Fluosol emulsion stability

Poloxamers are neutral block copolymers such as 12, consisting of two terminal hydrophilic polyoxyethylene blocks flanking a central hydrophobic polyoxypropylene block. Poloxamer 188 (e.g., Pluronic F-68) was used in the first generation PFC emulsions, but was far from adequate Its surface activity is relatively poor, translating into low emulsions stability the purity of the commercial products is usually rather low its cloud point ( 110-115°C) prevents sterilization at the standard temperature of 121°C its tendency to form gels limits the PFC concentration in the emulsions and, finally, Pluronic F-68 has been found to be responsible for the unpredictable transientcomplement activation-mediated anaphylactic reaction observed in some patients in response to the injection of Fluosol. ... 

Perfluorodecalin (FDC), used in the first generation of fluorochemical blood substitutes, has a half-retention time in organs of only 6 days, but the stability of its emulsions is insufficient [5]. Perfluorotripropylamine is added to perfluorodecalin in Fluosol-DA to increase emulsion stability. However, the retention time of perfluorotripropylamine in the body is longer than that of perfluorodecalin. Fluosol-DA is stored frozen and diluted with two aqueous solutions containing electrolytes and additives. 

The first commercially developed emulsion, Fluosol-DA (Green Cross Corp. Osaka, Japan), was stabilized using a mixture of 6 and F-tripropylamine (FTPA, 7, 30% of total PFC) (Table 2). However, the product s stability was still poor Fluosol had to be frozen for shipment and storage, and reconstituted prior to use. Fluosol utilized a surfactant system that included poloxamer-188 (Pluronic F-68) with smaller amounts of EYP and potassium oleate. The poloxamer provided steric stabilization, and potassium oleate introduced negative charges on the droplets, likely to oppose flocculation. 

Fluosol s shortcomings included prolonged organ retention of F-tripropylamine (reticuloendothelial system (RES) half-life 65 days), complement activation, and hemodynamic effects due to Pluronic, excessive dilution, limited intravascular persistence, insufficient stability, and lack of user-friendliness. The product came as three separate preparations the frozen stem emulsion and two annex salt solutions. The stem emulsion had to be carefully thawed, then admixed sequentially to the annex solutions, and the reconstituted product had to be used within 8 h. This cumbersome procedure, the short window for use, the further need for administering a small-test dose to patients prior to infusion in order to identify those patients who were sensitive to Pluronic, contributed to compromising the product s commercial success. 

A concentrated (60% w/v) PFOB/PFDB emulsion (Oxygent AF0144) is currently being produced in a commercial-scale facility. The emulsion is steam-sterilized in a rotary autoclave at or above 121 °C, using a procedure that achieves uniform heat penetration, maintains emulsion integrity, and provides the required probability of less than one non-sterile unit in 10 . As compared to Fluosol, Oxygent is characterized by use of PFCs having some lipophilic character, use of phospholipids as the emulsifier instead of polox-amer, a several-fold increase in PFC concentration, simplification of the overall formulation, considerable increase in stability, and consequently, far superior convenience of use. 

Clinical tests of perfluorochemical oxygen carriers revealed three major problems (1) insufficient stability evidenced by coarsening of the emulsion, (2) toxicity, and (3) unsatisfactory retention time of the fluorochemical in blood and in organs. The toxicity and stability are to some extent related. The biocompatibility of perfluorochemical emulsions is impaired by an increase in particle size [35]. The coarsening of fluorochemical emulsions has been attributed the progressive increase in particle size to Ostwald ripening [94-99]. The diameter profiles for the emulsified perfiuorocarbon droplets in Fluosol-DA and Fluosol 43 have been determined by sedimentation field-flow fractionation [96]. 

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