Induction of Instability in Water-in-Oil-in-Water Double Emulsions by Freeze−Thaw Cycling

Abstract

Individual water-in-oil-in-water (W1/O/W2) double-emulsion globules loaded with fluorescently labeled bovine serum albumin (FITC-BSA) were optically monitored within cylindrical capillaries during freeze-thaw cycling. Coalescence of internal aqueous droplets (W1) and external aqueous phase (W2), termed external coalescence, was not observed before or during freezing of the oil phase (O). On the other hand, this instability mechanism was readily promoted during thawing. This realization confirms the previously suggested potential of W1/O/W2 double emulsions to trigger release upon oil thawing and demonstrates that it is a direct result of globule breakage through external coalescence. The presented results also identified a threshold in the relative W1 droplet size above which instability occurred, while smaller droplets remained unperturbed and therefore indicate that optimization of the delivery can be achieved by tuning the size of W1 droplets. In addition, we propose a possible explanation for the occurrence of instability during oil thawing and its dependence on the size of W1 droplets. Because this alternative globule-breakage mechanism simply uses temperature increase (solid-to-liquid-phase transition) as external stimulus, W1/O/W2 double-emulsion delivery systems can be easily tailored by choosing an oil phase with the appropriate phase-transition temperature.

Oil-Frozen W1/O/W2 Double Emulsions for Dermal Biomacromolecular Delivery Containing Ethanol as Chemical Penetration Enhancer

“…As reported in previous works, 39,40 thawing of the oil phase in oil-frozen DEs leads to a destabilization process cause by surfactant "zone refining," 51 which is the expulsion of chemical species from a phase or interface due to solidification. When the DE is brought back to room temperature, melting of the oil phase occurs faster than the return of expelled surfactant molecules to the internal and external oil-water interfaces; this leads to oil-globule instability, and breakage and release of W 1 droplets into the W 2 continuous phase.…”

“…The heat transport, coalescence of the oil globules, and phase separation dynamics are most responsible for this duration because it has been shown that induced thawing of individual DE-globule breakage is a very fast process. 39 Incorporation of ethanol in the formulation allows a higher amount of W 1 globules to be destabilized, speeding this process. Thawing will occur even faster if the formulation is rubbed on the skin because the thermal resistance will be lower due to the reduced film thickness and the rubbing will promote destabilization and breakage.…”

“…38 This instability problem can be overcome by selecting an oil phase, which upon freezing preserves the mechanical stability of the oil globule and its contents, thus preventing mass transport between phases. Subsequent thawing triggers coalescence of the droplets of W 1 with W 2 phase, 39,40 termed external coalescence. [40][41][42][43] DEs have been regarded as suitable carriers for parenteral administration of vaccines, 44 and the shearing of emulsification procedures did not affect significantly the molecular weight 45 or the in vivo antigenicity of antigen.…”

Cationic liposomes in double emulsions for controlled release

“…Freeze-thaw cycles have been reported as an approach to effectively trigger release of substances from double emulsions [25,26]. It has been demonstrated that the stability of W 1 /O/W 2 double emulsions is maintained during and after freezing of the O-phase.…”

“…As a compartmentalized structure, W 1 /O/W 2 double emulsions can provide high capacity of entrapment, protection of fragile compounds, encapsulation of incompatible substances in different phases, and controlled release [24]. By combining double emulsions and liposomes in a single delivery system, and freezing the emulsion's oil phase [25][26][27], double-encapsulation formulations allow the liposomes and their contents to stay well protected, while also achieving a more efficient cutaneous delivery. In addition, loading penetration enhancers in the external aqueous phase (W 2 ) can potentially facilitate the interaction of liposomes and active components with the skin.…”