CN102985078A - 用于动物的口服递送的微粒 - Google Patents
用于动物的口服递送的微粒 Download PDFInfo
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- CN102985078A CN102985078A CN2011800227151A CN201180022715A CN102985078A CN 102985078 A CN102985078 A CN 102985078A CN 2011800227151 A CN2011800227151 A CN 2011800227151A CN 201180022715 A CN201180022715 A CN 201180022715A CN 102985078 A CN102985078 A CN 102985078A
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Abstract
用于一种或多种生理学或药理学活性物质的控释的系统,所述系统包含微粒或颗粒形式的组合物,特别地用于畜牧学和/或兽医领域,所述微粒包括核心,所述核心包含一种或多种具有药理作用的物质、食物补充物或者诊断介质,所述一种或多种物质的特征在于在它们的化学结构内存在碱性官能团,特别地包括胺官能团。所述核心还包含一种或多种羧酸和/或它们的盐以及最终的一种或多种赋形剂。所述核心被脂肪或蜡的外层包覆,并且优选被脂肪酸的甘油酯的混合物包覆。
Description
本申请要求2010年4月7日提交的美国专利申请系列号61/321,604的优先权,其整体援引加入本文。
背景技术
本发明一般涉及微粒形式的组合物,更具体地,涉及预期用于畜牧学领域和/或兽医领域的微粒。
在畜牧学领域中口服给予活性物质是不易解决的问题,特别是关于确保足够剂量的所述物质的肠吸收的可能性,避免它们在通过动物的消化道期间大量降解,尤其是在反刍动物的情况下。
在许多专著中详细公开反刍动物以及其他所谓的伴侣动物或生产用畜的消化道的生理学方面。在这些中,一些还综述与这类动物中口服给予活性成分相关的问题,以及在配制技术方面可能的解决方案(Development andformulation of veterinary dosage forms 2nd Edition,G.E.Hardee,J.D.Baggot(Edts)Marcell Dekker,New York 1998;S.H.W.Wu,A.Papas,Rumen stabledelivery systems,Advanced drug delivery reviews 28(1997)323-334)。动物饮食的活性成分和补充物在消化系统的近端道中进行酶促和化学降解,然后到达所述物质的吸收部位肠腔。在反刍动物中,特别地这种降解主要是由于瘤胃中微生物区系的存在,所述微生物区系主要降解通过瘤胃的许多物质。还必须考虑所述物质通过瘤胃的缓慢。这引起仅小部分的活性物质或食物补充物在肠水平被反刍动物吸收,因为几乎100%的这些分子被瘤胃的微生物区系降解。因此,为了允许这类物质在肠中吸收并发挥它们的有效性,必须保护它们避免在瘤胃水平降解。事实上已知例如物质如胆碱或其盐在瘤胃后水平直接给予时能够增加牛的奶产量(S.R.Haretewell et ah,J.Dairy Sci.(2000)83,2097-2017和K.N.Deulcher et al,J.Dairy Sci,(1998)81,238-242)。
美国专利第4,533,557号公开颗粒或片剂形式的用于反刍动物的补充物的组合物,其包含生物学活性物质、壳聚糖和保护材料的混合物,所述保护材料由具有14-22个碳原子链的饱和或不饱和脂肪族一元羧酸构成。该发明背后的概念在于使用疏水性物质建立能够减缓其中的生物学流体的渗透的基质,结果引起物质的较慢释放。因此目的是通过减少其通过瘤胃期间释放的量来延长物质释放时间。此外,壳聚糖的存在应当提供对瘤胃环境的特异性保护:瘤胃中包含的流体的pH在5-8之间变化;壳聚糖在这个pH范围中几乎不溶,但是在酸性pH (<5)中溶解。因此,这种类型的聚合物的存在应当在瘤胃保持期间给予基质更大完整性。
美国专利第5,190,775号公开用于口服给药的颗粒或颗粒(particles orgranules)的组合物,其具有0.3-2g/ml的相对密度,包含用疏水性包衣包覆的生物活性物质,所述疏水性包衣优选由通过一层表面活性剂包覆在它们表面的氢化植物油构成,以防止其漂浮在瘤胃内。在其中生物活性物质为氯化胆碱的情况下,其吸附在来源于谷物的植物基底上。在授予MorganManufacturing Co.,Inc.的另一专利(美国专利第5,496,571号)中,公开用于制备微囊的方法,所述微囊旨在用于口服给予,并且设计为保护氯化胆碱免受瘤胃细菌引起的降解,以增加反刍动物的奶产量。这些微囊包含用脂类物质的外层包覆的氯化胆碱的液体组合物,所述脂类物质选自氢化和非氢化动物脂肪或者氢化植物油。
一系列其他专利要求保护使得通过材料包覆包含生物活性物质的核心的方法和组合物,所述材料能够承受至少部分瘤胃降解,并且能够在反刍动物的皱胃或肠的远端部分中溶解和/或降解。在这些专利中,可以提及例如美国专利第4,713,245号、第3,451,204号和第4,876,097号。
美国专利第4,832,967号要求保护用于饲养反刍动物的组合物,其由两个保护层包覆的包含生物活性物质的核心构成。所述包衣的第一层为能够形成膜的聚合物质,所述膜在pH>5下稳定,但是在pH<3.5下能够释放生物活性物质。第二层包衣为疏水性物质。授予Massachusetts Institute ofTechnology的US-5,912,017要求保护用于药物、肥料、杀虫剂和化学指示剂的控释的多层聚合物微球的制备
美国公开申请第2005/0019413号描述颗粒形式的组合物,其包含以瘤胃保护形式给予的氯化胆碱。所述颗粒由双重保护层包覆的核心构成:外层为巴西棕榈蜡的连续层,内层为疏水性物质如氢化大豆油的连续层,所述核心主要由晶体粉末形式的氯化胆碱组成。此外,所述核心可以包含其他物质,作为流动改性剂(硅酸盐、硅铝酸盐、沸石、硅、珠光体),其量不超过所述核心重量的8%,和/或作为对水分具有屏障功能的结合剂(硬脂酸盐),其量等于所述核心重量的7%。
美国公开申请第2006/0067984号描述用于生理学活性物质的控释的小球形式的组合物,其用于畜牧学用途。这些组合物包含:i)由生理学活性物质以及巴西棕榈蜡和/或微晶蜡的基质构成的核心;ii)第一疏水包衣层,其由属于脂肪、脂肪酸、氢化油、脂肪酸单甘油酯或二甘油酯、脂肪酸酯或长链醇(12-22个碳原子)类别的具有40-74<0>C的熔点的材料组成;iii)所述第一包衣层上的第二包衣层,其由具有80-100<0>C的熔点的微晶蜡、石蜡、植物蜡和合成蜡构成。
WO 2008015203A2描述旨在用于畜牧学领域和/或更一般用于兽医领域的0.1-5000微米大小的微粒或颗粒,其由包含一种或多种具有药理作用的物质、食物补充物或诊断介质的核心构成,所述物质或多种物质的特征在于在它们的化学结构内存在阳离子官能、阴离子官能或者中性但可以容易地电离以获得净电荷的官能,与能够吸收水并引起可逆肿胀的镁、铝、钙和钠的水合硅酸盐充分混合或吸附;将所述核心用两种脂肪或蜡构成的双脂肪层包覆,其中具有最高熔点的一种构成内层(与核心接触),而具有最低熔点的一种排列以形成外层。
发明内容
本发明使得能在动物,特别是反刍动物的胃肠道中控释活性成分。所述的技术和制剂能够控制一种或多种具有药理作用或作为饲料添加物发挥作用的物质的释放。在这类组合物中,微粒携带的物质或多种物质受到保护以免于可以存在于消化道的第一部分,特别是瘤胃中的降解,并且相反地可以在肠中释放和吸收。
在一实施方案中,本发明为微粒形式的组合物,其活性成分的含量为至少30%。在另一实施方案中,本发明为微囊形式的组合物,其具有活性成分改进的释放;特别是24小时溶出测试后的释放少于所述活性成分含量的30%。
附图说明
图1为餐后0-20小时基线之上释放的称为CBTC的受保护的胆碱的水平图。
图2为餐后0-20小时基线之上释放的称为DSMcp/d的受保护的胆碱的水平图。
图3为3种产物P1BT(x)和P2BT(●)与赖氨酸HCl(◆)相比,餐后0-20小时基线之上释放的赖氨酸的水平图。
具体实施方式
本发明的方法和组合物涉及用于一种或多种生理学或药理学活性物质的控释的系统,所述系统为0.1-5000微米大小的微粒的形式,并且旨在用于畜牧学领域和/或兽医领域。所述组合物包括核心,所述核心包含一种或多种具有药理作用或作为饲料补充物发挥作用的物质(以下称为活性成分)和一种或多种羧酸和/或它们的盐以及最终的一种或多种赋形剂。所述核心被脂肪或蜡的外层包覆,并且优选被脂肪酸的甘油酯的混合物包覆。
所述活性成分或多种活性成分的特征在于在它们的化学结构内存在胺官能团,或者更一般地包括具有碱性特征的官能团;所述核心还包括一种或多种羧酸和/或它们的盐,特征在于在它们的化学结构内存在酸性官能团,在所述核心本身中充分混合或添加在其表面上。这些羧酸或盐的特征在于存在至少一个羧基和亲脂性官能团:酸性官能与活性成分的碱性官能相互作用,并且亲脂性官能团有助于增加核心的亲脂性,促进外脂肪层与核心本身粘附。
适合上文所述目的的具有碱性官能团的活性成分的实例包括但不限于:异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、色氨酸、缬氨酸、丙氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、脯氨酸、硒代半胱氨酸、丝氨酸、酪氨酸、精氨酸、组氨酸、胆碱、甜菜碱、肉碱、硫胺素、吡哆醇、链霉素、粘菌素、硫姆林、新霉素、精氨酸、葡糖胺、烟酰胺以及它们的盐,特别是氯化胆碱、盐酸甜菜碱、盐酸赖氨酸、盐酸硫胺素、一硝酸硫胺素、盐酸吡哆醇、硫酸粘菌素和富马酸硫姆林。适合上文所述目的的具有酸性官能团的羧酸的实例包括但不限于:中至长链饱和和不饱和脂肪酸及它们的盐如月桂酸、棕榈酸、硬脂酸、油酸、花生酸及它们的盐,芳香羧酸如苯甲酸及其盐,二羧酸如己二酸、癸二酸及它们的盐。
任选地可以将赋形剂加入本发明的微粒的核心。这些赋形剂能够改善核心的形成,并且还可以在它们的化学结构中包括碱性官能。适合上文所述目的的赋形剂的实例包括但不限于:粘土、玉米芯粉(cob meal)、二氧化硅、硅酸盐、微晶纤维素、聚乙烯吡咯烷酮、磷酸钙、淀粉、藻酸盐、氨基改性二氧化硅、氨基改性粘土、氨基改性纤维素、具有胺基团的丙烯酸类聚合物、壳聚糖以及明胶。这些赋形剂典型地以核心总重量的0-40%的量使用。
所述核心被脂肪或蜡的外层包覆,并且优选被脂肪酸的甘油酯的混合物包覆。有效控释的能力由两种现象的协同作用决定:核心中碱性官能与羧基之间的相互作用,以及外脂肪层的屏障作用。
本发明的控释系统通过包括如下文所述的步骤的方法制备微粒来提供。
制备混合物,所述混合物包含活性成分或多种活性成分以及羧酸或多种羧酸。活性成分或多种活性成分的量为所述混合物的重量的30-100%,并且优选50-100%,甚至更优选60-100%。羧酸或多种羧酸的量为0-70%,并且优选0-50%,甚至更优选0-40%。混合可以用常规的固定或旋转体混合器进行,因为对于预期的结果,混合器类型的选择不是特别关键。从所述混合物开始,通过药物领域以及食品或饲料工业中造粒或团聚过程通常描述的技术形成微颗粒。这方面的实例在专业文献中大量描述,例如Pharmaceutical principles of solid dosage forms,J.T.Carstensen(Ed.)(1993),Technomic Publishing Co.,Lancaster(USA),或Pharmaceutical PellettizationTechnology I.Ghebre-Sellassie(Ed.)(1989),Marcel Dekker,New York(USA),或Principi di tecnologie farmaceutiche,P.Colombo et al.(Eds.)(2004),CasaEditrice Ambrosiana,Milan(Italy),并且例如挤出滚圆、流化床造粒、旋转盘造粒、高速造粒、湿法造粒、熔融造粒、熔融挤出、熔融团聚过程。
作为上文所述方法的替代,可以通过将核心的粉末用包括活性成分或多种活性成分的水溶液喷洒或者将核心的粉末与包括活性成分或多种活性成分的水溶液混合来将所述核心的粉末转换为微颗粒。在这种情况下,所述溶液的浓度为0.05-0.95g/ml,并且优选0.2-0.8g/ml。加入的活性物质的溶液的量使得活性成分的量为核心的0.1-50重量%,并且优选核心的0.5-40重量%,甚至更优选核心的1-30重量%。
还是在这种情况下,用于制备颗粒的方法可以为例如挤出滚圆、流化床造粒、旋转盘造粒、高速造粒、湿法造粒、熔融造粒、熔融挤出以及熔融团聚。
作为上文所述方法的替代,可以通过将羧酸或多种羧酸喷洒在预先形成的微颗粒的表面上来将所述羧酸或多种羧酸加入核心。还是在这种情况下,羧酸或多种羧酸的量为核心的0-70重量%,并且更优选0-50重量%,甚至更优选0-40重量%。熔化所述酸或多种酸之后,可以通过所谓的流化床或喷雾冷凝技术或者通过圆筒混合机包覆,或者在任何情况下用包覆方法如专著包衣药物剂型(Coated pharmaceutical dosage forms)中所示的那些包覆方法,将所述酸或多种酸施用于如较早所述制备的核心的表面。基础、制备技术、生物制药方面、测试方法以及原料,K.H.Bauer,K.Lehmann,H.P.Hosterwald,G.Rothgang(Edts),CRC Press,Boca Raton 1998。
任选地可以将赋形剂加入核心,所述赋形剂能够改善微颗粒的形成,赋形剂的量为核心的重量的0-40%,并且优选0-30%。这些赋形剂可以作为粉末加入核心或溶于水溶液。
如果活性成分以其纯(>96%)的形式作为颗粒可用,那么可以不需要赋形剂来例如吸附液体产物。在这种情况下,用于制备核心的赋形剂的优选浓度为0-20%。
在上文所述的所有制备方法中,一旦获得颗粒或微颗粒,如果需要,用使用静态或动态床的干燥方法将其干燥。
将由此获得的核心用油、脂肪或蜡的层包覆,并且优选通过熔点为50-80℃、并且优选55-62℃的脂肪酸的甘油酯的混合物包覆。所述脂肪优选由氢化脂肪酸甘油酯的混合物构成。特别地,优选条件提供总脂肪酸含量的40-70%的C-16脂肪酸甘油三酯含量以及总脂肪酸含量的30-50%的C-18。
活性成分和核心的含水量不仅可以影响原料和成品的储存,而且还可以影响混合比例。由于初始混合过程中赖氨酸与优选的氢化植物油的相互作用,含水量还可以负面影响粘度。已明确证实赖氨酸的吸湿性。增加的水分会负面影响基质形成、通过缩合进行制备以及潜在的成品性能/稳定性。原料吸收水分的可能性使得需要过程中(in-process)粗赖氨酸的气候控制储存条件以及在接收和处理原料库存期间选择适当的储存材料和方法。
熔化所述脂肪之后,可以通过所谓的流化床或喷雾冷凝技术或者通过圆筒混合机包覆,或者在任何情况下用包覆方法如专著包衣药物剂型中所示的那些包覆方法,将所述脂肪施用于如较早所述制备的核心的表面。基础、制备技术、生物制药方面、测试方法以及原料,K.H.Bauer,K.Lehmann,H.P.Hosterwald,G.Rothgang(Edts),CRC Press,Boca Raton 1998。
施用的所述包衣脂肪的总量为微粒最终重量的10-60%,并且优选15-50%。
任选地可以将赋形剂加入包衣脂肪,所述赋形剂能够改善它们的物理特性如耐水性、粘度、可塑性、粘附性、应力和温度稳定性。
能够改善脂肪的物理特性的赋形剂的实例包括但不限于卵磷脂、粘土、二氧化硅、萜、甾醇、钙和钠盐。
本发明的特定特征是有效控制释放的能力,从而减少活性物质的瘤胃降解,这由两种现象的协同作用决定:核心中所含的活性物质的碱性官能与羧酸的酸性官能之间的相互作用;以及包衣脂肪层的屏障作用。碱性与酸性官能之间的相互作用有助于减缓活性物质的释放。这种控制释放的能力用24小时水溶出测试证实,所述24小时水溶出测试用USP桨装置(装置2)在100rpm和38℃下进行,24-小时溶出测试后的释放少于活性物质含量的30%。
实施例
通过非限制性证明的方式,此后列举与本发明的制备和特征相关的实施例。
实施例1基于包括充分混合于其中的活性成分和羧酸的核心的控释制剂
组成:
将干燥的一盐酸L-赖氨酸与液体碱性L-赖氨酸和硬脂酸在70℃下于犁铧式混合器中混合30分钟。然后将核心冷却至40℃,并且在65℃下通过在包衣锅(pan coater)中喷洒来施用包衣层。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的L-赖氨酸为18.7%,标准差0.8。
实施例2基于包括活性成分和加在它们表面的羧酸的核心的控释制剂
组成:
将干燥的一盐酸L-赖氨酸与液体碱性L-赖氨酸在45℃下于螺旋叶片式搅拌器中混合。利用喷嘴在2巴压力下于5分钟的时间内将液体喷洒在干燥的一盐水L-赖氨酸上。然后将颗粒在流化床中干燥。在70℃下,通过在包衣锅中喷洒来将硬脂酸加至预先形成的微颗粒的表面。然后将核心冷却至40℃,并且在65℃下通过在包衣锅中喷洒来施用包衣层。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的L-赖氨酸为6.0%,标准差0.6。
实施例3在包衣层中使用赋形剂
组成:
将干燥的一盐酸L-赖氨酸与液体L-赖氨酸在45℃下于旋转式造粒机中混合。然后将颗粒在流化床中干燥。在70℃下,通过在包衣锅中喷洒来将硬脂酸加至预先形成的微颗粒。然后将核心在40℃下冷却,并且在65℃下用包括卵磷脂的液体脂肪包覆。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的L-赖氨酸为13.8%,标准差0.4。
比较例4核心中没有羧酸的制剂
为了证实活性成分的碱性官能与羧酸之间的相互作用的重要性,还制备没有羧酸而仅具有包衣脂肪层的制剂,并且测试活性成分的释放。组成:
用70℃下将干燥的一盐酸L-赖氨酸用液体氢化植物油包覆。这在包衣锅中完成。然后将微粒在45℃下冷却。
用USP桨装置在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的L-赖氨酸为80%。
实施例5基于包括充分混合于其中的活性成分和羧酸盐的核心的控释制剂
组成:
C是根据专利WO2010072842A1制备的商业品牌产品,并且包括氯化胆碱和至少一种中至长链脂肪酸的盐。C用作核心,并且通过将其在包衣锅中喷洒来在65℃下用包括卵磷脂的液体脂肪包覆。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的氯化胆碱为12.9%,标准差0.6。
实施例6基于包括非常低浓度的赋形剂的核心的控释制剂
组成:
将干燥的DL-甲硫氨酸与淀粉和水在旋转式造粒机的室中混合。然后将颗粒在流化床中干燥。之后,在70℃下,通过在包衣锅中喷洒来将硬脂酸加至预先形成的微颗粒。然后将核心冷却至40℃,并且在65℃下施用包衣层。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的DL-甲硫氨酸为11.4%,标准差1.2。
实施例7基于包括高浓度赋形剂的核心的控释制剂
组成:
氯化胆碱70%(Choline Chloride 70%)是包括谷物载体上的氯化胆碱的干燥的商业产品。将其与液体碱性L-赖氨酸和硬脂酸在70℃下于犁铧式混合器中混合30分钟。然后将核心冷却至40℃,并且在65℃下通过在包衣锅中喷洒来施用包衣层。然后将微粒在45℃下冷却。
用USP桨装置(装置2)在38℃和100r.p.m下于700ml蒸馏水中进行释放溶出测试。
24小时后,释放的氯化胆碱为4.0%,标准差2.1。
实施例8瘤胃模型中产物的释放
体外瘤胃通过(by-pass)模型用来评价通过率。据证实这种模型产生与反刍动物中观察到的通过行为很好地相关的结果。
这种方法按照Goering和Van Soest (Goering,H.K.and P.J.Van Soest.1970.Forage fiber analysis.Agric.Handbook 379.ARS,USDA,Washington,D.C.)所述的步骤,如Bossen(Bossen,D.,D.R.Mertens,and M.R.Weisbjerg.2008.Influence of Fermentation Methods on Neutral Detergent FiberDegradation Parameters.Journal of Dairy Science.91:1464)所述对瘤胃接种体的制备和培养基有一些修改。提取的瘤胃不过滤(strain),而是在收集它的条件中使用。这种方法使得能够在提取的20分钟内将瘤胃液从各供体动物递送至温育容器,以限制对瘤胃原生动物的负面影响。一部分天然纤维层包括在提取物中,以帮助维持纤维降解微生物的天然群体的完整性。
评价甲硫氨酸产物的瘤胃通过率,所述甲硫氨酸产物通过通常利用喷雾冷却或喷雾冷冻进行的常规脂肪封装来制备。对于这种类型的瘤胃保护的甲硫氨酸,赖氨酸在氢化植物油中的最大包合率为约50%。
在12小时的时间中评价通过率。在模型系统中观察到64%的通过率。
还是在这些实验中,评价根据实施例1所述的方法制备的70%甲硫氨酸产物的瘤胃通过率。在瘤胃通过模型中观察到98%的通过率。
对根据实施例5所述的方法制备的受保护的胆碱以及标记的CBTC进行相似的实验。可以与胆碱产物比较瘤胃通过率,所述胆碱产物通过通常利用喷雾冷却或喷雾冷冻进行的常规脂肪封装来制备。然而,由于喷雾冷冻或喷雾冷却之前在熔化的氢化植物油中较高水平的活性成分增加的粘度,这些产物通常具有较低浓度的活性成分。这个实验中评价的产物利用喷雾冷冻技术来制备,并且标记DSMcp/d。结果显示两种产物均具有非常显著的瘤胃通过(图1和2)。根据本发明所述的方法制备的产物具有较好的瘤胃通过率。
实施例9在体内反刍动物试验中评价的通过率的改善
向牛喂食不同包裹的赖氨酸产物以及游离赖氨酸.HCl后的血液赖氨酸水平的分析可以用来证实为什么以前的解决方法不能用于包括较高水平的活性成分的产物。比较3种产物。第一种产物根据实施例2所述的方法制备并标记P1BT。第二种产物根据实施例1所述的方法制备并标记P2BT。
以下计算用来测量评价每只牛喂食150克的赖氨酸HCL(118g赖氨酸)的影响。
从0小时后血液赖氨酸测量的所有点减去0小时基线,以显示以umol/l测量的血液赖氨酸的绝对增加。
结果显示本发明所述产物的优秀通过率。产物P1BT和P2BT均产生比未受保护的盐酸赖氨酸更好的血浆赖氨酸水平(图3)。基线上的总面积代表在实验持续的20小时时间中超过对照动物的活性成分的总浓度增加。
前文的描述和图表包含本发明的说明性实施方案。前述实施方案和本文所述的方法可以基于本领域技术人员的能力、经验和偏好而变化。仅以一定顺序列出方法的步骤对所述方法的步骤的顺序不构成任何限制。前文的描述和图表仅解释和说明本发明,而本发明并不限于此,除非权利要求这样限制。具有本公开的本领域技术人员能够对其进行修改和变动而不偏离本发明范围。
Claims (15)
1.用于一种或多种生理学或药理学活性物质的控释的系统,所述系统包含微粒或颗粒形式的组合物,特别地用于畜牧学和/或兽医领域,所述组合物包含核心,所述核心包括一种或多种具有药理作用的物质、食物补充物或者诊断介质,所述一种或多种物质的特征在于在它们的化学结构内存在碱性官能团,所述核心被由两种脂肪或蜡构成的双脂肪层包覆,其中构成与所述核心接触的第一内层的脂肪层至少部分地由一种或多种游离脂肪酸构成,并且第二外层至少部分地由甘油酯与脂肪酸的混合物构成。
2.如权利要求1所述的系统,其中所述活性物质选自异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、色氨酸、缬氨酸、丙氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、脯氨酸、硒代半胱氨酸、丝氨酸、酪氨酸、精氨酸、组氨酸、胆碱、甜菜碱、肉碱、硫胺素、吡哆醇、链霉素、粘菌素、硫姆林、新霉素、精氨酸、葡糖胺、烟酰胺以及它们的盐,特别是氯化胆碱、盐酸甜菜碱、盐酸赖氨酸、盐酸硫胺素、一硝酸硫胺素、盐酸吡哆醇、硫酸粘菌素和富马酸硫姆林。
3.如权利要求1所述的系统,其中所述核心还包含能够改善颗粒或微粒形成的赋形剂。
4.如权利要求3所述的系统,其中所述赋形剂选自粘土、玉米芯粉、二氧化硅、微晶纤维素、聚乙烯吡咯烷酮、磷酸钙、淀粉、藻酸盐以及壳聚糖。
5.如权利要求4所述的系统,其中所述赋形剂以0.1-40重量%的量存在。
6.如权利要求1所述的系统,其还包含载体。
7.如权利要求6所述的系统,其中所述载体选自氨基改性淀粉、氨基改性二氧化硅、氨基改性粘土、氨基改性纤维素、具有胺基团的丙烯酸类聚合物、壳聚糖以及明胶。
8.如权利要求7所述的系统,其中所述载体以0.1-70重量%、优选0.1-50重量%、并且甚至更优选0.1-40重量%的量存在。
9.如权利要求1所述的系统,其中所述物质以所述核心的30-70%、优选50-100%、并且甚至更优选70-100%的量存在。
10.如权利要求1所述的系统,其中所述内层由脂肪酸构成,所述脂肪酸具有12-20个碳原子,并且优选16-18个碳原子。
11.如权利要求1所述的系统,其中所述外层的熔点为50-80℃,并且优选55-62℃。
12.如权利要求1所述的系统,其中所述外层包含氢化脂肪酸甘油酯的混合物。
13.如权利要求12所述的系统,其中所述氢化脂肪酸甘油酯包含总脂肪酸含量的40-70%的C-16脂肪酸甘油三酯含量以及30-50%的C-18脂肪酸甘油三酯含量。
14.如权利要求1所述的系统,其中包衣的总量为微粒最终重量的10-60%,并且优选25-50%。
15.如权利要求1所述的系统,其中内层比外层的比例为1:2.5-1:0.5。
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