Preparation of o/w nanosized emulsion (de novo method) [by permission from Elsevier (27)]. 

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... principle, the lipophilic drug molecules (thermostable) should however be incorporated by a de novo process as described earlier. Thus, the drug is initially solubilized or dispersed together with an emulsifier in suitable single-oil or oil mixture by means of heating. The water phase containing the osmotic agent with or without an additional emulsifier is also heated and mixed with the oil phase by means of high- speed mixers. Further homogenization takes place to obtain the needed small droplet size range of the emulsion. A terminal sterilization by filtration, or steam, then follows. The emulsion thus formed contains most of the drug molecules within its oil phase or its oil- water interface. This is a generally accepted and standard method to prepare lipophilic drug- loaded nanosized emulsions for parenteral, ocular, percutaneous, and nasal uses, as illustrated in Figure 2. This process is normally carried out under aseptic conditions and nitrogen or argon atmosphere to prevent both contamination and potential oxidation of sensitive excipients. Since many drugs of commercial interest generally have a solubility that is too low in FDA approved oils, Lance et al (29) proposed a method to incorporate such drugs into the interfacial o/w layer of the emulsion droplets. This can be achieved by initially dissolving the drug along with the phospholipid (emulsifier) in an organic solvent, instead of in the oil. Following the solvent evaporation, the obtained phospholipids/drug co-mixture is used in the de novo production of the emulsions (30). However, this approach suffers from possible drug nanocrystal formation and from the use of organic solvent during the emulsion preparation process. To overcome such drawbacks, a novel SolEmul ® technology was developed in which an additional high speed homogenization step is included to mix the drug with emulsion. The drug particles are micronized to the nanosize range prior to incorporation into the emulsion. By this technique, adequate amounts of lipophilic drugs can be substantially incorporated into the lipophilic core or intercalated between the selected emulsifier molecular films at the o/w interface of the emulsions. The drugs reported to have been incorporated by this novel approach are amphotericin B, carbamazepine and itraconazole (31-34). However, it should be emphasized that all the lipophilic drug molecules that have been incorporated into the emulsions by SolEmul ® technology are meant only for parenteral use (31-34) and so far no ocular, nasal and topical active agents have been incorporated by this approach although there appears to be no regulatory reason to exclude this technical improvement when designing emulsion formulations for these applications. Both extemporaneous drug addition (method A) into the preformed emulsion and de novo emulsion preparation (method B) are useful for the incorporation of heat labile molecules into the o/w nanosized emulsions. For example, cyclosporin A was successfully incorporated without drug degradation into the emulsion by following the de novo method (35). The extemporaneous addition of the solid drug or drug previously solubilized in another solvent or oil to the o/w nanosized emulsions is not a favoured approach as it might compromise the integrity of the emulsion. However, since therapeutic DNA and single stranded oligonucleotides (oligos) or siRNA are water soluble due to their polyanionic character, the aqueous solution of these compounds can be added directly to the o/w cationic nanosized emulsion in order to interact electrostatically with the cationic emulsion droplets and thus associate/link superficially at the oil-water interface of the emulsion (36-38). When administered via parenteral and ocular routes, the release of the DNA and oligos from the associated emulsion droplet surfaces should therefore initially be dependent on the affinity between the physiological anions of the biological fluid and cationic surface of the emulsion droplets. The mono- and di-valent anions in the biological fluid available in parenteral route is plasma and in ocular topical route is tear fluid, aqueous humor and vitreous. Moreover, these biofluids contain multitude of macromolecules and nucleases. There is a possibility that endogenous negatively charged biofluid’s components could dissociate the DNA In order and to oligos enable from the cationic nanosized emulsion. emulsion It to is noteworthy target inaccessible to conduct tissue during s, ho min the g preformulation devices/ligands development such as antibodies stages an and in vitro cell release recognition study proteins for therapeutic are usually DNA linked and onto oligos- the containing particle surface. cationic Various nanoemulsion methods have in these been biological employed fluids to couple and this ligands type to of the study surface could be of considered the nanosized as an emulsions indicator with for reactive the strength groups. of the These interaction can be occurring divided into between covalent DNA and or oligo noncovalent and the couplings. emulsion (39). Noncovalent Interestingly, binding the stability by simple of oligos physical (a 17-bases association oligonucleotide, of targeting partially ligands to phosphorothioated) the nanocarrier surface was validated has the using advantage a gel-electrophoresis of eliminating the use method. of rigorous, After incorporating destructive reaction the oligos agents into and the conditions. cationic nanosized Common covalent emulsion coupling as well as methods during in involve vitro experiments formation of of a oligo-containing disulfide bond, cross-linking emulsion in vitreous between two fluid primary at different amines, time reaction periods, between the emulsions a carboxylic were acid phase group separated and a primary by Triton amine, X- 100 reaction and ...

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... emulsion thus formed contains most of the drug molecules within its oil phase or its oil- water interface. This is a generally accepted and standard method to prepare lipophilic drug- loaded nanosized emulsions for parenteral, ocular, percutaneous, and nasal uses, as illustrated in Figure 2. This process is normally carried out under aseptic conditions and nitrogen or argon atmosphere to prevent both contamination and potential oxidation of sensitive excipients. ...