肠外营养纳米乳液制剂超声制备

背景

脂质纳米乳剂（纳米乳剂）是一种复杂的、动力学稳定的水包油分散体，借助一种或多种表面活性剂（乳化剂）进行均质化。在临床实践中，脂质纳米乳剂的一个主要应用是肠外营养，如Intralipid®等产品用于无法通过口服饮食获取营养的患者。用于肠外营养的传统纳米乳剂由红花油和/或大豆油制成，使用鸡蛋来源的磷脂作为乳化剂。这些纳米乳剂被称为长链甘油三酯乳剂，由ω-6多不饱和脂肪酸（亚油酸和亚麻酸）和长链非必需饱和脂肪酸组成。用于肠外营养的新型脂质纳米乳剂由大豆油或红花油与富含中链甘油三酯的油（如橄榄油和椰子油）和/或鱼油中含有的ω-3长链多不饱和脂肪酸的物理混合物组成。与新型多室袋结合使用时，这些脂质制剂在稳定性和安全性方面优于传统的大豆油和红花油纳米乳剂。富含ω-3脂肪酸的鱼油纳米乳剂可能将越来越多地被用于营养补充，以及生物和病理过程的调节。

Two parameters are measured to check toxicity and physical stability of nanoemulsions: 1) lipid globule mean droplet size (MDS) and 2) particle size distribution (PSD). United States Pharmacopeia (USP) adopted Chapter 729, entitled “Globule Size Distribution in Lipid Injectable Emulsions”, which sets two physical limits for nanoemulsions used for parenteral nutrition: 1) MDS < 500 nanometers (nm); 2) percent of lipid globules > 5 microns (um) or PFAT5 < 0.05%. This is of great significance for infusion safety: higher amounts (> 0.05%) of outsized (> 5 um) lipid droplets are associated with instability; moreover, intravenously administered lipid droplets exceeding 5 um have been shown to cause adverse effects, in particular, emboli in the lungs.

测量两个参数以检查纳米乳剂的毒性和物理稳定性：1）脂质球平均粒径（MDS）和2）粒径分布（PSD）。美国药典（USP）采用了第729章，标题为“脂质注射乳剂中的球体粒径分布”，该章为用于肠外营养的纳米乳剂设定了两个物理限制：1）MDS<500纳米（nm）；2）脂质球百分比>5微米（μm）或PFAT5<0.05%。这对输液安全具有重要意义：较大量（>0.05%）的过大（>5μm）脂质滴与不稳定性相关；此外，静脉注射超过5μm的脂质滴已被证明会引起不良反应，尤其是肺部栓塞。

PRODUCTION WITH HIGH-AMPLITUDE ULTRASOUND
Industrial Sonomechanics, LLC (ISM), offers bench and industrial-scale high-power ultrasonic processors for the production of nanoemulsions. The processors are based on our patented Barbell Horn Ultrasonic Technology (BHUT), which, as explained below, makes it possible to directly implement laboratory accomplishments in a production environment, guaranteeing reproducible and predictable results at any scale.

高幅超声波生产 工业声学机械有限公司（ISM）提供用于生产纳米乳液的台式和工业规模的高功率超声波处理器。这些处理器基于我们获得专利的杠铃式变幅杆超声波技术（BHUT），如下文所述，该技术使得实验室成果能够直接应用于生产环境，从而保证在任何规模下都能获得可重复且可预测的结果。 

High ultrasonic vibration amplitudes are required for efficient oil droplet size reduction. The necessary shear forces are created by ultrasonic cavitation, which produces violently and asymmetrically imploding vacuum bubbles and causes micro-jets that disperse and break up the droplets down to the nanometer scale. Known for many decades, this effect of high-amplitude ultrasound has been extensively studied and successfully used in laboratory-scale research. However, prior to the introduction of BHUT, none of the existing ultrasonic liquid processors could generate the required amplitudes on the industrial scale. Commercial implementation of high-power ultrasound has, therefore, been limited to processes for which low-amplitudes are sufficient (cleaning, simple deagglomeration, mixing, macro-emulsification, etc.).
为了有效减小油滴尺寸，需要较高的超声振动幅度。超声空化会产生必要的剪切力，该力会剧烈且不对称地使真空气泡内爆，并产生微射流，将油滴分散并破碎至纳米尺度。几十年来，高振幅超声的这一效应已被广泛研究，并成功应用于实验室规模的研究。然而，在引入气泡空化超声技术（BHUT）之前，现有的超声液体处理器都无法在工业规模上产生所需的振幅。因此，高功率超声的商业应用仅限于低振幅就已足够的过程（如清洁、简单解聚、混合、宏观乳化等）。

Why ISM’s Ultrasonic Technology?
Conventional high-power ultrasonic technology inherently forces all processes to run either at a small scale and high amplitude or a large scale and low amplitude. ISM has successfully overcome this limitation by developing BHUT, which permits constructing industrial-scale ultrasonic processors able to operate at extremely high amplitudes. The processors are directly scalable and can be used in the commercial production of high-quality nanoemulsions for the pharmaceutical industry. Our equipment is compact and relatively low-cost, needs little technical support, includes very few wetted parts, generally requires no special pre-treatment of precursors, and is potentially self-sterilizing due to antibacterial properties of high-intensity ultrasound. Examples of Intralipid-Type Nanoemulsions Produced Using ISM’s Ultrasonic Technology

为什么选择ISM的超声波技术？ 
传统的高功率超声技术本质上迫使所有工艺要么在小规模下以高振幅运行，要么在大规模下以低振幅运行。ISM通过开发BHUT成功克服了这一限制，该技术允许构建能够在极高振幅下运行的工业级超声处理器。这些处理器可直接扩展，可用于制药行业高质量纳米乳液的商业化生产。我们的设备结构紧凑、成本相对较低，几乎不需要技术支持，包含的湿部件极少，通常不需要对前体进行特殊预处理，并且由于高强度超声的抗菌特性，具有潜在的自我消毒功能。使用ISM超声技术生产的Intralipid型纳米乳液示例

Intralipid-type nanoemulsion consisting of soybean oil (10%), L-a-Phosphatilylcholine, Type IV-S (1.2%), glycerol (2.25%) and water (86.55%) was prepared using Industrial Sonomechanics’ (ISM) 1200 W bench-scale flow-through ultrasonic processor, BSP-1200, equipped with a piezoelectric transducer, flow-through reactor chamber and Full-wave Barbell Horn (FBH) operating at the ultrasonic amplitude of 75 microns. The results are presented on the left. The obtained Intralipid-type nanoemulsion’s quality exceeds USP standards. It should be emphasized that decreasing the ultrasonic amplitude to 25 microns (as in conventional industrial ultrasonic systems) results in a significant increase of MDS and PFAT5, both of which are well outside of the acceptable levels. This result clearly shows that ultrasonic amplitude plays a crucial role in the process of preparing high-quality nanoemulsions and justifies the importance of being able to scale up without sacrificing the amplitude.

使用Industrial Sonomechanics’（ISM）1200 W台式流通过程超声波处理器BSP-1200，该处理器配备压电换能器、流通过程反应室和全波杆状探头（FBH），在超声振幅为75微米的条件下，制备了由大豆油（10%）、L-α-磷脂酰胆碱（Type IV-S）（1.2%）、甘油（2.25%）和水（86.55%）组成的Intralipid型纳米乳液。结果见左图。所得Intralipid型纳米乳液的质量超过了美国药典（USP）标准。需要强调的是，将超声振幅降低至25微米（如传统工业超声波系统中的振幅）会导致平均粒径（MDS）和粒径分布的峰面积（PFAT5）显著增加，这两者均远超可接受水平。这一结果清楚地表明，超声振幅在制备高质量纳米乳液的过程中起着至关重要的作用，也证明了在不降低振幅的情况下实现规模化生产的重要性。