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

of the system at any given time, at the frontier between the growth and decrease of the droplets. Consequently, Ostwald ripening is reflected by a linear relationship between the cube radius and time.

In processes involved in nanoparticle engineering, i.e., for multi‐component emulsion droplets, by adding monomer, polymer, or simply surfactant or co‐surfactant, the above approximation is surpassed. The rate of ripening can be reduced by several orders of magnitude when the additive has a substantially lower solubility in the bulk phase than the main component of the droplet. This phenomenon has been widely studied (Buscall et al. 1979; Davis and Smith 1973; Davis et al. 1981; Higuchi and Misra 1962; Kabalnov et al. 1985, 1987; Smith and Davis 1973; Taylor and Ottewill 1994), since it appears to be an efficient method to reduce the Ostwald ripening rate, even when using small amounts of additives. In short, it is explained by the difference of solubility in the continuous phase between the dispersed phase noted (1) and the additive (2), less soluble in this example. The first step remains similar to the ripening without additives, since only the component (1) diffuses from the smaller to the larger droplets, due to the higher chemical potential of the materials within the smaller drops. Gradually, the chemical potential in the larger droplets increases due to the presence of the component (2), until the diffusion process of (1) is stopped. Equilibrium is reached between the two opposing effects and the limiting process becomes the diffusion of the less soluble additive (2), significantly reducing the ripening rate and the nanoemulsion destabilization.

      A final remark, which may be of importance here, concerns the influence on the nanosized emulsion destabilization of layer density and structure in the interfacial zone. Indeed, up to now it has been considered that Ostwald ripening is a diffusion‐controlled process, but this assumption does not take into account the fact that surfactants, polymeric emulsifiers or stabilizers can create a thick steric barrier at the droplet interface (Goldberg and Higuchi 1969; Yotsuyanagi et al. 1973). As a consequence, the diffusion of the inner material of the droplets may be slowed down, reducing the ripening rate. The substantial difference in stability between nanoemulsions and nanocapsules (another colloidal API delivery system having polymeric outer shells covered on the dispersed oil droplets) for instance, appears essentially from such details.

      Before proceeding into Chapter 2, a brief description concerning classification of nanosized emulsions is presented below.

       1.1.2.3. Classification of Oil‐in‐Water Nanosized Emulsions

Purely based on the emulsifier combinations used to stabilize the dispersed oil droplets of the emulsions, the o/w nanosized emulsions can be classified into three types (Fig. 1.2). First type includes emulsions prepared using the emulsifiers that are having the capacity to assemble at the o/w interface and able to produce a minus (negative) charge in the vicinity of dispersed oil droplets of the emulsions. The emulsions thus formed are termed as anionic or negatively‐charged emulsions. The emulsions made with the inclusion of emulsifiers that are assembled at the o/w interface and competent to confer a plus (positive) charge in the vicinity of dispersed oil droplets of the emulsions are called as cationic or positively‐charged emulsions. The literature suggests that neither triglycerides nor phospholipidic emulsifier's components of the conventional or anionic emulsions are able to significantly sustain the incorporated lipophilic API release in simulated or real physiological environments under sink conditions. Therefore, in an attempt to prolong and/or optimize the API release, cationic lipid or polysaccharide emulsifiers are added to the emulsions to elicit mucoadhesion with anionic ocular tissues by an electrostatic adhesion. Indeed, cationic emulsions prepared on the basis of stearylamine, oleylamine and chitosan can serve this purpose. It was initially believed and now has become clearer from many reports in the literature that an occurrence of electrostatic attraction between the cationic emulsified droplets and anionic cellular moieties of the ocular and topical skin surface tissues enhance the bioavailability of emulsions containing lipophilic APIs (Lallemand et al. 2003; Piemi et al. 1999; Tamilvanan et al. 2002; Vandamme 2002). There is another type of emulsions that are neutral in terms of the charge on the dispersed droplets. These are instead stabilized through steric effects exerted by the emulsifier molecule present in the emulsion formulation.

Figure 1.2. Classification of oil‐in‐water (o/w) nanosized emulsions based on emulsifier molecules.

      According to Capek (2004), the stability of the electrostatically‐ and sterically‐stabilized o/w nanosized emulsions can be controlled by the charge of the electrical double layer and the thickness of the droplet surface layer formed by non‐ionic emulsifier, respectively. In spite of the similarities between electrostatically‐ and sterically‐stabilized emulsions, there are large differences in the partitioning of molecules of ionic and non‐ionic emulsifiers between the oil and water phases and the thickness of the interfacial layers at the droplet surface (Capek 2004). The thin interfacial layer (the electrical double layer) at the surface of electrostatically stabilized droplets does not create any steric barrier for mass transfer. This may not necessarily be true for the thick interfacial layer formed by a non‐ionic emulsifier. The sterically‐stabilized oil droplets, however, can favor the transfer of materials within the intermediate agglomerates. Hence, the stability of electrosterically‐stabilized emulsion (δ_k) is controlled by the ratio of the thickness of the non‐ionic emulsifier adsorption layer (δ) to the thickness of the electrical double layer (k⁻¹) around the oil droplets (Capek 2004).

      (1.5)

1.2. CONCLUSION

      This section says that although the o/w nanosized emulsions belong to MS category in terms of stability aspects, many competing forces actually determine the stability of emulsions. The group of API molecules suitable to be incorporated into the o/w nanosized emulsions is carefully revived by interpreting the physicochemical properties (molecular size and structure, melting point, log P value, etc.) of individual APIs along with their solubility and permeability characteristics.

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