CN1160059C - 生产水不溶性化合物的亚微粒子的方法 - Google Patents

生产水不溶性化合物的亚微粒子的方法 Download PDF

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CN1160059C
CN1160059C CNB998096660A CN99809666A CN1160059C CN 1160059 C CN1160059 C CN 1160059C CN B998096660 A CNB998096660 A CN B998096660A CN 99809666 A CN99809666 A CN 99809666A CN 1160059 C CN1160059 C CN 1160059C
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G·W·帕斯
G·M·瓦雄
K·A·米斯拉
�������ɭ
I·B·亨里克森
V·克鲁科尼斯
A·戈迪纳斯
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Abstract

通过使化合物和表面修饰剂的液化气体溶液快速膨胀进入含水介质，同时用表面修饰剂分子稳定所述物质的微粒悬浮体，并任选用高压均化器对由此形成的含水悬浮体进行均化，从而制备水不溶性化合物、尤其药物的亚微颗粒。

Description

生产水不溶性化合物的亚微粒子的方法
本发明提供生产具有生物用途化合物的微米和亚微米级颗粒制剂的方法，这些化合物为水不溶性或水溶性差，尤其水不溶性的药剂。
               发明背景及概述
配制生物活性化合物的主要问题是它们的水溶性差或不溶于水。例如，在收录于美国药典的药物中，超过三分之一的药物为水不溶性或水溶性差。具有生物用途的水不溶性药物或化合物的口服制剂通常显示出较差和不稳定的生物利用率。另外，药物的不溶性是药剂师和药物科学家在开发新药时所面临的最棘手的问题之一。水不溶性问题延误或彻底阻碍了许多新药或其它生物用途化合物的开发，或阻止对当前市场上流行药物的非常需要的重新配制。尽管一些水不溶性化合物可以通过增溶于有机溶剂或表面活性剂水溶液来进行配制，但在许多情况下，这种增溶可能不是传递用于生物用途的水不溶性试剂的优选方法。例如，目前许多供注射用的水不溶药物制剂在其标签上对它们增溶时所用的洗涤剂和其它试剂注有重要的不利的警告。
配制水不溶的生物活性化合物的另一种方法为表面稳定的颗粒制剂。通常需要将药物配制成小粒度从而增大表面积、生物利用率以及溶出要求。Pace等(“不溶性药物的新的注射制剂”，药学技术，1999年3月)对水不溶性或溶解性差的注射药物的微粒制剂的应用进行了综述。
Haynes在美国专利第5091187和5091188号描述了使用磷脂作为表面稳定剂以生产水不溶性药物的亚微级颗粒的水悬浮体。这些悬浮体被认为首先用于表面改性的微粒的水悬浮体，其含有由纯药物核组成的颗粒并且用天然或合成的双极性类脂(包括磷脂和胆固醇)进行稳定。因此，已经有人对采用这些要素的传递系统进行了描述(G.G.Liversidge等，美国专利第5145684号；K.J.Illig等，美国专利第5340564号和H.William Bosch等，美国专利第5510118号)，其重点为采用颗粒的水悬浮体的药物传递方法的用途。
Haynes在美国专利第5246707号中描述了采用磷脂包膜的微晶在水溶性生物分子如多肽和蛋白质的传递中的应用。这些蛋白质通过络合具有不溶性并且所得物质形成磷脂包膜颗粒的固体核。
这些专利和其它文献采用基于由机械方法如磨擦、空化、高剪切、冲击等来减小粒度的方法，这些机械方法通过对水悬浮体的介质研磨、高压均化、超声和微流化(microfluidization)来获得。然而，这些减小粒度的方法具有某些缺陷，如长的处理时间(高压均化或微流化)和污染(介质研磨和超声波处理)。此外，这些方法可能不适用于在这些方法中普遍存在的pH、高温和高压条件下的水性介质中的具有有限稳定性的化合物的水悬浮体。
解决这些问题的替代方法的一种是采用液化气来生产微粒制剂。在一种这样的方法中，对液化气溶液进行喷雾以形成微细固体颗粒从中沉淀的气雾剂形式。可以观察到从超临界流体沉淀出固体的现象，并且早在1879年已由Hannay，J.B.和Hogarth，J.在“固体在气体中的溶解性”(Proc.Roy.Soc.London 1879 A29，324)中进行了叙述。
Krukonis(1984)对在超临界区域中的液化气溶液快速膨胀第一次进行了综合性研究，他对有机、无机和生物材料微粒进行了排列。据报导，有机材料如lovastatin、多羟基酸以及mevinolin的粒度范围大多为5-100微米。通过将乙烷膨胀至粘稠的明胶溶液从而抑制聚集颗粒的后膨胀，可以形成β-胡萝卜素的纳米颗粒(300nm)。Mohamed，R.S.等在(1988)“超临界混合物膨胀后形成的固体”(超临界科学和技术，Johnston，K.P.和Penninger，J.M.L.编)中对固体萘和lovastatin的超临界二氧化碳溶液和突然减小压力以获得所述溶质的微细颗粒进行了描述。压力的突然减小降低了超临界流体的溶剂性能(power)，使溶质以微细颗粒的形式沉淀出来。
Tom，J.W.和Debenedetti，P.B.(1991)在“用超临界流体形成颗粒-综述”(J.Aerosol.Sci.22：555-584)中描述了超临界溶液技术的快速拓展以及它们在无机物、有机物、药物以及聚合物中的应用。这种技术适用于粉碎冲击敏感的固体、生成无定形材料的紧密混合物、形成聚合物微球以及沉积薄膜。
从超临界流体中快速膨胀有机物的大多数研究均采用超临界的二氧化碳。然而，对于β-胡萝卜素而言，由于某些化学作用，乙烷优于二氧化碳。通常优选单独或与共溶剂组合的二氧化碳。微量加入共溶剂可以明显影响溶剂性质。当共溶剂用于超临界溶液的快速膨胀时，要注意防止由于在喷嘴上溶剂冷凝而引起的颗粒的脱溶解。通常通过在膨胀前将超临界流体加热至喷嘴尖端没有观察到冷凝物(水雾)来实现它。
当采用二氧化碳时出现了相似的问题。在绝热膨胀(冷却)时，除非向喷嘴提供足够的热量从而保持气态，否则二氧化碳将分成两相。多数研究者注意到了这种现象并增大预膨胀温度从而防止喷嘴的冷凝和冷冻。需要高的热量输入(40-50kcal/kg)来保持二氧化碳为气态。如果这种能量通过增大预膨胀温度来提供，那么密度将减小并因此降低超临界流体的溶剂化能力。这将引起过早的沉淀和喷嘴的堵塞。
液化气的溶剂性质在很大程度上受接近流体临界点时它们的流体密度的影响。在液化气溶液的快速膨胀中，不挥发性溶质溶于保持超临界或次临界相的液化气中。通过液化气快速膨胀至大气条件下来降低溶液密度，从而触发成核和结晶。为实现这一点，通常将液化气通过长径比(L/D)5-100、内径10-50微米的喷嘴进行喷雾。高水平的过饱和导致快速成核和有限的晶体生长。快速传播的机械搅动和高度过饱和的结合为液化气溶液快速膨胀的显著特征。这些条件导致形成具有较窄粒度分布的极小颗粒。
在液态和超临界流体状态下，采用压缩二氧化碳作为形成具有亚微颗粒特性材料的溶剂或反溶剂(anti-solvent)时具有许多优点。有机溶剂在超临界二氧化碳流体中的扩散系数通常比在常规液体溶剂中高1-2个数量级。另外，二氧化碳为小的线性分子，在液体中的扩散要快于其它的反溶剂。在反溶剂的沉淀过程中，在各个方向上加速的传质可以促进极快的相分离并由此生产具有亚微特性的材料。在本方法的末尾易于通过简单的减压来循环超临界流体溶剂。由于超临界流体没有表面张力，因此可以通过毛细力在不破坏结构的前提下来脱除它们。从产物中脱除溶剂非常快。在产物中没有残余的二氧化碳，并且二氧化碳具有许多其它所需的特性，例如，它无毒、不燃并且便宜。另外，由于反溶剂与溶剂之比通常为30∶1，可大大减少废溶剂。
Henriksen等在WO 97/14407中提出的这些理论，公开了采用压缩流体来生产具有生物用途的水不溶性化合物尤其水不溶性药物的亚微粒度颗粒的方法，它通过从化合物溶于其中的超临界溶液中快速膨胀来沉淀化合物，或者通过将所述化合物溶于其中的溶液喷雾到与所述溶液可以混溶、但为所述化合物的反溶剂的压缩气体、液体或超临界流体中来进行沉淀。可以这种方式用压缩流体反溶剂(压缩流体反溶剂)进行沉淀。
本方法的基本要素是使用磷脂和其它的表面修饰剂改性药物颗粒的表面从而防止颗粒的聚集并因此提高它们的贮存稳定性和药物动力学特性。这种方法结合或组合磷脂或其它合适的表面修饰剂如以水溶液或分散体(其中对超临界溶液进行喷雾)的形式存在的表面活性剂。当使用二氧化碳用作超临界溶液时，选择对化合物-水界面具有活性的表面活性剂，但不能选择对二氧化碳-有机溶剂或二氧化碳-化合物界面具有活性的表面活性剂。在没有颗粒聚集或絮凝的条件下，可以通过压缩流体反溶剂的方法，在水介质中采用表面修饰剂来制备亚微颗粒。
                     附图简述
图1图示了由实施例3生产的环孢菌素的粒度分布(相对体积对粒度nm)，和
图2图示了由实施例4生产的环孢菌素的粒度分布(相对体积对粒度nm)。
                     发明综述
然而，在这种先有方法中，需要对超临界溶液进行非常长时间的喷雾才能获得大量所需的产品。长时间的喷雾过程可以归因于表面修饰剂分子或它们的聚集体在含有新的沉淀溶质颗粒的水介质中的慢速缔合。
在上面所述WO 97/14407方法的实验中，人们惊奇地发现：在超临界(或次临界)液化气中加入表面修饰剂，以及在不溶性物质中加入表面修饰剂可以很快地生产表面稳定的纳米至微米级的颗粒悬浮体。本发明的主要特性被认为是在药物和从其液化气溶液的极快沉淀过程中，快速获得溶解药物和表面修饰剂的紧密接触。
由于快速沉淀是溶质从液化气中沉淀的一个特性，与表面修饰剂的快速紧密接触可以通过将表面修饰剂溶于含有溶解药物的液化气中来获得。表面修饰剂与新形成的颗粒药物之间的快速紧密接触基本抑制了新形成颗粒的晶体生长。另外，如果要获得非常小的稳定颗粒，如果表面修饰剂没有加入溶解药物中，那么含有药物的液化气液滴与反溶剂接触时的速率要慢许多。因此本发明的关键特性是本方法的高生产率。
尽管在本发明方法中应有至少一种(第一)表面修饰剂与需降低尺寸的水不溶性物质一起溶于液化气，但具有相同或不同化学特性的另一种(第二)表面修饰剂也可包括在水介质中。另外，在沉淀中或其后，可以将所述流体通过高压均化器来施加另外的高剪切力、空化或湍流，从而促进颗粒表面与表面修饰剂的紧密接触。因此，在将表面修饰剂分散至水介质中的情况下，可以通过高压均化器，采用另外的高剪切力、空化或湍流来促进颗粒表面和表面修饰剂的紧密接触。
因此，本发明的总目标是开发包含超临界流体技术的、基于采用液化气溶剂的高生产率方法，这种方法可以得到表面修饰剂稳定的水不溶性药物，其平均粒度为50nm至约2000nm并且具有窄的粒度分布。本方法是成熟的、规模化方法并且广泛适用于具有生物用途的水不溶性化合物。
                  发明详述
本发明包括采用超临界流体或压缩流体来形成表面修饰的颗粒，其粒度可高达约2000nm，通常小于1000nm，理想小于500nm，优选小于约200nm，并且通常为5-100nm的范围内。颗粒的粒度是指水介质中悬浮的这些颗粒的容重平均直径。
本发明提供一种制备水不溶性或基本不溶于水的、具有生物活性化合物的、粒度高达2000纳米的亚微米颗粒悬浮体的方法，其包括下述步骤：
(a)将水不溶性或基本不溶于水的生物活性化合物和第一表面修饰剂溶于液化的压缩气体溶剂中并形成溶液；和
(b)使步骤(a)制备的压缩流体溶液膨胀进入水或含有第二表面修饰剂和任选的、另外的水增溶剂的水溶液或分散体中，由此制得颗粒悬浮体。
本发明方法还可包括以下步骤(c)和(d)之一或两者：
(c)高压均化由步骤(b)所得的悬浮体，和
(d)回收所制得的微颗粒。
在包含第二表面修饰剂的情况下，第一和第二表面修饰剂可以相同或不同。
本发明方法包括形成水不溶性或水溶性差的化合物的含水的微粒悬浮体，同时通过使液化气中的化合物和表面修饰剂从压缩溶液快速膨胀至水性介质中，从而使表面修饰剂分子稳定所述物质(液化气溶液的快速膨胀，RELGS)。
本发明的另一个实施方案包括形成水不溶性或水溶性差的化合物的含水微粒悬浮体，同时通过使液化气中的化合物和表面修饰剂从压缩溶液快速膨胀至水性介质中，从而使表面修饰剂分子稳定所述物质，并用高压均化器均化由此形成的含水悬浮体(液化气溶液的快速膨胀和均化，RELGS-H)。
不希望受到具体理论的束缚，本发明方法被认为在表面修饰剂的存在下，使溶于液化气的药物和其它生物活性物质快速成核，从而在极短的时间内形成所需粒度分布的颗粒。如果需要，可以将磷脂或其它合适的表面修饰剂(如表面活性剂)以液化气的溶液或分散体的形式加入本方法中。另外表面修饰剂可选择以其水介质的溶液或分散体的形式加入。或者，可以将一些表面修饰剂与水不溶性物质一起溶于液化气中并且膨胀至所述制剂的其余表面修饰剂的均化的含水分散体中。在上述方法中引入的合适的表面修饰剂用来稳定生成的小颗粒并且在形成颗粒时，抑制颗粒的聚集或生长。
我们所指的工业上有用的不溶性或溶解性差的化合物包括具有生物用途的化合物、显影剂、药物，尤其用于人类和动物的药物。通常水不溶性的化合物为那些在水中溶解性差的化合物，即在生理pH6.5-7.4时溶解性小于5mg/ml的化合物，也可能是水溶性小于1mg/ml，甚至小于0.1mg/ml的化合物。
一些优选的水不溶性药物的例子包括抑制免疫和具有免疫活性的药剂，抗病毒剂和抗真菌剂、抗肿瘤药、止痛剂和消炎药、抗生素、镇癫痫药、麻醉剂、催眠剂、镇静剂、精神抑制剂、精神安定药、抗抑郁剂、抗焦虑药、抗惊厥药、拮抗剂、神经元阻滞剂(neuronblocking agents)、抗胆碱能药和类胆碱能药、抗毒蕈碱药和毒蕈碱药、抗肾上腺素能药和抗心律失常药、抗高血压药、抗肿瘤药、荷尔蒙和营养素。这些和其它合适的药物可参见雷明顿药物科学(第18版，1990，Mack Publishing Co.Philadelphia，PA)。
在先有技术中对超临界或次临界流体相中的压缩气体进行了广泛的报导(如美国专利第5776486号以及Tom，J.W.和Debenedetti，P.B.(1991)的“用超临界流体形成颗粒-综述”J.Aerosol.Sci.22：555-584)，从中可以选择合适的气体用于本发明目的。这些气体包括但并不局限于气体氧化物如二氧化碳和氧化亚氮；烷烃如乙烷、丙烷、丁烷和戊烷；烯烃如乙烯和丙烯；醇如乙醇和异丙醇；酮如丙酮；醚如二甲醚或二乙醚；酯如乙酸乙酯；卤代化合物包括六氟化硫、含氯氟烃如三氯氟甲烷(CCl3F，也称氟利昂11)、二氯氟甲烷(CHCl2F，也称氟利昂21)、二氟氯甲烷(CHClF2，也称氟利昂22)、以及碳氟化合物如三氟甲烷(CHF3，也称氟利昂23)；以及元素液化气体如氙和氮以及本领域熟知的其它液化压缩气体。
在下面的实施例中，液化二氧化碳用于制备药物的快速膨胀溶液。二氧化碳的临界温度为31.3度，临界压力为72.9个大气压(1072psi)，化学活性差、生理学上安全并且成本较低。另一种优选的超临界流体为丙烷。
合适的表面修饰剂的实例包括：(a)天然表面活性剂如酪蛋白、明胶、天然磷脂、黄蓍胶、包囊树脂(enteric resins)、阿拉伯胶、明胶以及胆固醇，(b)非离子表面活性剂如聚氧乙烯脂肪醇醚、脱水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯、脱水山梨醇酯、单硬脂酸甘油酯、聚乙二醇、十六醇、十六醇和十八醇的混合物、十八烷醇、poloxamers、polaxamines、甲基纤维素、羟基纤维素、羟丙基纤维素、羟丙基甲基纤维素、非晶体纤维素以及合成磷脂，(c)阴离子表面活性剂如月桂酸钾、硬脂酸三乙酸醇胺、月桂基硫酸钠、烷基聚氧乙烯基硫酸盐、海藻酸钠、二辛基磺基琥珀酸钠、带负电的磷脂(磷脂酰甘油、磷脂酰肌醇、磷脂酰丝氨酸、磷脂酸和它们的盐)、带负电的甘油酯、羧甲基纤维素钠和羧甲基纤维素钙，(d)阳离子表面活性剂如季铵化合物、氯化苯甲烃铵、十六烷基三甲基溴化铵和月桂基二甲基苄基氯化铵，(e)膨润土如皂土和胶体镁铝硅酸盐，(f)天然或合成的磷脂，例如磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、磷脂酸、溶血磷脂、卵磷脂或大豆磷脂或其组合。可以对磷脂进行盐化或脱盐、氢化或部分氢化或者所述磷脂可以为天然的、半合成的或合成的磷脂。这些表面活性剂的详细描述可以参见雷明顿药物科学(第18版，1990，Mack Publishing Co.PA)和药品工业的理论和实践(Lachman等，1986)。
以下实施例进一步解释并说明本发明：
实施例1
压缩液化气中的水不溶性化合物的相行为
为了评估在液化气中是否可以将一种特定的水不溶性化合物从其溶液配制成含水的亚微颗粒悬浮体，需要对测试药物的溶解性进行测量。
为制备具有恒定摩尔组成的溶液，将定量的药物(非诺贝特)加入恒定体积的观察池。温度保持恒定在60℃。通过泵入压缩液化气进入观察池使压力在1300-4000psi范围内变化。通过目测观察固体药物开始溶解时的压力来确定相行为。非诺贝特在液化的二氧化碳、丙烷和乙烷中的溶解性列于表I。当在溶剂中的溶解性大于1％(w/w)时，可以由这些溶剂来制备微细颗粒。
表I非诺贝特在60℃的液化二氧化碳、丙烷和乙烷中的溶解性
    液化气体     压力(psi)   溶解性(％，w/w)
    二氧化碳     1800     0.01
    2000     0.08
    2800     1.4
    丙烷     1500     2.5
    2000     2.3
    乙烷     1300     0.016
    2000     0.79
    3000     1.80
    4000     1.90
实施例2
通过RELGS法形成非诺贝特微粒
将加压至3000psi的、含有非诺贝特(2g)、类脂E-80(0.2g)、吐温-80(0.2g)的液体二氧化碳溶液膨胀通过50mm的孔板进入大气压和室温(22℃)下的水中。得到平均粒度约200nm的非诺贝特的微细悬浮体。使用亚微粒度仪-Autodilute Model 370(NICOMP Particle SizingSystems，Santa Barbara，CA)，通过光子相关的光谱(photon correlationspectroscopy)进行粒度测试。该仪器提供数量重量、强度重量和容积重量的粒度分布以及多形态的粒度分布(如果存在的话)。
实施例3
用具有63.5mm内径的PEEK毛细管制成微细喷嘴。该PEEK喷嘴用M-100 Minitight阳螺母进行固定并且连到Upchurch SS20V联合体上，该联合体通过适当大小的SwagelokTM牌连接件进一步连接至1/4英寸的高压歧管上。除了PEEK管外，所有其它元件均由316不锈钢制成。通过1/4英寸的高压歧管，将水不溶性物质的高压液化气溶液(＞1000psig)导入63.5mm的PEEK喷嘴，从而膨胀进入水介质中。向液化气溶液容器中注入1g环孢菌素和0.2g吐温-80。用5000psig的二氧化碳填充所述容器并加热至约24℃。静置所述容器约20分钟以完成溶解并达到平衡。在6000psi下，使用Avestin Emulsiflex C50均化器(Avestin Inc，Ottawa，Canada)，单独对在5.5％甘露醇溶液中的2％(w/w)卵磷脂(来自Lipoid GmbH的Lipoid E80)悬浮体均化15分钟，生成清澈分散体。在均化前，用氢氧化钠水溶液调节磷脂悬浮体的pH至8.0。使24℃、5000psig下放置的环孢菌素和吐温-80的二氧化碳溶液膨胀进入卵磷脂的水分散体中。以极快的速度(约3分钟)获得约23纳米粒度的透明水悬浮体(参见图1)。这个实施例通过将几个这样的PEEK喷嘴置于歧管内，同时膨胀进入含有适量水性介质的储罐中，从而提供一个简单的可放大的方法。PEEK喷嘴被认为是惰性的并且很便宜。制造这种喷嘴非常简单，不到10分钟即可制成。
实施例4
由RELGS-H法形成环孢菌素微粒
RELGS-H(液化气溶液的快速膨胀和均化)法包括形成水不溶性或水溶性差的化合物的含水微粒悬浮体，同时通过使液化气中的化合物和表面修饰剂从压缩溶液快速膨胀至水性介质中，从而使表面修饰剂分子稳定所述物质，并用高压均化器均化由此形成的含水悬浮体。
制备含有甘露醇(5.5％)、Lipoid E-80(2％)和吐温80(2％)的水悬浮体。还制备环孢菌素和吐温-80(见实施例3)的液化气溶液，填充二氧化碳(见实施例3)并保持在2000psig和60℃下。通过63.5mmPEEK喷嘴，使该溶液膨胀进入水悬浮体中。以这种方法制备约3g环孢菌素的悬浮体。在6000psig下，均化所得悬浮体8次。均化后，用亚微粒度仪-Autodilute Model 370(NICOMP Particle Sizing Systems，Santa Barbara，CA)进行测量，最终的平均粒度为86纳米，99％为150纳米(参见图2)。
虽然本发明是参照目前认为最实用并且优选的实施方案进行描述，但应该理解的是本发明并不受限于所公开的实施方案，但另一方面，本发明覆盖包括在所附权利要求的精神和范围内的各种变化和相当的配置。

Claims (14)

1.制备其粒度大小为5至2000nm的水不溶的生物活性化合物的亚微颗粒悬浮体的方法，该方法包括以下步骤：
(a)将水不溶的生物活性化合物和第一表面修饰剂溶于液化的压缩气体溶剂中，并形成在该溶剂中所述的化合物的溶解性大于1％w/w的溶液；
(b)使步骤(a)制备的压缩流体溶液膨胀进入水或含有第二表面修饰剂和水可溶性的试剂的水溶液或分散体中，第一表面修饰剂和第二表面修饰剂具有不同的化学性质，由此生成微颗粒悬浮体；和
(c)在高压中均化由步骤(b)所得的悬浮体。
2.根据权利要求1的方法，其包括另一个步骤：
(d)回收所生成的微粒。
3.根据权利要求1的方法，其中第一表面修饰剂和第二表面修饰剂的任何一种或两种表面修饰剂为表面活性剂。
4.根据权利要求1的方法，其中第一表面修饰剂和第二表面修饰剂的任何一种或两种表面修饰剂为两种或多种表面活性剂的混合物。
5.根据权利要求1的方法，其中任何一种或两种表面修饰剂不含磷脂。
6.根据权利要求1的方法，其中任何一种或两种表面修饰剂为聚氧乙烯脱水山梨醇脂肪酸酯、环氧乙烷和环氧丙烷的嵌段共聚物、源于顺序添加环氧乙烷和环氧丙烷至乙二胺中所得的四官能嵌段共聚物、烷基芳基聚醚磺酸盐、聚乙二醇、羟丙基甲基纤维素、十二烷基硫酸钠、脱氧胆酸钠、十六烷基三甲基溴化铵或其组合。
7.根据权利要求1的方法，其中任何一种或两种表面修饰剂为磷脂。
8.根据权利要求7的方法，其中表面修饰剂为卵磷脂、植物磷脂、半合成磷脂或可任选被脱盐或者可以被部分氢化或完全氢化的合成磷脂。
9.根据权利要求8的方法，其中磷脂选自磷脂酰胆碱、氢化的磷脂酰胆碱，二肉豆蔻酰磷脂酰甘油钠盐或其组合。
10.根据权利要求1的方法，其中所述生物活性化合物为环孢菌素、非诺贝特或阿发克萨隆(alphaxalone)。
11.根据权利要求1的方法，其中所制颗粒的粒度大小为5至500纳米。
12.根据权利要求11的方法，其中所制颗粒的粒度大小为5纳米至200纳米。
13.根据权利要求1的方法，其中所制颗粒的99％其粒度大小为5至2000纳米。
14.根据权利要求1的方法，其中液化压缩气体为超临界或次临界相的二氧化碳。
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