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

The final oil‐phase concentration in emulsions meant for ocular use is now widely accepted to be at or below 5% w/w taking into account that the emulsion must be kept in a low‐viscosity range of between 2 and 3 centipoises, which also is the optimal viscosity for ocular preparations (Lee and Robinson 1986). This viscosity range may be suitable to take the emulsion into the syringe (i.e., syringeability) for parenteral application into human body. However, for all other medical uses, the amount of oil may be varied but generally is within 5–20% w/w. Sometimes, a mixture of oils may be employed to facilitate API solubilization in the oil phase. Jumaa and Müller (1998, 1999) reported the effect of mixing castor oil with medium‐chain triglycerides (MCT) on the viscosity of castor oil. Mixing of castor oil with MCT at a ratio of 1 : 1 (w/w) led to a decrease in the viscosity of castor oil and simultaneously to a decrease in the interfacial tension of the oil phase. The presence of free fatty acids in the castor oil (may be as an impurity) can act as coemulsifiers to lower the interfacial tension between dispersed oil droplets and continuous aqueous medium and subsequently to produce a more stable emulsion formulation in comparison with the other oil phases. In addition to the digestible oils from the family of triglycerides, including soybean oil, sesame seed oil, cottonseed oil, and safflower oil, which are routinely used for making medical emulsions, alternative biocompatible ingredients such as α‐tocopherol and/or other tocols were also investigated for API delivery purposes via o/w emulsions (Constantinides et al. 2004, 2006). But the emulsions formed from tocols are often considered as microemulsion systems with few exceptions (Constantinides et al. 2004, 2006). Very recently, it was shown that playing with oil combinations could generate the dispersed oil droplets with bi‐compartmental structure possessing different polarity and thus paving the strategy of dual API loading in the o/w macro‐ and nano‐sized emulsions (Puri et al. 2019). The details of this type of emulsions are discussed in Chapter 7.

Not only the chemical nature of emulsifiers but also their concentration used determine the type of emulsion produced. For example, the spontaneously forming thermodynamically stable microemulsion systems require a high emulsifier/surfactant concentration [usually at 20% and higher (w/w)] along with an alkanol component. But the kinetically stable nanosized emulsions can be prepared by using relatively lower surfactant concentrations. For example, a 20% o/w nanosized emulsion may only require a surfactant concentration of 1–5%. The kinetic stability of the nanosized emulsions can be achieved by creating a barrier at the oil–water interface, protecting the emulsion from breakage (Capek 2004). These barriers may be of electrostatic or steric nature and prevent emulsion droplets from direct contact. The most common way to stabilize emulsions is by surfactant adsorbed at the interface between the dispersed oil droplets and continuous aqueous dispersion medium. Surfactant adsorption layers do not only reduce the interfacial tension but can also provide an electrical charge to the emulsion droplets (ionic surfactants) or create the strong steric barrier via bulky molecular groups directed toward the dispersion medium (nonionic surfactants).

Traditionally, lecithins or phospholipids are the emulsifiers of choice to produce o/w nanosized emulsions, because the phospholipid emulsifier molecule structure is more or less similar to the endogenous phospholipids, which build the cells and/tissues. However, additional emulsifiers preferably dissolved in the aqueous phase are usually included in the emulsion composition. A typical example of the aqueous soluble emulsifiers are nonionic surfactants (e.g., Tween 20), which are preferred because they are less irritant than their ionic counterparts. The nonionic block copolymer of polyoxyethylene‐polyoxypropylene (PEO‐PPO), Pluronics F68 (Poloxamer 188) is included to stabilize the emulsion through strong steric repulsion. However, surfactants such as Miranol MHT (lauroamphodiacetate and sodium tridecethsulfate) and Miranol C 2M (cocoamphodiacetate) were also used in earlier ophthalmic emulsions (Muchtar and Benita 1994). It should be added that commercially available cyclosporin A‐loaded anionic emulsion (Restasis ®) contains only polysorbate 80 and carbomer 1,342 at alkaline pH to stabilize the anionic emulsion. To prepare a cationic emulsion, cationic lipids (stearyl‐and oleyl‐amines) or polysaccharides (chitosan) are added to the formulation. Strikingly, a stable emulsion prepared based on chitosan–lecithin combination was also reported (Ogawa et al. 2003). Conversely, a cationic emulsion based on an association of poloxamer 188 and chitosan without the incorporation of lecithin was prepared and also demonstrated adequate stability (Calvo et al. 1997; Jumaa and Müller 1999). Similarly, a report from our group also indicated the stability of oil droplets through the cation conferring chitosan along with poloxamer 188 as a mixed emulsifier (Tamilvanan et al. 2010). Since the free fatty acid generating phospholipid emulsifier molecule is omitted from the nanosized emulsion system, the stable nanosized emulsion produced from chitosan–poloxamer emulsifier combination would significantly reduce the generation of microclimate acidic pH in the vicinity of oil phase, oil–water interface, and water phase of the emulsion (Tamilvanan et al. 2010). These non‐phospholipid‐based emulsions should therefore pave the way to incorporate the acid‐labile molecules like therapeutic peptides and proteins, and to delineate the scope of applying lyophilization process for the development of a solid or dry emulsion. With the addition of suitable cryo‐ or lyo‐protectant at optimum concentration, the preparation of lyophilized solid dry‐powder form of non‐phospholipid‐based o/w nanosized emulsions is possible in recent years. Figure 2.1shows the o/w nanosized emulsions in liquid form (before lyophilization) and solid‐dry powder form after the addition of different cryo‐ or lyo‐protectant molecules.

Oil‐in‐water emulsion compositions based on α‐tocopherol (or α‐tocopherol derivative) as the disperse phase has been described in a patent granted to Dumex (Sonne 2015). Interestingly, the emulsifying agent used to make tocol‐based emulsions are restricted to vitamin E TPGS (D‐alpha‐tocopheryl polyethylene glycol 1000 succinate) taking into consideration of toxicological issues. According to a patent by Nakajima et al. (2003), functional emulsions for use in food, APIs, and cosmetics were reported. These emulsions were stabilized with various span products such as Span 80, Span 40, etc. There is a group of emulsions that were not prepared by using the traditional anionic, cationic, and nonionic surfactant molecules. These emulsions do contain the oil or oil combination and therefore they can be termed as “surfactant‐free emulsions.” Another group of colloidal dispersions whose final appearance is white similar to the traditional emulsions but these dispersions do not contain both surfactants and oil or oil combination. Taking the physical appearance (white color) into consideration, these colloidal dispersions get the term “surfactant‐ and oil‐free emulsions.” Both of these two emulsions (surfactant‐free and surfactant‐ and oil‐free) are briefly discussed in Chapter 7.

Figure 2.1. Freeze‐dried emulsions using different cryo‐ or lyo‐protectants and reconstitution of freeze‐dried powder into nanosized emulsion.