Bulk Manufacture of Concentrated Oxygen Gas-Filled Microparticles for Intravenous Oxygen Delivery
Bulk Manufacture of Concentrated Oxygen Gas-Filled Microparticles for Intravenous Oxygen Delivery
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DOI：
10.1002/adhm.201200350
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发表时间：
2013-08-01
影响因子：
10
通讯作者：
McGowan, Francis X.
中科院分区：
文献类型：
--
作者：
Kheir, John N.;Polizzotti, Brian D.;McGowan, Francis X.
已经开发了自组装的、浓缩的、基于脂质的氧气微粒（L0M），以在静脉内注射时施用氧气，从而防止动物模型中的全身性低氧血症引起的器官损伤和死亡。与血液代用品不同，LOM是一种单向氧载体，旨在抢救因气道阻塞或严重肺损伤而导致危及生命的低氧血症的患者。在此，我们描述了使用在线、再循环、高剪切均化器制造大量LOM的方法，其可以在10分钟内产生高达4升的微粒乳液，其中颗粒含有0.93微米的中值直径和60体积%的气相。使用该过程，我们筛选了30种常用赋形剂的组合，以确定其形成稳定LOM的能力。由1：1摩尔比的DSPC和胆固醇组成的L0M在100天的观察期内是稳定的，并且直径超过10微米的颗粒数量不会随时间增加。当在体外与血液混合时，LOMs在接触的3.95秒内完全溶解血液，并且不会引起溶血或补体激活。L0M可以通过高剪切均质化批量制造，并且似乎具有值得进一步测试的稳定性和尺寸特征。
Self-assembling, concentrated, lipid-based oxygen microparticles (LOMs) have been developed to administer oxygen gas when injected intravenously, preventing organ injury and death from systemic hypoxemia in animal models. Distinct from blood substitutes, LOMs are a one-way oxygen carrier designed to rescue patients who experience life-threatening hypoxemia, as caused by airway obstruction or severe lung injury. Here, we describe methods to manufacture large quantities of LOMs using an in-line, recycling, high-shear homogenizer, which can create up to 4 liters of microparticle emulsion in 10 minutes, with particles containing a median diameter of 0.93 microns and 60 volume% of gas phase. Using this process, we screen 30 combinations of commonly used excipients for their ability to form stable LOMs. LOMs composed of DSPC and cholesterol in a 1:1 molar ratio are stable for a 100 day observation period, and the number of particles exceeding 10 microns in diameter does not increase over time. When mixed with blood in vitro, LOMs fully oxygenate blood within 3.95 seconds of contact, and do not cause hemolysis or complement activation. LOMs can be manufactured in bulk by high shear homogenization, and appear to have a stability and size profile which merit further testing.