Release from multiple emulsion

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)... 

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

Figure 7.25 Effect of the external aqueous phase pH on the release profile of vitamin Bi from multiple emulsions stabilized with WPI/xantlian gum as the external (secondary7) emulsifier ( ) pH = 7, (A) pH = 4, ( ) pH = 2. Reproduced from Benichou et al. (2004) with permission.

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

Although, forming a protective barrier on the skin is important, some cosmetic products also contain physiologically active ingredients that will improve skin conditions only if they penetrate the skin [35]. Having the product formulated as an emulsion has additional benefits when it comes to the delivery of active ingredients which, for example, are released more slowly from multiple emulsions than from pure solutions containing the same substances [149]. 

Law TK, Florence AT, Whateley TL. 1984. Release from multiple W/O/W emulsions stabilized by interfacial complexation. J Pharm Pharmacol 36(suppl) 50. 

Pandit JK, Mishra B, Chand B. 1987. Drag release from multiple W/O/W emulsions. 

Garti N, Aserin A, Cohen Y. 1994. Mechanistic considerations on the release of electrolytes from multiple emulsions stabihzed by BSA and nonionic surfactants. / Controlled Release 29 41-51. 

It is well established that the release of electrolytes from multiple emulsions in the presence of monomeric emulsifiers takes place even if the droplets are very stable to coalescence and even if the osmotic pressure of the two phases has been equilibrated (Garti and Benichou, 2001 Garti and Benichou, 2003). The model adopted for the release of matter from polymeric matrices is the Stehle and Higuchi model (Stehle and Higuchi, 1972). The model was worked out and tested by a modified release equation. The release factor B was plotted against the time t, and reciprocal initial concentrations of the solute (1/Co). 

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 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. ... 

S. Magdassi andN. Garti A KineticModelforReleaseof Electrolytes from W/OAV Multiple Emulsions. J. Controlled Release 3,273 (1986). 

Protein-polysaccharide conjugates can also act as the stabilizers of multiple emulsions. Fechner et al. (2007) reported that, under acidic conditions, conjugate-containing water-in-oil-in-water emulsions were more stable to coalescence than the corresponding emulsions made with just sodium caseinate. They also observed that the extent of vitamin B]2 release from the inner aqueous phase of the conjugate-based system was significantly lower. This result could be useful for preparing double emulsions with variable release behaviour. 

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. 

In the other procedure, Rojas et al. [215] optimized the encapsulation of BLG within PLGA microparticles prepared by the multiple emulsion solvent evaporation method. The role of the pH of the external phase and the introduction of the surfactant tween 20, in the modulation of the entrapment and release of BLG from microparticles were studied. Better encapsulation of BLG was noticed on decreasing the pH of the external phase. Addition of tween 20 increased the encapsulation efficiency of BLG and considerably reduced the burst release effect. 

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 5. Release of components of internal aqueous phase from multiple water-isopropyl myristate-water emulsions placed in dialysis sacs at 37 C, compared with release rates of equivalent concentrations of solutions of the same substances (----—).

On the other hand, a combination of the above events may take place. Comparison of release of methotrexate, metoclopramide and sodium chloride from type A, B and C multiple emulsions (Fig. 5) is... 

Another important use of the PHS-PEO-PHS block copolymer is the formation of a viscoelastic film around water droplets [11, 12] this results from the dense packing of the molecule at the W/O interface, which leads to an appreciable interfacial viscosity. The viscoelastic film prevents transport of water from the internal water droplets in the multiple emulsion drop to the external aqueous medium, and this ensures the long-term physical stability of the multiple emulsion when using polymeric surfactants. The viscoelastic film can also reduce the transport of any a.i. in the internal water droplets to the external phase. This is desirable in many cases when protection of the ingredient in the internal aqueous droplets is required and release is provided on application of the multiple emulsion. 

In vivo studies were undertaken to compare insulin release profiles between microparticles prepared from the simple solid-in-oil dispersion and those prepared from the novel multiple emulsion technique. With the former, a significant initial insulin rise was observed. This rise peaked at 6 h and insulin release was essentially exhausted by 24 h. With the latter, the initial burst was strongly suppressed, and glucose control was achieved for 2 weeks. Insulin release continued for as along as 20 d, although the levels of insulin were not adequate to achieve normal glucose levels for this entire study period. ... 

Abnormal regions C and B also exhibit low-stability emulsions, a feature that is consistent with the fact that the emulsion type, and thus the interface curvature, is opposite to the one favored by the fomtulation effect. Since multiple emulsions are often made in these regions, a closer look is warranted. For instance, a multiple Wi/O/Wi emulsion i.s found in the C" region. W represents the most internal phase, i.e.. the water dnqtlcts that are located inside the oil drops. It may be considered that the principal" or outside" 0/W2 emulsion has the W,/0 inside" emulsion as internal phase. Since the W,/0 inside emulsion matches the expected type from formulation effects, it is certainly stable, whereas the outside emulsion is not. Thus, such a W,/0/W emulsion would quickly decay in a two-layer system, consisting of a W. phase and an oil layer that would actually be a W /0 emulsion, which is expected to be quite stable if the formulation is sufficiently away from optimum. This means that such unstable" multiple emulsions do not necessarily yield a quick and complete phase separation unless the formulation is q>propriate. e.g.. near-optimum. This feature could be useful for applications dealing with controlled release or capture through mass transfer. 

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).

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