Introduction

Nanoparticulate drug carriers in their broadest sense are currently under intensive investigation. Under development are liposomes, oil-in-water (o/w) emulsions, and solid nanoparticles made from polymers or natural or synthetic macromolecules. The use of parenteral o/w emulsions for parenteral nutrition started in the middle of the 1950s; about one decade later, interest started focusing on their use for intravenous drug delivery. Nowadays, drug-loaded intravenous emulsions are established as a carrier system on the market. However, there are only a very limited number of active compounds incorporated in these systems (diazepam, etomidate, and propofol), also resulting in a low number of market products. One of the reasons for this is that the solubility of poorly water-soluble drugs that are of commercial interest is too low in the currently available registered oils (e.g., soya oil, MCT). Potential sales figures do not justify the investment for performing extensive toxicity studies for new oil excipients.

Up to now, a reasonable number of liposomal products have appeared on the market; a decent number is in the clinical phases. However, the number of products is still far behind the expectations from the 1980s and 1990s of the last century. The reasons for this are manifold; examples are physical stability problems and the high cost of liposomes. Products such as Amphotericin liposomes need to be lyophilized for long-term storage; a tedious reconstitution procedure is necessary (e.g., Ambisome). There are no "cheap" liposomes available; the high costs are a large obstacle for the broad introduction of these carriers to the market. For example, the costs of daily treatment with the product Fungizone are only $24 a day, and treatment with Amphotericine liposomes as a product is about $1300 a day [1].

Almost 30 years of intensive research have been invested in nanoparticles since their development by Speiser et al. in the middle of the 1970s. Many review and research articles have reported the benefits of these systems for controlled drug delivery; however, as market products, they are practically nonexistent. Again, the problems are manifold. There is a lack of regulatorily accepted polymers; newly synthesized polymers have many nice features, but require expensive tox-icity studies before acceptance by the regulatory authorities. Even polymers regulatorily accepted for use as implants can show cytotoxic effects when delivered as nanoparticles or very small microparticles [2]. Other problems are also the cost of production, especially the lack of large-scale production methods able to be qualified, validated, and leading to a product being acceptable to the regulatory authorities. There are interesting data in academic research; however, there is a lack of concepts to transfer these successes to the industrial scale, and finally to products with benefit for the patient.

To summarize, there is still a definite need for a nano-particulate carrier system possessing the benefits of the above-mentioned "traditional" carriers, but simultaneously avoiding their major disadvantages. The first concept to realize a really versatile carrier was the development of solid lipid nanoparticles (SLNs) [3, 4]. The SLNs are nano-particles; the matrix is composed of a lipid that is solid at room temperature, but also at body temperature. One can simply derive the SLNs from o/w emulsions by replacing the

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Encyclopedia of Nanoscience and Nanotechnology Edited by H. S. Nalwa Volume 10: Pages (43-56)

liquid lipid (oil) by a solid lipid. They possess the advantages of the different traditional nanoparticulate carriers. Similar to emulsions and liposomes, they are composed of well-tolerated, accepted excipients, and can be produced on a large industrial scale by a simple high-pressure homoge-nization process. For topical delivery of SLNs, the full range of excipients in cosmetic and pharmaceutical topical products can be exploited. For oral SLNs, all lipids and surfactants used for tablets, capsules, and other oral products such as microemulsions can be used. For parenteral administration, the lipid matrix can be produced from glycerides that are composed of fatty acids contained in the glycerides of emulsions for parenteral nutrition. Existing production lines for parenteral emulsions can be used to produce SLN dispersions.

A major disadvantage of emulsions and liposomes is the lack of protection for chemically labile drugs; in addition, drug release takes place as a burst (emulsions) or at least relatively fast (from liposomes). In contrast to this, SLNs possess a solid lipid matrix identical to nanoparticles from polymers and macromolecules. The solid matrix slows down drug release; SLNs have many more possibilities of modulating the release [5]. To summarize, SLNs definitely possess major advantages over the existing previous carriers; simultaneously, they also avoid some of their major disadvantages. Another major advantage of SLNs is that they are "low-cost" products. Excipients and production lines are relatively inexpensive, and production costs are not that much higher compared to a parenteral emulsion.

The first patents for SLNs were filed in 1991, one by Müller and Lucks [3] describing the production of SLNs by high-pressure homogenization, and another by Gasco [4] describing the production via microemulsions. Generally, for the high-pressure homogenization technique, the drug is dissolved in the melted lipid, the drug-containing lipid melt is dispersed in a hot surfactant solution by stirring, and the obtained preemulsion is homogenized at a temperature about 5 °C above the melting point of the lipid. The obtained hot o/w nanoemulsion is cooled, the lipid recrystallizes, and forms SLNs. The microemulsion technique involves the formation of a hot microemulsion based on the melted lipid. The drug-containing microemulsion is then poured into cold water, and SLNs are precipitated. The new carrier system attracted much attention, as is clearly indicated by the number of research groups; an overview is given in the first SLN review published in 1995 [6]. The success continued within the first decade of SLN research, clearly evident from the latest two SLN reviews published in 2000 [7] and 2001 [8].

However, the SLNs were the first generation of a solid lipid nanoparticulate carrier. They can be considered as a solid development with interesting applications; however, there was still some room for improvements, which were realized in the next generation, the so-called nanostructured lipid carriers (NLCs) [9]. The basic difference is that, in the NLC concept, controlled nanostructuring of the lipid matrix is performed to increase drug load, physical stability, to give more flexibility in the modulation of drug release, and also to provide an improved, smarter production technology.

This chapter describes the features of the novel NLCs, and highlights the improvements compared to the firstgeneration SLNs.

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