## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Incorporation and Release of Bioactives
This means that the solubility of a bioactive in the lipid matrix decreases during the cooling process (to solidify). Once the aqueous phase becomes oversaturated with the bioactive as a result of cooling, the lipophilic bioactive tends to migrate to the dispersed phase (lipid). Here, it should be noted that, during the solidification process, both the bioactive and the molten lipid may crystallize, and phase separate. If the molten lipid of hot nanoemulsions first crystallizes to form a bioactive-free solid lipid nanoparticle, a core-shell SLN with a bioactive-enriched shell (Figure 4a, middle) is obtained, since the concentration of the bioactive in the remaining aqueous phase continuously increases. On the other hand, a core-shell SLN with bioactive-enriched core (Figure 4a, right) is formed when the bioactive precipitates prior to the crystallization of the molten lipids. In addition to the temperature-related effect, the incorporation of bioactives into SLNs is also affected by the emulsifier concentration in the aqueous phase; higher the emulsifier concentration, the greater the saturation solubility of the bioactive in the aqueous phase. In this case, a core-shell SLN with bioactive-enriched shell may be more favorably formed at higher emulsifier concentrations. Regarding the location of a bioactive in NLCs, it is generally recognized that the location of the bioactive is closely related to the liquid lipid ratio (relative to solid lipid) and the relative miscibility of the bioactive in the liquid or solid lipids. Bioactives with a high lipophilicity, e.g., \(\gamma\)-oryzanol and \(\beta\)-carotene, are apt to retain in the liquid lipid or liquid  
Figure 4: (**a**) Three models for the incorporation of bioactives into SLNs: homogenous matrix model (left), core-shell models with bioactive-enriched shell (middle), and bioactive-enriched core (right). (**b**) The release kinetics of bioactives from the SLNs with the corresponding three models (above). compartments in the lipid matrix of NLCs and, as a result, the expulsion of the bioactives from the lipid matrix during the cooling decreases [45,46]. Coenzyme Q\({}_{10}\) is an interesting lipophilic nutraceutical with a relatively low melting temperature of approximately 50 \({}^{\circ}\)C. In the hot HPH case, this bioactive is present in a liquid molten state, which can be well miscible with the molten solid lipid matrix. Previous works indicated that the localization of coenzyme Q\({}_{10}\) in the tripalmitin SLN was dependent on its concentration; at low concentrations of coenzyme Q\({}_{10}\) (below 10% of the lipid matrix), this bioactive was located inside the crystalline structure of the lipid matrix, while at high concentrations, it was located on the surface of the particles forming a supercooled lipid phase [47]. In fact, coenzyme Q\({}_{10}\)-loaded SLNs at high concentrations of coenzyme Q\({}_{10}\) are considered to be a variety of NLCs, with the supercooled lipid phase of coenzyme Q\({}_{10}\) serving as the liquid lipid. The release behavior of bioactives from SLNs (or NLCs) is highly determined by the localization of bioactives in the lipid matrix of SLNs (Figure 4). As mentioned above, the localization of bioactives in an SLN is dependent on the production temperature (hot vs. cold HPH) and emulsifier concentration (in the aqueous phase). The release behavior of a bioactive from an SLN or NLC is generally biphasic--that is, an initial burst release followed by a prolonged release [11]. The extent of burst release can be modulated by adjusting the production temperature and emulsifier concentration. Additionally, the surface modifications of the SLNs may modulate the bioactive or drug release behavior of SLNs or NLCs [23].