Preparation of solid lipid nanoparticles by a solvent emulsification–diffusion technique

Abstract

A preparation method for nanoparticles based on the emulsification of a butyl lactate or benzyl alcohol solution of a solid lipid in an aqueous solution of different emulsifiers, followed by dilution of the emulsion with water, was used to prepare glyceryl monostearate nanodispersions with narrow size distribution. To increase the lipid load the process was conducted at 47±2 °C and in order to reach submicron size a high-shear homogenizer was used. Particle size of the solid lipid nanoparticles (SLN) was affected by using different emulsifiers and different lipid loads. By using lecithin and taurodeoxycholic acid sodium salt, on increasing the GMS percentage from 2.5 to 10% an increase of the mean diameter from 205 to 695 nm and from 320 to 368 nm was observed for the SLN prepared using benzyl alcohol and butyl lactate, respectively. Transmission electron micrographs of SLN reveal nanospheres with a smooth surface.

Introduction

The use of nanoparticles as drug-carrier system is a very attractive possibility to achieve controlled drug release. A clear advantage of solid lipid nanoparticles (SLN) over polymeric nanoparticles is the fact that the lipid matrix is made from physiological lipids, which decreases the danger of acute and chronic toxicity (Mehnert and Mader, 2001).

The techniques commonly used to produce SLN are based on high-pressure homogenization, dilution of microemulsions or solvent removal from oil-in-water emulsions. There are two general approaches within the homogenization technique, hot and cold homogenization: in both cases, a preliminary step involves drug incorporation into the lipid melt. Hot homogenization (Muller and Lucks, 1996, Muller and Runge, 1998) can therefore be regarded as homogenization of an emulsion, while cold homogenization (Jahnke, 1998) is effectively high-pressure milling of a suspension. Most SLN produced by hot homogenization are characterized by an average particle size below 500 nm and low microparticle content. In general, compared to hot homogenization, larger particle size and broader size distribution are observed in cold homogenized samples (Mehnert and Mader, 2001). Cold homogenization minimizes thermal exposure of the drug but does not avoid it completely, due to the melting of the drug–lipid mixture in the initial step. Other problems of hot homogenization, such as drug entrapment and crystallization, can however, be overcome.

Gasco (1993) developed an SLN preparation technique based on dilution in cold water of an oil-in-water microemulsion. For a microemulsion to be formed with a solid lipid at room temperature, it must be heated above the melting point of the lipid. Surfactants and co-surfactants include lecithin and bile salts, but also alcohols such as butanol, which is less favorable in regulatory terms. Subsequent addition of the microemulsion to water leads to precipitation of the lipid phase forming fine particles. Large-scale production of SLN by the microemulsion technique also appears feasible (Carli, 1999).

Another proposed technique to produce SLN is the solvent emulsification–evaporation method (Sjostrom and Bergenstahl, 1992, Siekmann and Westesen, 1996). The lipid matrix is dissolved in a water-immiscible organic solvent (e.g. chloroform) that is emulsified in an aqueous phase. Upon evaporation of the solvent under reduced pressure, a nanoparticle dispersion is formed by precipitation of the lipid in the aqueous medium. Depending on the fat load and emulsifier used, particles with average diameters of 30–100 nm can be obtained. An important advantage of this technique is the avoidance of any heat. On the other hand, solvent emulsification–evaporation suspensions are fairly dilute, due to the limited solubility of the lipids in the organic solvents used. Furthermore, in contrast to hot homogenization, the solvent-evaporation method may create toxicological problems arising from solvent residues.

In a previous study (Trotta et al., 2001) drug nanosuspensions were prepared from emulsions containing partially water-miscible solvents with low toxicity, such as benzyl alcohol or butyl lactate, by a solvent diffusion technique. The process is based on the water miscibility of these solvents. Upon transferring a transient oil-in-water emulsion into water, the drug dissolved in the organic solvent solidifies instantly due to diffusion of the organic solvent from the droplets to the continuous phase. Using optimized formulations, drug nanoparticles below 100 nm with very low polydispersity were obtained.

Recent studies, however, have corroborated that water immiscibility of a disperse solvent is not a prerequisite for making emulsions for preparing microspheres; the solvent diffusion technique using ethyl formate, methylethyl ketone or benzyl acohol (Sah, 2000, Sah et al., 1996, Leroux et al., 1995) lead to successful fabrication of good quality drug-loaded PLGA microspheres.

The aim of this study was to investigate the feasibility of preparing glyceryl monostearate nanoparticles from solvent-in-water emulsions by the diffusion technique, using solvents and surfactants accepted as having low toxicity.