Lipid Injectable Emulsions: Pharmacopeial and Safety Issues

Abstract

Lipid injectable emulsions have been routinely used in patients worldwide for over 40 years as a nutritional supplement in patients requiring parenteral nutrition. They can be given as a separate infusion or added into total parenteral nutrition admixtures. Despite such broad use, no pharmacopeial standards exist with respect to the optimal pharmaceutical characteristics of the formulation. Several attempts to establish standard physical and chemical attributes have been attempted by various pharmacopeias around the world, but without success largely due to technical issues regarding the creation of globule size limits. Recently, the United States Pharmacopeia has revised its previous efforts and developed two methods and criteria (under Chapter <729>) to measure the mean droplet size (Method I), and the large-diameter tail > 5 mum (Method II) of the globule size distribution to verify the stability of lipid injectable emulsions. Importantly, it is the latter size limits of Method II that have the greatest implications for infusion safety. The major safety issues involving lipid injectable emulsions include impairments in plasma clearance in susceptible patients, and the infusion of an unstable emulsion containing large quantities of potentially embolic fat globules. Recent animal studies investigating the toxicity from the infusion of unstable lipid injectable emulsions have shown evidence of oxidative stress and tissue damage to the liver when recommended globule size limits determined by Method II of the USP are exceeded. Adoption of Chapter <729> of the USP seems appropriate at this time.

Prolonged Laboratory Interference After Administration of Intravenous Lipid Emulsion Therapy

“…It is unclear what factors contribute to the degree of laboratory interference, but it is possible that infusion of multiple or large doses of ILE could result in decreased ILE clearance and increased serum persistence, leading to prolonged laboratory interferences. Lipid emulsions are often classified by their mean droplet size (MDS); in general, intravenous lipid emulsion (ILE) formulations have a MDS less than 1.0 μm [13]. These formulations are typically metabolized by lipoprotein lipase found along the vascular endothelium, while larger lipid formulations (MDS greater than 1.0 μm) are metabolized by reticuloendothelial system (RES) macrophages found in the microvasculature of the l u n g s , l i v e r, s p l e e n , a n d b o n e m a r r o w [ 1 3 ] .…”

Tryptanthrin-Loaded Nanoparticles for Delivery into Cultured Human Breast Cancer Cells, MCF7: the Effects of Solid Lipid/Liquid Lipid Ratios in the Inner Core

“…Improving the poor solubility of this drug for delivery into target organs is an important issue which is one of the key points in the development of pharmaceutics. 13) We characterized the drug delivery carriers and determined the feasibility of nanoparticles for delivering tryptanthrin. We found that tryptanthrin-loaded SLNs, NLCs, and LEs overcame the insolubility problem, and allowed tryptanthrin to successfully penetrate breast cancer cells, especially when using the NLC system.…”

Lipid rescue: the use of lipid emulsions to treat local anaesthetic toxicity

“…The phagocytosis process produces reactive oxygen species, the liver being the principal organ injured in this process. 52 Shortly after commencement of infusion of an unstable lipid emulsion, a pyrogenic response typified by fever, chest pain and signs of an anaphylactic-type reaction can manifest. This type of reaction is rare nowadays due to improved manufacturing processes.…”

“…60 In addition, allergic reactions, thrombophlebitis, muscle weakness, seizures in children, increased intracranial pressure after traumatic head injury, warfarin resistance (because lipids facilitate the anticoagulant binding to albumin), and impaired immune, reticuloendothelial and inflammatory responses have all been reported. 47,52 Availability of lipid emulsions in southern Africa Intralipid ® (Fresenius Kabi, South Africa) is available as a 20% solution and is packaged in 100 ml and 500 ml bags. It has a shelf life of 18 months from the date of manufacture.…”