W. Mehnert

Solid lipid nanoparticles: Production, characterization and applications

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

Solid lipid nanoparticles (SLN) for controlled drug delivery – Drug release and release mechanism

Solid lipid nanoparticles (SLN) are particulate systems for parenteral drug administration with mean particle diameters ranging from 50 up to 1000 nm. The model drugs tetracaine, etomidate and prednisolone were incorporated (1, 5 and 10%) to study the drug load, effect of drug incorporation on the structure of the lipid matrix and the release profiles and mechanism. SLN were produced by high pressure homogenization of aqueous surfactant solutions containing the drug-loaded lipids in the melted or in the solid state (500/1500 bar, 3/10 cycles). In case of tetracaine and etomidate, high drug loadings up to 10% could be achieved when using Compritol 888 ATO and Dynasan 112 as matrix material. The melting behavior of the drug loaded particles revealed that little or no interactions between drug and lipid occurred. A burst drug release (100% release < 1 min) was observed with tetracaine and etomidate SLN, which was attributed to the large surface area of the nanoparticles and drug enrichment in the outer shell of the particles. In contrast, prednisolone loaded SLN showed a distinctly prolonged release over a monitored period of 5 weeks. Depending on the chemical nature of the lipid matrix, 83.8 and 37.1% drug were released (cholesterol and compritol, respectively). These results demonstrate the principle suitability of SLN as a prolonged release formulation for lipophilic drugs.

Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production, characterization and sterilization

Abstract Solid lipid nanoparticles (SLN) were produced by high pressure homogenization of a melted lipid (Dynasan 112) dispersed in water at increased temperature (70°C). Soy lecithin and poloxamer 188 were used as surfactants and stabilizers of the particles. The effect of homogenization parameters (pressure, cycle number) was studied and optimized to yield solid lipid nanoparticles of a quality suitable for intravenous injection. Particles were characterized by photon correlation spectroscopy (PCS) and zeta potential measurements, the fraction of large particles being the limiting factor for i.v. injection was determined using a Coulter Counter. The optimum formulation was suitable for i.v. injection (monograph ‘Particulate Matter’, USP XXII). SLN stabilized with soy lecithin could be sterilized by autoclaving.

Cytotoxicity of Solid Lipid Nanoparticles as a Function of the Lipid Matrix and the Surfactant

AbstractPurpose. Assessment of the in vitro cytotoxicity of solid lipid nanoparticles (SLNs) as a function of lipid matrix (Dynasan 114, Compritol ATO 888), and stabilizing surfactant (poloxamers, Tween 80, soya lecithin, and sodium dodecyl sulphate). Comparison with other colloidal carriers should determine their potential use in the clinic. Methods. SLNs were produced by high pressure homogenisation. Cytotoxicity was assessed by measuring the viability of HL60 cells and human granulocytes after incubation with SLNs. Particle internalisation was quantified by chemiluminescence measurements. Results. The nature of the lipid had no effect on viability; distinct differences were found for the surfactants. Binding to the SLN surface reduced markedly the cytotoxic effect of the surfactants, e.g., up to a factor of 65 for poloxamer 184. The permanent HL60 cell line— differentiated from cells with granulocyte characteristics by retinoic acid treatment—yielded results identical to freshly isolated human granulocytes. In general, the SLNs showed a lower cytotoxicity compared to polyalkylcyanoacrylate and polylactic/glycolic acid (PLA/ GA) nanoparticles. Conclusions. Because the results are identical when using human granulocytes, differentiated HL60 cells can be used as an easily accessible in vitro test system for i.v. injectable SLN formulations. The SLNs appear suitable as a drug carrier system for potential intravenous use due to their very low cytotoxicityin vitro.

Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN)

Solid lipid nanoparticles (SLN) of a quality acceptable for i.v. administration were freeze-dried. Dynasan 112 and Compritol ATO 888 were used as lipid matrices for the SLN, stabilisers were Lipoid S 75 and poloxamer 188, respectively. To study the protective effect of various types and concentrations of cryoprotectants (e.g. carbohydrates), freeze-thaw cycles were carried out as a pre-test. The sugar trehalose proved to be most effective in preventing particle growth during freezing and thawing and also in the freeze-drying process. Changes in particle size distribution during lyophilisation could be minimised by optimising the parameters of the lyophilisation process, i.e. freezing velocity and redispersion method. Lyophilised drug-free SLN could be reconstituted in a quality considered suitable for i.v. injection with regard to the size distribution. Loading with model drugs (tetracaine, etomidate) impairs the quality of reconstituted SLN. However, the lyophilisate quality is sufficient for formulations less critical to limited particle growth, e.g. freeze-dried SLN for oral administration.

Solid lipid nanoparticles as drug carriers for topical glucocorticoids.

Recent investigations both in vitro and in human subjects proved the benefit/risk ratio of prednicarbate (PC) to exceed those of halogenated topical glucocorticoids about 2-fold. To obtain a further highly desired increase by drug targeting to viable epidermis, PC was incorporated into solid lipid nanoparticles (SLN). Keratinocyte and fibroblast monolayer cultures, reconstructed epidermis and excised human skin served to evaluate SLN toxicity and PC absorption. Well-tolerated preparations (e.g. cellular viability 94.5% following 18 h incubation of reconstructed epidermis) were obtained. PC penetration into human skin increased by 30% as compared to PC cream, permeation of reconstructed epidermis increased even 3-fold. The present study shows the great potential of SLN to improve drug absorption by the skin.

Phagocytic Uptake and Cytotoxicity of Solid Lipid Nanoparticles (SLN) Sterically Stabilized with Poloxamine 908 and Poloxamer 407

Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure homogenisation of melted lipids (glycerolbehenate, cetylpalmitate). Their surface was modified by using hydrophilic poloxamine 908 and poloxamer 407 blockcopolymers in order to reduce the phagocytic uptake by the reticuloendothelial system (RES) after i. v. injection. The phagocytosis reducing effect of the polymers was investigated in vitro in cultures of human granulocytes, uptake was quantified by chemiluminescence. Modification of the SLN with poloxamine 908 and poloxamer 407 reduced the phagocytic uptake to appr. 8-15% compared to the phagocytosis of hydrophobic polystyrene particles. The modified SLN proved more efficient in avoiding phagocytic uptake than polystyrene particles surface-modified with these blockcopolymers (48% and 38%, respectively). Viability determinations revealed the SLN to be 10 fold less cytotoxic than polylactide nanoparticles and 100 fold less than butylcyanoacrylate particles.

Drug Targeting by Solid Lipid Nanoparticles for Dermal Use

Long term topical glucocorticoid treatment can induce skin atrophy by the inhibition of fibroblasts. We, therefore, looked for the newly developed drug carriers that may contribute to a reduction of this risk by an epidermal targeting. Prednicarbate (PC, 0.25%) was incorporated into solid lipid nanoparticles of various compositions. Conventional PC cream of 0.25% and ointment served for reference. Local tolerability as well as drug penetration and metabolism were studied in excised human skin and reconstructed epidermis. With the latter drug recovery from the acceptor medium was about 2% of the applied amount following PC cream and ointment but 6.65% following nanoparticle dispersion. Most interestingly, PC incorporation into nanoparticles appeared to induce a localizing effect in the epidermal layer which was pronounced at 6 h and declined later. Dilution of the PC-loaded nanoparticle preparation with cream (1:9) did not reduce the targeting effect while adding drug-free nanoparticles to PC cream did not induce PC targeting. Therefore, the targeting effect is closely related to the PC-nanoparticles and not a result of either the specific lipid or PC adsorbance to the surface of the formerly drug free nanoparticles. Lipid nanoparticle-induced epidermal targeting may increase the benefit/risk ratio of topical therapy.

Physicochemical Investigations on Solid Lipid Nanoparticles and on Oil-Loaded Solid Lipid Nanoparticles: A Nuclear Magnetic Resonance and Electron Spin Resonance Study

AbstractPurpose. Recently, colloidal dispersions made of mixtures from solid and liquid lipids have been described to combine controlled-release characteristics with higher drug-loading capacities than solid lipid nanoparticles (SLNs). It has been proposed that these nanostructured lipid carriers (NLCs) are composed of oily droplets that are embedded in a solid lipid matrix. The present work investigates the structure and performance of NLCs. Methods. Colloidal lipid dispersions were produced by high-pressure homogenization and characterized by laser diffraction, photon correlation spectroscopy, wide-angle x-ray scattering, and differential scanning calorimetry. Proton nuclear magnetic resonance spectroscopy and electron spin resonance experiments were performed to investigate the mobility of the components and the molecular environment of model drugs. Furthermore, a nitroxide reduction assay with ascorbic acid was conducted to explore the accessibility of the lipid model drug from the outer aqueous phase. Results. Proton nuclear magnetic resonance spectra clearly demonstrate that NLC nanoparticles differ from nanoemulsions and from SLNs by forming a liquid compartment that is in strong interaction to the solid lipid. The electron spin resonance model drug was found to be accommodated either on the particle surface with close water contact (SLN) or additionally in the oil (NLC). The oil compartment must be localized on the particle surface, because it can be easily reached by ascorbic acid. Conclusion. Neither SLN nor NLC lipid nanoparticles showed any advantage with respect to incorporation rate or retarded accessibility to the drug compared with conventional nanoemulsions. The experimental data let us conclude that NLCs are not spherical solid lipid particles with embedded liquid droplets, but they are rather solid platelets with oil present between the solid platelet and the surfactant layer.

Atomic Force Microscopy Studies of Solid Lipid Nanoparticles

AbstractPurpose. Solid Lipid Nanoparticles (SLN) are an alternative carrier system for the controlled delivery of drugs. In most cases prednisolone loaded SLN show a biphasic release behaviour. The initial phase is characterised by a fast drug release, which is followed by a sustained drug release over several weeks. Methods. The particles are produced by high pressure homogenisation of a lipid (e.g. compritol, cholesterol) dispersed in an aqueous surfactant solution. In this study atomic force microscopy was used to image the original unaltered shape and surface properties of the particles. The crystallinity of the nanoparticles was investigated by differential scanning calorimetry. Results. The AFM investigations revealed the disc like shape of the particles. From differential scanning calorimetry data it can be concluded that the particle core is in the crystalline state. Additionally it was proven that the particles are surrounded by a soft layer. Conclusions. Thus it is conceivable that the fast initial drug release during in vitro dissolution tests takes place by drug release of the outer non-crystalline layers of the particles. The following sustained drug release can be assigned to the predisolone release of the inner crystalline particle layers.