Nanostructured lipid matrices for improved microencapsulation of drugs

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Abstract

At the beginning of the nineties solid lipid nanoparticles (SLN) have been introduced as a novel nanoparticulate delivery system produced from solid lipids. Potential problems associated with SLN such as limited drug loading capacity, adjustment of drug release profile and potential drug expulsion during storage are avoided or minimised by the new generation, the nanostructured lipid carriers (NLC). NLC are produced by mixing solid lipids with spatially incompatible lipids leading to special structures of the lipid matrix, i.e. three types of NLC: (I) the imperfect structured type, (II) the structureless type and (III) the multiple type. A special preparation process–applicable to NLC but also SLN–allows the production of highly concentrated particle dispersions (>30–95%). Potential applications as drug delivery system are described.

Introduction

The use of solid lipid matrices for the prolonged release of drugs is known in pharmacy for many years, i.e. drug release from lipid pellets. Based on this, consequently it was only a matter of time until the production of lipid microparticles, e.g. by spray-congealing by Speiser et al. (Eldem et al., 1991). In the next step the first generation of lipid nanoparticles was produced, the so-called lipid nanopellets for oral administration (Speiser, 1990). For certain reasons this development was not continued. At the beginning of the nineties the second generation was developed, the solid lipid nanoparticles (SLN) either produced by high pressure homogenisation (Müller and Lucks, 1996) or alternatively using the microemulsion precipitation technique (Gasco, 1993). A detailed review of the state of the art of the SLN is given in recently published reviews (Müller et al., 2000, Mehnert and Mäder, 2001).

The development of SLN overcame many problems related to ‘traditional’ nanoparticulate carrier technologies which limited the use (e.g. liposomes, i.v. emulsions) or even prevented the introduction to the market (e.g. polymeric nanoparticles). SLN can be prepared from regulatorily accepted excipients, these excipients are well tolerated, large scale production by high pressure homogenisation is possible – even using existing production lines for i.v. emulsions, and the technology and the product itself are low cost. However, there are also some potential limitations. Especially the review by Mäder and Mehnert critically highlights potential limitations which might occur:

  • 1

    limitation in drug loading capacity;

  • 2

    drug expulsion during storage;

  • 3

    high water content of aqueous SLN dispersions (70–95%).

This consequently led to a new, improved generation of lipid nanoparticles, the NLC. In contrast to SLN being produced from solid lipids, the NLC are produced by controlled mixing of solid lipids with spatially incompatible liquid lipids leading to special nanostructures with improved drug incorporation and release properties. The paper describes the different types of NLC including production of highly concentrated particle dispersions and their application as drug delivery system.

Section snippets

Materials and methods

The lipids (e.g. Imwitor 900) were obtained from Condea (Witten, Germany) or alternatively (e.g. Compritol 888ATO, Precifac ATO) from Gattefossé (Weil am Rhein, Germany). The surfactants Miranol etc. were obtained from Rhodia (Frankfurt, Germany). All other materials were purchased from Sigma Chemicals (Deisenhofen, Germany).

Particle production was performed using a Micron LAB 40 (APV Systems GmbH, Unna, Germany). Typically particle production was performed at 500 bar applying different numbers

Types of NLC

Since many years it is well known from suppositories that drug expulsion can occur during storage. The lipid transforms to the more perfect β-modification, the increase in perfection of the crystal leaves less space to accommodate drug molecules thus leading to drug expulsion. The same phenomenon can potentially occur when producing SLN.

SLN are produced by dissolving or dispersing the drug in the lipid melt, the lipid melt is dispersed in a hot aqueous surfactant mixture by high speed stirring

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