CN105188681A - 阴离子药理学活性物质的持续释放脂质预浓缩物和包含其的药物组合物 - Google Patents
阴离子药理学活性物质的持续释放脂质预浓缩物和包含其的药物组合物 Download PDFInfo
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- CN105188681A CN105188681A CN201380068020.6A CN201380068020A CN105188681A CN 105188681 A CN105188681 A CN 105188681A CN 201380068020 A CN201380068020 A CN 201380068020A CN 105188681 A CN105188681 A CN 105188681A
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- acid
- sustained release
- preconcentrate
- release lipid
- anhydro sorbitol
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Abstract
本发明公开了一种持续释放脂质预浓缩物,其包含:a)至少一种液晶形成剂;b)至少一种磷脂;c)至少一种液晶硬化剂;和d)至少一种二价或多价金属盐,其中所述持续释放预浓缩物在不存在水性流体时作为脂质液相存在并且在暴露于水性流体后形成液晶。所述持续释放脂质预浓缩物被配置成通过二价或多价金属盐与阴离子药理学活性物质之间的离子相互作用而增强所述阴离子药理学活性物质的持续释放。
Description
技术领域
本发明涉及阴离子药理学活性物质的持续释放脂质预浓缩物,以及包含其的药物组合物。
背景技术
作为减少由多次剂量的药理学活性物质(这是在特定的时期内维持血流中所述物质的有效血浆浓度所必需的)或给药频率引起的副作用的有希望的剂型出现,已经透彻地研究了持续释放制剂。持续释放制剂是一种被设计成在特定时期内以有效的浓度释放单次剂量的药理学活性物质的药物递送系统(DDS)。
PLGA[聚(乳酸-共-乙醇酸)]是由美国食品和药物管理局(FDA)批准用于持续释放的当前使用的可生物降解材料的代表。PLGA是这样一种共聚物,其中乳酸或丙交酯和乙醇酸或乙交酯以不同的比率共聚合,并且在美国专利号5,480,656中记载了经由PLGA在体内在特定时期内降解成乳酸和乙醇酸而允许药理学活性物质的持续释放。然而,PLGA的酸性降解产物引起炎症,减少细胞生长(K.Athanasiou,G.G.Niederauer和C.M.Agrawal,Biomaterials(生物材料),17,93(1996))。对于持续释放,必须注射其中包括药物的直径为10~100微米的PLGA固体颗粒。PLGA固体颗粒的注射伴有疼痛或炎症。。因此,需要新的持续释放制剂,所述持续释放制剂在改进的患者顺应性情况下供应有效血浆浓度的药理学活性物质达延长的时期。
之前,本发明人介绍了一种持续释放预浓缩物,其包含:a)至少一种液晶形成剂;b)至少一种磷脂;和c)至少一种液晶硬化剂,其在不存在水性流体时作为脂质液相存在并且在暴露于水性流体后形成液晶。
当向其施加中性或脂溶性药理学活性物质时,发现本发明人所介绍的预浓缩物以持续释放方式释放所述药理学活性物质,长时间维持有效的血浆浓度。然而,与中性或脂溶性药物相比,对于阴离子药物或净电荷为(-)的药物,所述预浓缩物表现出高的初始释放率,和短的维持有效血浆浓度的时间。
因此需要用于在没有初始突释的情况下的持续释放的方法,通过所述方法,阴离子药物可以在体内维持有效浓度达延长的时间。
最后,在本发明中,本发明人对持续释放制剂的深入透彻的研究带来这样的发现:包含a)至少一种液晶形成剂,b)至少一种磷脂,c)至少一种液晶硬化剂,和d)至少一种二价或多价金属盐的持续释放脂质预浓缩物,在不存在水性流体时作为脂质液相存在,并且在水性流体中形成液晶,具有高的体内安全性和生物降解性,并且当与e)至少一种阴离子药理学活性物质缔合时,所述预浓缩物可以在长时间节段内以有效浓度释放所述活性物质。
现在参考与本申请相关的现有技术。
国际专利公布号WO2005/117830记载了一种预制剂,其包含至少一种中性二酰脂质和/或至少一种生育酚,至少一种磷脂,和至少一种生物相容的、含氧的低粘性有机溶剂。国际专利公布号WO2006/075124公开了包含下述粘度混合物的预制剂:至少一种二酰基甘油、至少一种磷脂酰胆碱,至少一种含氧甘油有机溶剂,和至少一种生长抑素类似物。所有这些预制剂允许药理学活性物质在体内持续释放两周以上,但是,发现所用的有机溶剂引起一些药物活性的减少(H.Ljusberg-Wahre,F.S.Nielse,298,328-332(2005);H.Sah,Y.Bahl,JournalofControlledRelease(可控释放杂志)106,51-61(2005))。与本发明的另一个区别是二价或多价金属盐不是必需成分。
美国专利号7,731,947公开了一种包含下述的组合物:包含干扰素、蔗糖、甲硫氨酸和柠檬酸盐缓冲液的颗粒制剂,和包含诸如苯甲酸苄酯的溶剂的混悬赋型剂(suspendingvehicle)。在一个实施例中,其描述了磷脂酰胆碱连同维生素E(生育酚)溶解在有机溶剂中并用于将颗粒制剂分散在其中。然而,该组合物不同于本发明的透明且可滤过的溶解制剂,因为该组合物用于分散固体颗粒并且不允许形成液晶。
美国专利号7,871,642公开了制备用于递送药理学活性物质的分散体的方法,所述方法包括将磷脂、聚氧乙烯助乳化剂、甘油三酯和乙醇的均匀混合物分散在水中,其中所述聚氧乙烯助乳化剂选自聚氧乙烯化的脱水山梨醇脂肪酸酯(聚山梨醇酯)或聚氧乙烯化的维生素E衍生物。然而,通过将亲水聚合物聚氧乙烯分别缀合到脱水山梨醇脂肪酸酯和维生素E上衍生的聚氧乙烯化的脱水山梨醇脂肪酸酯和聚氧乙烯化的维生素E衍生物在结构上完全不同于脱水山梨醇脂肪酸酯和维生素E。它们通常被用作利用聚氧乙烯的性质的亲水表面活性剂,其不同于本发明的成分。
美国专利号5,888,533记述了用于在体内原位形成固体可生物降解的植入物的可流动组合物,其包含:非聚合的水不溶性可生物降解材料;和生物相容的有机溶剂,所述生物相容的有机溶剂至少部分溶解所述材料,并且在水或体液中是可混溶的或可分散的,并在放置在体内时能够从组合物扩散出或浸出到体液中,由此所述非聚合的材料凝结或沉淀以形成固体植入物。在该组合物中,固醇、胆甾醇酯、脂肪酸、脂肪酸甘油酯、蔗糖脂肪酸酯、脱水山梨醇脂肪酸酯、脂肪醇、脂肪醇与脂肪酸的酯、脂肪酸的酸酐、磷脂、羊毛脂、羊毛脂醇以及它们的组合被描述为非聚合材料,并且使用乙醇用作溶剂。然而,与本发明的不同在于,该组合物不能形成液晶,并且设计成通过水不溶性材料的简单凝结或沉淀形成固体植入物,并且必然使用许多有机溶剂。
国际专利公布号WO2010/139278公开了负载药物的水包油乳剂的制备方法,所述乳剂包含磷脂酰胆碱作为表面活性剂,包含α-生育酚乙酸酯作为抗氧化剂。然而,该组合物在水性流体中不形成液晶,并且进一步与本发明在下述方面不同:使用磷脂酰胆碱作为负责溶解到油相火在水相中分散的表面活性剂,使用α-生育酚乙酸酯作为抗氧化剂。
韩国专利公布号10-2011-0056042公开了一种纳米分散体形式的肿瘤靶向药物组合物,其包含抗癌药作为药理学活性物质,二价或三价过渡金属或碱土金属离子,和油,以及透明质酸或其盐。其进一步描述所述油可以是α-生育酚或其盐,而所述表面活性剂是脱水山梨醇单油酸酯。由于所述组合物具有通过沉淀纳米分散液得到的纳米颗粒的最终形式,其与本发明形成液晶的组合物不同。另外,二价或三价过渡金属或碱土金属离子起作用将透明质酸或其盐缔合到所述纳米颗粒上表面上。
国际专利公布号WO2005/048930记载了一种可注射组合物,其包含表面活性剂、溶剂和有益试剂,其中当暴露于亲水性环境时,所述表面活性剂和溶剂形成粘稠的凝胶,并且所述有益试剂分散或溶解在凝胶中。磷脂或PEG化的磷脂用作在亲水性环境中形成粘稠凝胶的表面活性剂,而乙醇或生育酚作为疏水溶剂。因此,所述在疏水环境中形成粘稠凝胶的的组合物与本发明的当暴露于水性流体时变成液晶的组合物不同。
国际专利公布号2010/108934公开了一种囊泡药物递送系统,其包含至少一种包绕至少一个水性腔的脂双层;至少一种包含在水性腔中的干扰核糖核酸(siRNA)分子;和至少一种包埋在所述脂双层中的疏水性药物物质,以及任选地选自胆甾醇、聚乙二醇(PEG)和生育酚的药用赋型剂。然而,磷脂酰胆碱与赋型剂生育酚在暴露于水性流体后不能形成液晶,这不同于本发明。
在国际专利公布号WO2005/049069中,一种可注射的储库凝胶组合物包括凝胶赋型剂(gelvehicle),其包含可生物蚀解的、生物相容的聚合物和水不混溶的溶剂,并且使用调节释放模式和稳定有益试剂的赋型剂(excipient)。特别的赋型剂是pH改变剂,包括无机盐、有机盐,及其组合,和抗氧化剂,包括d-α-生育酚乙酸酯和dl-α-生育酚乙酸酯。然而,在本发明中不存在作为组合物的基本物质的可生物蚀解的、生物相容的PLGA。与本发明的另一个区别在于使用金属盐作为pH改变剂,使用生育酚乙酸酯作为抗氧化剂。
国际专利公布号WO2005/110360记载了一种脂质组合物,其包含至少一种生物活性化合物,含有磷脂酰胆碱的膜脂质,具有的液晶相转变温度低于40℃,至少一种混溶性药用有机溶剂,药用载体液和其他适于注射目的的添加剂。当暴露于水性环境时,该组合物转化为液晶状态的粘性脂质基质,由此能够允许生物活性化合物的逐渐释放。然而,在该组合物中起重要作用的物质是膜脂质,其不同于本发明的液晶形成剂。
国际专利公布号WO2008/139804介绍了一种低分子量含药纳米颗粒,其具有带负电荷的基团,该负电荷基团通过用金属离子疏水处理(hydrophobizing)具有负电荷基团的低分子药物并将疏水处理的产物与PLGA再反应而产生。然而,与本发明的不同在于在PLGA纳米颗粒的制备中使用过量的有机溶剂,以及在药物的疏水处理中使用金属离子。另外,该组合物具有仅针对低分子量带负电荷的药物的有限应用,并且在体内药物释放行为中完全没有提及。
发明的公开内容
技术问题
因此,本发明的目的是基于从脂质液相到液晶的相变提供持续释放脂质预浓缩物,以允许阴离子药理学活性物质的持续释放,通过二价或多价金属盐与所述阴离子药理学活性物质之间的离子相互作用而增强持续释放。
本发明的另一个目的是提供持续释放脂质预浓缩物,其在存在二价或多价金属盐的情况下仍保持稳定性和生物降解性。
问题的解决方案
根据其一个方面,本发明提供一种持续释放脂质预浓缩物,其包含:a)至少一种液晶形成剂;b)至少一种磷脂;c)至少一种液晶硬化剂;和d)至少一种二价或多价金属盐,其在不存在水性流体时作为脂质液相存在并且在暴露于水性流体后形成液晶。
根据其另一个方面,本发明提供一种药物组合物,其包含e)至少一种阴离子药理学活性物质加上所述持续释放脂质预浓缩物,其中所述阴离子药理学活性物质由于与所述持续释放脂质预浓缩物的二价或多价金属盐的离子相互作用而表现出增强的持续释放。
以下,将给出每种组分的详细描述。
a)液晶形成剂
用于本发明的液晶形成剂负责形成非层状液晶,并且可以选自由下述组成的组:脱水山梨醇不饱和脂肪酸酯、单酰甘油、二酰甘油和它们的组合。
对于在本发明中作为液晶形成剂的用途,所述脱水山梨醇不饱和脂肪酸酯优选地在极性头中具有两个以上的-OH(羟基)基团。该脱水山梨醇不饱和脂肪酸酯可由以下化学式1表示。化学式1的化合物是脱水山梨醇单酯,其中R1=R2=OH,R3=R,和脱水山梨醇二酯,其中R1=OH,R2=R3=R,R是具有至少一个不饱和键的4-30个碳原子的烷基酯基团。
[化学式1]
详细地,本发明的脱水山梨醇不饱和脂肪酸酯可以获自鲸油和鱼油以及植物油和动物油脂。优选的植物油实例包括可可脂,琉璃苣油,糙米油,绿茶油,大豆油,大麻籽油,芝麻油,樱桃籽油,菜籽油,罂粟子油,南瓜子油,葡萄籽油,杏仁油,椰子油,山茶油,月见草油,葵花子油,介花油(canolaoil),松子油,胡桃油,榛子油,鳄梨油,扁桃仁油,花生油,希蒙得木油(jojobaoil),棕榈油,蓖麻油,橄榄油,玉米油,棉籽油,红花子油,和报春花油。优选的动物油脂的实例包括乳脂、牛脂、哺乳动物油、爬行动物油和鸟油。优选地,其可以选自脱水山梨醇单酯、脱水山梨醇倍半酯、脱水山梨醇二酯,其具有由鲸油和鱼油以及它们的组合得到的脂肪酸。
脱水山梨醇单酯是其中一个脂肪酸基团经由酯键与脱水山梨醇结合的化合物,并且可以选自脱水山梨醇单油酸酯、脱水山梨醇单亚油酸酯、脱水山梨醇单棕榈油酸酯、脱水山梨醇单肉豆蔻脑酸酯和它们的组合。
脱水山梨醇倍半酯是其中平均1.5个脂肪酸基团经由酯键与脱水山梨醇结合的化合物,并且可以选自脱水山梨醇倍半油酸酯、脱水山梨醇倍半亚油酸酯、脱水山梨醇倍半棕榈油酸酯、脱水山梨醇倍半肉豆蔻脑酸酯和它们的组合。
脱水山梨醇二酯是其中两个脂肪酸基团经由酯键与脱水山梨醇结合的化合物,并且可以选自脱水山梨醇二油酸酯,脱水山梨醇二亚油酸酯,脱水山梨醇二棕榈油酸酯,脱水山梨醇二肉豆蔻脑酸酯,及其组合。
为了用于本发明,脱水山梨醇不饱和脂肪酸酯优选选自脱水山梨醇单油酸酯、脱水山梨醇单亚油酸酯、脱水山梨醇单棕榈油酸酯、脱水山梨醇单肉豆蔻脑酸酯、脱水山梨醇倍半油酸酯和它们的组合。
在本发明中可用作液晶形成剂的单酰甘油由其间经由酯键连接的作为极性头的甘油和作为尾的一个脂肪酸组成,而二酰甘油包含作为极性头的甘油,以及经由酯键与其相连的相同或不同的两个脂肪酸尾。本发明中使用的经由酯键与单酰甘油或二酰甘油连接的脂肪酸基团,脂肪酸可以包含4-30个相同或不同数目的碳原子,并且可以独立地是饱和的或不饱和的。脂肪酸可以能够选自由下述组成的组:棕榈酸,棕榈油酸,月桂酸,丁酸,戊酸,己酸,庚酸,辛酸,壬酸,癸酸,肉豆蔻酸,肉豆蔻脑酸,硬脂酸,花生酸,辣木子油酸,木蜡酸,蜡酸,亚麻酸,α-亚麻酸(ALA),二十碳五烯酸(EPA),二十二碳六烯酸(DHA),亚油酸(LA),γ-亚油酸(GLA),双高γ-亚油酸(DGLA),花生四烯酸(AA),油酸,异油酸,反油酸,花生酸,芥酸,神经酸,及其组合。
详细地,本发明的单酰甘油可以选自:甘油单丁酸酯,甘油单辣木子油酸酯,甘油单辛酸酯,甘油单月桂酸酯,甘油单甲基丙烯酸酯,甘油单棕榈酸酯,甘油单硬脂酸酯,甘油单油酸酯,甘油单亚油酸酯,甘油单花生酸酯,甘油单花生四烯酸酯,甘油单芥酸酯,及其组合。优选的单酰甘油的实例是由下述化学式2表示的甘油单油酸酯(GMO)。
[化学式2]
本发明的二酰甘油可以选自:甘油二辣木子油酸酯,甘油二月桂酸酯,甘油二甲基丙烯酸酯,甘油二棕榈酸酯,甘油二硬脂酸酯,甘油二油酸酯,甘油二亚油酸酯,甘油二芥酸酯,甘油二肉豆蔻酸酯,甘油二蓖麻酸酯,甘油二棕榈油酸酯,及其组合。优选的二酰甘油的实例是由下述化学式3表示的甘油二油酸酯(GDO)。
[化学式3]
b)磷脂
常规技术中,磷脂对于层状结构如脂质体的构建是必要的,但自身不能形成非层状相结构,如液晶。然而,本发明的磷脂参与液晶形成剂形成的非层状相结构,并且有助于液晶的稳定。
本发明的磷脂来源于植物或动物,并且包含饱和的或不饱和的4-30个碳原子的具有极性头的烷基酯基团。根据极性头的结构,磷脂可以选自:磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰甘油,磷脂酰肌醇,磷脂酸,鞘磷脂,及其组合。在磷脂中,烷基酯基团包括饱和的脂肪酸酯,如单棕榈酰基和二棕榈酰基、单肉豆蔻酰基和二肉豆蔻酰基、单月桂酰基和二月桂酰基,和单硬脂酰基和二硬脂酰基,以及不饱和脂肪酸链,如单亚油酰基或二亚油酰基、单油酰基和二油酰基、单棕榈油酰基和二棕榈油酰基、单肉豆蔻脑酰基和二肉豆蔻脑酰基。饱和的和不饱和的脂肪酸酯可以共存在磷脂中。
c)液晶硬化剂
本发明的液晶硬化剂本身不能形成非层状结构(这与液晶形成剂不同),也不能形成诸如脂质体的层状结构(这与磷脂不同)。然而,液晶硬化剂通过增加非层状结构的曲率参与非层状相结构并且有助于提高油和水的有序共存。为了该功能,有利地需要液晶硬化剂在其分子结构内部具有高度限定的极性结构部分和庞大的非极性结构部分。
然而,在实践中,可以仅通过直接和重复的实验将可注射到身体中的生物相容分子选择作为本发明的液晶硬化剂。作为结果,适合于本发明组合物的液晶硬化剂具有彼此不同的分子结构,并且因此不能解释为一种分子结构。通过鉴定所有适用于本发明的组合物的液晶硬化剂观察到的共同结构特征是,它们不含可离子化基团,如羧基和胺基,并具有包含15至40个碳原子的大的三酰基或碳环结构的疏水结构部分。
本发明的液晶硬化剂可以不含可离子化基团,如羧基和胺基,并具有至多一个羟基和酯基团作为弱极性头,以及包含20至40个碳原子的大的三酰基或碳环结构的疏水结构部分。本发明的液晶硬化剂的优选实例可以选自,但不限于,甘油三酯,棕榈酸视黄酯,生育酚乙酸酯,胆甾醇,苯甲酸苄酯,泛醌,及其组合。优选地,所述液晶硬化剂可以选自生育酚乙酸酯,胆甾醇,及其组合。
d)二价或多价金属盐
在含有磷脂的脂质体或胶束结构中,带正电荷的金属离子与磷脂带负电荷的磷酸基团缔合(JournalofLipidResearch(脂质研究杂志)8(1967)227-233)。另外,金属盐的存在减少磷酸基团的负电荷之间的排斥力,增加脂质体或胶束结构的紧固性(ChemistryandPhysicsofLipids(脂质化学和物理学)151(2008)1-9)。与液晶结构内的阴离子药理学活性物质以及磷脂的磷酸基团部分或完全形成离子键,本发明的二价或多价金属盐防止阴离子药理学活性物质从液晶结构快速逃逸。归因于这种离子相互作用,金属离子可以显著减少初始突释,并且增强阴离子药理学活性物质的持续释放。参考图1,示意性显示了阴离子药理学活性物质与液晶结构内的二价或多价金属盐之间的离子相互作用。
在本发明的二价或多价金属盐中,药用盐的实例包括铝、钙、铁、镁、锡、钛和锌的盐,优选锌、铝或钙的盐。
详细地,所述二价或多价金属盐可以选自,但不限于,碳酸铝,氯化铝,氢氧化铝,氧化铝,磷酸铝,硫酸铝,溴化钙,碳酸钙,氯化钙,氢氧化钙,硝酸钙,氧化钙,磷酸钙,硅酸钙,硫酸钙,醋酸钙,氯化铁,氢氧化铁,氧化铁,硫酸铁,碳酸镁,氯化镁,氢氧化镁,硝酸镁,氧化镁,磷酸镁,硅酸镁,硫酸镁,氯化亚锡,氟化亚锡,氢氧化亚锡,氧化亚锡,硫酸亚锡,二氧化钛,碳酸锌,氯化锌,氢氧化锌,硝酸锌,氧化锌,磷酸锌,硫酸锌,醋酸锌,及其组合。
二价或多价金属盐的优选实例可以选自氯化铝、氢氧化铝、磷酸铝、溴化钙、氯化钙、氢氧化钙、氧化钙、碳酸锌、氯化锌、氢氧化锌、醋酸锌和它们的组合。
e)阴离子药理学活性物质
术语“阴离子药理学活性物质”用在本文中是指带负电荷或净电荷为(-)的药理学活性物质。
本发明的阴离子药理学活性物质可以是采用选自下述中的至少一种的形式:羧酸,亚磺酸,磺酸,膦酸,磷酸,硼酸,烃基硼酸(borinicacid),芳香醇,酰亚胺或季铵卤化物盐。
可用于本发明的阴离子药理学活性物质的具体的实例包括硼替佐米(bortezomib),甲氨蝶呤(methotrexate),奥洛他定(olopatadine),噻托溴铵(tiotropium),异丙托品(ipratropium),格隆溴铵(glycopyrronium),阿地溴铵(aclidinium),umeclidinium,托斯必姆(trospium),阿仑膦酸(alendronicacid),伊班膦酸(ibandronicacid),英卡膦酸(incadronicacid),帕米膦酸(pamidronicacid),利塞膦酸(risedronicacid),唑来膦酸(zoledronicacid),依替膦酸(etidronicacid),氯膦酸(clodronicacid),替鲁膦酸(tiludronicacid),奥帕膦酸(olpadronicacid),奈立膦酸(neridronicacid),双氯芬酸(diclofenac),左卡巴司汀(levocabastine),吲哚美辛(indomethacin),布洛芬(ibuprofene),氟比洛芬(flurbiprofen),非诺洛芬(fenoprofen),酮洛芬(ketoprofen),萘普生(naproxene),双氯芬酸,依托度酸(etodolac),舒林酸(sulindac),托美汀(tolmetin),水杨酸(salicylicacid),difiunisal,奥沙普嗪(oxaprozin),硫加宾(tiagabine),加巴喷丁(gabapentin),环丙沙星(ciprofloxacin),左氟沙星(levofloxacin),夫西地酸(fusidicacid),氨基酮戊酸(aminolevulinicacid),氨基己酸,异丙碘铵(isopropamideiodide),trihexethylchloride,头孢氨苄(cephalexin),阿司匹林(aspirin),吲哚洛芬(indoprofen),左旋多巴(levodopa),甲基多巴(methyldopa),佐美酸(zomepirac),头孢孟多(cefamandole),阿氯芬酸(alclofenac),甲芬那酸(mefenamicacid),氟芬那酸(flufenamicacid),赖诺普利(lisinopril),依那普利(enalapril),依那普利拉(enalaprilat),卡托普利(captopril),雷米普利(ramipril),福辛普利(fosinopril),贝那普利(benazepril),喹那普利(quinapril),替莫普利(temocapril),西拉普利(cilazapril),缬沙坦(valsartan),丙戊酸(valproicacid),色甘酸(cromoglicicacid),曲尼司特(tranilast),泛酸(pantothenicacid),甲嗪酸(metiazinicacid),芬替酸(fentiazac),芬布芬(fenbufen),普拉洛芬(pranoprofen),洛索洛芬(loxoprofen),右布洛芬(dexibuprofen),阿明洛芬(alminoprofen),噻洛芬酸(tiaprofenicacid),醋氯芬酸(aceclofenac),萘啶酸(nalidixicacid),壬二酸(azelaicacid),霉酚酸(mycophenolicacid),甲酰四氢叶酸(leucovorin),依他尼酸(ethacrynicacid),氨甲环酸(tranexamicacid),熊去氧胆酸(ursodeoxycholicacid),叶酸(folicacid),甲氯芬那酸(meclofenamicacid),羧苄西林(carbenicillin),瑞巴派特(rebamipide),西替利嗪(cetirizine),非索非那定(fexofenadine),来托司坦(letosteine),丙磺舒(probenecid),高泛酸(hopantenicacid),巴氯芬(baclofen),呋塞米(furosemide),吡咯他尼(piretanide),甲基多巴(methyldopa),普伐他汀(pravastatin),三碘甲状腺氨酸(liothyronine),左甲状腺素(levothyroxine),米诺膦酸(minodronicacid),p-氨基水杨酸(P-aminosalicylicacid),葡糖酸(gluconicacid),生物素(biotin),利拉鲁肽(liraglutide),依泽那太(exenatide),他司鲁肽(taspoglutide),阿必鲁泰(albiglutide),利西拉来(lixisenatide),干扰素α(interferonalpha),干扰素β(interferonbeta),干扰素γ(interferongamma),胰高血糖素样肽(glucagon-likepeptides),促肾上腺皮质激素(adrenocorticotropichormone),胰岛素及胰岛素样生长因子(insulinandinsulin-likegrowthfactors),甲状旁腺素及其片段(parathyroidhormoneanditsfragments),促红血球生成素α(darbepoetinalpha),重组人类红细胞生成素α(epoetinalpha),重组人类红细胞生成素β(epoetinbeta),重组人类红细胞生成素δ(epoetindelta),英夫利昔单抗(infliximab),胰岛素(insulin),胰高血糖素(glucagon),胰高血糖素样肽(glucagon-likepeptides),促甲状腺素激素(thyrotropinhormone),促甲状腺激素(thyroidstimulatinghormone),甲状旁腺素(parathyroidhormone),降钙素(calcitonin),促肾上腺皮质激素(adrenocorticotropichormone)(ACTH),促卵泡激素(folliclestimulatinghormone),绒毛膜促性腺激素(chorionicgonadotropin),促性腺素释放素(gonadotropinreleasinghormone),生长激素(somatropin),GRF,赖氨酸加压素(lypressin),促黄体激素(luteinizinghormone),白介素(interleukin),生长激素(growthhormone),前列腺素(prostaglandin),血小板来源的生长因子(platelet-derivedgrowthfactors)(PDGF),角质形成细胞生长因子(keratinocytegrowthfactors)(KGF),成纤维细胞生长因子(fibroblastgrowthfactors)(FGF),表皮生长因子(epidermalgrowthfactors)(EGF),转化生长因子-α(TGF-α),转化生长因子-β(TGF-β),红细胞生成素(erythropoietin)(EPO),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),肿瘤坏死因子-α(TNF-α),肿瘤坏死因子-β(TNF-β),集落刺激因子(CSF),血管细胞生长因子(vascularcellgrowthfactor)(VEGF),trombopoietin(TPO),间质细胞来源的因子(stromalcell-derivedfactors)(SDF),胎盘生长因子(placentagrowthfactor)(PIGF),肝细胞生长因子(HGF),粒细胞巨噬细胞集落刺激因子(GM-CSF),神经胶质来源的神经营养因子(glial-derivedneurotropinfactor)(GDNF),粒细胞集落刺激因子(G-CSF),睫状节神经细胞营养因(ciliaryneurotropicfactor)(CNTF),骨生长因子,骨形态生成蛋白(BMF),coaqulation因子,人胰岛激素释放因子(humanpancreashormonereleasingfactor),它们的类似物和衍生物,它们的药用盐,及其组合。
优选地,所述阴离子药理学活性物质可以选自由下述组成的组:硼替佐米,甲氨蝶呤,奥洛他定,利拉鲁肽(liraglutide),依泽那太(exenatide),他司鲁肽(taspoglutide),阿必鲁泰(albiglutide),利西拉来(lixisenatide),干扰素α,干扰素β,干扰素γ,噻托溴铵(tiotropium),异丙托品,格隆溴铵,阿地溴铵,umeclidinium,托斯必姆,阿仑膦酸,伊班膦酸,英卡膦酸,帕米膦酸,利塞膦酸,唑来膦酸,依替膦酸,氯膦酸,替鲁膦酸,奥帕膦酸,奈立膦酸,胰高血糖素样肽,促肾上腺皮质激素,胰岛素和胰岛素样生长因子,甲状旁腺素及其片段,促红血球生成素α(darbepoetinalpha),重组人类红细胞生成素α,重组人类红细胞生成素β,重组人类红细胞生成素δ,双氯芬酸,左卡巴司汀,吲哚美辛,布洛芬,氟比洛芬,非诺洛芬,酮洛芬,萘普生,双氯芬酸,依托度酸,舒林酸,托美汀,水杨酸,difiunisal,奥沙普嗪,硫加宾,加巴喷丁,环丙沙星,左氟沙星,夫西地酸,氨基酮戊酸,其药用盐,以及它们的组合。
更优选地,所述阴离子药理学活性物质可以选自由下述组成的组:噻托溴铵,异丙托品,格隆溴铵,阿地溴铵,umeclidinium,托斯必姆,它们的药用盐,及其组合。
应该理解,可用于本发明的持续释放脂质预浓缩物的阴离子药理学活性物质不限于前述药物实例。只要其带负电荷,任何药理学活性物质都可用于本发明。
关于本发明的组合物的pH,没有给予具体的限制,只要其落入典型的生理学可接受的范围内即可。当需要时,可以使用pH调节剂。其可以选自,但不限于,盐酸,硫酸,硼酸,磷酸,乙酸,氢氧化钠,乙醇胺,二乙醇胺,和三乙醇胺。
用于本文时,术语“水性流体”旨在包括水和体液,如粘膜液、泪液、汗液、唾液、胃肠液、血管外液、细胞外液、间质液和血浆。当暴露于水性流体时,本发明的组合物经历从脂质液相到具有半固体外观的液晶相的转变。即,本发明的组合物是这样的预浓缩物,其在施用到人体之前作为脂质液态存在并且在体内转变成使得持续释放有希望的液晶相。
由本发明的组合物形成的液晶具有非层状相结构,其中油和水处于有序的混合物和排列中,在内相和外相之间没有差别。油和水的有序排列提供中间相的非层状相结构,这是液体与固体之间的物质中间态。本发明的预浓缩物不同于已被广泛应用于设计药物制剂的形成层状结构(如胶束、乳剂、微乳剂、脂质体和脂质双层)的常规组合物。这种层状结构是采取水包油(o/w)或油包水(w/o)类型,其中具有内相和外相的清楚区分,并且因此不同于本发明的液晶。
因此,术语“液体结晶”用于本文是指在暴露于水性流体后自预浓缩物形成具有非层状相结构的液晶。
在本发明的预浓缩物中,组分a)与b)之间的重量比为10:1至1:10,优选为5:1至1:5。a)+b)与c)的重量比为1,000:1至1:1,并且优选为50:1至2:1。再看a)+b)+c)与d)的重量比,其为1,000:1至10:1,并且优选为500:1至20:1。给出这些重量范围,所述组分有效地保证归因于液晶的持续释放和二价或多价金属离子诱导的持续释放的改进。
通常,本发明的药物组合物可以包含重量比为10,000:1至1:1的a)+b)+c)+d)与e),所述重量比可以依据药理学活性物质的种类、所施用的制剂的类型、需要的释放模式和医学领域中需要的药理学活性物质的剂量而改变。
本发明的持续释放脂质预浓缩物可在室温由a)至少一种液晶形成剂,b)至少一种磷脂,c)至少一种液晶硬化剂,和d)至少一种二价或多价金属盐制备,如果必要,通过加热或使用均化器制备。所述均化器可以是高压均化器、超声均化器、珠磨(beadmill)均化器等。
如上所述,本发明的持续释放脂质预浓缩物可以是这样的药物组合物,其在不存在水性流体时作为脂质液相存在并在水性流体存在下形成液晶。由于其表现为可以使用选自注射、涂敷、滴注、填充、口服施用和喷雾的途径施用到身体的药物组合物,本发明的预浓缩物优选地可以配制成多种剂型,包括注射剂、软膏剂、凝胶剂、洗剂、胶囊剂、片剂、溶液、混悬剂、喷雾剂、吸入剂、滴眼剂、粘合剂、硬膏剂和压敏粘合剂,并且更优选配制成注射剂。
具体地,当采取注射途径时,取决于使用的药理学活性物质的性质,本发明的预浓缩物可通过皮下或肌内注射施用。
本发明的药物组合物可以优选地采用选自下述的制剂形式:注射剂、软膏剂、凝胶剂、洗剂、胶囊剂、片剂、溶液、混悬剂、喷雾剂、吸入剂、滴眼剂、粘合剂、硬膏剂和压敏粘合剂,并且更优选地配制成注射剂。
本发明的药物组合物可以通过将药理学活性物质添加到本发明的预浓缩物中而制备。当需要时,可以在本发明的药物组合物的制备中使用加热或均化器,但是这不是本发明的限制因素。
本发明的药物组合物的剂量遵循所用的药理学活性物质的公知的剂量,并且可以依据包括患者状况、年龄和性别在内的多种因素而改变。其可以口服或肠胃外施用。
根据其另外的方面,本发明预期通过将本发明的药物组合物施用给包括人在内的哺乳动物经由药理学活性物质的持续释放而保持药学功效的方法,和所述药物组合物用于持续释放药理学活性物质的应用。
发明的有益效果
如迄今为止所述,基于在所形成的液晶内的二价或多价金属盐与阴离子药理学活性物质之间的离子相互作用,根据本发明的持续释放脂质预浓缩物和药物组合物保证所述药理学活性物质的极好的持续释放。
附图简述
图1是示意图,其显示在持续释放脂质预浓缩物内的二价或多价金属盐与阴离子药理学活性物质之间的部分或完全的离子相互作用。
图2显示实施例1和3的持续释放脂质预浓缩物、实施例21和27的药物组合物和比较例3和5的脂质预浓缩物的体内生物降解性。
图3显示实施例21与比较例21和29的组合物的药理学活性物质(噻托溴铵(tiotropiumbromide))的体内药物释放行为。
图4显示实施例26与比较例22的组合物的药理学活性物质(硼替佐米)的体内药物释放行为。
图5显示实施例4与比较例22和27的组合物在暴露于水性流体后的相变行为。
发明的方式
通过下述实施例可以获得对本发明的更好的理解,描述所述实施例是为了举例说明,而不应该解释为限制本发明。
用于本发明的添加剂和赋形剂满足韩国药典的需要,并且购自Aldrich,Lipoid,Croda和Seppic。
[实施例1-20]制备包含二价或多价金属盐的脂质预浓缩物
以下表1给出的重量比,将液晶形成剂、磷脂、液晶硬化剂和二价或多价金属盐任选地在溶剂中混合。
在实施例1-20中,在保持在20~75℃的水浴中使用均化器(PowerGenmodel125,Fisher)以1,000~3,000rpm将所述物质均匀混合0.5~3小时。然后,将得到的脂质溶液放置在室温以在25℃达到热平衡,然后装载到1cc一次性注射器中。将脂质溶液注射到水(2g去离子水)中来提供本发明的包含金属盐的预浓缩物。
[表1]
[实施例21-32]具有药理学活性物质的药物组合物
以下表2中给出的重量比,任选地在溶剂中混合液晶形成剂、磷脂、液晶硬化剂、二价或多价金属盐和阴离子药理学活性物质。
在实施例21-32中,在保持在20~75℃的水浴中使用均化器(PowerGenmodel125,Fisher)以1,000~3,000rpm将所述物质均匀混合0.5~3小时。将得到的脂质溶液放置在室温以在25℃达到热平衡,然后向其中加入下述各种药理学活性物质:噻托溴铵,异丙托溴铵(ipratropiumbromide)和硼替佐米。然后,将所述物质均化约1~5小时以提供在溶液相中的药物组合物。
[表2]
[比较例1-20]制备不含二价或多价金属盐的预浓缩物
以下表3中给出的重量比,在溶剂中混合液晶形成剂、磷脂和液晶硬化剂。
在比较例1-20中,在保持在20~75℃的水浴中使用均化器(PowerGenmodel125,Fisher)以1,000~3,000rpm将所述物质混合0.5~3小时。然后,将得到的脂质溶液放置在室温以在25℃达到热平衡,然后装载到1cc一次性注射器中。将脂质溶液注射到水(2g去离子水)中来提供根据比较例1-20的预浓缩物。
[表3]
[比较例21-26]制备不含二价或多价金属盐的药物组合物
以下表4中给出的重量比,任选地在溶剂中混合液晶形成剂、磷脂、液晶硬化剂和阴离子药理学活性物质。
在比较例21-26中,在保持在20~75℃的水浴中使用均化器(PowerGenmodel125,Fisher)以1,000~3,000rpm将所述物质均匀混合约0.5~3小时。将得到的脂质溶液放置在室温以在25℃达到热平衡,然后向其中加入下述各种药理学活性物质:噻托溴铵,异丙托溴铵和硼替佐米。然后,将所述物质均化约1~5小时以提供在溶液相中的药物组合物。
[表4]
[比较例27和28]制备不含液晶形成剂的预浓缩物
通过在保持在20~75℃的水浴中使用均化器(PowerGenmodel125,Fisher)以1,000~3,000rpm将聚氧乙烯脱水山梨醇单油酸酯、磷脂酰胆碱和生育酚乙酸酯均匀混合约0.5~3小时而制备比较例27和28的预浓缩物。此处,聚氧乙烯脱水山梨醇单油酸酯在脱水山梨醇极性头上具有取代-OH基团的聚氧乙烯基团,并且与用于本发明的脱水山梨醇单油酸酯不同。聚氧乙烯脱水山梨醇单油酸酯通常用作亲水性表面活性剂。
[表5]
[比较例29和30]未加载到预浓缩物的阴离子药理学活性物质的制剂
对于比较例29的制剂,将2.2μg噻托溴铵加入到1mL生理盐水中,然后在室温均化。
比较例30的制剂通过在室温将5mg硼替佐米溶解在7mL生理盐水和300μl乙醇的混合物中而制备。
[实验例1]体外安全性测定
使用提取集落测定(ExtractionColonyAssay)进行细胞毒性检测,以检验本发明的组合物的体外安全性。
在18mL补充有10%胎牛血清的Eagle’s最小必需培养基(EMEM)中提取(extracted)2g实施例1、5、21和27以及比较例3和5的各种组合物。将L929细胞(小鼠成纤维细胞,美国典型培养物中心)以1x102个细胞/孔的密度接种到6孔平板中,并且在37℃在5%CO2湿润的培养箱中稳定24小时。将提取物在EMEM中稀释(0,5,25,50%),然后以2mL/孔的量放置与稳定的L929细胞接触。
在37℃在5%CO2湿润的培养箱中培养7天后,用10%福尔马林溶液固定细胞,并且用Giemsa溶液染色,以计数集落。结果总结在下表6中。
[表6]
*相对集落形成率(%)=测试培养基上的集落数/0%培养基上的集落数x100(%)
**提取培养基%=提取培养基/(稀释的培养基+提取培养基)x100(%)
从表6的数据了解,比较例3和5的组在每种稀释培养基(5%,25%和50%)中以正常速率生长,在实施例1、5、21和27以及比较例3和5的组之间观察到生长速率的相似性。因此,证明本发明的脂质预浓缩物和药物组合物是对身体高度安全的。
[实验例2]体内生物降解性测定
如下评价本发明的组合物的体内生物降解性。
将实施例1、3、21和27的每种组合物以300mg的剂量皮下注射到SD大鼠的背部,并且监测预定的时间。为了比较,以相同的方式检测比较例3和5的组合物。注射后一个月对注射部位拍照,并且显示在图2中。
在图2中可以看出,注射后一个月,在比较例3和5的组中,液晶凝胶体积减少到初始体积的约1/3至2/3,这表明组合物的生物降解。
类似地,在注射后一个月,施用实施例1、3、21和27的组合物的SD大鼠的肿胀组织体积减少到初始体积的1/3至2/3。因此,本发明的组合物可以在体内降解到与比较例3和5的那些相似的程度。
为参照,已知常规广泛使用的持续释放基质PLGA[聚(乳酸-共-乙醇酸)]保持不降解达2~3个月之久。
因此,本发明的包含二价或多价金属盐的脂质预浓缩物表现出与不含金属盐的组合物相似的生物降解性,并且克服了常规持续释放制剂的缺陷,即甚至在药物释放结束后载体仍然在体内保留长时间。
[实验例3]体内检测噻托溴铵的持续释放
在下述检测中检验噻托溴铵自本发明的组合物的药物释放行为。
使用一次性注射器,将实施例21的组合物以0.4mg/kg的噻托溴铵剂量皮下注射到6只9周龄平均体重为300g的SD大鼠(雄性)中。
使用LC-MS/MS(液相色谱-串联质谱)分析取自SD大鼠的血浆样品中的噻托溴铵浓度,以绘制PK特征曲线(药代动力学特征曲线)。SD大鼠中的PK特征曲线显示在图3中。
为了比较PK特征曲线,将比较例29的组合物以0.01mg/kg的噻托溴铵剂量皮下注射到背部,同时将不含二价或多价金属盐的比较例21的组合物以0.4mg/kg的噻托溴铵剂量通过皮下注射施用到背部。比较例29的组合物的量是每天一次剂量,其比持续释放制剂的剂量低30倍。
在图3中可以看出,与缺少二价或多价金属盐的比较例21的组合物相比,实施例21的组合物的初始突释显著更低,并且表现出更高的持续释放。
[实验例4]体内检测硼替佐米的持续释放
在下述检测中在体内检验硼替佐米自本发明的组合物的药物释放行为。使用一次性注射器,将实施例26的组合物以0.6mg/kg的硼替佐米剂量皮下注射到6只9周龄平均体重为300g的SD大鼠(雄性)的背部。
使用LC-MS/MS(液相色谱-串联质谱)分析取自SD大鼠的血浆样品中的硼替佐米浓度,以绘制PK特征曲线(药代动力学特征曲线)。SD大鼠中的PK特征曲线显示在图4中。为了检验二价或多价金属盐对持续释放的影响,将缺少二价或多价金属盐的比较例22的组合物以0.6mg/kg的硼替佐米剂量皮下注射到背部。
在图4中可以看出,与缺少二价或多价金属盐的比较例22的组合物相比,实施例26的组合物的初始突释显著更低,并且保持有效的浓度,显示出高的持续释放。
[实验例5]在水性流体中形成液晶
如下评价本发明的组合物在水性流体中形成液晶的能力。
在填装到注射器中后,将实施例4和22以及比较例27的组合物滴到2gPBS(pH7.4)中,结果显示在图5中。
观察到实施例4和22的组合物在注射前在不存在水性流体时作为脂质液相存在,但是在暴露于水性流体后形成液晶。基于聚氧乙烯脱水山梨醇不饱和脂肪酸酯(聚氧乙烯脱水山梨醇单油酸酯)的比较例27的组合物在不存在水性流体时以液相形式存在,并且在注射到水性流体后不形成液晶,而是分散在水性流体中。因此,本发明的持续释放组合物可以从不存在水性流体时的液相快速转变为暴露于水性流体后(体内环境)的液晶相,以致其可以适用于医学药剂的持续释放制剂。
在液晶内,存在大量的与默比乌斯带(Moebiusstrip)相似的纳米尺寸(低于20nm)的双连续的水通道。所述水通道由双连续的脂质层围绕。由此,一旦脂质组合物形成半固体相的液晶,药理学活性物质可以仅在其通过众多的水通道和脂质层后才能从液晶结构中释放出来,这增强了药理学活性物质的持续释放效果。
Claims (28)
1.持续释放脂质预浓缩物,其包含:
a)至少一种液晶形成剂;
b)至少一种磷脂;
c)至少一种液晶硬化剂;和
d)至少一种二价或多价金属盐,
其中所述持续释放预浓缩物在不存在水性流体时作为脂质液相存在并且在暴露于水性流体后形成液晶。
2.权利要求1的持续释放脂质预浓缩物,其中所述液相形成剂选自由下述组成的组:脱水山梨醇不饱和脂肪酸酯、单酰甘油、二酰甘油,及其组合。
3.权利要求2的持续释放脂质预浓缩物,其中所述脱水山梨醇不饱和脂肪酸酯在极性头中具有两个以上的-OH(羟基)基团。
4.权利要求2的持续释放脂质预浓缩物,其中所述脱水山梨醇不饱和脂肪酸酯选自由下述组成的组:脱水山梨醇单油酸酯,脱水山梨醇单亚油酸酯,脱水山梨醇单棕榈油酸酯,脱水山梨醇单肉豆蔻脑酸酯,脱水山梨醇倍半油酸酯,脱水山梨醇倍半亚油酸酯,脱水山梨醇倍半棕榈油酸酯,脱水山梨醇倍半肉豆蔻脑酸酯,脱水山梨醇二油酸酯,脱水山梨醇二亚油酸酯,脱水山梨醇二棕榈油酸酯,脱水山梨醇二肉豆蔻脑酸酯,及其组合。
5.权利要求2的持续释放脂质预浓缩物,其中所述脱水山梨醇不饱和脂肪酸酯选自由下述组成的组:脱水山梨醇单油酸酯,脱水山梨醇单亚油酸酯,脱水山梨醇单棕榈油酸酯,脱水山梨醇单肉豆蔻脑酸酯,脱水山梨醇倍半油酸酯,及其组合。
6.权利要求2的持续释放脂质预浓缩物,其中所述单酰甘油具有由甘油组成的极性头,以及通过酯键连接到所述极性头的脂肪酸尾。
7.权利要求2的持续释放脂质预浓缩物,其中所述二酰甘油具有由甘油组成的极性头,以及各自通过酯键连接到所述极性头的两个脂肪酸尾,所述两个脂肪酸尾相同或彼此不同。
8.权利要求2的持续释放脂质预浓缩物,其中所述通过酯键连接到所述单酰甘油或所述二酰甘油的脂肪酸基团包含4至30个碳原子,并且选自由下述组成的组:棕榈酸,棕榈油酸,月桂酸,丁酸,戊酸,己酸,庚酸,辛酸,壬酸,癸酸,肉豆蔻酸,肉豆蔻脑酸,硬脂酸,花生酸,辣木子油酸,木蜡酸,蜡酸,亚麻酸,α-亚麻酸(ALA),二十碳五烯酸(EPA),二十二碳六烯酸(DHA),亚油酸(LA),γ-亚油酸(GLA),双高γ-亚油酸(DGLA),花生四烯酸(AA),油酸,异油酸,反油酸,花生酸,芥酸,神经酸,及其组合。
9.权利要求2的持续释放脂质预浓缩物,其中所述单酰甘油选自由下述组成的组:甘油单丁酸酯,甘油单辣木子油酸酯,甘油单辛酸酯,甘油单月桂酸酯,甘油单甲基丙烯酸酯,甘油单棕榈酸酯,甘油单硬脂酸酯,甘油单油酸酯,甘油单亚油酸酯,甘油单花生酸酯,甘油单花生四烯酸酯,甘油单芥酸酯,及其组合。
10.权利要求2的持续释放脂质预浓缩物,其中所述单酰甘油是甘油单油酸酯(GMO)。
11.权利要求2的持续释放脂质预浓缩物,其中所述二酰甘油选自由下述组成的组:甘油二辣木子油酸酯,甘油二月桂酸酯,甘油二甲基丙烯酸酯,甘油二棕榈酸酯,甘油二硬脂酸酯,甘油二油酸酯,甘油二亚油酸酯,甘油二芥酸酯,甘油二肉豆蔻酸酯,甘油二蓖麻酸酯,甘油二棕榈油酸酯,及其组合。
12.权利要求2的持续释放脂质预浓缩物,其中所述二酰甘油是甘油二油酸酯(GDO)。
13.权利要求1的持续释放脂质预浓缩物,其中所述磷脂选自由下述组成的组:磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰甘油,磷脂酰肌醇,磷脂酸,鞘磷脂,及其组合,具有4至30个饱和或不饱和的碳原子。
14.权利要求1的持续释放脂质预浓缩物,其中所述液晶硬化剂不含可离子化基团,并且其疏水结构部分具有15至40个碳原子的三酰基或碳环结构。
15.权利要求1的持续释放脂质预浓缩物,其中所述液晶硬化剂选自由下述组成的组:甘油三酯,棕榈酸视黄酯,生育酚乙酸酯,胆甾醇,苯甲酸苄酯,泛醌,及其组合。
16.权利要求1的持续释放脂质预浓缩物,其中所述液晶硬化剂选自由下述组成的组:生育酚乙酸酯,胆甾醇,及其组合。
17.权利要求1的持续释放脂质预浓缩物,其中所述二价或多价金属盐的金属选自由下述组成的组:铝,钙,铁,镁,锡,钛和锌。
18.权利要求1的持续释放脂质预浓缩物,其中所述二价或多价金属盐的金属选自由下述组成的组:铝,钙,和锌。
19.权利要求1的持续释放脂质预浓缩物,其中a)与b)的重量比为10:1至1:10。
20.权利要求1的持续释放脂质预浓缩物,其中a)+b)与c)的重量比为1,000:1至1:1。
21.权利要求1的持续释放脂质预浓缩物,其中a)+b)+c)与d)的重量比为10,000:1至10:1。
22.药物组合物,其包含:
权利要求1至21中任一项的持续释放脂质预浓缩物;和
e)至少一种阴离子药理学活性物质,
其中所述持续释放预浓缩物的二价或多价金属盐通过与所述阴离子药理学活性物质形成离子键而增强所述阴离子药理学活性物质的持续释放。
23.权利要求22的药物组合物,其中所述阴离子药理学活性物质选自由具有至少一种下述结构的药理学活性物质组成的组:羧酸,亚磺酸,磺酸,膦酸,磷酸,硼酸,烃基硼酸,芳香醇,酰亚胺或季铵卤化物盐,其药用盐,以及它们的组合。
24.权利要求22的药物组合物,其中所述阴离子药理学活性物质选自由下述组成的组:硼替佐米,甲氨蝶呤,奥洛他定,利拉鲁肽,依泽那太,他司鲁肽,阿必鲁泰,利西拉来,干扰素α,干扰素β,干扰素γ,噻托溴铵,异丙托品,格隆溴铵,阿地溴铵,umeclidinium,托斯必姆,阿仑膦酸,伊班膦酸,英卡膦酸,帕米膦酸,利塞膦酸,唑来膦酸,依替膦酸,氯膦酸,替鲁膦酸,奥帕膦酸,奈立膦酸,胰高血糖素样肽,促肾上腺皮质激素,胰岛素和胰岛素样生长因子,甲状旁腺素及其片段,促红血球生成素α,重组人类红细胞生成素α,重组人类红细胞生成素β,重组人类红细胞生成素δ,双氯芬酸,左卡巴司汀,吲哚美辛,布洛芬,氟比洛芬,非诺洛芬,酮洛芬,萘普生,双氯芬酸,依托度酸,舒林酸,托美汀,水杨酸,difiunisal,奥沙普嗪,硫加宾,加巴喷丁,环丙沙星,左氟沙星,夫西地酸,氨基酮戊酸,其药用盐,以及它们的组合。
25.权利要求22的药物组合物,其中所述阴离子药理学活性物质选自由下述组成的组:噻托溴铵,异丙托品,格隆溴铵,阿地溴铵,umeclidinium,托斯必姆,其药用盐,以及它们的组合。
26.权利要求22的药物组合物,其中a)+b)+c)+d)与e)的重量比为10,000:1至2:1。
27.权利要求22的药物组合物,其被配制成选自下述的剂型:注射剂、软膏剂、凝胶剂、洗剂、胶囊剂、片剂、溶液、混悬剂、喷雾剂、吸入剂、滴眼剂、粘合剂、硬膏剂和压敏粘合剂。
28.权利要求27的药物组合物,其中所述剂型是注射剂。
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KR10-2012-0157582 | 2012-12-28 | ||
PCT/KR2013/012265 WO2014104788A1 (en) | 2012-12-28 | 2013-12-27 | Sustained-release lipid pre-concentrate of anionic pharmacologically active substances and pharmaceutical composition comprising the same |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113018254A (zh) * | 2021-04-13 | 2021-06-25 | 安徽中医药大学 | 一种用于治疗原发性痛经的布洛芬液晶凝胶经皮制剂及其制备方法 |
CN113490487A (zh) * | 2019-02-18 | 2021-10-08 | Imd制药有限公司 | 缓释型脂质预浓缩物及包含其的脂质溶液形式的缓释型注射用药物组合物 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101494594B1 (ko) | 2011-08-30 | 2015-02-23 | 주식회사 종근당 | 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
KR101586791B1 (ko) | 2012-12-28 | 2016-01-19 | 주식회사 종근당 | GnRH 유도체의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
HUE033790T2 (en) | 2013-01-31 | 2017-12-28 | Chong Kun Dang Pharmaceutical Corp | CETP inhibitor biaryl or heterocyclic biaryl substituted cyclohexene derivatives |
KR101809908B1 (ko) | 2014-07-21 | 2018-01-25 | 주식회사 종근당 | 5-알파환원효소억제제를 포함하는 조성물 |
DK3512495T3 (da) * | 2016-09-15 | 2022-12-05 | Camurus Ab | Formuleringer af prostacyklinanaloger |
CA3141337A1 (en) * | 2019-05-24 | 2020-12-03 | Piedmont Animal Health Inc. | Long-acting injectable formulations and use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101014319A (zh) * | 2004-06-04 | 2007-08-08 | 卡穆鲁斯公司 | 液体贮库制剂 |
CN101678113A (zh) * | 2007-05-14 | 2010-03-24 | 日本株式会社Ltt生物医药 | 缓释性的含有带负电荷基团的低分子药物的纳米粒子 |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3706036A1 (de) * | 1987-02-25 | 1988-09-08 | Basf Ag | Polyacetale, verfahren zu deren herstellung aus dialdehyden und polyolcarbonsaeuren und verwendung der polyacetale |
SE518578C2 (sv) * | 1994-06-15 | 2002-10-29 | Gs Dev Ab | Lipidbaserad komposition |
EP0825852B1 (en) * | 1995-04-18 | 2004-07-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Liposome drug-loading method and composition |
US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
TR199901008T1 (xx) * | 1997-09-09 | 2000-02-21 | Select Release, L.C. | Kaplanm�� partik�ller, yap�m� ve kullan�m y�ntemleri. |
TWI241915B (en) | 1998-05-11 | 2005-10-21 | Ciba Sc Holding Ag | A method of preparing a pharmaceutical end formulation using a nanodispersion |
US20030070679A1 (en) * | 2001-06-01 | 2003-04-17 | Boehringer Ingelheim Pharma Kg | Capsules containing inhalable tiotropium |
WO2003032947A2 (en) * | 2001-09-06 | 2003-04-24 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | A method for preparing liposome formulations with a predefined release profile |
US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
EP1682091B1 (en) * | 2003-11-07 | 2017-03-29 | Camurus Ab | Compositions of lipids and cationic peptides |
US20050106214A1 (en) | 2003-11-14 | 2005-05-19 | Guohua Chen | Excipients in drug delivery vehicles |
SE526127C2 (sv) | 2003-11-14 | 2005-07-12 | Nilar Int Ab | En packning, ett bipolärt batteri och en metod för tillverkning av ett bipolärt batteri med en sådan packning |
WO2005110360A2 (en) | 2004-05-18 | 2005-11-24 | Phares Pharmaceutical Research N.V. | Compositions for injection |
RU2390331C2 (ru) * | 2004-06-04 | 2010-05-27 | Камурус Аб | Жидкие депо-препараты |
JP5171262B2 (ja) | 2005-01-14 | 2013-03-27 | カムルス エービー | ソマトスタチン類似体製剤 |
US9060935B2 (en) * | 2005-01-21 | 2015-06-23 | Camurus Ab | Pharmaceutical lipid compositions |
EP1712220A1 (en) * | 2005-04-15 | 2006-10-18 | PARI GmbH Spezialisten für effektive Inhalation | Pharmaceutical aerosol composition |
US20080102128A1 (en) * | 2006-07-28 | 2008-05-01 | Flamel Technologies, Inc. | Modified-release microparticles based on amphiphilic copolymer and on active principles(s) and pharmaceutical formulations comprising them |
GB0716385D0 (en) * | 2007-08-22 | 2007-10-03 | Camurus Ab | Formulations |
AU2010227549B2 (en) | 2009-03-25 | 2014-02-27 | Novartis Ag | Pharmaceutical composition containing a drug and siRNA |
CN101904814A (zh) | 2009-06-04 | 2010-12-08 | 上海恒瑞医药有限公司 | 制备载药乳剂的方法 |
KR20110056042A (ko) * | 2009-11-20 | 2011-05-26 | 주식회사유한양행 | 종양세포 표적지향을 위한 나노 입자 및 이의 제조방법 |
KR101494594B1 (ko) * | 2011-08-30 | 2015-02-23 | 주식회사 종근당 | 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
-
2012
- 2012-12-28 KR KR1020120157582A patent/KR101586790B1/ko not_active IP Right Cessation
-
2013
- 2013-12-27 CN CN201380068020.6A patent/CN105188681A/zh active Pending
- 2013-12-27 RU RU2015131109A patent/RU2632436C2/ru not_active IP Right Cessation
- 2013-12-27 US US14/440,059 patent/US20150290322A1/en not_active Abandoned
- 2013-12-27 NZ NZ710471A patent/NZ710471A/en not_active IP Right Cessation
- 2013-12-27 JP JP2015550322A patent/JP6166382B2/ja not_active Expired - Fee Related
- 2013-12-27 CA CA2888801A patent/CA2888801C/en not_active Expired - Fee Related
- 2013-12-27 MX MX2015008402A patent/MX2015008402A/es unknown
- 2013-12-27 EP EP13868908.8A patent/EP2938333A4/en not_active Withdrawn
- 2013-12-27 WO PCT/KR2013/012265 patent/WO2014104788A1/en active Application Filing
- 2013-12-27 BR BR112015015713A patent/BR112015015713A2/pt not_active IP Right Cessation
- 2013-12-27 AU AU2013371098A patent/AU2013371098B2/en not_active Ceased
-
2015
- 2015-06-29 PH PH12015501554A patent/PH12015501554A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101014319A (zh) * | 2004-06-04 | 2007-08-08 | 卡穆鲁斯公司 | 液体贮库制剂 |
CN101678113A (zh) * | 2007-05-14 | 2010-03-24 | 日本株式会社Ltt生物医药 | 缓释性的含有带负电荷基团的低分子药物的纳米粒子 |
Non-Patent Citations (1)
Title |
---|
JESSICA S. YUAN ETAL: ""Linker-based lecithin microemulsions for transdermal delivery of lidocaine"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113490487A (zh) * | 2019-02-18 | 2021-10-08 | Imd制药有限公司 | 缓释型脂质预浓缩物及包含其的脂质溶液形式的缓释型注射用药物组合物 |
CN113018254A (zh) * | 2021-04-13 | 2021-06-25 | 安徽中医药大学 | 一种用于治疗原发性痛经的布洛芬液晶凝胶经皮制剂及其制备方法 |
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WO2014104788A1 (en) | 2014-07-03 |
KR20140086740A (ko) | 2014-07-08 |
JP6166382B2 (ja) | 2017-07-19 |
EP2938333A1 (en) | 2015-11-04 |
RU2015131109A (ru) | 2017-02-03 |
AU2013371098B2 (en) | 2016-11-17 |
PH12015501554A1 (en) | 2015-09-21 |
BR112015015713A2 (pt) | 2017-07-11 |
AU2013371098A1 (en) | 2015-08-13 |
US20150290322A1 (en) | 2015-10-15 |
RU2632436C2 (ru) | 2017-10-04 |
KR101586790B1 (ko) | 2016-01-19 |
NZ710471A (en) | 2016-04-29 |
EP2938333A4 (en) | 2016-06-15 |
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