Injection emulsion

JB Boyett, CW Davis. Injectable emulsions and suspensions. In HA Lieberman, HA, MM Rieger, GS Banker, eds. Pharmaceutical Dosage Forms Disperse Systems, Vol. 2, New York Marcel Dekker, 1989, pp 379 -16. 

Driscoll, D. F., Ling, P. R., and Bistrian, B. R. (2007), Physical stability of 20% lipid injectable emulsions via simulated syringe infusion effects of glass versus plastic product packaging, J. Parenteral Enteral Nutr., 31(2), 148-153. 

Injectable lipid emulsions are used to provide parenteral nutrition and their use can be traced back to the 1920s. However, because they are particulate systems by their very nature, administration of emulsions into the blood system must be viewed with care, requiring precautions and special requirements. Indeed, until the 1950s it was not realized that one essential requirement for injectable emulsions was that the droplet diameter must be below 1 pm in diameter. Otherwise there is always a finite risk of blocking the smaller blood vessels. 

Another associated issue was the possibility of inactivating the LRES (lym-phoreticuloendothelial system). By analogy with other injectable systems, it could also be deduced that the injectable emulsion system needed to be sterile and apy-rogenic and free of acute or chronic toxicities from components or their associated degradation products. It also followed that the injectable system required to be stable, although how stability was to be determined and, more to the point, measured, has remained an issue to the present day. This is mainly because emulsions are thermodynamically unstable although their stability can be extended by formulation. As a result emulsion products are now available that are submicron in diameter, sterile, and stable for several years after preparation. In major part this has been due to the use of phospholipids as stabilizers and emulsifiers, in particular the mixed products identified as the lecithin of commerce. 

As noted, the key to successful preparation of an injectable emulsion product proved to be the selection of a suitable commercial source of lecithin, in this case a purified material obtained from the yolk of hen eggs. Lecithin can also be obtained from a number of natural sources such as soy beans and comprises a number of different phospholipids. These include phosphatidylcholine (PC) andphosphatidylethanolamine... 

Approximate Constitution of Purified Lecithin Used to Stabilize Injectable Emulsions... 

On this point, phospholipids as a class are readily oxidized by air and hydrolyzed in the presence of water. It follows that injectable emulsions should be handled with care in order to prevent degradation. 

Hydrolysis that occurs to some degree on autoclaving and storage results in the production of corresponding lyso-compounds, phospholipids without one of the acyl chains. These materials are called lyso- because, on their own, lyso-compounds produce lysis of red blood cells and are generally regarded as toxic. Analytically it is not difficult to demonstrate that there are significant quantities of these compounds present in injectable emulsions but there have never been any clinical reports of toxicity. The probability is that these materials form some type of association complex with the other phospholipids present and are not available on their own to exert any effect which would result in toxicity. 

From a pharmaceutical perspective, phospholipids-stabilized emulsions are remarkable. For example, they are relatively stable, with shelf lives of 18 months to 2 years being obtained after the initial heat sterilization. They resist the increased shear rates as the bottles are transported from producer to user and they can tolerate the addition of a wide variety of monovalent electrolytes for at least short periods prior to administration. However, they cannot resist freezing and changes in droplet size following exposure to freeze-thaw cycles can be used as a measure of the stability of the emulsion system. Most injectable emulsions are sensitive to multivalent cations such as calcium or magnesium salts, which rapidly flocculate the phospholipids-stabilized systems. 

Propofol has a remarkably simple structure resembling that of phenol disinfectants. Because the substance is water-insoluble, an injectable emulsion is prepared by means of soy oil, phosphatide, and glycerol. The effect has a rapid onset and decays quickly, being experienced by the patient as fairly pleasant. The intensity of the effect can be well controlled during prolonged administration. Possible adverse reactions include hypotension and respiratory depression, and a potentially fatal syndrome of bronchospasm, hypotension, and erythema. 

Injection, Emulsion An emulsion consisting of a sterile, pyrogen-free preparation intended to be administered parenterally. 

An effective method to increase the efficiency of a fluid drive is to plug the thief zone(s), direct fluids to areas of higher oil saturation and thus improve the ratio of oil produced to fluid injected. Emulsions have been shown to be effective permeability modification agents, but little work has been reported on their use. 

These experiments were conducted at constant flow rate. Blocking effects at constant pressure (more similar to field conditions) would probably show more dramatic effect. In all of the experiments with injected emulsions, the effective permeability to water was decreased far more than an equivalent amount of residual... 

Permeability reductions were also observed by McAuliffe (9), and his results are shown in Figure 14. He used a Boise sandstone core with an initial permeability of 1600 mD and injected a 0.5% OAV emulsion having average oil-droplet sizes of 1 and 12 xm. The small-diameter emulsion reduced the permeability from 1600 to 900 mD after 10 pore volumes of the injected emulsion the 12-fxm emulsion was much more effective in reducing the core permeability. After 10 pore volumes had been injected, the permeability was reduced to 30 mD, almost a 50-fold reduction. 

Floyd, A.G. Jain, S. Injectable emulsions and suspensions. 36. In Pharmaceutical Dosage Forms Dispersed Systems, 2nd... 

A relative wealth of information relating to the application of zeta potential to injectable emulsions has been documented with respect to the use of total nutrient admixtures (TNA). Total nutrient admixtures are prepared by mixing the lipid emulsion with other components (i.e., dextrose, amino acids, and electrolytes) in a single container prior to administration. Depending on composition, the mixtures vary widely in their stability and may show clinically unacceptable coalescence after different periods of storage time. 

The effect of pH on the stability of an injectable emulsion was also followed by measuring its zeta... 

Sodium metabisulflte and EDTA have been used individually as microbiological preservatives in different approved formulations of propofol injectable emulsion. The choice of antioxidant must be made with care as some are restricted by use and/or concentration in different countries. BHA is widely used in fixed oils and fats at concentrations up to 0.02% but is permitted up to 0.1% in some essential oils. Its close relative, BHT, is recommended as an alternative to tocopherol at concentrations up to 10 ppm for the stabilization of liquid paraffin. Other antioxidants widely used in emulsion formulations include the propyl, octyl and dodecyl esters of galhc acid at concentrations up to 0.001% (fixed oils and fats) and up to 0.1% (essential oils). ... 

---