Vitamin A-loaded solid lipid nanoparticles for topical use: drug release properties.

Burst release as well as sustained release has been reported for SLN suspensions. For dermal application, both features are of interest. Burst release can be useful to improve the penetration of a drug. Sustained release becomes important with active ingredients that are irritating at high concentrations or to supply the skin over a prolonged period of time with a drug. Glyceryl behenate SLN were loaded with vitamin A and the release profiles were studied. Franz diffusion cells were used to assess the release kinetic over a period of 24 h. Within the first 6 h retinol SLN displayed controlled release. After longer periods (12-24 h) the release rate increased and even exceeded the release rate of comparable nanoemulsions. Pure SLN dispersions are characterised by low viscosity. In contrast to membranous vesicles, SLN can also be stably incorporated in convenient topical dosage forms like hydrogels or creams. In the Franz diffusion cell these preparations showed a controlled release over 12-18 h. Similar to SLN dispersions an increase in release rate over a 24-h period was found. A good correlation between polymorphic transitions and increased drug release was observed in this study. Sustained release was often related to the metastable beta' polymorph. Drug expulsion is explained by a reduction of amorphous regions in the carrier lattice due to a beta'-->beta(i) polymorphic transition. This transformation can be controlled with surfactant mixtures or, in the case of the hydrogel and oil/water cream, with humectants or gelling agents. Thus, the release rate for the topical route of application is adjustable.

Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin.

To evaluate the potential use of solid lipid nanoparticles (SLN) in dermatology and cosmetics, glyceryl behenate SLN loaded with vitamin A (retinol and retinyl palmitate) and incorporated in a hydrogel and o/w-cream were tested with respect to their influence on drug penetration into porcine skin. Conventional formulations served for comparison. Excised full thickness skin was mounted in Franz diffusion cells and the formulations were applied for 6 and 24 h, respectively. Vitamin A concentrations in the skin tissue suggested a certain drug localizing effect. High retinol concentrations were found in the upper skin layers following SLN preparations, whereas the deeper regions showed only very low vitamin A levels. Because of a polymorphic transition of the lipid carrier with subsequent drug expulsion following the application to the skin, the drug localizing action appears to be limited for 6-24 h. Best results were obtained with retinol SLN incorporated in the oil-in-water (o/w) cream retarding drug expulsion. The penetration of the occlusion sensitive drug retinyl palmitate was even more influenced by SLN incorporation. Transepidermal water loss (TEWL) and the influence of drug free SLN on retinyl palmitate uptake exclude pronounced occlusive effects. Therefore enhanced retinyl palmitate uptake should derive from specific SLN effects and is not due to non-specific occlusive properties.

Comparison of wax and glyceride solid lipid nanoparticles (SLN).

The present study compares solid lipid nanoparticles (SLN) formulated with either wax or glyceride bulk material. While most published data deal with glyceride SLN, little knowledge is reported on wax carriers. The two types were compared with respect to drug encapsulation efficacy, particle size distribution after production and storage, and crystal packing. The inclusion of retinol as a model drug was investigated. Retinol is chemically unstable in water and rather stable in lipid phases. Thus, rapid degradation of retinol indicates rapid drug expulsion from the carrier. Good stability indicates an effective drug encapsulation in the lipid phase of the nanoparticles. Particle size distribution was measured by laser diffractometry. Subcell packing and assignment of polymorphic forms was investigated by WAXS measurements. Glyceride SLN showed good drug encapsulation, while physical stability was poor. In contrast, wax SLN possessed good physical stability but lacked sufficient drug encapsulation in the solidified state. These differences were attributed in part to different crystal packing. Less ordered crystal lattices favour successful drug inclusion, as in the case of glyceryl monosterate and glyceryl behenate SLN. The highly ordered crystal packing of wax SLN comprised of beeswax or cetyl palmitate, for instance, leads to drug expulsion, but also to superior physical stability.

Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids.

A drug carrier of colloidal lipid particles with improved payloads and enhanced storage stability was investigated. Based on the experiences with hard fats nanoparticles, a new type of solid lipid nanoparticles (SLN) has been developed by incorporating triglyceride containing oils in the solid core of said particle. The structure and mixing behaviour of these particles were characterised and practical implications on controlled release properties tested. Nanoparticles were characterised by their melting and recrystallisation behaviour as recorded by differential scanning calorimetry (DSC). Polymorphic form and bilayer arrangement were assigned by wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS). Size distribution and storage stability were investigated by laser diffractometry (LD). Release properties were studied by drug release model according to Franz. A medium chain triglyceride oil was incorporated successfully in a matrix of a solid long chain glyceride. The crystal order was greatly disturbed, however, the carrier remained solid. The oil inside the particle remained in a liquid state and induced a slight shift form the beta' polymorph to the beta(i) form. Long spacings varied within 0.1 nm with increasing oil loads. Nanoparticles with low oil concentrations showed sustained release properties. Improved drug load levels were encapsulated by lipid particles supplemented with oily constituents. Thus, the presented carrier adds additional benefits to the well-known opportunities of conventional SLN and is suited for topical use.

Solid lipid nanoparticles (SLN) based on binary mixtures of liquid and solid lipids: a (1)H-NMR study.

SLN with improved payloads and enhanced storage stability were investigated. Based on the experiences with solid lipid nanoparticles, a new type of solid lipid nanoparticle has been developed by incorporating triglyceride containing oils in the solid shell of the particle. The structure and mixing behaviour of these particles was characterised by DSC and (1)H-NMR. DSC yields information on the melting and crystallisation behaviour of the solid and liquid constituents of the particles. NMR is especially suited for the characterisation of the liquid oil domains inside the SLN. In this study a medium chain triglyceride oil was successfully incorporated in a matrix of a solid long chain glyceride (glyceryl behenate). The resulting particles were solid but the oil inside the particle remained in a liquid state. The relation between oil supplementation and melting point depression of glyceryl behenate proved to be linear. Mobility of the oil molecules inside the particles was considerably reduced compared to the emulsified oil. Moreover, two different chemical shifts for each of the lipid signals were observed indicating two different chemical environments. The experimental data is in line with a model describing uniform distribution of the oil molecules in the glyceryl behenate for low oil loads. However, at higher oil loads our data indicate the formation of oil clusters within the solid nanoparticle.

Encapsulation of retinoids in solid lipid nanoparticles (SLN).

SLN have been suggested for a broad range of applications, such as intravenous injection, peroral, or dermal administration. The incorporation of the drug in the core of the SLN has to be ensured for these applications, but the inclusion of drugs in SLN is poorly understood. This study is a contribution to further describe the inclusion properties of colloidal lipids and to propose incorporation mechanisms. Besides the well known methods to investigate entrapment of actives in nanoparticles such as DSC or microscopy, the present study focussed on yet a different approach. Based on the different chemical stability of retinoids in water and in a lipid phase, a method to derive information on the distribution of the drug between SLN-lipid and the water phase was established. Comparing different lipids, glyceryl behenate gave superior entrapment compared to tripalmitate, cetyl palmitate and solid paraffin. Comparing three different drugs, entrapment increased with decreasing polarity of the molecule (tretinoin < retinol < retinyl palmitate). The encapsulation efficacy was successfully enhanced by formulating SLN from mixtures of liquid and solid lipids. These particles were solid and provided better protection of the sensitive drugs than an emulsion. X-ray investigations revealed that good encapsulation correlated with a low degree of crystallinity and lattice defects. With highly ordered crystals, as in the case of cetyl palmitate, drug expulsion from the carrier was more pronounced.

Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization.

Solid lipid nanoparticles (SLN) were produced by high pressure homogenization using piston-gap homogenizers. Batch sizes varied between 40 ml and 50 l. Because of the different batch sizes, different homogenizer types were used, but the same functional principles were maintained, and the change from 40 ml to 50 l was not critical. With increasing batch sizes, the product quality in terms of particle size distribution and physical storage stability improved. Medium scale (30 l and 50 l) drug-free and drug-loaded SLN batches could be produced reproducibly and batch-to-batch uniformity was proven: within one batch particle sizes were homogeneous. This study revealed the influence of pressure and temperature for the hot homogenization technique A change of pressure between 300-500 bars induced only minor differences in particle size, but some influence of the heating temperature was found. More important than control of the heating process was the control of the cooling process of the final product. A too rapid cooling deteriorated the product quality: cooling with water of 18 degrees C proved to be the optimum cooling condition.