氧化剂、增白剂、粘结剂、调味剂、流动助剂、芳香剂、渗透促进剂,颜料、增塑剂、聚合物、成孔剂或稳定剂。
所述剂型可以是包衣剂型,其包含芯和包覆到所述芯上的聚合物包衣,所述芯包含活性成分,优选营养制品活性成分,其中所述包衣包含聚合物膜,该聚合物膜衍生自在成膜工艺过程中所述聚合物粒子的聚集。所述剂型的形式可以是例如包衣或未包衣的丸粒、包衣或未包衣的片剂、填充有丸粒的胶囊、小袋等。
所述剂型可以是基体剂型,其包含包埋在聚合物基体中的活性成分,优选营养制品活性成分,所述聚合物基体衍生自在基体形成过程中所述聚合物粒子的聚集。
活性成分释放
具有用根据本发明的组合物包衣的含有药物活性成分、营养制品活性成分或化妆品活性成分的芯的剂型在pH 1.2下1或2小时后可表现出10%或更少的活性成分释放(在根据USP 41方法2的介质中,桨速100rpm)。
具有用所公开的组合物包衣的含有药物活性成分、营养制品活性成分或化妆品活性成分的芯的剂型在pH 1.2的介质中2小时后可表现出10%或更少的活性成分释放,并且在随后的pH 6.8介质中60分钟后可表现出40%或更多,优选42%或更多的活性成分释放(根据USP 41方法2的介质,桨速100rpm)。
具有用所公开的组合物包衣的含有药物活性成分、营养制品活性成分或化妆品活性成分的芯的剂型在pH 1.2的介质中2小时后可表现出10%或更少的活性成分释放,并且在随后的pH 6.8介质中90分钟后可表现出70%或更多,优选80%或更多的活性成分释放(根据USP 41方法2的介质,桨速100rpm)。
药物、营养制品或化妆品活性成分
药物、营养制品或化妆品活性成分可选自益生元和选自益生菌。在一个实施方案中,所述成分选自以下物质,这些物质能够产生打嗝、刺激粘膜或对胃中的酸性环境敏感,例如鱼油、大蒜油、辣椒提取物、维生素和酶。
药物以及还有营养制品或化妆品活性成分可选自镇痛剂、抗生素或抗感染剂、抗体、抗癫痫剂、植物抗原、抗风湿剂、β阻滞剂、苯并咪唑衍生物、β-阻滞剂、心血管药物、化疗药物、CNS药物、洋地黄糖苷、胃肠道药物,例如质子泵抑制剂、酶、激素、液体或固体天然提取物、寡核苷酸、肽激素蛋白、治疗性细菌、肽、泌尿学药物和疫苗。
在一个实施方案中,所述药物活性成分、营养制品活性成分或化妆品活性成分选自鱼油、大蒜油、辣椒提取物、维生素、酶、矿物质、绿茶、草药、精油、大麻、益生菌、益生元、纤维、氨基酸、桉树油、橙油、哈勒姆油、人参、生姜、真菌、磷脂酰胆碱、天然提取物、氨基葡萄糖、软骨素、硫辛酸或它们的混合物。
药物活性成分
本发明优选可用于以下药物活性成分,其中在所述包衣配制剂中或在所述聚合物基体形成剂(formation)中的羧酸基团的总量应保持是较低的,但所述活性成分释放预期在pH 4.3至5.8的范围内就已经开始。
在所公开的剂型中使用的药物(以及还有营养制品或化妆品)活性成分的治疗和化学类别可选自镇痛剂、抗生素或抗感染剂、抗体、抗癫痫剂、植物抗原、抗风湿剂、β阻滞剂、苯并咪唑衍生物、心血管药物、化疗药物、CNS药物、洋地黄糖苷、胃肠道药物,例如质子泵抑制剂、酶、激素、液体或固体天然提取物、寡核苷酸、肽激素蛋白、治疗性细菌、肽、泌尿学药物和疫苗。
药物活性成分的实例可以是:阿坎酸、七叶皂苷、淀粉酶、乙酰水杨酸、肾上腺素、5-氨基水杨酸、金霉素、杆菌肽、巴沙拉嗪、β胡萝卜素、比卡鲁胺比沙可啶、菠萝蛋白酶、菠萝蛋白酶、布地奈德、降钙素、卡马西平(carbamacipine)、卡铂、头孢菌素、西曲瑞克、克拉霉素、氯霉素、西咪替丁、西沙必利、克拉屈滨、苯二氮卓(clorazepate)、克罗马林(cromalyn)、1-脱氨基半胱氨酸-8-D-精氨酸-加压素、德伦环烷、地肽瑞里、右兰索拉唑、双氯芬酸、去羟肌苷、洋地黄毒苷和其它洋地黄糖苷、二氢链霉素、聚二甲基硅氧烷、双丙戊酸盐(divalproex)、屈螺酮、度洛西汀、酶、红霉素、埃索美拉唑、雌激素、依托泊苷、法莫替丁、氟化物、大蒜油、胰高血糖素、粒细胞集落刺激因子(G-CSF)、肝素、氢化可的松、人生长激素(hGH)、布洛芬、艾普拉唑、胰岛素、干扰素、白细胞介素、内含子A、酮洛芬、兰索拉唑、醋酸亮丙瑞林(leuprolidacetat)脂肪酶、硫辛酸、锂、激肽、美金刚、美沙拉嗪、乌洛托品、哌甲酯、米拉美林、矿物质、米诺拉唑(minoprazole)、萘普生、纳他霉素、呋喃妥因、新生霉素、奥沙拉嗪、奥美拉唑、乳清酸盐(orothate)、胰酶、泮托拉唑、甲状旁腺激素、帕罗西汀、青霉素、吡帕拉唑(perprazol)、吲哚洛尔、多粘菌素、钾、普伐他汀、泼尼松、丙谷美辛(preglumetacin)普罗加比、原-生长抑素(pro-somatostatin)、蛋白酶、喹那普利、雷贝拉唑、雷尼替丁、雷诺嗪、瑞波西汀、芸香苷(rutosid)、生长抑素(somatostatin)链霉素、枯草菌素、柳氮磺胺吡啶、氨苯磺胺(sulphanilamide)、坦索罗辛、替那拉唑、胰蛋白酶(thrypsine)、丙戊酸、加压素、维生素、锌,包括它们的盐、衍生物、多晶型体、同晶型体或它们的一种或多种混合物或组合。合适的药物活性成分是例如二羟丙茶碱。
营养制品和/或化妆品活性成分
营养制品和/或化妆品对于本领域技术人员是公知的。营养制品和化妆品经常被定义为声称对人类健康具有医疗作用的食物提取物。因此,营养制品和/或化妆品活性成分也可能表现出药物活性:营养制品活性成分的实例可以是作为抗氧化剂的得自葡萄产品的白藜芦醇,可溶性膳食纤维产品,例如用于降低过高胆固醇血症的洋车前子壳,作为癌症保护剂的花椰菜(硫烷),和改善动脉健康的大豆或三叶草(异黄酮类化合物)。因此,很明显,越来越多的被列为营养制品或化妆品的物质也可以被指示为药物活性成分。
根据地域、具体应用、地方当局的立法和分类,相同的物质可能被列为药物活性成分或列为营养制品或化妆品活性成分,或者列为药物或营养制品或化妆品组合物或甚至两者兼而有之。因此,对于本领域技术人员来说显而易见的是,在术语药物活性成分、营养制品活性成分和/或化妆品活性成分与药物组合物或营养制品组合物或化妆品组合物各自之间存在广泛的重叠。
营养制品,化妆品,或营养制品活性成分和化妆品活性成分有时被定义为声称对人类健康具有医疗作用的食物提取物。
营养制品,化妆品,或营养制品活性成分和化妆品活性成分还可包括益生菌和益生元。益生菌是被认为在食用时支持人类或动物健康的活的微生物,例如乳杆菌(Lactobacillus)属或双歧杆菌(Bifidobacterium)属的某些菌株。益生元是诱导或促进人类或动物肠道中有益微生物生长或活性的营养制品或营养制品活性成分。
所述营养制品和化妆品活性成分可通常以处方剂量包含在诸如胶囊、片剂或粉末的医药形式中。营养制品或化妆品的实例是作为抗氧化剂的来自葡萄产品的白藜芦醇或来自浆果的(原-)花青素,可溶性膳食纤维产物,例如用于降低过高胆固醇血症的洋车前子壳,作为癌症保护剂的花椰菜(硫烷),和改善动脉健康的大豆或三叶草(异黄酮类化合物)。其它营养制品的实例是黄酮类、抗氧化剂、得自亚麻籽的α-亚油酸、得自金盏花花瓣的β-胡罗卜素或得自浆果的花青素。有时,表述“保健品”(neutraceutical)或“功效营养素”(nutriceutical)作为“营养制品”(nutraceutical)的同义词使用。
药物、营养制品或化妆品辅料
药物、营养制品或化妆品辅料是本领域技术人员公知并广泛用于制药、营养制品和化妆品中的辅料。所述药物、营养制品或化妆品辅料是任选的辅料并且不同于根据本发明的基本组分a)、b)以及c)和/或d)。
所述组合物可进一步包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计0至400重量%或0.1至400重量%,优选0至200重量%或0.1至200重量%,最优选10至100重量%的额外的药物辅料、营养制品辅料或化妆品辅料。
优选地,所述额外的药物辅料、营养制品辅料或化妆品辅料选自以下类别:抗氧化剂、增白剂、调味剂、流动助剂、芳香剂、渗透促进剂、颜料、增塑剂、聚合物、成孔剂或稳定剂或它们的组合。
术语“药物、营养制品或化妆品辅料”是本领域技术人员公知的。辅料通常在制药中使用,但也在营养制品或化妆品领域中使用,有时它们也被称为常规添加剂。当然,所使用的所有辅料或常规添加剂总是必须在毒理学上是可接受的并且可特别用在药品、营养制品或化妆品中而不会对顾客或患者构成风险。
尽管在药物领域中的要求通常较高,但用于药物目的的辅料与用于营养制品或化妆品目的的辅料存在广泛的重叠。通常,所有药物辅料均可用于营养制品或化妆品目的,并且至少大量的营养制品辅料也被允许用于药物目的。可以将辅料添加到本发明的配制剂中,优选作为用于喷涂的悬浮液的掺混物。
用途
本发明描述了所公开的组合物作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的用途(用作用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的组合物)。
增塑剂
所述组合物可包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计2至40重量%的增塑剂。也可以包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计小于2重量%的增塑剂或根本不包含增塑剂。
增塑剂可被如下定义,它们通过与聚合物的物理相互作用实现了玻璃化转变温度的降低并促进了成膜,这取决于添加的量。合适的物质通常具有在100至20,000之间的分子量并且在分子中包含一个或多个亲水基团,例如羟基酯或氨基基团。
所述增塑剂可选自柠檬酸烷基酯、甘油酯、邻苯二甲酸烷基酯、癸二酸烷基酯、蔗糖酯、脱水山梨醇酯和聚乙二醇。
所述增塑剂可选自柠檬酸三乙酯(TEC)、乙酰基柠檬酸三乙酯(ATEC)、癸二酸二乙酯和癸二酸二丁酯(DBS)、甘油、丙二醇、聚乙二醇200至12,000和蓖麻油。
可再分散粉末
所述组合物可以水性分散体的形式存在,并且然后可以被喷雾干燥以得到可再分散粉末。
水性分散体
所述组合物可以水性分散体的形式存在,所述水性分散体包含水和5至50重量%,优选8至40重量%,更优选8至20重量%的所述组合物。
典型组合物
典型组合物可包含:
a)所述至少一种(甲基)丙烯酸酯共聚物a);
b)基于a)的总重量计1至25重量%的硬脂酸钠,
以及c)或d)或者二者
c)基于a)计的5至15重量%的羟丙基甲基纤维素和/或甘油三硬脂酸酯;
d)基于a)计的40至60重量%的滑石和/或硬脂酸镁;
其中所述组分a)、b)、c)和d)总计达100%干重。
项目
本发明可特征在于以下项目:
1.适合作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的组合物,其包含以下组分,优选以固体、溶解或以分散的形式:
a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和
b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%,优选5至18重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,
以及c)或d)或者c)和d)二者
c)基于a)的总重量计2至25重量%,优选2至20重量%,更优选5至15重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山萮酸酯和甘油单硬脂酸酯的化合物,和/或
d)基于a)的总重量计25至90重量%,优选25至75重量%,更优选40至60重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素的化合物。
2.根据项目1所述的组合物,其中所述(甲基)丙烯酸酯共聚物a)包含总的单体组成,该单体组成按重量计包含由以下物质形成的聚合单元:10至30重量%的甲基丙烯酸甲酯、50至70重量%的丙烯酸甲酯和5至15重量%的甲基丙烯酸。
3.根据项目1或2所述的组合物,其中所述具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐选自以下羧酸的碱金属盐或铵盐:癸酸(羊蜡酸,C10)、十一烷酸、十二烷酸(月桂酸,C12)、十三烷酸、十四烷酸、十五烷酸、十六烷酸(hexadecenoic acid)(棕榈酸,C16)、十七烷酸、十八烷酸(硬脂酸,C18)、十九烷酸、二十烷酸(花生酸,C20)、二十一烷酸(山萮酸,C22)、二十二烷酸、二十三烷酸、二十五烷酸、二十六烷酸(蜡酸(ceratic acid))、二十七烷酸、二十八烷酸、二十九烷酸和三十烷酸(蜂花酸,C30)。
4.根据前述项目中任一项所述的组合物,其中所述饱和脂族单羧酸的碱金属盐是硬脂酸钠。
5.根据前述项目中任一项所述的组合物,其中包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计最高至400重量%的额外的药物、营养制品或化妆品辅料。
6.根据前述项目中任一项所述的组合物,其中包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计最高至200重量%的额外的药物、营养制品或化妆品辅料。
7.根据项目5或6所述的组合物,其中包含药物、营养制品学或化妆品辅料,其选自抗氧化剂、增白剂、调味剂、流动助剂、芳香剂、渗透促进剂、颜料、增塑剂、聚合物、成孔剂或稳定剂或它们的组合。
8.根据前述项目中任一项所述的组合物,其中基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计,增塑剂的存在量为2至40重量%。
9.根据前述项目中任一项所述的组合物,其中存在增塑剂,其选自柠檬酸烷基酯、甘油酯、邻苯二甲酸烷基酯、癸二酸烷基酯、蔗糖酯、脱水山梨醇酯和聚乙二醇。
10.根据前述项目中任一项所述的组合物,其中存在增塑剂,其选自柠檬酸三乙酯(TEC)、乙酰基柠檬酸三乙酯(ATEC)、癸二酸二乙酯和癸二酸二丁酯(DBS)、甘油、丙二醇、数均分子量为200至12,000g/mol的聚乙二醇,所述数均分子量优选是使用聚苯乙烯标准品通过GPC测量的,和蓖麻油。
11.根据前述项目中任一项所述的组合物,其为水性分散体的形式。
12.根据前述项目中任一项所述的组合物,其为可再分散粉末的形式。
13.根据前述项目中任一项所述的组合物,其包含
a)所述至少一种(甲基)丙烯酸酯共聚物a);
b)基于a)的总重量计1至25重量%的硬脂酸钠,
以及c)或d)或者二者
c)基于a)计的5至15重量%的羟丙基甲基纤维素和/或甘油三硬脂酸酯;
d)基于a)计的40至60重量%的滑石和/或硬脂酸镁;
其中所述组分a)、b)、c)和d)总计达100%干重。
14.根据前述项目中任一项所述的组合物,其中在所述组合物中的至少一种(甲基)丙烯酸酯共聚物a)的固体含量为基于所述组合物的总重量计的至少5重量%,优选20至90重量%。
15.水性分散体,其包含水和5至50重量%的根据前述项目中任一项所述的组合物。
16.剂型,其包含药物、营养制品或化妆品活性成分和聚合物包衣或聚合物基体,其中所述聚合物包衣或所述聚合物基体包含根据前述项目中任一项所述的组合物。
17.根据项目16所述的剂型,其包含用根据前述项目中任一项所述的组合物包衣的含有药物、营养制品或化妆品活性成分的芯,并且其中在pH 1.2下,在1小时,优选2小时后,活性成分释放为10%或更少。
18.根据项目16或17所述的剂型,其包含用根据项目1至14中任一项所述的组合物包衣的含有药物、营养制品或化妆品活性成分的芯,并且其中在pH 1.2的介质中,在2小时后,活性成分释放为10%或更少,和在随后的pH 6.8的介质中,在60分钟后,活性成分释放为40%或更多,优选42%或更多。
19.根据项目16至18中任一项所述的剂型,其包含用根据项目1至14中任一项所述的组合物包衣的含有药物、营养制品或化妆品活性成分的芯,并且其中在pH 1.2的介质中,在2小时后,活性成分释放为10%或更少,和在随后的pH 6.8的介质中,在120分钟后,优选90分钟后,活性成分释放为70%或更多,优选88%或更多。
20.根据项目16至19中任一项所述的剂型,其包含的药物、营养制品或化妆品活性成分选自益生元或益生菌。
21.根据项目16至20中任一项所述的剂型,其包含的药物、营养制品或化妆品活性成分选自镇痛剂、抗生素或抗感染剂、抗体、抗癫痫剂、植物抗原、抗风湿剂、β阻滞剂、苯并咪唑衍生物、心血管药物、化疗药物、CNS药物、洋地黄糖苷、胃肠道药物,例如质子泵抑制剂、酶、激素、液体或固体天然提取物、寡核苷酸、肽激素,蛋白、治疗性细菌、肽、泌尿学药物和疫苗。
22.根据项目1至14中任一项所述的组合物作为用于药物、营养制品或化妆品活性成分的包衣剂或粘结剂的用途。
具体实施方式
实施例
组合物的制备
使用的材料:
biotic分散体是一种30重量%的(甲基)丙烯酸系共聚物的水性分散体,所述共聚物含有25重量%的甲基丙烯酸甲酯单元,65重量%的丙烯酸甲酯单元,10重量%的甲基丙烯酸单元。
硬脂酸钠购自Sigma-Aldrich。
甘油三硬脂酸酯(118)购自Cremer。
滑石M购自Imerys。
气相法二氧化硅Aerosil200,其具有的比表面积BET=200m2/g。
柠檬酸三乙酯(TEC)购自Merck。
甘油单硬脂酸酯(GMS Imwitor 900K)购自Cremer。
实施例1:
将2.76g硬脂酸钠在99.04g加热到70℃的去矿物质水中的溶液在搅拌下添加到80.0gbiotic分散体中。形成pH=7.2的低粘度水性分散体。在没有额外加热的情况下,将滑石M(12.0g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌5分钟。将所得的悬浮液通过0.25mm的筛子筛分并使用小型喷雾干燥器Büchi B-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
实施例2:
将2.76g硬脂酸钠在60.64g加热到70℃的去矿物质水中的溶液在搅拌下添加到80.0gbiotic分散体中。形成pH>7.0的低粘度水性分散体。在没有额外加热的情况下,将甘油三硬脂酸酯(/>118,2.4g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌5分钟。将所得的混合物通过0.25mm的筛子过滤并使用小型喷雾干燥器Büchi B-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
实施例3:
将8.23g硬脂酸钠在167.76g加热到70℃的去矿物质水中的溶液在搅拌下添加到217.5gbiotic分散体中。形成pH=7.2的低粘度水性分散体。在没有额外加热的情况下,将甘油三硬脂酸酯(/>118,6.52g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌20分钟。将所得的混合物通过0.25mm的筛子过滤并使用小型喷雾干燥器Büchi B-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
对比例1:
将4.46g辛酸钠在152.69g加热到70℃的去矿物质水中的溶液在搅拌下添加到217.5gbiotic分散体中。形成pH=6.7的低粘度水性分散体。在没有额外加热的情况下,将甘油三硬脂酸酯(/>118,6.52g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌15分钟。将所得的混合物通过0.25mm的筛子过滤并使用小型喷雾干燥器Büchi B-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
对比例2:
将1.13g柠檬酸三乙酯(TEC)在87.02g加热到70℃的去矿物质水中的溶液在搅拌下添加到75.0gbiotic分散体中。形成pH>7.0的低粘度水性分散体。在没有额外加热的情况下,将滑石M(11.25g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌5分钟。将所得的混合物通过0.25mm的筛子过滤并使用小型喷雾干燥器BüchiB-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
对比例3:
将1.72g硬脂酸钠在37.88g加热到70℃的去矿物质水中的溶液在搅拌下添加到50.0gbiotic分散体中。形成pH>7.0的低粘度水分散体。在没有额外加热的情况下,将气相法二氧化硅(/>200,1.50g)在搅拌下添加到所得的分散体中,并在13000rpm下继续搅拌5分钟。将所得的混合物通过0.25mm的筛子过滤并使用小型喷雾干燥器Büchi B-290进行喷雾干燥(入口温度:80℃,出口温度46-47℃)以获得具有表1中明确的组成的粉末。
表1:在本发明的实施例和对比例中使用的组合物,其具有柠檬酸咖啡因丸粒:
a聚合物=(甲基)丙烯酸系共聚物,其含有25重量%的甲基丙烯酸甲酯单元,65重量%的丙烯酸甲酯单元,10重量%的甲基丙烯酸单元。
实施例4-10和对比例4-9
具有活性组分的包衣柠檬酸咖啡因丸粒的制备
基底
柠檬酸咖啡因丸粒含有40.0重量%的活性药物成分,并具有707-1410μm的粒子尺寸(不超过10.0%可保留在网目尺寸为1410μm的14号筛(ASTM)中;不超过10.0%可穿过网目尺寸为707μm的25号筛(ASTM))。
二羟丙茶碱丸粒含有52.3重量%的活性药物成分,并具有800-1000μm的粒子尺寸。
包衣悬浮液的制备
在室温(约22℃)下,在用叶轮搅拌器进行搅拌的情况下,通过将粉末添加到去矿物质水(粉末/水=20重量%/80重量%)中来实现经喷雾干燥粉末的再分散。继续搅拌1小时。
包衣二羟丙茶碱或柠檬酸咖啡因丸粒的制备
使用如上所述制备的分散体,在Hüttlin Mycrolab装置中使100g二羟丙茶碱或柠檬酸咖啡因丸粒经由喷雾干燥进行包衣。表1总结了二羟丙茶碱丸粒的包衣条件。
在实施例10中,根据上述程序有效地再分散实施例3的组合物,但没有制备包衣丸粒。在对比例4中,对比例1的组合物(具有辛酸钠代替硬脂酸钠)甚至在剧烈搅拌1.5小时后也不能被分散。该组合物不适合于提供可再分散材料。
表2:用于包衣基底丸粒的条件
入口温度(℃) | 29-40 |
出口温度(℃) | 23-28 |
空气流量(m3/h) | 14-29m3/h |
喷嘴孔(mm) | 0.8 |
雾化压力(巴) | 0.8 |
喷雾速率(g/min) | 0.5-6.5 |
喷雾时间为66-111分钟,这取决于所施加的包衣组合物的量(相对于基底质量为4-15重量%)。对通过喷雾过程获得的包衣丸粒进行活性成分(二羟丙茶碱或柠檬酸咖啡因)释放的测试。
使用BP方法II桨设备(PTWS型,Pharmatest,德国海恩堡)对包含活性成分(二羟丙茶碱或柠檬酸咖啡因)的包衣丸粒进行溶出(释放)测试。溶出介质的体积为900mL,保持在37±0.5℃下,并采用100rpm的桨速。通过UV分光光度计(对于二羟丙茶碱为271nm)测定从包衣片剂或丸粒中释放的活性成分的量。首先将所述丸粒放入到0.1N HCl(pH=1.2)中120分钟,并随后放入到pH=6.8的磷酸盐缓冲液中。
表3总结了实施例4-9和对比例4-9的释放测试。在pH=1.2下120分钟释放<10%的活性组分表明相应的包衣具有充分的耐胃液性,释放超过10%的活性成分表明包衣组合物不适合作为耐胃液包衣。对于在肠中的有效释放,在目标pH水平(6.8)下180分钟后,优选90分钟后,应可释放至少70%,优选80%,更优选90%的活性组分。如可从表3中看出的,根据本发明的组合物既提供了耐胃液性,又提供了在pH=6.8下有效的活性组分释放。特别重要的是,实施例5和6表明了本发明的组合物可以储存相对较长的时间(至少3-6个月),并且仍然适合于合成在pH=6.8下具有有效释放的耐胃液包衣。相反,对比例2的组合物(使用TEC代替硬脂酸钠)虽然在所施加的特定量的包衣下是酸稳定的,但在pH=6.8的情况下未提供足够的释放。对比例3的组合物(200用作助流剂)在pH=1.2下是不稳定的。
表3:释放测试
实施例编号=根据本发明的实施例;对比例编号=对比例。
a储存3个月后;b储存6个月后;cD=二羟丙茶碱;C=柠檬酸咖啡因
咖啡因微晶纤维素芯丸粒的制备
组合物的制备
使用的材料:
biotic分散体是一种30重量%的(甲基)丙烯酸系共聚物的水性分散体,所述共聚物含有25重量%的甲基丙烯酸甲酯单元,65重量%的丙烯酸甲酯单元,10重量%的甲基丙烯酸单元。在以下实施例和对比例中的下述量是指所述(甲基)丙烯酸系共聚物的干重的量,而不是/>biotic分散体的总重量。例如,如果描述了含有总组合物1%的/>biotic,则它意味着使用了1%的(甲基)丙烯酸系共聚物,其仅占/>biotic的30重量%,即使用了3.33%的可商购获得的/>biotic水性分散体。
咖啡因购自Aarti Drugs Ltd.
微晶纤维素PH 101购自JRS Pharms
Vivapur MCG 611P,一种微晶纤维素,购自JRS Pharma
硬脂酸钠购自Tokyo Chemical Indrustry Co.,Ltd
柠檬酸三乙酯购自Vertellus
瓜尔胶购自Polygal AG
滑石购自IMERYS
购自RIBUS Inc.
购自RIBUS Inc.
HPMC(5cps)购自JRS Pharma
甘油单硬脂酸酯购自IOI Oeo
硬脂酸镁购自Prachin Chemical
玉米淀粉购自Universal Starch Chem Allied Ltd.
咖啡因微晶纤维素芯丸粒含有
成分 | 重量% |
咖啡因 | 35.0 |
微晶纤维素PH 101 | 50.0 |
Vivapur MCG 611P | 25.0 |
纯净水 | q.s. |
合计 | 100.0 |
咖啡因微晶纤维素芯丸粒的制备方法
I.使用#30ASTM筛选咖啡因、微晶纤维素和Vivapur MCG 611 P
II.将过筛的掺混物在快速混合物制粒机中混合10分钟并用纯净水造粒。
III.将步骤II的经造粒的掺混物用于挤出,并随后使用Fuji Paudal滚圆机进行滚圆
挤出参数
挤出类型 | 锥型 |
挤出螺杆 | 单一 |
螺杆速度(rpm) | 40-60 |
筛孔直径(mm) | 1 |
挤出压力(巴) | 2-2.5 |
进料速率(g/分钟) | 100-200 |
挤出温度(℃) | 25-30 |
滚圆参数
滚圆板类型 | 缺口圆形 |
滚圆板尺寸(mm) | 2.0 |
滚圆速度(rpm) | 1500-1700 |
滚圆负载(g) | 400-600 |
含有活性物质的芯丸粒的干燥和分级
I.所有经滚圆的丸粒都在流化床处理器中于60℃入口温度下干燥,直至所述丸粒的最终LOD低于5重量%。
II.使用筛摇机对经干燥的丸粒进行分级,以获得14/25ASTM网目的丸粒级分。
III.14/25ASTM网目丸粒级分用于包衣。
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实验和对比实验的包衣分散体的制备
用于丸粒包衣的包衣分散体的制备:对比例10
I.在搅拌下向热纯净水(约70℃)中添加硬脂酸钠直至它形成澄清溶液
II.在1000-1200rpm顶置搅拌器下将biotic添加到步骤-1的溶液中,变成粘性分散体,搅拌约30分钟。
III.使所述包衣分散体穿过40号ASTM筛(425μm)并用于如下一部分中描述的片剂的包衣。
用于丸粒包衣的包衣分散体的制备:对比例11,实施例11、13、15、18、20、21、22和23
I.在搅拌下向热纯净水(约70℃)中添加硬脂酸钠直至它形成澄清溶液
II.在1000-1200rpm顶置搅拌器下将biotic添加到步骤-1的溶液中,变成粘性分散体,搅拌约30分钟。
III.在搅拌下将滑石、硬脂酸镁、瓜尔胶、甘油山萮酸酯或甘油单硬脂酸酯添加到步骤-2的分散体中。继续搅拌另外20分钟
IV.使所述包衣分散体穿过40号ASTM筛(425μm)并用于如下一部分中描述的丸粒的包衣。
用于丸粒包衣的包衣分散体的制备:实施例12、14、16、17、19和24
V.在搅拌下向热纯净水(约70℃)中添加硬脂酸钠直至它形成澄清溶液
VI.在1000-1200rpm顶置搅拌器下将biotic添加到步骤-1的溶液中,变成粘性分散体,搅拌约30分钟。
VII.在步骤2的分散体中添加柠檬酸三乙酯,并搅拌分散体
VIII.在搅拌下将滑石、HPMC 5cps或硬脂酸镁添加到步骤-2的分散体中。继续搅拌另外20分钟
IX.使所述包衣分散体穿过40号ASTM筛(425μm)并用于如下一部分中描述的丸粒的包衣。
用于丸粒包衣的包衣分散体的制备:对比例12类似于US 5644011中的实施例4,使用Biotic
I.将Eudraguard biotic与在水中的甘油单硬脂酸酯乳液(通过在高剪切均化下将其分散在热水(70℃)中制备的甘油单硬脂酸酯乳液)混合。
丸粒的包衣
使用流化床处理器(GPCG 1.1),采用以下参数,使用前一部分中描述的包衣分散体包衣装载有咖啡因药物的丸粒
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包衣丸粒的评价
评价包衣丸粒的表面外观和在0.1N HCl中120分钟,然后在pH 6.8磷酸盐缓冲液中180分钟的肠溶出
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Claims (15)
1.适合作为用于药物活性成分、营养制品活性成分或化妆品活性成分的包衣剂或粘结剂的组合物,其包含以下组分:
a)至少一种(甲基)丙烯酸酯共聚物a),其包含由以下物质形成的聚合单元:5至25重量%的甲基丙烯酸和75至95重量%的甲基丙烯酸的C1至C4烷基酯和/或丙烯酸的C1至C4烷基酯,和
b)基于至少一种(甲基)丙烯酸酯共聚物a)的总重量计1至25重量%的具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐,
以及c)或d)或者c)和d)二者
c)基于a)的总重量计2至25重量%的至少一种选自甘油三硬脂酸酯、羟丙基甲基纤维素、甘油山酸酯和甘油单硬脂酸酯的化合物,和/或
d)基于a)的总重量计25至90重量%的至少一种选自滑石、粉末形式的稻壳、硬脂酸镁、玉米淀粉和微晶纤维素的化合物。
2.根据权利要求1所述的组合物,其中所述至少一种(甲基)丙烯酸酯共聚物a)包含总的单体组成,该单体组成按重量计包含由以下物质形成的聚合单元:10至30重量%的甲基丙烯酸甲酯、50至70重量%的丙烯酸甲酯和5至15重量%的甲基丙烯酸。
3.根据权利要求1或2所述的组合物,其中所述具有10至30个碳原子的饱和脂族单羧酸的碱金属盐或铵盐选自以下羧酸的碱金属盐或铵盐:癸酸(羊蜡酸,C10)、十一烷酸、十二烷酸(月桂酸,C12)、十三烷酸、十四烷酸、十五烷酸、十六烷酸(棕榈酸,C16)、十七烷酸、十八烷酸(硬脂酸,C18)、十九烷酸、二十烷酸(花生酸,C20)、二十一烷酸(山酸,C22)、二十二烷酸、二十三烷酸、二十五烷酸、二十六烷酸(蜡酸)、二十七烷酸、二十八烷酸、二十九烷酸和三十烷酸(蜂花酸,C30)。
4.根据权利要求1至3中任一项所述的组合物,其中所述饱和脂族单羧酸的碱金属盐是硬脂酸钠。
5.根据权利要求1至4中任一项所述的组合物,其中包含基于所述至少一种(甲基)丙烯酸酯共聚物a)的总重量计最高至400重量%的额外的药物辅料、营养制品辅料或化妆品辅料。
6.根据权利要求5所述的组合物,其中药物辅料、营养制品辅料或化妆品辅料选自以下类别:抗氧化剂、增白剂、调味剂、流动助剂、芳香剂、渗透促进剂、颜料、增塑剂、聚合物、成孔剂或稳定剂或它们的组合。
7.根据权利要求1至6中任一项所述的组合物,其中基于所述至少一种甲基丙烯酸酯共聚物a)的总重量计,增塑剂的存在量为2至40重量%。
8.根据权利要求1至7中任一项所述的组合物,其中存在增塑剂,其选自柠檬酸烷基酯、甘油酯、邻苯二甲酸烷基酯、癸二酸烷基酯、蔗糖酯、脱水山梨醇酯和聚乙二醇。
9.根据权利要求1至8中任一项所述的组合物,其中存在增塑剂,其选自柠檬酸三乙酯(TEC)、乙酰基柠檬酸三乙酯(ATEC)、癸二酸二乙酯和癸二酸二丁酯(DBS)、甘油、丙二醇、聚乙二醇200至12,000和蓖麻油。
10.根据权利要求1至9中任一项所述的组合物,其为水性分散体的形式。
11.根据权利要求1至9中任一项所述的组合物,其为可再分散粉末的形式。
12.根据权利要求1至11中任一项所述的组合物,其包含
a)所述至少一种(甲基)丙烯酸酯共聚物a);
b)基于a)的总重量计1至25重量%的硬脂酸钠,
以及c)或d)或者这二者:
c)基于a)计的5至15重量%的羟丙基甲基纤维素和/或甘油三硬脂酸酯;
d)基于a)计的40至60重量%的滑石和/或硬脂酸镁;
其中所述组分a)、b)、c)和d)总计达100%干重。
13.水性分散体,其包含水和5至50重量%的根据权利要求1至12中任一项所述的组合物。
14.剂型,其包含药物活性成分、营养制品活性成分或化妆品活性成分和聚合物包衣或聚合物基体,其中所述聚合物包衣或所述聚合物基体包含根据权利要求1至12中任一项所述的组合物。
15.根据权利要求1至12中任一项所述的组合物作为用于药物活性成分、营养制品活性成分或化妆品活性成分的包衣剂或粘结剂的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP21184702 | 2021-07-09 | ||
EP21184702.5 | 2021-07-09 | ||
PCT/EP2022/068831 WO2023280962A1 (en) | 2021-07-09 | 2022-07-07 | Composition comprising a (meth)acrylate copolymer, an alkali or ammonium salt of a saturated aliphatic monocarboxylic acid and specific glidants |
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EP (1) | EP4366710A1 (zh) |
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JP2917799B2 (ja) * | 1994-03-11 | 1999-07-12 | 田辺製薬株式会社 | 消化管内適所放出型製剤 |
DE9414065U1 (de) | 1994-08-31 | 1994-11-03 | Röhm GmbH & Co. KG, 64293 Darmstadt | Thermoplastischer Kunststoff für darmsaftlösliche Arznei-Umhüllungen |
DE9414066U1 (de) | 1994-08-31 | 1994-11-03 | Röhm GmbH & Co. KG, 64293 Darmstadt | Überzugs- und Bindemittel für Arzneiformen sowie damit hergestellte Arzneiform |
MX2011009669A (es) * | 2009-03-18 | 2011-12-14 | Evonik Roehm Gmbh | Composición farmacéutica de liberación controlada con resistencia a la influencia de etanol mediante un revestimiento compuesto de una mezcla polimérica y excipientes. |
CN103920156B (zh) * | 2014-04-04 | 2016-06-01 | 成都科特包衣技术有限公司 | 一种口服给药肠道定位释药薄膜包衣预混辅料及其制备方法 |
CA3121333A1 (en) | 2018-12-05 | 2020-06-11 | Evonik Operations Gmbh | Process for preparing polymeric particles |
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CA3223775A1 (en) | 2023-01-12 |
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