## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Poorly Soluble Bioactive Compounds
#### 4.2.3 Phytosterols and Phytostanols  
Plant sterols (or phytosterols) are a family of compounds with structures similar to cholesterol, which have been well shown to lower cholesterol levels when administered orally, irrespective of the present form (esterified or free) [162; 163]. In 2000, the FDA allowed a health claim for reducing the risk of coronary heart disease for foods containing plant stanyl and steryl esters, as long as the foods were low in saturated fat and low in cholesterol [164]. Aside from their cholesterol-lowering properties, phytosterols (andphytostanols) possess anti-cancer, anti-inflammatory, anti-atherogenicity, and anti-oxidant activities [162]. In early efforts to utilize these properties, relatively large dosages of free phytosterols contained in phytosterol-enriched products were required to ensure their cholesterol-lowering benefits [164]. Currently, however, if formulated at optimized conditions, a low dosage (e.g., 1-3 g per day) of phytosterols or their conjugates is enough to exhibit health benefits. Due to this, lipid nanoparticles (SLNs and NLCs) are promising nanavehicles for improving the bioavailability and cholesterol-lowering efficacy of phytosterols, thanks to the good compatibility between them. To date, only a limited number of works investigated the potential and effectiveness of using lipid nanoparticles as vehicles for improving the stability, release, and bioactivities of phytosterols [165, 166, 167, 168]. Such lipid nanoparticles, in this case, are generally NLCs, in agreement with the fact that free phytosterols are poorly soluble in the lipid matrix, and very prone to aggregation and crystallization when crystallization of the phytosterol-containing lipid matrix occurs. [PERSON] et al. [165] fabricated a series of \(\beta\)-sitosterol (a major phytosterol)-loaded NLCs, through a melt emulsification-cooling process, by dissolving it in chloroform prior to the addition of the solution into the melted lipid phase (at 85 \({}^{\circ}\)C). In so doing, they confirmed the effectiveness of NLCs, acting as efficient nanavehicles for \(\beta\)-sitosterol, with high EE values of 71-86%. They demonstrated that the \(\beta\)-sitosterol-loaded NLCs exhibited a much greater free oxygen radical scavenging capacity, compared free \(\beta\)-sitosterol (92% vs. 36.5%), and greater \(\beta\)-sitosterol-sustained release behavior, as compared to their counterpart nanoemulsions [165]. In this previous work, it was further indicated that, before the mixing of phytosterol and the melted lipid, the addition of a natural antioxidant, e.g., green tea extract, even at a low concentration, was able to significantly improve the encapsulation performance and antioxidant potential of phytosterols in such nanoparticles. Although the solubility of phytosterols in common edible triacylglycerols at room temperature is very limited (2-3 wt%), it progressively increases up to 40-50 wt% (in MCT or trilaturin) at temperatures of around 100 \({}^{\circ}\)C [166]. According to this solubility-temperature profile, [PERSON] et al. [167] successfully fabricated \(\beta\)-sitosterol-loaded NLCs consisting of propolis wax and pongernate seed oil (PSO) as the solid and liquid lipids, respectively. They utilized the conventional melt-emulsification (ultransication)-cooling process, wherein \(\beta\)-sitosterol, at concentrations up to 15% (relative to total lipid content), was directly formulated in the melted lipid phase. At optimal processing conditions, the EE of \(\beta\)-sitosterol in the NLCs reached 97%, and more importantly, the majority of the crystalline \(\beta\)-sitosterol particles were transformed into the amorphous form [167]. If melt emulsification (to form nanoemulsions) is performed using a microfluidizer (or ultrahigh HP homogenizer), phytosterol-loaded SLNs with an amorphous phytosterol state in the lipid matrix can be formed through a rapid temperature-quenching process, thanks to the formation of finer and more homogenous nanoemulsions [166].