CN1191822C - 脂质混合物以及含该脂质混合物的磷脂悬浮物的制备 - Google Patents

脂质混合物以及含该脂质混合物的磷脂悬浮物的制备 Download PDF

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CN1191822C
CN1191822C CNB998021024A CN99802102A CN1191822C CN 1191822 C CN1191822 C CN 1191822C CN B998021024 A CNB998021024 A CN B998021024A CN 99802102 A CN99802102 A CN 99802102A CN 1191822 C CN1191822 C CN 1191822C
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P·K·许
J·E·比肖普
小E·S·马德里加
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Abstract

本发明描述了制备脂质混合物和含该脂质混合物的均匀可过滤的磷脂悬浮物的方法，该悬浮物可用作超声造影剂。

Description

脂质混合物以及含该脂质混合物的磷脂悬浮物的制备
                     发明领域
本发明一般涉及脂质混合物以及含该脂质混合物的均匀可过滤磷脂悬浮物的制备方法，这种悬浮物可用作超声造影剂。
                     发明背景
磷脂造影剂的生产可以分为以下步骤：(1)制备脂质混合物；(2)混匀所述本体溶液(bulk solution)，包括脂质混合物在基本水介质中水合和分散产生脂质悬浮物；(3)经除菌过滤器过滤所述本体溶液从而使得所述悬浮物不含微生物污染物；(4)在受控无菌区将所述无菌悬浮物分配装入各个管制瓶中；(5)把所分装的管制瓶载入冷冻干燥器室以用全氟丙烷气(PFP)替代管制瓶上部气体；(6)将气体交换后密封的管制瓶转移至高压灭菌器以进行最后的灭菌。在该方法中有三个主要障碍：(1)所述脂质混合物的均匀性；(2)所述脂质混合物的水合作用；(3)所述悬殊浮物的均匀性和颗粒大小；以及(4)所述悬浮物经除菌过滤器无菌过滤。
通常将需要的脂质溶解或悬浮于合适的水溶剂或非水溶剂体系中，然后经冷冻或蒸馏减少体积，从而生产磷脂混合物。理想的是，该方法生产高度的含量均匀性和高纯度的混合固体物。然而，尽管在小的实验室规模可较好实施，但是该简单方法一旦扩大到生产规模的量时常常是有问题的。难点包括：(1)在溶剂去除步骤中保持含量的均匀性(由于不同溶解度引起的)；(2)保持纯度(当使用水时由于水解副反应引起的常见问题)；(3)提高纯度；(4)最小化溶剂体积；和(5)回收最后的固体(例如从大反应器刮出固体不是可行的)。
生产脂质混合物后，最后的混合通常包括把所述混合物加入水介质中。因为磷脂是疏水性的并难溶于水，所以磷脂或脂质混合物直接加入水溶液中引起所述脂质粉聚合形成非常难以分散的团块。因此，所述水合作用过程不能控制在合理的过程时间范围内。磷脂或脂质混合物在水介质中的直接水合作用产生颗粒范围0.6μm-100μm的混浊悬浮液。由于较大的颗粒大小分布，所以当所述悬浮液温度低于脂质的凝胶到液晶(gel-to-liquid crystal)的相变温度时，所述悬浮液不能在室温下过滤。所述脂质将累积在过滤器中，导致流速受限，在大多数情况下，不久所述过滤器就完全阻塞。通过常规的分批法，即使用常规使用的船舶式螺旋桨(marine propeller)在温度升高(例如40℃-80℃)下延长混合时间(例如6小时)后，也不能获得所述悬浮物颗粒大小的进一步减小。
尽管在温度升高即高于脂质的相变温度的情况下过滤是可能的，但是当使用正常过滤压时，仍然要除去大量的较大的脂质颗粒。所述无菌过滤物的浓缩在批与批文间同样有不同的脂质含量，脂质含量取决于所述脂质开始时如何进行水合的，而其水合作用又由所述原料的物理特征例如形态学所决定。
直接水合所述脂质或脂质混合物以产生均匀悬浮物和经除菌过滤器过滤所述悬浮物的方法可能是困难的，并且放大到任何合理的工业规模例如＞20L的成本高昂。
因此，目前要求保护的生产脂质混合物以及随后的磷脂悬浮物的方法，目的是通过提供切实可行的方法解决上述问题，该方法容易放大并可用于各种生产设备而不需要大改变或定制现有设备。
                 发明概述
因此，本发明的目的之一是提供一种制备脂质混合物的新方法。
本发明的另一目的是提供一种制备得自所述脂质混合物的磷脂悬浮物的新方法。
本发明人的发现已经实现了这些目的以及其它目的，这些目的在以下详细说明书中将变得显而易见，所述发现是在加入水溶液前将脂质混合物溶解于合适非水溶剂中使得可以生产磷脂悬浮物。
                 发明详述
本发明提供了一种制备脂质混合物的方法，包括：
(a)使至少两种脂质溶解于第一种非水溶剂中；
(b)浓缩该溶液至稠密凝胶；
(c)使稠密凝胶在第二种非水溶剂中淤浆化，然后离心或真空过滤形成固体；以及
(d)收集所得的固体。
本发明还提供了一种制备脂质悬浮物的方法，包括：
(1)使上述脂质混合物与非水溶剂接触，由此使所述脂质混合物溶解于所述非水溶剂中，以及
(2)使得自步骤(1)的溶液与水溶液接触形成脂质悬浮物。[1]因此，在第一个实施方案中，本发明提供一种制备磷脂悬浮物的新方法，包括：
(1)使脂质混合物与非水溶剂接触，由此使得所述脂质混合物基本上溶解于所述非水溶剂中；以及，
(2)使步骤(1)的溶液与水溶液接触形成脂质悬浮物。
[2]在一个优选的实施方案中，所述非水溶剂选自丙二醇、乙二醇和聚乙二醇300。
[3]在一个更优选的实施方案中，所述非水溶剂是丙二醇。
[4]在另一优选的实施方案中，所述脂质混合物包括：
(a)1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱；
(b)1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐；和，
(c)N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐。
[5]在另一优选的实施方案中，在步骤(1)中，所述非水溶剂在与所述脂质混合物接触前加热至温度约30-70℃。
[6]在另一更优选的实施方案中，所述非水溶剂在与所述脂质混合物接触前加热至温度约50-55℃。
[7]在另一优选的实施方案中，脂质混合物与非水溶剂的比率为从每mL非水溶剂含脂质混合物约5mg至约15mg/mL。
[8]在另一更优选的实施方案中，脂质混合物与非水溶剂的比率为约10mg/mL。
[9]在另一优选的实施方案中，在步骤(2)中，所述水溶液选自水、盐水、盐水/甘油混合物和盐水/甘油/非水溶剂混合物。
[10]在另一更优选的实施方案中，所述水溶液是盐水和甘油的混合物。
[11]在另一更优选的实施方案中，所述水溶液是盐水、甘油和丙二醇的混合物。
[12]在另一更优选的实施方案中，存在氯化钠6.8mg/mL、存在甘油0.1mL/mL、存在丙二醇0.1mL/mL以及存在所述脂质混合物约0.75-1.0mg/mL。
[13]在甚至更优选的实施方案中，存在脂质混合物0.75mg/mL。
[14]在另一更优选的实施方案中，存在脂质混合物1.0mg/mL。
[15]在另一优选的实施方案中，在步骤(2)中，所述水溶液在与步骤(1)的溶液接触前加热至温度约45-60℃。
[16]在另一更优选的实施方案中，所述水溶液在与步骤(1)的溶液接触前加热至温度约50-55℃。
[17]在另一优选的实施方案中，所述方法还包括：
(3)加热步骤(2)的脂质悬浮物至温度约等于或高于存在于所述悬浮物中的脂质的凝胶到液晶的最高相变温度。
[18]在另一更优选的实施方案中，在步骤(3)中，所述脂质悬浮物加热至温度至少约67℃。
[19]在另一更优选的实施方案中，所述方法还包括：
(4)经除菌过滤器过滤所述脂质悬浮物。
[20]在另一甚至更优选的实施方案中，在步骤(4)中，用两个除菌过滤柱进行过滤。
[21]在另一更优选的实施方案中，在步骤(4)中，所述除菌过滤柱的温度从约70℃至80℃。
[22]在另一还优选的实施方案中，在步骤(4)中使用0.2μm亲水性滤膜。
[23]在另一甚至更优选的实施方案中，所述方法还包括：
(5)将步骤(4)的过滤溶液分配装入管制瓶中。
[24]在另一更优选的实施方案中，所述方法还包括：
(6)用全氟烃气交换步骤(5)的管制瓶上部的气体。
[25]在另一甚至更优选的实施方案中，所述全氟烃气是全氟丙烷。
[26]在另一甚至更优选的实施方案中，用冷冻室进行上部气体的交换。
[27]在另一甚至更优选的实施方案中，所述方法还包括：
(7)灭菌步骤(6)的管制瓶。
[28]在甚至更优选的实施方案中，在步骤(7)中，所述管制瓶于约126-130℃灭菌1-10分钟。
[29]在第二个实施方案中，本发明提供一种制备脂质混合物的新方法，包括：
(a)使至少两种脂质与第一种非水溶剂接触；
(b)浓缩所述溶液成为稠密的凝胶；
(c)使所述稠密凝胶与第二种非水溶剂接触；以及，
(d)收集所得的固体物。
[30]在一个优选的实施方案中，在步骤(a)中，所述脂质是：
(i)1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱；
(ii)1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐；和，
(iii)N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐。
[31]在另一优选的实施方案中，在步骤(a)中，第一种非水溶剂是乙醇和甲苯的混合物。
[32]在另一优选的实施方案中，在步骤(c)中，第二种非水溶剂是甲基叔丁基醚。
[33]在另一优选的实施方案中，在步骤(a)中，所述溶液加热至足以使所述脂质完全溶解入所述溶剂中的温度。
[34]在另一更优选的实施方案中，在步骤(a)中，所述溶液加热至约25-75℃。
[35]在另一优选的实施方案中，在步骤(d)，所收集的固体物用甲基叔丁基醚洗涤并真空干燥。
[36]在第三个实施方案中，本发明提供一种新的磷脂悬浮物，它包括：
(a)悬浮物的脂质混合物量约0.75-1.0mg/mL。
(b)悬浮物的氯化钠量约6.8mg/mL。
(c)悬浮物的甘油量约0.1mL/mL。
(d)悬浮物的丙二醇量约0.1mL/mL；和
(e)水；
其中所述悬浮物用所述方法制备，该方法包括：
(1)使脂质混合物与非水溶剂接触，由此使得所述脂质混合物基本上溶解于非水溶剂中；
(2)使步骤(1)溶液与水溶液接触形成脂质悬浮物；
(3)加热步骤(2)的脂质悬浮物至温度约等于或高于存在于所述悬浮物中的脂质的凝胶到液晶的最高相变温度。
(4)经除菌过滤器过滤所述脂质悬浮物。
[37]在另一优选的实施方案中，所述脂质混合物包含：
(a)1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱；
(b)1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐；和，
(c)N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐。
[38]在另一更优选的实施方案中，所述非水溶剂在与所述脂质混合物接触前加热至温度约50-55℃。
[39]在另一更优选的实施方案中，脂质混合物与非水溶剂的比率约10mg/mL。
[40]在另一更优选的实施方案中，所述水溶液是盐水、甘油和丙二醇的混合物。
[41]在一个甚至更优选的实施方案中，存在脂质混合物0.75mg/mL。
[42]在另一更优选的实施方案中，所述水溶剂在与步骤(1)的溶液接触前加热至温度约50-55℃。
[43]在另一更优选的实施方案中，在步骤(3)中，所述脂质悬浮物加热至至少约67℃。
[44]在另一更优选的实施方案中，在步骤(4)中，使用二个0.2μm亲水性滤膜。
                        配方
打算从至少数克规模、一公斤规模、数公斤规模或工业规模实施本发明。作为本文所用的数克规模最好是其中至少一种原料物质以10g或10g以上、更优选至少50g或50g以上、甚至更优选至少100g或100g以上存在的规模。作为本文所用的数公斤规模是指其中使用至少一种原料物质为一公斤以上的规模。作为本文所用的工业规模是指非实验室规模并且足以供应足够用于临床试验或分销给消费者的产品的规模。
作为本文所用的脂质混合物或磷脂混合物是指已经混合的两种或两种以上的脂质。所述脂质混合物一般为粉末形式。最好是至少一种脂质是磷脂。所述脂质混合物最好含有1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐(DPPA)和N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐(MPEG5000-DPPE)。存在于所述混合物的各种脂质的量将取决于所需要的最终产品。各种脂质的优选比率描述于实施例部分。在本发明方法中可以使用种类繁多的其它脂质，例如描述于Unger等的美国专利第5,469,854号中的脂质，该专利内容通过引用结合到本文中。
作为本文所用的磷脂是含一个油性(疏水的)烃链和一个极性(亲水的)磷首基的脂肪物质。磷脂类是两亲的。它们在水介质中自然形成界面和密闭小泡。磷脂构成动物细胞浆膜物质的约50％。
               脂质混合物的制备
所述脂质混合物可以通过水悬浮物-冷冻干燥法或使用有机溶剂的有机溶剂溶解-沉淀法制备。在水悬浮物-冷冻干燥法中，所需要的脂质悬浮于温度升高的水中，然后经冷冻干燥浓缩。最好使用溶解法。
步骤(a)：
所述有机溶剂溶解-沉淀法包括使需要的脂质(例如DPPA、DPPC和MPEG5000 DPPE)与第一种非水溶剂系统接触。该系统通常是溶剂的组合物，例如CHCl3/MeOH，CH2Cl2/MeOH和甲苯/MeOH。第一种非水溶剂系统最好是甲苯和甲醇的混合物。最好是加热所述脂质溶液至足以达到完全溶解的温度。该温度最好为约25-75℃，更优选约35-65℃。
溶解后，需要通过热过滤或冷却至室温后过滤除去不需要的外来物质。可以使用已知的过滤方法(例如重力过滤、真空过滤或压力过滤)。
步骤(b)：
然后浓缩所述溶液至稠密凝胶/半固体。最好是经真空蒸馏进行浓缩。也可以使用其它方法，例如旋转蒸发浓缩该溶液。该步骤的温度最好为约20-60℃，更优选30-50℃。
步骤(c)：
然后将所述稠密凝胶/半固体分散于第二种非水溶剂。最好在接近室温(例如15-30℃)下，使该混合物淤浆化。有用的第二种非水溶剂是使得所述脂质从过滤溶液沉淀的非水溶剂。第二种非水溶剂最好是甲基叔丁基醚(MTBE)。可以使用其它醚类和醇类。
步骤(d)：
然后收集在加入第二种非水溶剂后产生的固体物。所收集的固体物最好用另一部分的第二种非水溶剂(例如MTBE)洗涤。最好是在室温下通过真空过滤或离心进行收集。收集后，最好是所述固体物于温度约20-60℃下真空干燥。
相对于所述水悬浮物/冷冻干燥法，优选使用有机溶剂溶解-沉淀法，原因如下：
(1)因为所述脂质易溶于甲苯/甲醇，所以溶剂体积明显减少(相对于所述水溶液法)。
(2)因为溶解度增加，所述方法的温度也相对低于水溶液法，由此避免脂肪酸酯的水解不稳定性。
(3)当温度回降至室温时，脂质的甲苯/甲醇溶液保持均质，使得可以室温过滤以去除固体外来物质。
(4)MTBE沉淀使得可以快速简便地分离脂质混合物固体。而所述水溶液法，要使用耗时的冷冻干燥过程分离物质。
(5)MTBE沉淀还使得可以去除进入过滤的废水流中的可溶于MTBE的任何杂质。当直接浓缩溶液或冷冻干燥至固体时，不能实现去除杂质的潜力。
(6)本发明方法提供均匀固体。
                      脂质悬浮物的制备
步骤(1)：
在第一步中，脂质混合物与非水溶剂接触，因此所述脂质混合物基本上溶解于非水溶剂中。或者，可以使单独的脂质依次与所述非水溶剂接触，所述脂质次序为：DPPC、DPPA和MPEG5000-DPPE；DPPC、MPEG5000-DPPE和DPPA；MPEG5000-DPPE、DPPA和DPPC；或MPEG5000-DPPE、DPPC和DPPA。不首先加入脂质溶解最少以及脂质含量最少的DPPA。在加入DPPA前或与其同时加入一种其它脂质有助于DPPA的溶解。在另一替代方法中，各种脂质可以以其固体形式组合，该固体组合物与非水溶剂接触。
当脂质混合物和非水溶剂的混合物变透明时，一般表示基本溶解。如前所述，磷脂一般不是水溶性的。因此，磷脂混合物直接加入水环境中引起所述脂质混合物聚集形成非常难以分散的团块。本发明通过将脂质混合物在加入水溶液前溶解于非水溶剂中，从而克服该制约。这使得人们可以将脂质混合物均匀地分散到液体中。然后该液体分散物可以加入到所需要的水环境中。
非水的是指一种溶剂或溶剂的混合物，其中存在的水量足够低以便不影响所述脂质混合物的溶解。所需要的非水溶剂的量取决于脂质混合物的溶解度，并且还取决于各个组分的最终需要浓度。作为一个普通技术人员应该认识到，存在于非水溶剂中的可允许的水的水平随脂质混合物中的各种脂质的水溶解度而改变。各种磷脂的水溶解度越高，可以存在于步骤(1)中的水越多。最好是使用丙二醇作非水溶剂。然而，可以使用其它多羟基化合物家族成员，例如乙二醇和聚乙二醇300。
机械混合脂质混合物和非水溶剂可能是达到完全溶解所必需的。本领域普通技术人员将认识到，可用各种混合方法。最好使用高剪切均化器。
本领域技术人员应该认识到，升高溶剂的温度有助于脂质混合物的溶解。在可实施步骤(1)的温度范围可以从室温至选定溶剂的沸点温度。所述温度优选为约30-70℃，更优选为约45-60℃，甚至更优选为约50、51、52、53、54或55℃。当使用乙二醇或聚乙二醇300时，所述温度优选为约50℃-约60℃，而更优选为约55℃。保持所述溶液于较高温度将降低溶液粘度并便于配制。
溶解所述脂质混合物的优选方法如下：(a)将丙二醇加至合适称量容器中。(b)在热浴中加热丙二醇至约40-80℃。(C)称量脂质混合物装入分开的容器。(d)当丙二醇达到所需要的温度范围时，将该溶液转移入装有所述脂质混合物的容器中。(e)把该容器放回热浴中，直到所述溶液变为透明。(f)机械混合所述脂质混合物/丙二醇溶液以进一步保证完全溶解以及均匀分散所述脂质混合物。
当然，脂质混合物与非水溶剂的比率受限于所述脂质混合物的溶解度。该比率也将受到最终制剂中的脂质混合物的需要量的影响。优选的所述比率为从每mL溶剂约1mg脂质混合物(mg/mL)至约100mg/mL。更优选的是，所述脂质混合物以约5、6、7、8、9、10、11、12、13、14或15mg/mL存在。甚至更优选的是，所述脂质混合物以约10mg/mL存在。
步骤(2)：
第二步包括使步骤(1)的溶液与水溶液接触形成脂质悬浮物。所述水溶液可以是水、盐水、盐水/甘油混合物或盐水/甘油/非水溶剂混合物。按如上定义，非水溶剂最好是丙二醇。作为本文所用的悬浮物是指其中不溶性颗粒分散于液体介质的分散物。
在所述脂质混合物达到完全溶解(步骤(1))后，可将所得的溶液加至水溶液中。该水溶液可以含有一种或多种选自氯化钠、甘油和非水溶剂的组分。该水溶液优选含有甘油和氯化钠。最好是，在加入步骤1的溶液前，在所述水溶液中存在足够量的丙二醇，以便达到所需要的丙二醇终浓度。
不希望所需组分的加入次序会严重影响所生成的脂质悬浮物。然而，所述脂质混合物液优选加至已经含有上述另外组分的水中。然后可以加入所需要的另外组分。更优选的是，所述脂质混合物液加至水和氯化钠的溶液(即盐水)中。还优选的是，所述脂质混合物液加至水、氯化钠和甘油的溶液中。甚至更优选的是，所述脂质混合物液加至水、氯化钠、甘油和丙二醇的溶液中。
优选的是，每mL制剂存在6.8mg氯化钠。优选每mL制剂存在0.1mL甘油。优选终浓度为每mL制剂0.1mL丙二醇。所述制剂的最终pH优选为约5.5-7.0。所述脂质混合物液最好是以每mL制剂0.75-1.0mg的量存在。
水溶液的温度范围可以是从室温到70℃。该温度优选为约45-60℃，甚至更优选50、51、52、53、54或55℃。为了达到完全溶解，需要振荡所述混合物，最好是搅拌。此外，可能需要根据所需要的最终制剂调节所述溶液的pH。可以加入酸(例如盐酸)或碱(例如氢氧化钠)以进行该调节。
所述脂质悬浮物将含有不同大小的液体颗粒。本发明的益处之一是能够恒定地获得几乎均匀大小的小颗粒。因此，最好是获得的大部分颗粒直径小于100nm，更优选小于50nm。
溶解所述脂质混合物的优选的方法如下：(a)将注射用水(WFI)加入混合容器。(b)开始混合并保证温度为50-55℃。(c)将氯化钠加至混合容器。在进行下一步前，等待直到所述固体完全溶解。(d)将甘油加至所述混合容器中。使其有足够时间以完全混合。(e)加入非所述脂质混合物/丙二醇溶液中的余下丙二醇。给予足够时间以充分混合。(f)降低混合率以减少混合容器中的湍流。(g)将所述脂质混合物/丙二醇溶液加至混合容器中。(h)再调节混合至原初速率。(i)必要时，加入另外的WFI。(j)连续混合约25分钟并保证完全混匀。(k)检验并调节该溶液至目标pH。
步骤(3)：
第三步包括加热得自步骤(2)的脂质悬浮物至温度约等于或高于存在于该溶液中的脂质的凝胶至液晶的最高相变温度。
该步骤的目的之一是提供可过滤的悬浮物。假如在正常的过程中流速没有明显的下降而在该过滤系统中压力下降无明显的增加时，则认为溶液/悬浮物是可过滤的。
实验数据显示，所述制剂中的脂质应该超过其凝胶到液晶的相变，以便简化无菌过滤。当所述脂质低于所述相变温度时，所述悬浮物颗粒是刚性的。然而，当它们高于其相应的凝胶-液晶相变温度时，它们是更疏松结构的构型，因此更容易过滤。
DPPC和DPPA分别显示相变温度为41℃和67℃。MPEG5000-DPPE溶于水，因此它不表现出为大多数水合脂质悬浮物的特征的凝胶-液晶相变。因为优选的制剂中的脂质均显示不同的凝胶到液体的相变，所以最好使用最高相变温度67℃过滤所述溶液。通过维持温度于67℃或高于67℃，使得所有脂质高于其相应的相变，从而保证疏松的构型而通过所述过滤器。
通过于所述混合容器外套上热交换线圈可以实现加热。得自可控来源(例如热水浴或热水器)的热水/蒸气就会传递足够的热以维持所述混合液于设定的温度。也可以使用本领域技术人员已知的其它热源。
步骤(4)：
通过除菌过滤器过滤所述脂质悬浮物从而进行第四步。该步骤之后的目的是提供基本上无菌的悬浮物。当过滤物含至少一个形成菌落的微生物的概率小于10-6时，则认为该过滤物基本上无菌。
最好用除菌过滤柱进行过滤。此外，可能需要强制溶液通过所述过滤器的手段(例如泵送或加压)。由于进行过滤的溶液需要保持在存在于溶液中的脂质的凝胶到液晶最高相变温度或高于该温度下，所以过滤应该在大致相同的温度下进行。为此，最好将过滤器(例如除菌过滤柱)密封在护套式过滤器外壳中，该外壳不断加热(例如通过来自温控水浴的热水流)，以保证所述悬浮物高于脂质相变温度。除菌过滤器的温度优选为50-100℃，更优选为60-90℃，甚至更优选70、71、72、73、74、75、76、77、78、79或80℃。
可以使用一个或多个除菌滤膜过滤所述悬浮物。需要的滤膜数目将取决于其除菌效果。最好使用两个滤膜。滤膜孔的大小受限于提供无菌悬浮物的需要。最好使用0.2μm亲水性滤膜。
优选配方的本体溶液通过两个0.2μm亲水性滤膜以约1L/分钟(1L/min)流速连续过滤长达3小时，即所述悬浮液通过过滤器总计180L。实验结果表明，无明显的滤膜阻塞。脂质分析表明，在所述过滤过程中没有可检测的脂质丢失(由于过滤介质累积引起的)。
优选配方的本体溶液于40℃-80℃混合，所述悬浮物在无菌过滤前冷却至室温。未观察到明显的滤膜阻塞，表明所述悬浮物颗粒大小分布完全低于0.2μm的滤膜孔大小。最好是在过滤过程中应用加热以便保证脂质混合物在无菌过滤物中的最大回收(即使脂质颗粒在过滤介质中的潜在保留最小化)。
过滤脂质悬浮物的优选方法如下：(a)保证所有装套的过滤器于70℃-80℃。(b)保证过滤装置中的阀关闭。(c)连接过滤入口软管至混合容器的出口。(d)打开阀使溶液通过所述滤器。(e)在收集过滤物前使3升溶液通过过滤器进行冲洗。(f)连续过滤直至完成。
步骤(5)：
将所述过滤液分配装入管制瓶从而完成第五步。最好是在可控无菌区进行该步骤。本领域一般技术人员应该认识到，选定的管制瓶和传递至管制瓶的悬浮物的量应该取决于所设想的脂质悬浮物的最终用途。通过各种方法可以实现分装，包括吸管、手动注射器式分配器(例如Filamatic注射器式分配器)或工业自动分配器(例如Cozzli或TL自动灌装机)。
步骤(6)：
用全氟烃气交换得自步骤5的管制瓶的上部气体，从而进行第六步。交换的优选方法是把已分装的管制瓶载入冷冻干燥器室，用全氟烃气替换管制瓶上部气体。优选的气体是全氟丙烷(PFP)。可以使用本领域技术人员已知的上部气体交换的其它方法。
在完成所述管制瓶上部气体交换循环后，密封管制瓶。当所述冷冻干燥器压力下降回到大气压时，用PFP充入该室。固定管制瓶塞以封闭该管制瓶。
步骤(7)：
第七步包括在步骤6后最后灭菌管制瓶。一种终末灭菌的方法是使用高压灭菌器。此外，所述密封管制瓶可以最后在蒸汽灭菌器中灭菌，以进一步提高所述产品的无菌保证。在灭菌过程中必须小心注意，因为可观察到高压灭菌引起的一定程度的脂质降解。最好是所述管制瓶于126-130℃灭菌1-10分钟。
本发明的其它特征在以下示例性实施方案的说明过程中将变得显而易见，给出所述实施方案是为了说明本发明而不是用来对其进行限制。
                                                             实施例
                                                   表1：脂质混合物的目标组成
    脂质名称     通用名     Wt％   摩尔％
    DPPA     1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐     6.0   10
    DPPC     1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱     53.5   80
    MPEG5000-DPPE     N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐     40.5   8
                 脂质混合物的生产方法
Figure C9980210200211
将甲苯(3.3L)、甲醇(1.2L)、DPPA(59.6g)、DPPC(535g)和MPEG5000 DPPE(405g)装入一个烧瓶中。用0.9L甲醇冲洗固体接触表面后，将该淤浆加热至45-55℃直到完全溶解。
过滤该溶液，然后于35-45℃真空浓缩成为稠密凝胶。加入甲基叔丁基醚(MTBE，5.4L)，将该混合物于15-30℃淤浆化。经离心或真空过滤收集白色固体，并用MTBE(0.9L)洗涤。然后将该固体放入真空炉中，并于40-50℃干燥至恒重。所干燥的脂质混合物转移至瓶中并保藏于-15-25℃。
在本发明脂质混合物生产方法的另一实施方案中，也可以使用以下方法。
                脂质混合物的替代生产方法
Figure C9980210200221
根据分析证明“使用(Use As)”值的纯度调节磷脂量。该实验的批量大小(合并的磷脂重量)是2kg。
向旋转式蒸发瓶依次装入甲苯(3,300mL)、甲醇(1,200mL)、DPPA(122.9g，校正的“使用”纯度为97.0％)、DPPC(总量1，098.5g；500.8g取自98.4％“使用”纯度的一批，597.7g取自96.7％“使用”纯度的一批)和MPEG5000 DPPE(815.7g；校正的“使用”纯度为99.3％)。用甲醇(900mL)把残余的固体冲洗入所述烧瓶后，烧瓶放置于旋转蒸发器上(非真空)，将淤浆加热至45-55℃(外部)。完全溶解后，使所述外部温度降至35-45℃，采用真空，使溶液浓缩成白色半固体。从蒸发器取出烧瓶，用刮勺粉碎固体。烧瓶再用于蒸发器，继续浓缩。达到终点(最终真空压力为220mbar；白色颗粒型坚固固体)后，经旋转式蒸发器的加入管加入MTBE(5,400mL)，终止真空，所述混合物于15-30℃淤浆化15-45分钟。经离心或真空过滤分离固体，用MTBE(3,800mL)冲洗，在真空炉(40-50℃)中干燥至恒重。在转移至带聚丙烯盖的聚乙烯瓶中以前，使固体过筛(0.079英寸目)去除固体块，提供为白色固体的脂质混合物(SG896)1，966.7g(98％)。
优选的脂质悬浮物含有：
1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐(DPPA)；
1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)；
N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐(MPEG5000-DPPE)；
聚乙二醇，USP；
甘油，USP；
氯化钠，USP；和，
注射用水，USP。
                                  表2：优选的对照剂配方
组分     A*     B*
氯化钠，USP     6.8mg/mL     6.8mg/mL
甘油，USP     0.1mL/mL     0.1mL/mL
聚乙二醇，USP     0.1mL/mL     0.1mL/mL
脂质混合物**     1mg/mL     0.75mg/mL
全氟丙烷     ＞65％     ＞65％
pH     6.0-7.0     6.0-7.0
*配方A的脂质混合物浓度为1mg/mL；配方B的脂质混合物浓度为0.75mg/mL。**该脂质混合物包含：DPPC 53.5wt.％，DPPA 6.0wt.％和MPEG5000-DPPE 40.5wt％。
       表3：优选的容器和封闭
    组分 类型
    管制瓶 Wheaton 2802，B33BA，2cc，13mm，I型，火石玻璃管形瓶
    瓶塞 West V50 4416/50，13mm，灰色丁基lyo的硅化塞
    密封 West 3766，白色13mm，轻按脱落式铝密封
成品的装量体积可以为1.0-2.0mL/管制瓶。
在优选配方的制备中，当所述脂质混合物与含注射用水、氯化钠、甘油和丙二醇的水基质溶液直接水合时，与过滤前的本体溶液相比，所述过滤物的脂质含量较少。脂质的丢失量变化范围12％-48％。这些结果证实，所述无菌过滤过程是不能有效控制的，因此成品的脂质含量是高度变异的。
相反，用目前描述的方法，所述脂质的分析结果表明脂质在所述过滤过程中全部回收。分析结果在理论值附近的变化是在正常的分析方法变异范围内。由在丙二醇中的第一种溶解脂质混合物制备的悬浮物的数目、体积和反射密度的颗粒大小分布表明，在55℃以及70℃的过滤前本体溶液中，大多数颗粒小于50nm。颗粒分布型过滤后没有变化。
                       应用部分
现在要求保护的方法用于制备超声造影剂。这类造影剂应该可用于各种成像应用，包括在超声心动图和放射性超声显像中增强对比度。
显然，根据上述内容对本发明进行各种改进和改变是可能的。因此，理所当然的是，在后附的权利要求范围内，可以如本文所具体描述的其它内容实施本发明。

Claims (36)

1.一种制备脂质混合物的方法，包括：
(a)使至少两种脂质溶解于第一种非水溶剂中；
(b)浓缩该溶液至稠密凝胶；
(c)使稠密凝胶在第二种非水溶剂中淤浆化，然后离心或真空过滤形成固体；以及
(d)收集所得的固体。
2.按照权利要求1的方法，其中在步骤(a)中，所述脂质是：
(i)1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱；
(ii)1，2-二棕榈酰基-sn-甘油基-3-磷脂酸一钠盐；和
(iii)N-(甲氧基聚乙二醇5000氨基甲酰基)-1，2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺一钠盐。
3.按照权利要求2的方法，其中在步骤(a)中，所述第一种非水溶剂是甲醇和甲苯的混合物。
4.按照权利要求2的方法，其中在步骤(c)中，所述第二种非水溶剂是甲基叔丁基醚。
5.按照权利要求2的方法，其中在步骤(a)中，将所述溶液加热至足以使所述脂质完全溶解到所述溶剂中的温度。
6.按照权利要求5的方法，其中在步骤(a)中，将所述溶液加热至25-75℃。
7.按照权利要求2的方法，其中在步骤(d)中，所收集的固体用甲基叔丁基醚洗涤并在真空干燥。
8.一种制备脂质悬浮物的方法，包括：
(1)使权利要求1-7中任何一项方法制备的脂质混合物与非水溶剂接触，由此使所述脂质混合物溶解于所述非水溶剂中，以及
(2)使得自步骤(1)的溶液与水溶液接触形成脂质悬浮物。
9.按照权利要求8的方法，其中所述非水溶剂选自丙二醇、乙二醇和聚乙二醇300。
10.按照权利要求9的方法，其中所述非水溶剂是丙二醇。
11.按照权利要求9的方法，其中所述非水溶剂在与所述脂质混合物接触前加热至温度30-70℃。
12.按照权利要求11的方法，其中所述非水溶剂在与所述脂质混合物接触前加热至温度50-55℃。
13.按照权利要求9的方法，其中脂质混合物与非水溶剂的比率为每mL非水溶剂含5mg脂质混合物至15mg/mL。
14.按照权利要求13的方法，其中脂质混合物与非水溶剂的比率为10mg/mL。
15.按照权利要求9的方法，其中在步骤(2)中，所述水溶液选自水、盐水、盐水/甘油混合物和盐水/甘油/非水溶剂混合物。
16.按照权利要求15的方法，其中所述水溶液是盐水和甘油的混合物。
17.按照权利要求15的方法，其中所述水溶液是盐水、甘油和丙二醇的混合物。
18.按照权利要求17的方法，其中存在的氯化钠为6.8mg/mL，存在的甘油为0.1mL/mL，存在的丙二醇为0.1mL/mL以及存在的所述脂质混合物为0.75-1.0mg/mL。
19.按照权利要求18的方法，其中存在的脂质混合物为0.75mg/mL。
20.按照权利要求18的方法，其中存在的脂质混合物为1.0mg/mL。
21.按照权利要求9的方法，其中在步骤(2)中，所述水溶液在与得自步骤(1)的溶液接触以前加热至温度45-60℃。
22.按照权利要求21的方法，其中所述水溶液在与得自步骤(1)的溶液接触前加热至温度50-55℃。
23.按照权利要求8的方法，其中所述方法还包括：
(3)加热得自步骤(2)的脂质悬浮物至温度等于或高于存在于所述悬浮物中的脂质的凝胶到液晶的最高相变温度。
24.按照权利要求23的方法，其中在步骤(3)中，将所述脂质悬浮物加热至温度至少67℃。
25.按照权利要求23的方法，其中所述方法还包括：
(4)所述脂质悬浮物通过无菌过滤器过滤。
26.按照权利要求25的方法，其中在步骤(4)中，用两枝除菌过滤柱进行过滤。
27.按照权利要求26的方法，其中在步骤(4)中，所述除菌过滤柱的温度70-80℃。
28.按照权利要求27的方法，其中在步骤(4)中，使用0.2μm的亲水性滤膜。
29.按照权利要求25的方法，其中所述方法还包括：
(5)将得自步骤(4)的过滤的溶液分装入管形瓶中。
30.按照权利要求29的方法，其中所述方法还包括：
(6)用全氟烃气替换得自步骤(5)的管形瓶上部空间的气体。
31.按照权利要求30的方法，其中所述全氟烃气为全氟丙烷。
32.按照权利要求31的方法，其中用冷冻干燥室进行上部空间气体的交换。
33.按照权利要求30的方法，其中所述方法还包括：
(7)灭菌得自步骤(6)的管形瓶。
34.按照权利要求33的方法，其中在步骤(7)中，所述管形瓶于126-130℃灭菌1-10分钟。
35.根据权利要求1-7中任何一项制备的脂质混合物在制备超声造影剂中的应用。
36.根据权利要求8-34中任何一项制备的脂质悬浮物在制备超声造影剂中的应用。
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