PFC emulsions

Medical appHcations of PFC emulsions for organ perfusion and intravenous uses have received much attention in recent years. The first commercial blood substitute (Fluosol DA 20%, trademark of the Green Cross Corp.) employed perfluorodecalin, and improved, second generation products based on this PFC, or perfluorooctylbromide, are now under development (20,21). The relatively high oxygen dissolving capabiHty of PFCs undedies these appHcations (see Blood, artificial). 

Further issues concern the design of appropriate protocols for evaluation of efficacy of a blood substitute so different from blood, the definition of indications, and conditions of use that befit PFC emulsions and provide maximum benefit for the patient. The latter issues depend largely on our understanding of the in vivo behavior of PFCs and PFC emulsions. 

The first commercially developed PFC emulsion, Fluosol, consisted of a mixture of F-decalin and F-tiipropylamine emulsified with Pluronic F-68 [a poly(oxyethy-lene) poly(oxypropylene) block co-polymer] as the main surfactant. It gained... 

Contrast MRI requires incorporation of paramagnetic material onto the PFC-based targeted particles [48,49]. Incorporation of a gadolinium(lll) complex into the lipid monolayer that coats targeted emulsion droplets provides contrast agents useful for both US and MRI modalities. Paramagnetic fibrin-specific PFC emulsion droplets allowed sensitive detection and localization of thrombi by MRI and may allow early identification of fibrin deposits in vulnerable atherosclerotic plaques. The emulsion droplets had both an antifibrin... 

PFCs have been extensively investigated for cell culture [63]. A PFC emulsion was recently found to prevent the adhesion of certain jS-cell lines to cell culture plastic and promoted the formation of pseudo-islets capable of insulin secretion [64],... 

Intravenous infusion of the plasma-insoluble PFCs into animals results in fatal embolisms. However, following extensive research with a large number of PFCs and emulsifiers, the development of several PFC emulsions dispersed in isotonic solution has produced promising results. The first commercial product, Fluosol-DA 20% (F-DA), available in 1978, consists of perfluorodecalin (14%) and perfluorotripropylamine (6%) in emulsifiers260. 

This entry will first survey the reasons for developing blood substitutes and outline the principles of oxygen delivery by PFC emulsions. It will then focus on the main challenges encountered in the development of such emulsions, namely the selection of an appropriate excretable PFC and the preparation of a stable, biocompatible emulsion. It will also allude to questions related to raw material procurement, product manufacture, and cost. Further sections will concern the pharmacokinetics, efficacy, and side effects of these oxygen carriers. Finally, the potential applications of these products will be outlined, including the status of their clinical trials, and some forward looking comments will be made. 

Obtaining stable, biocompatible, small-sized, narrowly distributed emulsions of an excretable PFC was crucial. The extreme hydrophobicity of PFCs can, however, render the obtaining of a stable emulsion difficult. Further critical aspects of PFC emulsion development involve emulsion formulation, physical and biological characteristics, scale-up, sterilization, and packaging, as well as its user-friendliness and strategy of use. 

Introducing a PFC emulsion into the circulation is akin to increasing the O2 solubility of the plasma compartment of blood. The principles that underlie O2 transport by the PFC and plasma are essentially the same. In both cases dissolution is proportional to PO2 simply, the solubility of O2 in PFCs is typically... 

Hemoglobin is exquisitely well adapted to supporting life in earth s atmosphere, but the conditions available in the operating room or critical care unit are different, and adjustable. A valuable consequence of O2 dissolution in PFCs following Henry s law is that the transport capacity of a PFC emulsion can be increased by a factor of five by just increasing the fraction of O2 in the air inspired by the patient (Fi02). 

When normovolemic hemodilution is performed, there is normally a substantial increase in cardiac output as a result of increased fluidity of the diluted bloodJ This increase in cardiac output is preserved when PFC emulsions are administered, which further enhances their 02-delivery capacity, ° while cell-free Hb products, because of vasoconstrictive effects, classically display an unchanged or reduced cardiac output that can negate the benefit of increased fluidityJ ... 

Proper selection of a biocompatible emulsifier or emulsifier system was also essential for successful PFC emulsion development. One of the emulsifier s roles is to reduce the large interfacial tension ([Pg.342]

Another is to stabilize the emulsion once it is formed. The only two surfactants used in PFC emulsion development so far are poloxamers and phospholipids. 

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. ... 

EYP have been chosen as the emulsifier in all second generation PFC emulsions. EYP, whose major constituents are the amphiphilic amphoteric phosphatidylcholines 13, provide significantly better emulsion stability than poloxamers. The stabilization effect is particularly remarkable with Emulsions... 

Stability is an essential condition for PFC emulsions to be of practical use. The principal mechanism for irreversible droplet growth in submicronic PFC emulsions during storage is molecular diffusion (also known as Ostwald ripening or isothermal distillationj.P Coalescence may contribute to instability when mechanical stress is applied and at higher temperatures, as during heat sterilization. Sedimentation and flocculation are fully reversible and pose no problem. 

Molecular diffusion in emulsions can be effectively slowed down by including in the dispersed phase a small amount of a component with lesser water solubility, in the case of a PFC emulsion, a secondary, higher MW ( heavier ) PFC.t This is the role of 7 in Fluosol and of 8 in Perftoran, however, at the cost of longer organ half-lives of 65 and 90 days, respectively. 

Fluorinated surfactants (or fluorosurfactants, i.e., surfactants with hydrophobic tails comprising a fluorocarbon moiety) provide an alternative means of achieving extremely stable PFC emulsions, as they can provide very low PFC/water interfacial tensions [cr , another factor in Eq. (2)]. d s yet, this option has not been developed, in part because of the added cost involved in the evaluation for approval of a novel active excipient. A further means of effectively increasing the stability of EYP-based PFC emulsion consists of supplementing standard phospholipids with mixed fluorocarbon-hydrocarbon diblock compounds, such as 14 or 15. Such diblocks, which have fluorophilic-lipophilic amphiphilic properties, are expected to improve the adhesion of the phospholipid film onto the PFC droplet. 

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