Nanostructured Lipid Carriers

SLNs produced by high-pressure homogenization at elevated temperature (hot homogenization technique) are formed during the cooling process of the hot o/w emulsion as mentioned above.

To summarize occurring disadvantages, the immediate formation of a perfect crystal or formation during the long-term storage can cause drug expulsion. To avoid this, a less ordered lipid matrix with many imperfections is desirable for better accommodation of the drug, especially to avoid drug expulsion during storage. This approach was realized in the NLCs.

SLNs are made from solid lipids, in very special cases even highly purified lipids, which means that at least the lipid molecules are relatively similar, allowing the formation of structures with few imperfections. In contrast to this, NLCs are produced from lipid blends made from chemically very different molecules, which means mixing solid lipids with liquid lipids (oils, e.g., MCT). Due to the different chain lengths of the fatty acids and the mixture of mono-, di-, and triglycerides, the matrix is not able to form a highly ordered structure. There are many imperfections which are able to accommodate the drug. NLCs based on this principle are called the "imperfect crystal type" (type I).

The occurrence of crystallization was identified as the basic mechanism leading to drug expulsion. Consequently, one can avoid drug expulsion by avoiding lipid crystallization, which means creating solid particles of an amorphous lipid structure. This can be achieved by mixing special lipids which no longer recrystallize after homogenization and cooling down, for example, hydroxyoctacosanylhydroxystearate and isopropylmyristate [39]. This is the "amorphous type" of NLCs (type II).

For a number of drugs, the solubility in liquid lipids (oils) is higher than in solid lipids. A typical example is retinol [40]. Conventional SLNs could only be loaded with 1% retinol [41]. Therefore, to improve the loading capacity, the "multiple type" of NLCs (type III) was developed. This type is derived from water-in-oil-in-water emulsions, which means that it is, in fact, an oil-in-fat-in-water dispersion. Tiny oil nanocompartments are created inside the solid lipid matrix of the lipid nanoparticles. Of course, it is not possible to create tiny oily nanocompartments in lipid nanoparticles of, for example, a diameter of 300 or 400 nm by mechanical means. The trick is that these nanocompartments are generated by a phase-separation process. A melted lipid and a hot oil are blended; the prerequisite is that the two lipids show a miscibility gap at the used concentrations approximately at 40 °C. A hot o/w nanoemulsion is produced at higher temperature (80 °C); the lipid droplets are cooled when reaching the miscibility gap, and the oil precipitates, forming tiny oil droplets in the melted solid lipid. Subsequent solidification of the solid lipid as a solid nanoparticle matrix leads to fixation of the oily nanocompartments. The solubility of a number of drugs in the oil is higher, for example, the drug load of retinol could be increased from 1% in SLNs to about 5% in the multiple NLC type [41].

To summarize, there are three different types of NLCs offered:

I. imperfect crystal type

II. amorphous type

III. multiple type.

Comparing SLNs and NLCs, one can summarize that the novel NLCs can be used for any purpose that the SLNs have previously been exploited for. However, using the NLC system can provide additional benefits, such as drug load and avoidance or minimization of drug expulsion during storage because the spatially very different molecules are less capable of forming perfect crystalline structures.

It has been published that aqueous dispersions of SLNs are physically stable for up to three years [42]. However, it is also described that particle aggregation can occur in case a subobtimal surfactant mixture has been employed. Especially for surfactant mixtures having lecithin as one component, particle aggregation or even gel formation can occur [29, 43] (Table 2). However, for certain reasons, it might be desirable to use just a certain surfactant mixture, for example, in case the surfactants are regulatorily accepted. Examples are combinations of lecithin with Tween 80 or Poloxamer 188 for IV administration.

Also, for other administration routes, it is desirable that the lipid particle dispersions maintain their high dispersitiv-ity. To fully exploit the benefits of lipid nanoparticle dispersions, they should be finely dispersed in the gastrointestinal tract after administration as a capsule, tablet, or drink suspension. Factors leading to particle aggregation are the free diffusion of the particles, random collision and flocculation, or aggregation when overcoming the electrostatic or steric repulsion. Aqueous SLN dispersions according to the patent

Table 2. Long-term stability data of SLN formulations stabilized with different surfactants. PCS mean diameter and polydispersity index (PI).

1% Lipoid S 75 + 0.5% Poloxamer 188 5% Poloxamer 188

1% Lipoid S 75 + 0.5% Poloxamer 188 5% Poloxamer 188

Table 2. Long-term stability data of SLN formulations stabilized with different surfactants. PCS mean diameter and polydispersity index (PI).

Emulsifier Lipid

2.5% Witepsol E85

2.5% Compritol 888 ATO

2.5% Witepsol E85

2.5% Compritol 888 ATO

Size (nm)

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