Multiple emulsions drug release from

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)... 

We have shown that the NMR self-diffusion method is sensitive to the mean displacement of a molecule of interest on the time scale of the NMR experiment (A). This fact allows us to measure molecular transport inside the emulsion droplets, as in the case of determination of droplet sizes, and the exchange between the emulsion droplets, as in the case of highly concentrated emulsions. In more complex systems the NMR self-diffusion method is sensitive to the molecular exchange between the emulsion droplets and the continuous phase, as in the case of multiple emulsions. Many emulsion systems are currently used as carriers for drugs or other bioactive substances, such as pesticides. The selective measurement of the diffusivity of the individual components within flic emulsion system is therefore of theoretical and practical relevance. The NMR self-diffusion technique is an appropriate tool to study the drug release from emulsion droplets. This useful information may be obtained in a rapid and nondestructive way. 

Brodin AF, Kavaliunas DR, Frank SG. 1978. Prolonged drug release from multiple emulsions. Acta Pharm Suec 15 1-10. 

Brodin AF. 1978. Drug release from oil-water-oil (O/W/O) multiple emulsion systems. Acta Pharm Suec 15 111-113. 

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. 

Omotosho, J.A. Whateley, T.L. Florence, A.T. Release of 5-fluorouracil from intramuscular w/o/w multiple emulsions. Biopharm. and Drug Disposit 1989,10, 257-268. 

Figure 19 Drug release studies from various Rifampicin formulations W/O/W multiple emulsions uneoated (X), coated ( ), uncoated formulation with serum (V), coated formulation with serum (+), plain drug (O). drug with albumin (A) (125).

Multiple emulsions usually refer to series of complex two-phase systems that result from dispersing an emul sion into its dispersed phase. Such systems are often referred to as water-in-oil-in-water (W/OAV) or oil-in-water-in-oil (O/W/0) emulsions, depending on the type of internal, intermediate, and continuous phase. Multiple emulsions were early recognized as promising systems for many industrial applications, such as in the process of immobilization of proteins in the inner aqu eous phase (37) and as liquid membrane systems in extraction processes (38). W/O/W emulsions have been discussed in a number of technical applications, e.g., as prolonged drug-delivery systems (39-44), in the context of controlled-release formulations (45), and in pharmaceutical, cosmetic, and food (46) applications. 

Figure 22 Drug-release profile of isoniazid from multiple emulsion based on imi/oligo/droplet internal phase. (From Ref 57.)...

Ketamine leaves the blood very rapidly to be distributed into the tissues. The recommended dosage of intravenous Ketamine is 2.5—20 mg/kg. The objective of the study was to test the concept that a multiple emulsion could be formulated which has high porosity and lower viscosity at 37°C consistent with its intended use for sustained drug release and to prolong the half-life of the anesthesia. The results showed that 8.2% of the Ketamine was released (100 mg/ml in the inner phase) after 10 min, 67.0% at 30 min, and 95.5% at 60 min from the Ketamine/OAV multiple emulsion in a well-controlled manner (Figs. 23 and 24). 

Multiple emulsions are complex systems wherein droplets of (he dispersed phase contain additional but smaller droplets, identical to or different from the continuous phase. Even so there are many interesting fields of potential research and applications, such as vaccine formulations, enzyme immobilization, and drug overdose treatment (122). Ttie disadvantages of current multiple emulsions are obvious. Internal droplet growth and release as well as degradation to heterogeneous O/W or W/O formulations results in shear sensitivity and bad long-term multiplicities. Besides, those systems are problematic to produce al industrial scale. 

Omotosho JA, Whateley TL, Law TK, Florence AT. 1989. Release of 5-fluorouracil from intramuscular W/O/W multiple emulsions. Biopharm Drug Disp 10 257-268. 

An attempt to reduce the inner oil phase solubility in the external oil phase was achieved by replacing it, for instance, MCT with a mixture of MCT-triacetin (3Ac) or MCT-glycerol monooleate (GMO). In these conditions it was possible to further reduce the release of the drug and the solubility of the inner oil phase into the external oil phase. Figures 7.17 and 7.18 describe the release profiles of flumethrin from multiple emulsions at 25°C where the inner oil phase (Oi) consists of a mixture of MCT and triacetin (3Ac) (Figure 7.17) or glycerol monooleate (GMO) (Figure 7.18) at different ratios. 

The absence of monomeric surfactant in the intermediate aqueous phase of the multiple emulsion prevented uncontrolled release of the drug through micellar diffusion controlled transport. Flumethrin release rates from the inner oil phase (Oi) imply that an interfacial barrier prolonged the release of the entrapped drug at a rate governed by its ability to partition into and to diffuse through the interfadal inner polymeric film as well as through the intermediate aqueous phase. 

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. 

From most of the studies described above, it can be noted that the multiple emulsions are proposed mainly for sustained release of anticancer drugs but not for drug targeting. One obvious reason is their large size, which is dependent on the size of internal aqueous phase droplets. If it was possible to reduce the size of the internal aqueous droplets to nanometers without coalescence, it may be possible to make multiple emulsions that are very small in size. A method for obtaining small-sized multiple emulsion with a solidified oil phase is reported by Morel et al. (1994) to avoid internal droplet coalescence and migration into external phase. 

Miyakawa T, Zhang W, Uchida T, Kim NS, Goto S. 1993. In vivo release of water-soluble drugs from stabilized water-in-oil-in-water (W/OAV) type multiple emulsions following intravenous administrations using rats. Biol Pharm Bull 16(3) 268-272. 

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

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. ... 

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