Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan Shunmugaperumal

which resulted in better interfacial adsorption. Synergistic stabilization of o/w emulsions by a mixture of nonionic surfactants and hydrophilic silica nanoparticles has recently been studied by Binks et al. (2007a, b) highlighting the importance of preparation protocol. Attachment energy of a silica particle at the oil–water interface was correlated to emulsion stability. Velev et al. (1996) reported that the adsorption of lysine onto negatively charged latex particles enabled interfacial adsorption due to the reduction of hydration forces and electrostatic repulsion between droplets and particles. The influence of droplet–particle electrostatic interaction on emulsion stability was studied by Binks and Catherine (2005) and Lan et al. (2007). Addition of cationic surfactant CTAB to negatively charged hydrophilic silica dispersions as the aqueous phase of emulsions resulted in enhanced stability at low CTAB concentrations, i.e., the region where CTAB is preferably adsorbed onto silica surface and promoted interfacial adsorption due to neutralization of surface charge and optimization of particle hydrophobicity. This synergistic emulsion stabilization comes from three sources: CTAB (1) hydrophobizes silica nanoparticles by charge neutralization, (2) promotes nanoparticle aggregation, and (3) reduces interfacial tension. However, when the CTAB concentration is such so that both droplets and silica are positively charged, interfacial adsorption and emulsion stability are lost and thus emulsion stability is dramatically reduced.

Simovic and Prestidge (2007) showed that nanoparticle layers significantly influence the release kinetics of a model lipophilic API [di‐butyl‐phthalate (DBP)] from polydimethylsiloxane o/w emulsions; either sustained or enhanced release can be achieved depending on the nanoparticle layer structure and API loading level. Nanoparticle layers can be engineered to facilitate a range of release behaviors and offer great potential in the delivery of poorly soluble APIs. Particle‐stabilized emulsions have been extensively studied in terms of stabilization mechanisms (Binks and Lumsdon 2000; Binks and Catherine 2005), synergy with common emulsifiers (Lan et al. 2007; Binks et al. 2007a, b), and interfacial properties (Simovic and Prestidge 2003, 2008). However, few reports have focused on their carrier properties as dermal delivery vehicles, e.g., penetration and targeting skin layers. Recently, the influence of nanoparticle coating of submicron (nanosized) o/w emulsion droplets on the in vitro release and dermal delivery characteristics, with particular emphasis on potential controlled release and targeted skin delivery of all‐trans‐retinol, was reported by Eskandar et al. (2009). MCT o/w emulsions have been stabilized with mixed interfacial layers composed of lecithin or oleylamine and hydrophilic silica nanoparticles using a simple cold high‐pressure homogenization technique. These emulsion‐based hybrid API delivery systems showed improved topical delivery of all‐trans‐retinol; nanoparticle layers significantly improved the performance of o/w emulsions as encapsulation and delivery systems for all‐trans‐retinol. Therefore, emulsion‐based hybrid API delivery systems should have a potential for future directions.

2.4. LIPOPHILIC API INCORPORATION PATTERN INTO NANOSIZED EMULSIONS

      There are four different approaches to incorporate lipophilic APIs or heat labile molecules into the oil phase or at the o/w interface of the nanosized emulsions, namely (Tamilvanan and Benita 2004),

       extemporaneous API addition,

       de novo emulsion preparation,

       an interfacial incorporation approach, which includes the recently developed SolEmul® technology, and

       incorporation of antibodies, DNA protein, oligonucleotide, or heat labile molecules.

2.4.1. Extemporaneous API Addition

Cohen et al. (1996), when looking for a new galenic presentation form for amphotericin B with better ocular tolerance over the commercially available Fungizone^® eye drops, incorporated the API directly into the preformed 20% emulsion, Intralipid^®. However, after addition of the solid API particles or API solution, several physical changes such as phase separation, precipitation, or creaming may occur thus limiting such practices in o/w nanosized emulsion preparations. Therefore, ocular active lipophilic agents are not normally incorporated into the emulsions by this extemporaneous addition method.

2.4.2. De Novo Emulsion Preparation

In principle, the lipophilic API molecules (thermostable) should however be incorporated by a de novo process as described earlier. Thus, the API 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 API molecules within its oil phase or its oil–water interface. This is a generally accepted and standard method to prepare lipophilic API‐loaded nanosized emulsions for parenteral, ocular, percutaneous, and nasal uses, as illustrated in Fig. 2.3. This process is normally carried out under aseptic conditions and nitrogen or argon atmosphere to prevent both contamination and potential oxidation of sensitive excipients.

2.4.3. Interfacial Incorporation Approach

      Since many APIs of commercial interest generally have a solubility that is too low in FDA‐approved oils, Lance et al. (1995) proposed a method to incorporate such APIs into the interfacial o/w layer of the emulsion droplets. This can be achieved by initially dissolving the API along with the phospholipid (emulsifier) in an organic solvent, instead of in the oil.

Following the solvent evaporation, the obtained phospholipids/API co‐mixture is used in the de novo production of the emulsions (Davis and Washington 1988). However, this approach suffers from possible API 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 API with emulsion. The API particles are micronized to the nanosize range prior to incorporation into the emulsions. By this technique, adequate amounts of lipophilic APIs 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 APIs reported to have been incorporated by this novel approach are amphotericin B, carbamazepine, and itraconazole (Buttle et al. 2002; Müller and Schmidt 2002; Akkar and Müller 2003a, b). However, it should be emphasized that all the lipophilic API molecules that have been incorporated into the emulsions by SolEmul^® technology are meant only for parenteral use (Buttle et al. 2002; Müller and Schmidt 2002; Akkar and Müller 2003a, b) and so far no ocular, nasal, and topical active agents have been incorporated by this approach although there is no regulatory reason to exclude this technical improvement when designing emulsion formulations for these applications.

Figure 2.3. Schematic diagram for preparation of nanosized emulsion.

2.4.4. Incorporation of Antibodies, DNA Protein, Oligonucleotide, or Heat Labile Molecules

Both extemporaneous API 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 (peptidic molecule) was successfully incorporated without API degradation into the emulsion by following the de novo method (Tamilvanan et al. 2001). The extemporaneous addition of the solid API or API previously solubilized in another solvent or oil to the o/w nanosized emulsions is not a favored approach in technology wise as it might compromise the integrity