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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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Mehnert and Mäder have listed a whole series of fats typically used in the production of SLNs.7 The lipid phase is made from physiological lipids, which decreases the chances of acute or chronic toxicity. These lipids can be subdivided into triglycerides and hard fat types. Whereas many medium chain triglycerides are used in cosmetics, the triglycerides used for SLNs are fats with a much higher crystallinity, such as tricaprin (tri-C10), trilaurin (tri-C12), trimyristin (tri-C14), tripalmitin (tri-C16) and tristearin (tri-C18). The higher crystallinity of these molecules is due to the identical nature of their side chains. Of the hard fat types, glyceryl monostearate, glyceryl behenate and stearic acid are especially used, while partial triglycerides and waxes like cetyl palmitate are only occasionally used.7 The choice of emulsifier is less critical; all classes of emulsifiers with respect to molecular weight and charge have been used to stabilize the lipid dispersions in SLNs and NLCs. It has been found that a combination of emulsifiers may prevent particle agglomeration more efficiently, similar to emulsion stabilization. The best results are often obtained with 5% sodium cholate or poloxamer 188, or 10% tyloxapol.
The concentration of surfactant is important and a sufficient amount must be used to cover the newly formed surface areas created during the high pressure homogenization process. In addition, this coverage must occur quickly since the timing of the redistribution process of emulsifier molecules varies between particle surfaces, water-solubilized monomers, and micelles or liposomes. In general, sodium lauryl sulfate and other low molecular weight surfactants rapidly achieve a new equilibrium, whereas redistribution takes longer with high molecular weight surfactants such as poloxamer and lecithin. However, it is not recommended to use rapidly distributing surfactants like SDS exclusively because their ability to cover surfaces rapidly is often combined with considerable water solubility and toxicity.7 This is why poloxamer 188, a polyoxyethylene polyoxypropylene block polymer, and tyloxapol, an oxyethylated-t-octylphenolpolymethylene polymer, are so popular for the production of SLNs and NLCs. The selection criteria for these materials are described later.
Actives in SLNs and NLCs
In 2007, a review article was published listing many well-known drugs that have been incorporated into lipid particles for administration onto the skin and/or mucosa.8 The list also included chemicals intended for cosmetic benefits. The drugs included betamethasone valerate, chloramphenicol, cortisone, dexamethasone, hydrocortisone, indomethacin, metronidazole, pilocarpine and progesterone; the cosmetic actives included the hair growth promoter benzyl nicotinate and the anti-dandruff agent ketoconazole.8 The interesting and logical characteristic in common between all these materials is that they are all lipophilic, which would be expected since they must be dissolved in the lipid melt to produce SLNs and NLCs.
In 2009, another review was published listing examples of APIs incorporated into NLCs as well as some well-known cosmetic actives: ascorbyl palmitate, beta-carotene and coenzyme Q10.3 Again, only lipophilic actives were incorporated. While the idea of incorporating more water-soluble actives is appealing from a thermodynamic point of view, it is unfavorable from a physicochemical point of view since during the heating process, the solubility of the active in the water phase will be increased to the point that the active will likely never return to the lipid phase of the SLN or NLC.
However, adsorption is a different option, which was attempted for proteins;9 although in this case, formulators must consider association efficiency rather than encapsulation efficiency. The association efficiency varied dramatically for the large peptides investigated, ranging from 2–5% for thymopentin with SLNs produced via the microemulsion technique, to 100% for bovine serum albumin with SLNs produced via hot high pressure homogenization as well as the microemulsion method; lysozymes with SLNs produced by cold high pressure homogenization; and streptavidin with SLNs produced by the microemulsion method (or dilution).10 Generally stated, it can be concluded that SLNs and NLCs have until now demonstrated their use as skin delivery systems for lipophilic APIs and cosmetic active ingredients only.