Phospholipid-stabilized emulsions stability

The administration of metabolizable vegetable oils as concentrated sources of nutrition has proved to be valuable for patients who are debilitated and who are unable to take nourishment orally. In addition, oils such as soy bean oil provide a source of essential fatty acids which can be rapidly depleted in a patient after starvation for only a few days. Wretlind and his colleagues devised the phospholipids-stabilized soy oil emulsion now marketed as Intralipid (Pharmacia, now Pfizer, New York, NY) in Sweden during the 1960s and this product has been modified to carry oil-soluble drugs such as diazepam. In Europe this is marketed as Diazemuls and it may be anticipated that other drugs may be presented in the same or similar vehicles. 

The fact that these phospholipids-stabilized emulsions are sterilized by heat may be surprising since most emulsions stabilized by almost any other surfactant is readily destabilized by heat. Indeed, the fact that the droplet size of phospholipids-stabilized emulsions actually decreases on the application of thermal stress is probably due to the behavior of the phospholipids which move from the aqueous phase to the oil phase, especially to the interfacial mesophase, during the heating process. 

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. 

Another complication is the fact that the phospholipids are not soluble in water, forming in many cases liposomal structures, but they are soluble in electrolyte solutions. Thus, the mere addition of an electrolyte to a phospholipids-stabilized emulsion may physically affect the structure of the mesophase and, hence, the stability of the whole system. 

Biologically active materials such as prostaglandin Ej have been reported to benefit from being incorporated into phospholipids-stabilized emulsions (Teagarden... 

Groves, M.J. and Herman, C.J. (1993), The redistribution of bulk aqueous phase phospholipids during thermal stressing of phospholipid-stabilized emulsions, J. Pharm. Pharmacol., 45, 592-596. 

Herman, C.J. and Groves, M.J. (1993) The in uence of free fatty acid formation on the pH of phospholipid-stabilized triglyceride emulsionS .harm. Res., 10 774-776. 

Wheeler, J. J., Wong, K. F., Ansell, S. M., et al. Polyethylene glycol modified phospholipids stabilize emulsions prepared from triacylglycerol. Pharm. Res. 83 1558-1564, 1994. 

Washington, C. The electrokinetic properties of phospholipid stabilized fat emulsions. III. Interdroplet potentials and stability ratios in monovalent electrolytes. Int. J. Pharm. 1990, 64, 67-73. 

Kabalnov A, Tarara T, Arlauskas R, Weers J. Phospholipids as emulsion stabilizers. 2. Phase behavior versus emulsion stability. J Colloid Interface Sci 1996 184 227-235. 

Rydhag, L. 1979. The importance of the phase behaviour of phospholipids for emulsion stability, Fette, Seifen, Anstrichmittel, 81, 168-173. 

C. Washington. The elecirokineiic properties of phospholipid-stabilized fat emulsions, II. Droplet mobility in mixed electrolytes. Ini. J. Pharm., 58 13—17. 1990. 

Phospholipid-stabilized intravenous emulsions have been widely used for parenteral nutrition and have also been introduced as drug carrier systems, especially for lipophilic compounds. The aim of the authors in the next papers we review here (50,51) was to consider in detail various mediods, c.g., PCS. nuclear magnetic resonance (NMR). transmission electron micnoscopiy (TEM). and small-angle x-ray diffraction studies (SAXS), to determine parameters related to the internal structure of the particle in a model intravenous emulsion stabilized by phospholipids. An emulsion with an extremely high fat load and a classical emulsifier was chosen. PCS measurements were used to derive a particle size distnbu-tion and this was then us ) to calculate the total oil droplet surface area. The result indicated that there should be an excess of surfactants of 150%. Such an excess was not confirmed by either NMR or SAXS measurements and the dis-... 

S Lundquist, M Malmsten, T Petersson Norted, B Siek-mamL Methods to study the physico-chemical properties of a drug containing phospholipid stabilized emulsion for intravenous administration. Twelflh httemational Symposium on Surfactants in Solution, 6-7 November, Stockholm, 1998, p 123. 

As a further important topic regarding intravenous administration the interaction of GMO-based systems with blood and blood components has also been studied. Information about the hemolytic potential of such particles is scarce and rather controversial. While Landh and Larsson claimed compatibility with red blood cells (without, however, providing experimental data) another study indicated an increased hemolytic potential as compared to phospholipid-stabilized fat emulsions. A very detailed study concerning the interaction of GMO/PX407-based nanoparticles with plasma and plasma components (albumin, HDL, LDL) revealed the instability of the particles in plasma. Lipolysis as well as interaction with the plasma components was observed. After intravenous administration to rats the injected GMO was rapidly cleared from the plasma. An incorporated lipophilic fluorescence probe did, however, show extended circulation which was attributed to its retention in cubosome "remnant" particles. 

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