Structural investigations on lipid nanoparticles containing high amounts of lecithin

https://doi.org/10.1016/j.ejps.2005.10.004Get rights and content

Abstract

Solid lipid nanoparticles (SLN), an alternative colloidal drug delivery system to polymer nanoparticles, emulsions and liposomes, possess inherent low incorporation rates resulting from the crystalline structure of the solid lipid. To increase the drug loading capacity of SLN, matrix modification by incorporation of the amphiphilic lipid lecithin within the lipid matrices has been proposed as a promising alternative. The objective of this work is to investigate the effects of the lecithin on the microstructure of matrix modified SLN. In addition, these systems were checked for the existence of aggregates like mixed micelles, liposomes, etc., which could possibly be formed by lecithin leakage into the aqueous phase during the preparation process. For this purpose, laser diffraction, photon correlation spectroscopy (PCS), small angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR) and transmission electron microscopy (TEM) were performed to investigate the structure, mobility, and molecular environment of the compounds. Lecithin incorporation within the lipid matrices resulted in a concentration dependent decrease in particle size up to a critical concentration of 30%. Lecithin incorporation up to 50% was investigated but caused no further particle size decrease. TEM revealed anisometrical and crystalline platelets of ellipsoidal to disc-like shape. Furthermore, SAXS and TEM showed no signs of lecithin and nonionic emulsifier derived aggregates in the aqueous phase. This points in agreement with NMR measurements to a strong attachment of both substances to the SLN surfaces. The proposed structure of the particles after melt emulsification consists of two different layers: a crystalline triglyceride-rich core is covered in dependence of the lecithin content either by a monomolecular or multimolecular lecithin/Solutol® HS15 (SOL) layer.

Introduction

Nanoparticles based on solid lipids (SLN) have been proposed as an alternative colloidal drug delivery system to polymer nanoparticles, emulsions and liposomes (Siekmann and Westesen, 1992, Müller and Lucks, 1996). SLN are in the submicron size range and are composed of solid lipids, such as triacylglycerols, waxes, and paraffins (Jenning and Gohla, 2000; de Vringer and de Ronde, 1995). Depending on the intended type of application, different pharmaceutical and cosmetic surfactants and surfactant blends, e.g. poloxamers, bile salts and polysorbates, can be used as stabilisers (Siekmann and Westesen, 1992, Schwarz et al., 1994, Friedrich and Müller-Goymann, 2003). SLN can be prepared by precipitation from microemulsions and emulsions containing organic solvents (Gasco, 1993, Siekmann and Westesen, 1996). Yet, the standard SLN production method is the melt emulsification preferably by high-pressure homogenisation avoiding organic solvent and allowing large-scale production. Drug incorporation is accomplished by dissolving/dispersing the drug in the molten lipid prior to high-pressure homogenisation. The encapsulation of active ingredients into the solid lipid matrix offers protection against chemical degradation of the active compound as well as a controlled drug delivery (zur Mühlen et al., 1998, Müller et al., 2000). Depending on drug solubility within the lipid matrix, SLN drug load related to the lipid matrix varies from less than 1% for iotrolan up to 50% as in the case of ubidecarenone (Mehnert et al., 1997, Westesen et al., 1997). So far, a wide variety of drugs, such as prednisolone, doxorubicin, retinal, etc., have been successfully incorporated into SLN (Mehnert et al., 1997, Cavalli et al., 1993, Jenning et al., 2000a). However, for most drugs the payload is low because of the crystalline structure of the lipid matrices and drug expulsion is observed upon storage (Westesen et al., 1997). Jenning et al. (2000c) attribute drug expulsion to a reduction of amorphous regions in the carrier lattice due to polymorphic transitions. These disadvantages led to the development of oil-loaded SLN (also described as nanostructured lipid carrier (NLC)), which are claimed to increase drug loading capacity and to minimise drug expulsion (Jenning et al., 2000d; Müller et al., 2002). Yet, Jores et al., 2003, Jores et al., 2004 demonstrated that the proposed structures of oil-loaded SLN do not exist and that this type of SLN possesses no advantages compared to conventional nanoemulsions.

Friedrich and Müller-Goymann, 2003, Friedrich and Müller-Goymann, 2004 used an alternative approach to increase SLN payload by modifying the lipid matrix by incorporation of the amphiphilic lipid lecithin. Previous studies from our group have shown that the solubilised amount of drug increases linearly with increasing lecithin concentration within the undispersed lipid matrix. The increase of the drug loading capacity of the undispersed lipid matrix has been attributed to a formation of reverse micelles in the melt allowing additional drug incorporation. Furthermore, it was postulated that these aggregates are even preserved after solidification of the lipid matrix. To obtain SLN with an increased payload and a matrix controlled drug release, however, it has to be ensured that the reverse micelles are still present within the lipid matrix of the dispersed particles after melt homogenisation and that no lecithin redistribution to the particle interface or even leakage of lecithin into the aqueous phase takes place. The objective of this work is to investigate the effects of lecithin on the microstructure of matrix modified SLN and whether other aggregates like mixed micelles, liposomes, etc., are formed from lecithin leakage into the aqueous phase during the preparation process. For this purpose, several analytical techniques including X-ray scattering, nuclear magnetic resonance (NMR) and transmission electron microscopy (TEM) were applied. Different SLN formulations containing 0–50% (w/w) lecithin within the lipid matrix were compared to reference systems to gain more detailed structural information of the final colloidal lipid suspension.

Section snippets

Materials

Softisan® 154 (S154), also called “hydrogenated palm oil”, was a gift from CONDEA (Witten, Germany). It is a triglyceride mixture of natural, hydrogenated, even chained and unbranched fatty acids with a melting point of about 55–60 °C.

Phospholipon® 90G (P90G) provided by Nattermann Phospholipid (Köln, Germany) is a purified, deoiled and granulated soy lecithin with a phosphatidylcholine content of at least 90% and an HLB value of 10. According to Ghyczy and Niemann (1992), the fatty acids of the

Particle size measurements

The particle size measurements of LNP (Table 1) revealed that the incorporation of lecithin up to 30% (w/w) within the lipid matrices led to a concentration dependent particle size reduction down to 100 nm. Further solubilisation of lecithin as far as 50% (w/w) within the lipid matrix was investigated, but caused no further particle size decrease. Particle sizes of LNP containing 5% and 15% of the lipid matrix were similar as well as polydispersity indices. The only exception is LNP(10) which

Conclusion

Crystalline anisometrical particles of ellipsoidal to disc-like shape derive from melt emulsification of lipid matrices containing high amounts of lecithin. The particles themselves are composed of two different layers: a crystalline core enriched with triglyceride is covered in dependence of the lecithin content either by a monomolecular or multimolecular lecithin layer in which the nonionic emulsifier SOL is incorporated, its hydrophilic polyethyleneglycol chains provide the outmost particle

Acknowledgements

The authors would like to thank BASF, Condea and Nattermann Phospholipid for kind support with materials, Professor Dr. L. Ernst and Dr. L. Preu for their discussions on NMR measurements.

References (36)

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