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

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

2.2.3. Importance of Charge‐Stabilized Nanosized Emulsions

At present, emulsions stabilized by positively charged, cationic surfactants are most often used as colloidal API carriers (Tamilvanan 2004). Kim et al. (2005) used an emulsion of squalene in water stabilized by the cationic surfactant 1,2‐dioleoyl‐sn‐glycero‐3‐trimethylammoniumpropane (DOTAP), which facilitated gene transfer in biological fluid even in the presence of 90% serum in the dispersion medium. The emulsion droplets play the role of mucosal gene carriers and can form stable complexes with DNAs. Here, the DNA was incorporated at the end of emulsion preparation by the de novo method. Compared with liposomal carriers, cationic emulsions demonstrated a 200‐fold increase in transfectional efficacy in both lungs and tissues (Kim et al. 2003, 2005). The nature of oil selected as the dispersed phase is another important factor that can affect the applicability of such emulsions for transfection. Three different oils were used for the disperse phase: soybean oil, linseed oil, and squalene (Kim et al. 2003). The transfection activities of the nanosized emulsion carriers in the presence of serum followed the order squalene > soybean oil > linseed oil, and the squalene emulsions were also most stable. From these data, the authors concluded that stability of a carrier system is a necessary requirement to form stable complexes with DNA, and this stability determines the in vivo transfection.

      It is known from the literatures that the interaction between cationic liposomes and polyanionic macromolecules like DNA is dependent on ± ratio, and at the ratio of maximum transfection there is a major aggregation leading to destabilization of formulation or desorption of DNA from the formulation (Liu et al. 1997). Furthermore, Simberg et al. (2003) suggest that an understanding of the interplay between lipoplex composition, its interaction with serum, hemodynamics, and target tissue properties (susceptibility to transfection) could explain the biodistribution and efficient in vivo transfection following intravenous administration of cationic lipid‐DNA complexes (lipoplexes) into mouse. However, it is interesting to see what could happen when the cationic nanosized emulsion is applied to in vitro cell culture models in the presence of serum. The serum stability of emulsion/DNA complex was reported (Yi et al. 2000). Further studies are, however, necessary to be carried out to understand clearly the origin of the serum stability of this emulsion. In addition, the transfection efficiency of this emulsion was not affected by time up to 2 h post‐emulsion/DNA complex formation. This means that the o/w cationic nanosized emulsion allows the experimenter to have a wider time window to work within during transfection study.

      The o/w nanosized emulsions stabilized by both cationic and anionic lipidic emulsifiers were investigated in order to compare the degree of binding and uptake by specific cells that over‐expressed tumor receptors (Goldstein et al. 2007a). Immunoemulsions were prepared by conjugating an antibody to the surfactant molecule via a hydrophobic linker and then the antibody‐conjugated surfactant was used to make the emulsion by the de novo method. The anionic stabilized emulsions showed decreased stability leading to phase separation after 20 days of storage. The reduced stability of anionic immunoemulsion could be attributed to the rapid decrease of the zeta‐potential caused by the positively charged conjugated antibody and consequently, due to a lower electrostatic repulsion between the colloidal droplets (Goldstein et al. 2007b). On the other hand, immunoemulsions stabilized by both anionic and cationic emulsifiers exhibited a multifold increase in cell binding in contrast to the emulsions without antibodies.

The cationic o/w nanosized emulsions were also found to be effective vehicles to improve the skin permeability of incorporated lipophilic molecules in dermatological applications (Yilmaz and Borchert 2005). Because epithelial cells of the skin carry a negative surface charge, they show high selectivity and permeability to positively charged solutes. Thus, positively charged nanosized emulsions are promising systems for enhancing the skin permeability for APIs included in the colloidal droplets. The authors also showed that ceramides could be successfully delivered in a transdermal route by means of nanosized emulsions stabilized by a positively charged interfacial layer of the naturally occurring molecule, phytosphingosine. Other applications of nanosized emulsions as carriers, stabilized by ionic surfactants, in the pharmaceutical and cosmetic fields have been briefly reviewed by Solans et al. (2005) and Tamilvanan (2008).

      Anionic phospholipids are also commonly utilized for the stabilization of API‐carrying nanosized emulsion droplets both individually and in binary mixtures (Trotta et al. 2002). Soybean lecithin and modified phospholipid, n‐hexanoyl lysolecithin (6‐PC), alone and as 1 : 1 mixtures were used as stabilizers of MCT droplets in water (Trotta et al. 2002). Although individual uncharged phospholipids provide emulsion droplets, a moderate negative charge for stabilization, mixed phospholipids produce much more stable emulsions and a large negative zeta‐potential value. A possible explanation for this phenomenon is related to the increased incorporation of polar compounds from the soya lecithin into the mixed interfacial film when 6‐PC is present. This interfacial film acts as a stabilizer by forming a high energy barrier that repels adjacent droplets and leads to the formation of stabilized emulsified droplets. The stability of the emulsion did not noticeably change, even in the presence of the model destabilizing API, indomethacin, demonstrating the high potential for such mixed emulsifiers for the formulation of colloidal API delivery systems (Trotta et al. 2002). Lysolecithin has one fatty acid ester chain removed from the glycerol backbone, in addition, lysolecithin is toxic (destroys RBC cell membranes). Furthermore, although the role of phospholipids is essential for the stability of the emulsions, possible cataractogenic effects due to the phosphatidyl choline (PC) and, basically, to a derivative of the same, lysophosphatidyl, have been described by different authors (Cotlier et al. 1975; Kador and Kinoshita 1978).

      A new class of surface‐active dialkyl maleates can be utilized for emulsion polymerization (Abele et al. 1997). Here, the emulsion droplets of monomeric maleates are self‐stabilized and simultaneously serve as liquid “reactive storage carriers.” Three types of head group in the dialkyl maleates were studied—nonionic, cationic, and zwitterionic with different lengths of hydrophobic alkyl chain. Cationic and zwitterionic dialkyl maleates with the longest alkyl chains ‐C₁₆H₃₃ and ‐C₁₇H₃₅ provided the best stability for o/w nanosized emulsions. When compared with the data obtained for the well‐known nonionic surfactant nonylphenol‐poly (ethylene oxide) (NPEO₁₀) and the cationic cetyltrimethyl ammonium bromide (CTAB), an excellent stabilizing capacity especially for the cationic maleates can be stated. Whereas nonionic dialkyl maleates show almost the same emulsifying ability and stability as NPEO₁₀, the cationic derivatives of these novel surfactants are more effective in stabilization than the traditional CTAB.

Sometimes anionic surfactants are especially added to emulsion droplets for the stabilization of “reactive storage carriers” subjected to further chemical transformation. Sodium dodecyl sulfate (SDS) was utilized to stabilize miniemulsion droplets, which in the subsequent step, were polymerized and formed poly(n‐butylcyanoacrylate) (PBCA) nanoparticles, suitable for targeting API delivery to specific cells (Weiss et al. 2007). It is worth mentioning that SDS is predominantly used to achieve required miniemulsion stability (Landfester 2006). In some cases, however, cationic surfactants are СКАЧАТЬ