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Delivering Actives via Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Part I
By: Johann W. Wiechers, PhD, JW Solutions, and Eliana B. Souto
Posted: September 29, 2010, from the October 2010 issue of Cosmetics & Toiletries.
- Figure 1. Schematic representation of SLNs (left) and NLCs (right); modified from Reference 4.
- Figure 2. The production process of lipid nanoparticles using cold (left, light gray) and hot (right, dark gray) high pressure homogenization; reproduced with permission from Reference 4.
- Figure 3. Models of actives incorporated in lipid nanoparticles, homogeneous matrix; a) type I SLNs, b) type II SLNs, and c) type III SLNs; modified from Reference 4.
- Figure 4. The effect of adding chemically different lipids to a pure lipid; at left, the melting and crystallization temperatures of a pure lipid are shown—both quite high and with a relatively small difference (i.e., supercooling).
- Figure 5. Summary of selection criteria of lipid materials to be used in SLNs and NLCs
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High pressure homogenization: High pressure homogenizing is by far the most popular method to produce both SLNs and NLCs. In fact, it is not too different from the normal production o/w emulsions. A schematic overview of both the hot and cold homogenization process is shown in Figure 2.
Similar to the emulsification procedure, the lipid phase is heated and the lipophilic cosmetic active or active pharmaceutical ingredient (API) is added. For emulsions, this is typically carried out at 80°C but for SLNs, this temperature must be above the melting point of the fat mixture; for NLCs, it must be above the melting point of the fat and oil mixture. The active or API is subsequently dissolved in this melted oil fraction, at which point the formulator has the choice to homogenize, under high pressure, a hot or a cooled pre-emulsion. The mixture can be immediately cooled so that it solidifies, a practice used particularly when working with thermolabile actives. The resulting lipid block is subsequently grinded to create lipid microparticles, which are then added to an aqueous surfactant formulation and mixed to create a cold pre-emulsion. Or, if the active ingredient is not thermolabile, the hot lipid/active ingredient melt can be dispersed in a hot surfactant solution in water and mixed to create a hot pre-emulsion.
Next, the cold or hot pre-emulsion is poured into the high pressure homogenizer and a thick, white paste or aqueous suspension emerges. Oftentimes, this cycle is repeated but typically there is no further reduction in particle size after three to five consecutive runs at 500–1,500 bar.7 It should be noted that especially for thermolabile actives, during each cycle, the temperature in the homogenizer and thus of the pre-emulsion will increase by roughly 10°C for every 500 bar of pressure since the speed with which the particles emerge from the high pressure chamber can be as high as 1,000 km/hr. This is why most high pressure homogenizers also have a temperature control function to cool the SLNs and NLCs produced.
At this point, the hot nano-emulsion must cool, which sounds simple but is in fact one of the most critical steps in the whole production process for SLNs and NLCs. The ratio between the lipid and active ingredient content will determine the type of SLN/NLC produced. Figure 3 provides a schematic representation.
As the preparation cools, the lipid phase will solidify, and depending on the lipid to active ratio, three different scenarios become possible. If the ratio is ideal, the lipid and active will precipitate together and create a nanoparticle with a constant concentration as a function of depth from the particle surface. This is called a Type I SLN/NLC. A second scenario occurs when there is relatively too much lipid; in such Type II nanoparticles, the lipid precipitates first, thus lowering the lipid content of the mixture until the ideal lipid to active ratio is reached and a constant content of active precipitates within the lipid. These nanoparticles will be active-enriched on the outside. Finally, if there is relatively too much active, the active will precipitate first, lowering the active content until the ideal lipid to active ratio is reached and a constant content of active precipitates with the lipid. Such Type III nanoparticles will be active-enriched on the inside.