CN112839680A - 用于包封活性物质的、允许控制所述活性物质的释放速率的脂质组合物 - Google Patents
用于包封活性物质的、允许控制所述活性物质的释放速率的脂质组合物 Download PDFInfo
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- CN112839680A CN112839680A CN201980067930.XA CN201980067930A CN112839680A CN 112839680 A CN112839680 A CN 112839680A CN 201980067930 A CN201980067930 A CN 201980067930A CN 112839680 A CN112839680 A CN 112839680A
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- Prior art keywords
- sorbitan
- lipid composition
- composition
- ethylene oxide
- esters
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Abstract
揭露了一种脂质组合物,每100%重量包含:‑按重量计从40%至99.9%的以下复合物,该复合物每100%重量包含按重量计从90%至0%的蜂蜡以及按重量计至多10%的至少一种其他脂质赋形剂,‑按重量计从0.1%至60%的至少一种亲脂性表面活性剂。
Description
本发明涉及一种脂质组合物、包含所述脂质组合物并且能够控制其含有的活性物质的释放速率的控制释放组合物、以及用于制造包含所述控制释放组合物的盖仑制剂(galenical formulation)的方法。
在人和兽用药物制剂中以及在来自食品补充剂工业的制剂中开发和使用的活性成分对环境因素敏感,无论在相关盖仑制剂形式的制造期间(尤其是对在某些方法中使用的高温、氧化现象等)和/或在所述盖仑制剂形式的寿命期间、和/或在人或动物体内消耗期间(当所述盖仑制剂形式与存在于使用者体内的降解和/或消化分子接触时)。
此外,构成存在于这些盖仑制剂形式中的全部或一些活性成分的分子可能具有与直接消耗时不一致的感官特性:味道差、气味不当等。
以提供营养或治疗优点为目标,引入胶囊、硬胶囊、片剂或甚至食品中的分子不应当以相同的速率并且在相同的环境中溶解。
尤其是由于这些不同原因,许多活性分子涉及被称为包封(encapsulation)的方法中,其目的是制备包含至少一种活性成分的组合物(CA)。该包封方法具有保护该至少一种活性成分免受与特定外部环境的不希望的相互作用的功能,并且具有将所述一种或多种活性成分转运至另一环境中的功能,在所述另一环境中的条件允许释放活性剂以便实现其预期的治疗或营养功能。该方法是被本领域技术人员称为“直接功能化”的方法的具体实例。
术语“直接功能化”理解为意指通过实施特定制剂和借助于特定方法来修饰活性药物成分的至少一种理化特性。
在最为人熟知的包封技术之中,可以提及主要采用亲水性化合物的技术,但也可以提及主要采用疏水性化合物的技术,例如“制粒(prilling)”技术,即包括以下步骤的技术:将含有至少一种活性剂的脂质形式雾化以便获得固体球状形式(也称为“喷雾冷冻”或“喷雾冷却”)、凝结、热熔包衣、热熔挤出、熔体造粒(melt granulation)、成丸粒(pelletization)、滚圆、热造粒(thermogranulation)等。
该“直接功能化”(尤其是借助于包封技术)可以因此呈现以下优点:使本身不稳定的某些化合物(诸如像挥发性化合物)稳定化、防止氧化现象、以及总体保护药物或营养活性。
该初始“直接功能化”步骤(尤其是借助于包封技术)还可以对活性剂在宿主有机体中的释放动力学产生影响。通常寻求这种影响,尤其是本着掩蔽味道、气味或为了获得活性剂在人或动物体内的目标生物学区域的延迟、控制释放的目的。
在开发治疗或预防或营养组合物的阶段期间,考虑了该“直接功能化”步骤对活性剂的释放曲线的影响。
然而,在过程中使用工业成型工具(这些工具涉及盖仑制剂形式上的机械应力)的放大(scale-up)阶段期间,与不要求使用此类工具的规模上最初测试的制剂相比,本领域技术人员发现他们自身面临控制释放曲线的不希望变化反复出现的问题。
作为实例,在使用于诱导显著机械应力的方法(诸如压缩方法)之后,“直接功能化”后的活性剂的释放曲线可以大幅修改、加速或减慢。因此,有可能通过在压缩期间削弱“保护壳”使由初始“功能化”诱导的脂质保护受损害,这可以诱导活性剂的加速的释放曲线。
在将这些延长释放制剂盖仑成型的下游步骤的过程中,观察到功能化后所获得和证明的活性剂的释放曲线可以受到显著影响,并且可以显示出相对于盖仑成型之前活性剂的释放曲线的显著差异。因此,在用于制备所述功能化活性剂的方法中实施涉及显著机械应力的步骤(诸如像压缩步骤)之后,可以大幅修改、加速或减慢功能化后活性剂的释放曲线。更特别地作为实例,由初始功能化诱导的脂质保护可以通过在压缩期间削弱“保护壳”而受损害,这可以导致活性剂的加速的且不期望的释放曲线。
到目前为止并且根据申请人的知识,本领域技术人员并没有使之有可能开发和制造以下制剂的解决方案:所述制剂包含以延迟或延长的方式释放的活性成分,并且所述活性成分的释放曲线没有被包括至少一个对所述制剂和/或盖仑制剂实施显著机械应力的步骤的制备方法所改变,其中所述盖仑形式制剂通过包括至少一个采用显著机械应力的步骤的方法制备。
本发明的解决方案是一种脂质组合物,所述脂质组合物每100%其重量包含:
-按重量计从40%至99.9%、更特别地从40%至98%、并且还更特别地从40%至95%的组分,所述组分每100%其重量包含按重量计从90%至100%的蜂蜡以及按重量计至多10%的至少一种其他脂质赋形剂,
-按重量计从0.1%至60%、更特别地按重量计从2%至60%、并且还更特别地按重量计从5%至60%的至少一种亲脂性表面活性剂,所述亲脂性表面活性剂选自聚乙氧基化脂肪酸、脂肪二酸和聚乙二醇的酯、聚甘油和脂肪酸的酯、丙二醇和脂肪酸的酯、丙二醇的酯和甘油的酯的混合物、脂肪酸甘油二酯、固醇和固醇的衍生物、脂肪酸和脱水山梨糖醇的酯、脱水山梨糖醇与聚乙二醇及脂肪酸的酯、聚乙二醇和烷基的醚、蔗糖酯、以及聚氧乙烯-聚氧丙烯嵌段共聚物。
根据本发明的组合物可以采取在环境温度下为固体的各种形式(珠粒、球体、鳞片、薄片、珠状物等)。它主要旨在用于在动物或人类药物、治疗性和/或预防性工业部门、食品补充剂和/或人类和动物食品工业中形成活性剂。
出于本发明的目的,术语“脂质赋形剂”理解为意指具有小于或等于120℃、优选地小于或等于100℃的熔点的赋形剂,其在环境温度(高于或等于15℃且低于或等于30℃)下是固体,并且其不溶于水或微溶于水。
在根据本发明的组合物中使用的蜂蜡是黄色的或白色的,也由编号E901表示并且具有在60℃与67℃之间的熔点。
关于亲脂性表面活性剂,在此指定术语“亲脂性的(lipophilic)”和“亲水性的(hydrophilic)”是相对的术语。通常用于表征非离子两亲性化合物的相对亲脂性和亲水性的经验参数是亲水性-亲脂性平衡,即称为“HLB”的值。
因此,具有更低HLB值的表面活性剂更亲脂并且在油中具有更大的溶解度,然而具有更高HLB值的表面活性剂更亲水并且在水溶液中具有更大的溶解度。
使用HLB值作为指示,亲水性表面活性剂通常被认为是具有大于或等于10的HLB值的化合物,并且也是HLB标度通常不适用的阴离子、阳离子或两性离子化合物。同样地,亲脂性表面活性剂是具有小于大约10的HLB值的化合物。在这两种情况下,提及术语“大约”是由于引起的变化。
视情况而定,根据本发明的脂质组合物可以具有以下特征中的一项或多项:
-脂质赋形剂选自动物蜡、植物蜡、矿物蜡、合成蜡或氢化植物油;
-亲脂性表面活性剂选自脂肪酸和糖的酯;
-亲脂性表面活性剂是来自脱水山梨糖醇酯家族的亲脂性表面活性剂,更特别地是来自由以下各项组成的组中的元素:脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯和脱水山梨糖醇单油酸酯,并且甚至更特别地是脱水山梨糖醇单棕榈酸酯或脱水山梨糖醇单硬脂酸酯,并且甚至更特别地是脱水山梨糖醇单硬脂酸酯;
-所述组合物包含按重量计从0%至20%、更特别地按重量计从0%至10%的一种或多种亲水性表面活性剂;
-一种或多种亲水性表面活性剂选自大豆卵磷脂、聚乙氧基化脱水山梨糖醇酯、聚乙氧基化醇、聚乙氧基化酸、聚甘油酯、葡萄糖醚以及环氧乙烷与环氧丙烷的嵌段共聚物;
-亲脂性表面活性剂是脱水山梨糖醇酯,并且亲水性表面活性剂选自聚乙氧基化脱水山梨糖醇酯;
-所述组合物包含:80%蜂蜡、20%脱水山梨糖醇硬脂酸酯;
-所述组合物包含:94%蜂蜡、1%脱水山梨糖醇硬脂酸酯、以及5%的用20摩尔的环氧乙烷聚乙氧基化的脱水山梨糖醇油酸酯(也称为聚山梨醇酯80);
-所述组合物包含:75%蜂蜡、20%脱水山梨糖醇硬脂酸酯、以及5%的用20摩尔的环氧乙烷聚乙氧基化的脱水山梨糖醇油酸酯(也称为聚山梨醇酯80);
-所述组合物包含:50%蜂蜡、45%脱水山梨糖醇硬脂酸酯、以及5%的用20摩尔的环氧乙烷聚乙氧基化的脱水山梨糖醇油酸酯(或聚山梨醇酯80);
-所述组合物包含按重量计从0至20%、并且更特别地按重量计从0至10%的至少一种包衣助剂;
-一种或多种包衣助剂选自稀释剂、调味剂、开胃剂、着色剂、抗氧化剂、增塑剂、消泡剂和崩解剂。
关于脂质赋形剂:
-对于动物蜡,可以提及:具有在52℃与55℃之间的熔点的鲸蜡、具有在37℃与44℃之间的熔点的羊毛脂、以及具有在77℃与90℃之间的熔点的紫胶;
-对于植物蜡,可以提及:具有在78℃与88℃之间的熔点的巴西棕榈蜡、具有在67℃-79℃之间的熔点的小烛树蜡、以及具有接近78℃的熔点的米糠蜡;
-对于矿物蜡,可以提及:具有在50℃与71℃之间的熔点的石蜡、以及具有在54℃与102℃之间的熔点的微晶蜡;
-对于合成蜡,可以提及:费-托(Fischer-Tropsch)蜡、聚乙烯(或聚丙烯)蜡、聚(环氧乙烷)或聚(环氧丙烷)蜡等;
-对于氢化植物油,可以提及:具有在58℃与62℃之间的熔点的棕榈油、以及具有在61℃与65℃之间的熔点的硬脂精。
在亲脂性表面活性剂之中,可以提及:
-脂肪酸和甘油的酯,所述脂肪酸选自硬脂酸、棕榈酸、酮硬脂酸、花生酸和山萮酸;
-脂肪醇和糖的醚,脂肪醇是硬脂醇、棕榈醇、酮硬脂醇、花生醇和山嵛醇;所述糖是例如还原糖,并且更具体地是葡萄糖、木糖、阿拉伯糖、甘露糖或蔗糖;
-脂肪酸的二价盐,诸如硬脂酸、棕榈酸、酮硬脂酸、花生酸和山萮酸的镁、锌或钙盐;
-与环氧丙烷和/或环氧丁烷缩合的脂肪醇;
-醇化物(乙烯、丙烯、丁烯等)的嵌段共聚物,其富含环氧丙烷或环氧丁烷;
-脂肪酸和糖的酯;所述脂肪酸选自硬脂酸、棕榈酸、酮硬脂酸、花生酸和山萮酸;所述糖是例如葡萄糖、山梨糖醇、甘露糖、甘露糖醇、蔗糖、甘露糖、木糖醇或木糖;
-在脂肪酸和糖的酯之中,可以特别提及脂肪酸和山梨糖醇的酯、以及脂肪酸和脱水山梨糖醇的酯。
在可以与为本发明主题的组合物组合的脱水山梨糖醇酯之中,可以提及:
-脱水山梨糖醇单月桂酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM20出售的、由禾大公司(Croda)以商标名SpanTM20出售的、以及由,
-脱水山梨糖醇单棕榈酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM40出售的以及由禾大公司(Croda)以商标名SpanTM40出售的,
-脱水山梨糖醇单硬脂酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM60出售的以及由禾大公司(Croda)以商标名SpanTM60出售的,
-脱水山梨糖醇单油酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM80出售的以及由禾大公司(Croda)以商标名SpanTM80出售的,
-脱水山梨糖醇三油酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM85出售的以及由禾大公司(Croda)以商标名SpanTM85出售的,
-脱水山梨糖醇倍半油酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM83出售的、由禾大公司(Croda)以商标名CrillTM43出售的、以及由,
-脱水山梨糖醇三硬酯酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM65出售的以及由禾大公司(Croda)以商标名SpanTM65出售的,
-脱水山梨糖醇单异硬脂酸酯,由赛比克公司(SEPPIC)以商标名MontaneTM70出售的以及由禾大公司(Croda)以商标名CrillTM6出售的。
根据本发明的组合物任选地包含从0至20%的一种或多种亲水性表面活性剂,所述亲水性表面活性剂选自大豆卵磷脂、乙氧基化脱水山梨糖醇酯、聚乙氧基化醇、聚乙氧基化酸、聚甘油酯、葡萄糖醚以及环氧乙烷与环氧丙烷的嵌段共聚物。
在可以与为本发明主题的组合物组合的乙氧基化脱水山梨糖醇酯之中,可以提及:
-用20摩尔环氧乙烷乙氧基化的脱水山梨糖醇单月桂酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM20出售的以及由禾大公司(Croda)以商标名TweenTM20出售的,
-用4摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单月桂酸酯,以商标名TweenTM21出售的,
-用6摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单月桂酸酯,由日光公司(Nikko)以商标名NikkolTMGL-I出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单棕榈酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM40出售的以及由禾大公司(Croda)以商标名TweenTM40出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单硬脂酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM60出售的以及由禾大公司(Croda)以商标名TweenTM60出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇三硬酯酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM65出售的以及由禾大公司(Croda)以商标名TweenTM65出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单油酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM80出售的以及由禾大公司(Croda)以商标名TweenTM80出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇三油酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM85出售的以及由禾大公司(Croda)以商标名TweenTM85出售的,
-用20摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单异硬脂酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM70出售的以及由禾大公司(Croda)以商标名TweenTM120出售的,
-用4摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单硬脂酸酯,由禾大公司(Croda)以商标名TweenTM61出售的,
-用5摩尔的环氧乙烷乙氧基化的脱水山梨糖醇单油酸酯,由赛比克公司(SEPPIC)以商标名MontanoxTM81出售的以及由禾大公司(Croda)以商标名TweenTM81出售的。
作为亲水性表面活性剂,在可以与为本发明主题的组合物组合的乙氧基化脂肪醇之中,可以提及用2摩尔的环氧乙烷乙氧基化的油醇、用3摩尔的环氧乙烷乙氧基化的油醇、用5摩尔的环氧乙烷乙氧基化的油醇、用10摩尔的环氧乙烷乙氧基化的油醇、用20摩尔的环氧乙烷乙氧基化的油醇、用4摩尔的环氧乙烷乙氧基化的月桂醇、用7摩尔的环氧乙烷乙氧基化的月桂醇、用9摩尔的环氧乙烷乙氧基化的月桂醇、用23摩尔的环氧乙烷乙氧基化的月桂醇、用2摩尔的环氧乙烷乙氧基化的十六烷醇、用10摩尔的环氧乙烷乙氧基化的十六烷醇、用20摩尔的环氧乙烷乙氧基化的十六烷醇、用2摩尔的环氧乙烷乙氧基化的硬脂醇、用10摩尔的环氧乙烷乙氧基化的硬脂醇、用20摩尔的环氧乙烷乙氧基化的硬脂醇或用100摩尔的环氧乙烷乙氧基化的硬脂醇。
作为亲水性表面活性剂,在可以与为本发明主题的组合物组合的乙氧基化脂肪酸之中,可以提及用在4摩尔与200摩尔之间的环氧乙烷乙氧基化的单月桂酸、并且更特别地用4摩尔的环氧乙烷乙氧基化的单月桂酸、用6摩尔的环氧乙烷乙氧基化的单月桂酸、用7摩尔的环氧乙烷乙氧基化的单月桂酸、用8摩尔的环氧乙烷乙氧基化的单月桂酸、用10摩尔的环氧乙烷乙氧基化的单月桂酸、用50摩尔的环氧乙烷乙氧基化的单月桂酸、用100摩尔的环氧乙烷乙氧基化的单月桂酸或用200摩尔的环氧乙烷乙氧基化的单月桂酸、用在4摩尔与200摩尔之间的环氧乙烷乙氧基化的单油酸、并且更特别地用1摩尔的环氧乙烷乙氧基化的单油酸、用2摩尔的环氧乙烷乙氧基化的单油酸、用4摩尔的环氧乙烷乙氧基化的单油酸、用5摩尔的环氧乙烷乙氧基化的单油酸、用6摩尔的环氧乙烷乙氧基化的单油酸、用8摩尔的环氧乙烷乙氧基化的单油酸、用9摩尔的环氧乙烷乙氧基化的单油酸、用10摩尔的环氧乙烷乙氧基化的单油酸、用50摩尔的环氧乙烷乙氧基化的单油酸、用100摩尔的环氧乙烷乙氧基化的单油酸或用200摩尔的环氧乙烷乙氧基化的单油酸、用在4摩尔与200摩尔之间的环氧乙烷乙氧基化的单硬脂酸、并且更特别地用1摩尔的环氧乙烷乙氧基化的单硬脂酸、用2摩尔的环氧乙烷乙氧基化的单硬脂酸、用4摩尔的环氧乙烷乙氧基化的单硬脂酸、用5摩尔的环氧乙烷乙氧基化的单硬脂酸、用6摩尔的环氧乙烷乙氧基化的单硬脂酸、用8摩尔的环氧乙烷乙氧基化的单硬脂酸、用9摩尔的环氧乙烷乙氧基化的单硬脂酸、用10摩尔的环氧乙烷乙氧基化的单硬脂酸、用50摩尔的环氧乙烷乙氧基化的单硬脂酸、用100摩尔的环氧乙烷乙氧基化的单硬脂酸、用200摩尔的环氧乙烷乙氧基化的单硬脂酸、用300摩尔的环氧乙烷乙氧基化的单硬脂酸或用1000摩尔的环氧乙烷乙氧基化的单硬脂酸。
作为亲水性表面活性剂,在可以与为本发明主题的组合物组合的氢化且乙氧基化的蓖麻油之中,可以提及用5摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用7摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用10摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用20摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用25摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用30摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用40摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用45摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用50摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用60摩尔的环氧乙烷乙氧基化的氢化蓖麻油、用80摩尔的环氧乙烷乙氧基化的氢化蓖麻油或用100摩尔的环氧乙烷乙氧基化的氢化蓖麻油。
根据本发明的组合物任选地包含从0至20%的至少一种选自稀释剂、增塑剂、消泡剂和崩解剂的包衣助剂。
在可以与为本发明主题的组合物组合的稀释剂之中,可以提及:乳糖、蔗糖、甘露醇、山梨醇、木糖、木糖醇、异麦芽酮糖醇、滑石、天然淀粉、硅土(silica)、二氧化硅(silicadioxide)和硬脂酸镁。
在可以与为本发明主题的组合物组合的增塑剂之中,可以提及:甘油、聚丙二醇、聚乙二醇或它们的与脂肪酸或脂肪醇缩合的衍生物、硬脂酸及其衍生物、乙酰化单甘油酯、柠檬酸的酯(诸如像柠檬酸三乙酯、乙酰基柠檬酸三乙酯或乙酰基柠檬酸三丁酯)、三乙酸甘油酯,山梨糖醇或癸二酸二丁酯(dibutyl seccate)。
在可以与为本发明主题的组合物组合的消泡剂之中,可以提及硅酮衍生物。
在可以与为本发明主题的组合物组合的崩解剂之中,可以提及:纤维素衍生物、交联聚维酮、交联羧甲基纤维素钠和羧甲淀粉钠。
应当注意的是,其他助剂诸如芳香剂、调味剂、开胃剂、着色剂、颜料和抗氧化剂,可以与为本发明主题的组合物组合。
本发明的主题还是控制释放组合物(CA),其包含:
-至少一种根据本发明的脂质组合物,以及
-至少一种活性药物、预防性或食品物质。
根据本发明的该组合物(CA)将优选地旨在用于人类或动物的口服施用。
根据另一优选的实施例,根据本发明的组合物(CA)将呈固体形式。
在药物活性成分之中,可以提及非甾体抗炎药和抗风湿药(酮洛芬、布洛芬、氟比洛芬、吲哚美辛、苯基丁氮酮、别嘌呤醇等)、镇痛药(对乙酰氨基酚、非那西丁、阿司匹林等)、镇咳药(可待因、可待乙碱、阿利马嗪等)、甾醇(氢化可的松、可的松、孕酮、睾酮、曲安西龙、地塞米松、倍他米松、帕拉米松、氟轻松、倍氯米松等)、巴比妥酸盐(巴比妥、阿洛巴比妥、苯巴比妥、戊巴比妥、异戊巴比妥等)、抗微生物剂(培氟沙星、司帕沙星和喹诺酮类别的衍生物、四环素、协同菌素(synergistins)、甲硝唑等)、旨在用于治疗过敏的药品、止喘药、维生素(维生素A、维生素B、维生素C、维生素E、D族维生素、维生素K)、解痉药和抗分泌剂(奥美拉唑)、心血管剂和脑血管扩张药(喹那卡诺、氧氧烯洛尔、心得安、尼麦角林等)、保脑剂、保肝剂、胃肠道治疗剂、疫苗、降压药和心脏保护剂(如β-阻断剂和硝基衍生物)。
在营养剂之中,可以提及通常在营养领域中使用的活性成分,诸如生物活性脂质、水溶性或水分散性微量元素盐、水溶性或脂溶性维生素、益生元、益生菌、乳蛋白和/或乳蛋白浓缩物、植物或动物酶、氨基酸、肽、糖、增味剂、调味剂、植物性成分(姜、姜黄素、圣约翰草(St.John's wort)、缬草的蔬菜提取物,蓝莓提取物,石榴提取物,小球藻(Chlorellavulgaris)提取物,洋蓟提取物,木槿属提取物)。
在生物活性脂质之中,可以提及植物甾醇,诸如从植物油中提取的那些,并且更特别地是沙棘油、玉米油或大豆油的提取物;从植物油中分离的植物甾醇络合物,例如像植物固醇(cholestatin)(由菜油甾醇、豆甾醇和菜籽甾醇构成);植物甾烷醇(phytostanol);类胡萝卜素,其属于萜类家族,提取自藻类、绿色植物、真菌或细菌;ω-3基团的多不饱和脂肪酸,例如像α-亚麻酸、二十碳五烯酸或docosahexanoic酸;ω-6基团的多不饱和脂肪酸,例如像亚油酸、γ-亚麻酸、酸,
在用为本发明主题的包衣组合物包衣的可摄取固体形式中使用的水溶性或水分散性的微量元素盐之中,可以提及碳酸亚铁、四水合氯化亚铁、六水合氯化铁、六水合柠檬酸亚铁、富马酸亚铁、四水合乳酸亚铁、一水合硫酸亚铁、七水合硫酸亚铁、氨基酸水合物的亚铁螯合物、甘氨酸铁螯合物;六水合碘酸钙、无水碘酸钙;碘化钠、碘化钾;四水合乙酸钴、一水合碱式碳酸钴、六水合碳酸钴、七水合硫酸钴、一水合硫酸钴、六水合硝酸钴;一水合乙酸铜、一水合碱式碳酸铜、二水合氯化铜、蛋氨酸铜、五水硫酸铜、氨基酸水合物的亚铜螯合物、甘氨酸水合物的亚铜螯合物、蛋氨酸羟基类似物的铜螯合物;碳酸锰、四水合氯化锰、三水合磷酸氢锰、四水合硫酸锰、一水合硫酸锰、氨基酸水合物的锰螯合物、甘氨酸水合物的锰螯合物、蛋氨酸羟基类似物的锰螯合物;钼酸铵、钼酸钠、亚硒酸钠、硒酸钠;由酿酒酵母产生的硒、硒代蛋氨酸(灭活的硒酵母)、和由酿酒酵母(灭活的硒酵母)产生的硒代蛋氨酸的有机形式。
在无机盐之中,可以提及金属阳离子的盐和有机阴离子的盐,所述金属阳离子例如像钠、钾、钙、镁、锌、锰、铁、铜、钴、银、钡、锆和锶阳离子,所述有机阴离子例如像具有至少一个以羧酸根形式的羧酸官能团的可食用有机阴离子,所述可食用有机阴离子选自由以下阴离子组成的组中的元素,该以下阴离子衍生自乙醇酸、柠檬酸、酒石酸、水杨酸、乳酸、扁桃酸、抗坏血酸、丙酮酸、富马酸、甘油磷酸、视黄酸、苯甲酸、曲酸、苹果酸、葡萄糖酸、半乳糖醛酸、丙酸、庚酸、4-氨基苯甲酸、肉桂酸、亚苄丙二酸、天冬氨酸和谷氨酸。
在无机盐之中,可以更特别地提及葡萄糖酸锌、葡萄糖酸钙、葡萄糖酸锰、葡萄糖酸铜、天冬氨酸镁、天冬氨酸钙、甘油磷酸钙、钙、甘油磷酸镁。
在水溶性或脂溶性维生素之中,可以提及维生素A,更特别是其视黄醇、乙酸视黄酯、棕榈酸视黄酯或β-胡萝卜素的形式、维生素D2,更特别是其麦角钙化醇或-羟基钙化醇的形式;维生素D3,更特别是其胆钙化醇的形式;维生素K,更特别是其叶绿醌(盐酸左旋咪唑(phytomenadione))或甲基萘醌的形式;维生素B1,更特别是其盐酸硫胺素、单硝酸硫胺素、单磷酸氯化硫胺素或焦磷酸氯化硫胺素的形式;维生素B2,更特别是其核黄素或核黄素5'-磷酸钠的形式;维生素B6,更特别是其盐酸吡哆醇、吡哆醇5'-磷酸或吡哆醛5'-磷酸的形式;维生素B12,更特别是其氰钴铵素、羟钴胺素、5'-脱氧腺苷钴胺素或甲基钴胺素的形式;维生素C,更特别是其L-抗坏血酸、L-抗坏血酸钠、L-抗坏血酸钙、L-抗坏血酸钾、6-棕榈酰基-L-抗坏血酸的钙盐或抗坏血酸单磷酸钠的形式;泛酸,更特别是其D-泛酸钙、D-泛酸钠、右泛醇或泛硫乙胺的形式;维生素PP,更特别是其尼克酸、烟酸、烟酰胺或肌醇六烟酸酯(肌醇六烟酸酯)的形式;维生素B9,更特别是其叶酸或叶酸酯的形式,更特别是其蝶酰单谷氨酸、L-甲基叶酸钙或呈葡萄糖胺盐形式的(6S)-5-甲基四氢叶酸的形式;维生素H2、B7或BW,更特别是其生物素、胆碱的形式,更特别是其氯化胆碱、柠檬酸二氢胆碱或酒石酸氢胆碱、肌醇、肉碱的形式,更特别是其L-肉碱或L-肉碱L-酒石酸盐或牛磺酸的形式。
在益生元之中,可以提及菊粉、反式低聚半乳糖、果聚糖和低聚甘露糖。
在益生菌之中,可以提及以下各项的各种菌株:酿酒酵母(Saccharomycescerevisiae)、蜡样芽孢杆菌东洋变种(Bacillus cereus var.toyoi)、单独或与地衣芽孢杆菌(Bacillus licheniformis)组合的枯草芽孢杆菌,或者以下各项的其他菌株:屎肠球菌(Enteroccocus faecium)、乳酸菌并且更特别地乳杆菌、双歧杆菌和链球菌。这些微生物菌株通常与固体载体(例如碳酸钙、右旋糖或山梨糖醇)组合。
在蛋白质和/或蛋白质浓缩物之中,可以提及由乳裂解产生的乳蛋白,诸如:呈冻干或雾化粉末形式的初乳;呈粉末形式、纯化的级分或富含IgG、乳铁蛋白或乳酸过氧化酶的级分形式的乳清。在植物酶或动物酶之中,可以提及蛋白变位酶(promutase)、超氧化物歧化酶(SOD)、3-植酸酶、6-植酸酶、内切-l,4-β-葡聚糖酶、内切-l,4-β-木聚糖酶、或还有其他改善或促进消化的酶。
在肽之中,可以提及鳄梨肽、羽扇豆肽、藜麦肽、玛咖肽、发酵的或非发酵的大豆肽、大米肽、存在于大穗金合欢(Acacia macrostachya)种子提取物中的肽或存在于西番莲种子提取物中的肽。
在氨基酸之中,可以提及丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、羟脯氨酸、吡咯赖氨酸、硒代半胱氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸、肌氨酸或鸟氨酸。
在糖之中,可以提及水溶性多糖、或低分子量的糖,诸如低聚糖或单糖或二糖(诸如像葡萄糖、乳糖或右旋糖)。
在增味剂之中,可以提及:谷氨酸盐,诸如像谷氨酸、谷氨酸单钠、谷氨酸单钾、二谷氨酸钙、谷氨酸铵或二谷氨酸镁;鸟苷酸盐,诸如像鸟苷酸(鸟苷酸单磷酸盐)、鸟苷酸二钠、鸟苷酸二钾或鸟苷酸钙;肌苷酸盐,诸如像肌苷酸、肌苷酸二钠、肌苷酸二钾或肌苷酸钙;或还有强甜味剂,诸如甜叶菊(Stevia)提取物或莱鲍迪甙(rebaudiosides)。
本发明的主题还是根据本发明的脂质组合物用于将用于人类或动物的活性药物、治疗性、预防性或食品物质包封在盖仑制剂中的用途。
出于本发明的目的,术语“包封”理解为意指使得可以将脂质组合物和一种或多种活性成分集合在一起的操作。一种或多种活性剂可以位于由该“冷却的”脂质组合物形成的壳内侧或分散在壳内。
最后,本发明的最终主题是用于制备包含根据本发明的组合物(CA)的盖仑制剂的方法,其至少包含:
a)制备根据本发明的脂质组合物的步骤,
b)将活性药物、预防性或食品物质与在步骤a)中制备的脂质组合物混合与包封以便获得根据本发明的组合物(CA)的步骤,以及
c)将步骤b)中制备的组合物(CA)盖仑成型的步骤,其涉及机械应力。
术语“机械应力”理解为意指作用在材料上并且可以改变所述材料的形状或特性的张力或压力。在本发明的上下文中,这是在组合物CA使用于制备最终盖仑制剂形式期间(步骤c)对其施加的应力。
仍然在本发明的上下文中,值得注意的是,在最终盖仑制剂形式中的活性物质的释放曲线与组合物CA中活性物质的释放曲线相似或没有很大差异。具体地,正是由于根据本发明的脂质组合物对机械应力的抗性,并且因此观察到释放曲线几乎没有或没有变化。
在步骤b)中所使用的包封方法之中,可以提及造粒(prilling)、喷雾冷冻或喷雾冷却、喷雾凝结(spray congealing)、热熔包衣(hot melt coating)、热熔挤出(hot meltextrusion)、熔体造粒(melt granulation)、成丸粒(pelletization)、滚圆(spheronization)、或热造粒(thermogranulation)等(尽可能插入法语翻译)。
术语“造粒(prilling)”表示通过将一种或多种活性成分溶解或分散在熔融的脂质组合物中,并且然后将其喷雾入环境空气或冷却空气中、或喷雾入冷却液体中来进行包衣的方法。
“喷雾冷冻”、“喷雾冷却”和“喷雾凝结(spray congealing)”方法是制粒(prilling)方法的特别方法。
术语“热熔包衣(hot melt coating)”表示通过将熔融的脂质组合物喷雾至由活性剂或活性剂的混合物组成的固体颗粒上来包衣的方法。
视情况而定,根据本发明的制造方法可以具有以下特征中的一项或多项:
-混合与包封步骤b)包括:第一子步骤:将在步骤a)中制备的脂质组合物加热至比所述脂质组合物的各种成分的最高熔点高10℃至15℃的温度,以便熔融所述脂质组合物;第二子步骤:将熔融的脂质组合物与呈分散或熔融形式的活性物质混合;以及第三子步骤:将在第二子步骤中获得的组合物喷雾入环境空气或冷却空气中或喷雾入冷却液体中,以便获得组合物(CA)的固化颗粒;术语“环境空气”理解为意指通常在25℃附近的环境温度下的空气;术语“冷却空气”或“冷却液体”理解为意指在小于环境温度、换言之小于25℃的温度下的空气或液体;
-涉及机械应力的盖仑成型步骤选自转化成固体口服剂型的方法,并且例如压缩、成型为硬胶囊(胶囊灌装/成型)、压制(压制、辊压)、包装、放入小袋、成型为条(条和小袋灌装)、挤出、造粒(granulat ion)、以及成丸粒(pelletization);这些技术可以致使制造以下形式(非穷举):口服粉末、珠粒、硬胶囊(胶囊)、颗粒、糖衣颗粒、珠状物、小丸、球(小球)、片、小袋、条、咀嚼剂、胶姆剂、咀嚼片、咀嚼胶姆剂。
根据本发明的脂质组合物使之有可能通过各种包衣技术使活性物质成型,与还未通过包括机械应力步骤的方法获得的盖仑制剂形式的活性物质的释放曲线相比,出乎意料地诱导了由此包衣的活性物质的释放曲线的稳定性。
换言之,本发明的主题使得可以维持最初寻求的活性物质的释放曲线,而不管所执行的下游盖仑成型过程,并且不管所施加的使活性剂转化为最终产品形式的机械应力(混合、压制、成型为硬胶囊、成型为条、压片等)。
出于本发明的目的,术语“根据用于包衣活性剂的技术成型”理解为意指任何主要技术或任何方法,其使得可以赋予包含所述活性剂的组合物以物理形式、优选地在环境温度下为固体的形式。
以下实例阐明本发明,然而不限制本发明。
实例
如上所描述的诱导了对下游盖仑步骤的机械应力的抗性的包封组合物的合格性,通过设立如下所描述的分析来确立。
选择活性剂作为主模型活性剂。注意,术语“活性剂”理解为意指活性物质。该活性物质是咖啡因,其具有在环境温度(25℃)下在水中的20g/l-25g/l的平均溶解度。
分子式:C8H10N4O2;分子量:194.194g/mol。
通过旋转盘造粒技术以20%至30%的比率用为本发明主题的组合物包封该活性剂。
旋转盘造粒技术:制备组合物M1的方法
对于每个测试,制备蜡质液体分散体。该蜡质液体分散体由以下组成:
·呈熔融形式的为本发明主题的组合物;
·呈分散的固体形式的模型活性剂。在通常情况下,应当记住的是,活性剂可以以分散或液体形式存在,这取决于其熔点的值。
为此,“预分散体”—为本发明主题的组合物的各种元素在液体状态下熔融和/或混合的结果—是预先制备的:混合物制备M0。
应当调节使该预分散体以及然后重建的分散体保持的温度,以便比组合物的各种成分的最高熔点高10℃-15℃。在开始制造方法之前,在维持先前确立的温度的同时,在机械搅拌下添加(在这种情况下分散)活性剂。
然后执行旋转盘造粒方法。分散体借助于隔热管道输送至位于空间/塔中的喷雾嘴,在喷雾后导致产生细液滴。然后将这些细液滴在冷的环境空气流中固化,导致形成小的球形珠粒,其特征在于按体积计50%的这些珠粒具有在300μm与500μm之间的直径。将注意的是,借助于以干路径使用的来自马尔文公司(Malvern)的Mastersizer 3000激光粒度仪在1巴的压力下测量珠粒的粒度分布。
二氧化硅或另一种流动/抗粘剂可以任选地预先添加至由此产生的微珠粒中,以便促进其后续处理。
同样地,可以在500μm筛上执行筛分以便去除具有大于或等于500μm的粒径的任何不期望的聚集体/残留物。
然后将由此获得的微珠粒掺入至与片剂型盖仑成型方法相容的等级的赋形剂的混合物中。选择片剂形式作为模型最终盖仑成型方法,因为它代表所诱导的机械应力的最极端情况之一。
压片是在仪表化的Dott Bonapace往复单冲压机或仪表化的Riva Piccola旋转8-冲压机上,在施用在5kN与20kN之间的压缩力下进行;由此制造了500mg的具有在80N与120N之间的断裂强度的片剂。
技术效果的证明:
按照欧洲药典第7.3版第2.9.3段(European Pharmacopoeia,version 7.3,paragraph 2.9.3)的推荐,借助于Erweka溶出试验仪来确立包衣在为本发明主题的组合物中并且然后掺入片剂形式中的活性剂的释放曲线。
主要选择的溶出介质是维持在37℃的温度下的pH 7.2的磷酸盐缓冲液。定期取样长达至6小时。然后通过具有UV检测的反相HPLC分析样品,以便确定存在于每个样品中的活性剂的量并由此确立待评价的每个样品的溶出曲线。
比较从组合物到组合物或在施加机械应力之前/之后的溶出曲线,以便确定两个曲线彼此是/否差异或者一个曲线相对于对照曲线是/否差异。
在以下情况下,由此判定两个曲线是相似的或不是非常不同的,并且因此判定组合物改善了对机械应力的抗性:
·时间-时间差值,其计算如下:
abs[%释放(Txi)片-%释放(Txi)μ珠粒]≤y%
其中:
%释放(Txi)片=当制剂已经经历压片方法时在取样点Txi释放的活性剂的%。
%释放(Txi)μ珠粒=当制剂未曾经历机械应力时在取样点Txi释放的活性剂的%
并且其用y值表示,在长达至2小时的溶出时间小于或等于30+/-2%,并且在剩余的评价时间内小于或等于20+/-2%。
当贯穿溶出测试的差值小于或等于15%时,可以判定曲线是相似的。
·从3小时的溶出时间开始,在施加机械应力之前和之后的值之间的变化率小于或等于30%。计算如下:
其中:
Txi>=180分钟
%释放(Txi)片=当制剂已经经历压片方法(涉及压缩步骤)时在取样点Txi释放的活性剂的%。
%释放(Txi)μ珠粒=当制剂未曾经历机械应力时在取样点Txi释放的活性剂的%
·实例1:
在该实例中,脂质组合物,其含有作为组分A的相同蜂蜡、相同量的聚山梨醇酯80、以及相同比例的作为组分B的各种亲脂性表面活性剂。将所制备的脂质组合物的组成记录在下表1中。用咖啡因作为活性成分,将这些脂质组合物使用于根据如上所描述的造粒方法的包衣。该实例的目的是,通过观察释放曲线随时间的维持或非维持来显示蜂蜡与某些亲脂性表面活性剂的组合用于通过活性剂咖啡因的造粒方法包衣的有效性,以便在蜂蜡和亲脂性表面活性剂的某些组合经受压缩步骤之前可能不认为它们是适当的。
表1
将活性剂以20%分散在组合物中。实施造粒方法。
获得具有在350μm与400μm之间的中值直径的微珠粒。
将这些微珠粒在避光、环境温度下稳定最低28个月的持续时间。
研究了微珠粒在制造方法之后或在28个月的最低保存期之后的溶出曲线。实现了各种取样次数;在120分钟点处进行了曲线的比较。
下表2给出了在120分钟取样点释放的咖啡因的百分比值:
表2下表3给出了在120分钟取样点处的时间-时间差值*的值:
表3
(*):在比较在T0处和稳定一段时间后的释放曲线的情况下,在此应当注意时间-时间差值的具体定义。因此,此处将时间-时间差值重新定义为由以下计算得到:
abs[%释放(120x'i)μ珠粒-%释放(120xi)μ珠粒]y%
其中:
%释放(120x'i)μ珠粒=当制剂已经在环境温度下储存限定的持续时间时,在120分钟取样点处释放的活性剂的%。
%释放(120xi)μ珠粒=当制剂未曾储存,在120分钟取样点处释放的活性剂的%,即在从微珠粒产生的T0处的值。
当在所考虑的取样点处,用y值表示的时间-时间差值小于或等于20+/-2%时,判定两个曲线具有相同的量级。
当时间-时间差值小于或等于15%时,可以判定曲线是相似的。
对于该实例,可以观察到组合物CL1'和CL2'使得可以随时间维持由造粒方法产生的微珠粒中含有的活性剂咖啡因的释放曲线。含有作为组分B的单硬脂酸甘油酯的组合物CL3'已经可以扣减。
·实例2:
在该实例中,脂质组合物,其含有作为组分A的蜡和来自各种来源的油,其使用于通过如上所描述的活性剂咖啡因的造粒方法的包衣。该实例的目的是证明蜂蜡与其他组分组合的特异性,用于使得可以在盖仑成型方法之后/在机械应力之后维持所包衣的活性剂的相似/不显著不同、或以其他方式的释放曲线。
因此平行使用以下组合物(表4):
表4
将活性剂以20%分散在组合物中。实施造粒方法。
获得具有在350μm与400μm之间的中值直径的微珠粒。
然后将这些微珠粒引入用于片剂的混合物中。由此,根据以下组合物制备了500mg的具有11mm的直径的片剂:对于按重量计40%的微珠粒,添加按重量计27%的微晶纤维素、按重量计29%的磷酸氢钙二水合物、按重量计3%的交联聚维酮和按重量计1%的硬脂酸镁。
研究了微珠粒在压缩方法之前和之后的溶出曲线。取样次数如下:60分钟、120分钟、180分钟、240分钟、300分钟以及360分钟。
下表5给出了所释放的咖啡因随时间变化的百分比值:
表5
下表6给出了在180分钟及其以上处的时间-时间差值的值和变化率:
表6
对于该实例,可以看出仅组合物CL1允许改善对机械应力的抗性,该应力在此通过片剂型盖仑成型方法来说明。
·实例3:
在该实例中,脂质组合物,其含有作为组分A的蜂蜡和小烛树蜡的比率,其使用于通过活性剂咖啡因的造粒方法的包衣。该实例的目的是证明以下可能性:将蜂蜡与另一种脂质化合物混合至某一比率,与其他组分组合,同时仍使得可以在盖仑成型方法之后/在机械应力之后维持所包衣的活性剂的相似/不显著不同、或以其他方式的释放曲线。
因此平行使用以下组合物:
表7
将活性剂以20%分散在组合物中。实施造粒方法。
获得具有在350μm与400μm之间的中值直径的微珠粒。
然后将这些微珠粒引入混合物中用于根据在实例2中描述的流程制备片剂。由此,制备了500mg的具有11mm的直径的片剂。
研究了微珠粒在压缩方法之前和之后的溶出曲线。取样次数如下:60分钟、120分钟、180分钟、240分钟、300分钟以及360分钟。
下表给出了所释放的咖啡因根据时间的百分比值:
表8
下表给出了在180分钟及其以上处的时间-时间差值的值和变化率:
表9
在该实例中,组合物CL1和CL5允许改善对机械应力的抗性,对于组合物CL1具有相似的曲线,并且对于组合物CL5具有不显著不同的曲线。
·实例4:
在该实例中,脂质组合物,其具有组分A(蜂蜡)和组分B(脱水山梨糖醇酯类型的亲水性表面活性剂),其使用于通过活性剂咖啡因的造粒方法的包衣。
该实例的目的是证明以下可能性:将组分A和组分B以某些比率混合,以在盖仑成型方法之后/在机械应力之后维持所包衣的活性剂的相似/不显著不同、或以其他方式的释放曲线。
因此平行使用以下组合物:
表10
将活性剂以20%分散在组合物中。实施造粒方法。
获得具有在350μm与400μm之间的中值直径的微珠粒。
然后将这些微珠粒引入混合物中用于根据在实例2中描述的流程制备片剂。由此,制备了500mg的具有11mm的直径的片剂。
研究了微珠粒在压缩方法之前和之后的溶出曲线。取样次数如下:30分钟、60分钟、120分钟、180分钟、240分钟、300分钟以及360分钟。
下表11给出了所释放的咖啡因随时间变化的百分比值:
表11
下表给出了在180分钟及其以上处的时间-时间差值的值和变化率:
表12
在该实例中,组合物CL8和CL9允许改善对机械应力的抗性。经由组合物CL7,观察到需要最少量的组分B。
Claims (18)
1.一种脂质组合物,每100%其重量包含:
-按重量计从40%至99.9%的以下组分,该组分每100%其重量包含按重量计从90%至100%的蜂蜡以及按重量计至多10%的至少一种其他脂质赋形剂,
-按重量计从0.1%至60%的至少一种亲脂性表面活性剂,所述亲脂性表面活性剂选自聚乙氧基化脂肪酸、脂肪二酸和聚乙二醇的酯、聚甘油和脂肪酸的酯、丙二醇和脂肪酸的酯、丙二醇的酯和甘油的酯的混合物、脂肪酸甘油二酯、固醇和固醇的衍生物、脂肪酸和脱水山梨糖醇的酯、脱水山梨糖醇与聚乙二醇及脂肪酸的酯、聚乙二醇和烷基的醚、蔗糖酯、以及聚氧乙烯-聚氧丙烯嵌段共聚物。
2.如权利要求1所述的脂质组合物,其特征在于,所述脂质赋形剂选自动物蜡、植物蜡、矿物蜡、合成蜡或氢化植物油。
3.如权利要求1和2中任一项所述的脂质组合物,其特征在于,所述亲脂性表面活性剂选自脂肪酸和糖的酯。
4.如权利要求1和3中任一项所述的脂质组合物,其特征在于,所述亲脂性表面活性剂是来自脱水山梨糖醇酯家族的亲脂性表面活性剂,更特别地是来自由以下各项组成的组中的元素:脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯和脱水山梨糖醇单油酸酯,并且甚至更特别地是脱水山梨糖醇单棕榈酸酯或脱水山梨糖醇单硬脂酸酯,并且甚至更特别地是脱水山梨糖醇单硬脂酸酯。
5.如权利要求1至4中一项所述的脂质组合物,其特征在于,所述组合物包含从0至20%的一种或多种亲水性表面活性剂。
6.如权利要求5所述的脂质组合物,其特征在于,所述一种或多种亲水性表面活性剂选自大豆卵磷脂、乙氧基化脱水山梨糖醇酯、聚乙氧基化醇、聚乙氧基化酸、聚甘油酯、葡萄糖醚以及环氧乙烷与环氧丙烷的嵌段共聚物。
7.如权利要求5所述的脂质组合物,其特征在于,所述亲水性表面活性剂是脱水山梨糖醇酯,并且所述亲水性表面活性剂选自聚乙氧基化脱水山梨糖醇酯。
8.如权利要求7所述的脂质组合物,其特征在于,所述组合物包含:
-75%蜂蜡,
-20%脱水山梨糖醇硬脂酸酯,以及
-5%用20摩尔的环氧乙烷聚乙氧基化的脱水山梨糖醇油酸酯(或聚山梨醇酯80)。
9.如权利要求7所述的脂质组合物,其特征在于,所述组合物包含:
-50%蜂蜡,
-45%脱水山梨糖醇硬脂酸酯,以及
-5%用20摩尔的环氧乙烷聚乙氧基化的脱水山梨糖醇油酸酯(或聚山梨醇酯80)。
10.如权利要求1至7中一项所述的脂质组合物,其特征在于,所述组合物包含从0至20%的至少一种包衣助剂。
11.如权利要求8所述的脂质组合物,其特征在于,一种或多种所述包衣助剂选自稀释剂、调味剂、开胃剂、着色剂、抗氧化剂、增塑剂、消泡剂和崩解剂。
12.一种控制释放组合物(CA),其包含:
-至少一种如权利要求1至11中一项所述的组合物,以及
-至少一种活性药物、预防性或食品物质。
13.如权利要求12所述的组合物(CA),其特征在于,该组合物旨在用于人类或动物的口服施用。
14.如权利要求12和13中任一项所述的组合物(CA),其特征在于,该组合物呈固体形式。
15.如权利要求1至11中一项所述的脂质组合物用于将用于人类或动物的活性药物、治疗性、预防性、或食品物质包封在盖仑制剂中的用途。
16.一种用于制造包含如权利要求12至14中一项所述的组合物(CA)的盖仑制剂的方法,其至少包括:
a)制备如权利要求1至11中一项所述的脂质组合物的步骤;
b)将活性药物、预防性或食品物质与在步骤a)中制备的所述脂质组合物混合与包封以便获得根据权利要求12至14中一项所述的组合物(CA)的步骤,以及
c)将步骤b)中制备的所述组合物(CA)盖仑成型的步骤,其涉及机械应力。
17.如权利要求16所述的制造方法,其特征在于,所述混合与包封步骤b)包括:
-第一子步骤:将在步骤a)中制备的所述脂质组合物加热至比所述脂质组合物的各种成分的最高熔点高10℃至15℃的温度,以便熔融所述脂质组合物,
-第二子步骤:将熔融的脂质组合物与呈分散或熔融形式的活性物质混合,以及
-第三子步骤:将在第二子步骤中获得的组合物喷雾入环境空气或冷却空气中或喷雾入冷却液体中,以便获得组合物(CA)的固化颗粒。
18.如权利要求16和17中任一项所述的制造方法,其特征在于,涉及机械应力的所述盖仑成型步骤选自压缩、成型为硬胶囊、压制、包装、放入小袋、成型为条、挤出、造粒、以及成丸粒。
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FR1859696 | 2018-10-19 | ||
FR1859696A FR3087445B1 (fr) | 2018-10-19 | 2018-10-19 | Composition lipidique pour l'encapsulation d'une substance active et permettant le controle de la vitesse de liberation de ladite substance active |
PCT/FR2019/052454 WO2020079367A1 (fr) | 2018-10-19 | 2019-10-16 | Composition lipidique pour l'encapsulation d'une substance active et permettant le contrôle de la vitesse de libération de ladite substance active |
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EP (2) | EP3866855A1 (zh) |
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CN (1) | CN112839680A (zh) |
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WO1991005548A1 (en) * | 1989-10-10 | 1991-05-02 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
CN101204393A (zh) * | 2007-12-19 | 2008-06-25 | 姚俊华 | 茴三硫软胶囊及其制备方法 |
CN103388037A (zh) * | 2012-05-08 | 2013-11-13 | 赵霞 | 一种羊皮制品清洁养护膏 |
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GB1541463A (en) * | 1975-10-11 | 1979-02-28 | Lion Dentifrice Co Ltd | Process for prparing a multiple emulsion having a dispersing form of water-phase/oil-phase/water-phase |
JPS6052682B2 (ja) * | 1978-02-13 | 1985-11-20 | 日本化薬株式会社 | ブレオマイシン固型製剤 |
JPS5951263B2 (ja) * | 1980-12-10 | 1984-12-13 | 味の素株式会社 | ジペプチド甘味料含有油脂組成物 |
BR9301968A (pt) * | 1993-06-08 | 1994-12-27 | Johnson & Johnson | Fio dental dotado de agentes quimioterápicos |
FR2754177B1 (fr) * | 1996-10-07 | 1999-08-06 | Sanofi Sa | Microspheres pharmaceutiques d'acide valproique pour administration orale |
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2018
- 2018-10-19 FR FR1859696A patent/FR3087445B1/fr active Active
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2019
- 2019-10-16 EP EP19806030.3A patent/EP3866855A1/fr active Pending
- 2019-10-16 US US17/286,135 patent/US20210378974A1/en active Pending
- 2019-10-16 WO PCT/FR2019/052454 patent/WO2020079367A1/fr unknown
- 2019-10-16 KR KR1020217014673A patent/KR20210079315A/ko unknown
- 2019-10-16 EP EP21211618.0A patent/EP3995151B1/fr active Active
- 2019-10-16 JP JP2021520588A patent/JP2022504958A/ja active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991005548A1 (en) * | 1989-10-10 | 1991-05-02 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
CN101204393A (zh) * | 2007-12-19 | 2008-06-25 | 姚俊华 | 茴三硫软胶囊及其制备方法 |
CN103388037A (zh) * | 2012-05-08 | 2013-11-13 | 赵霞 | 一种羊皮制品清洁养护膏 |
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FR3087445A1 (fr) | 2020-04-24 |
FR3087445B1 (fr) | 2021-12-17 |
KR20210079315A (ko) | 2021-06-29 |
EP3995151A1 (fr) | 2022-05-11 |
US20210378974A1 (en) | 2021-12-09 |
EP3995151B1 (fr) | 2023-09-13 |
EP3866855A1 (fr) | 2021-08-25 |
JP2022504958A (ja) | 2022-01-13 |
WO2020079367A1 (fr) | 2020-04-23 |
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