Release mechanisms, multiple emulsions

Mechanisms of drug release from multiple emulsion systems include diffusion of the dmg molecules from the internal droplets (1), from the medium of the external droplets (2), or by mass transfer due to the coalescence of the internal droplets (3), as shown in Fig. 7.16(b)... 

Other drug-delivery systems may include double emulsions, usually W/O/W, for transporting hydrophilic dmgs such as vaccines, vitamins, enzymes, hormones [441], The multiple emulsion also allows for slow release of the delivered drug and the time-release mechanism can be varied by adjusting the emulsion stability. Conversely, in detoxification (overdose) treatments, the active substance migrates from the outside to the inner phase. 

When applied to multiple emulsions during their destabilization these techniques should lead to a better understanding and control of the destabilization and release mechanisms. 

Multiple emulsion stability was significantly improved in the presence of amphiphilic proteins because of two important factors. First, the multianchoring flexible macromolecules act to improve the steric stabilization by forming a thick multilayered coating on the droplets. Second, the proteins used in the inner phase create a mechanical film barrier that prevents uncontrolled release of the entrapped ingredients. 

Grossiord JL, Seiller M. 2001. W/OAV multiple emulsions a review of the release mechanisms by break-up of the oily membrane. STP Pharma Sci 11 331-339. 

All the above-mentioned mechanisms have been well established. Yet it seems that the stability and the release patterns of these complex multiple emulsion systems depend on various parameters that simultaneously interplay and that a simplified or unique mechanism cannot explain all the in-parallel pathways that take place in the multiple emulsions (Figure 7.11). 

Most of release studies are done in W/OAV multiple-emulsion systems where an active water soluble molecule is present in the inner aqueous phase. Several attempts have been made to explain the transport phenomena of entrapped addenda from the inner to the outer phase of multiple-emulsion droplets. It has been demonstrated that for lipid soluble material dissolved in the oil phase, the release obeys first-order kinetics and is diffusion controlled with excellent accordance to Pick s law. Two mechanisms for the permeation through the oil intermediate phase are well accepted, the first being via the reverse micellar transport (Figure 7.10 ) and the second via diffusion across a very thin lamellae of surfactant phase formed in areas where the oil layer is very thin (Figure 10b). 

Stroeve and Varanasi (1984) examined the breakup of multiple-emulsion globules in a simple shear flow and reported that the multiple emulsion exhibits behavior that is similar to that of simple emulsions. The studies showed also that the mechanisms taking place during the breakup were complex and did not always lead to a total release of the entrapped electrolyte. Some phenomena such as a partial leakage of the internal aqueous compartment or the expulsion of the aqueous microglobules covered by a residual lipophilic film were able to restrict the release. 

New techniques were developed to prepare, characterize, and study the release kinetics in these complex systems. Progress was made in characterization of the parameters and mechanisms that are involved in the coalescence, aggregation, and rupture of the multiple emulsion droplets, and a good control of the rheological parameters was achieved by better understanding of their effect on the static and shear-induced stability. 

For drug delivery applications, it is clear that the release from W/O/W multiple emulsion occurs either by transport through the oily membrane or by its breakdown. In the first case, and depending on the affinity of the molecule for the oily phase, the transport is due to molecular diffusion (Fick diffusion) or to diffusion facilitated by certain surfactants that take on the role of carriers. Transport through the oily membrane will not be considered here. This chapter is devoted to an examination of the breakup mechanisms, as are produced by swelling or under shear. 

This review has focused on the release by breakup of the oily membrane, resulting either from a hypo-osmotic dilution or by shear application among the various release mechanisms of molecules initially entrapped in the internal aqueous phase of W/OAV multiple emulsions. Experimental studies have shown very interesting features that have practical application and allowed us to form some assumptions about the molecular mechanisms. In particular, it has been found that these mechanisms can be controlled by different emulsion formulations and/or application parameters as follows ... 

It is possible to take advantage of this great variety of parameters and control the release from the internal phase by one of these mechanisms, in developing applications of multiple emulsions for pharmaceuticals, cosmetics, and the food industries. 

Geiger S, Tokgoz S, Fructus A, Jager-Lezer N, Seiller M, Lacombe N, Grossiord JL. 1998. Kinetics of swelling-breakdown of a W/O/W multiple emulsions Possible mechanisms for the lipophilic surfactant effect. J Controlled Release 52 99-104. 

The release of electrolytes and drugs from multiple emulsions can, in principle, proceed via two possible mechanisms ... 

Prof. Garti has shown that the diffusion mechanism is a predominant factor in the migration of electrolytes from the inner to the outer phase in multiple emulsions. The release of the electrolyte is affected by its hydrophobicity and concentration but not by the viscosity of the internal phase. 

A kinetic model, adapted from that of Higuchi for release of dispersed drugs from polymeric matrices, was found to be suitable for the release of electrolytes from multiple emulsions. The existence of a diffusion-controlled mechanism was experimentally confirmed. This mechanism is facilitated as the concentration of reverse micelles formed in the oil phase increases. ... 

Since William Seifriz described for the first time in 1925 these intricate liquid systems having ternary, quaternary, or more complex structures that he named multiple emulsions, the literature has been flooded every year with tens of new examples demonstrating release patterns and control of active ingredients using these systems. Multiple emulsions, at least in theory, have significant potential in many applications because the internal droplets can serve as an entrapping reservoir for active addenda that can be released by a controlled transport mechanism. Many of the potential applications would be realized in the fields of agriculture, pharmaceuticals, cosmetics, and food. 

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