Physical Compatibility of Propofol-Sufentanil Mixtures.

BACKGROUND: Combined infusions of propofol and sufentanil preparations are frequently used in clinical practice to induce anesthesia and analgesia. However, the stability of propofol emulsions can be affected by dilution with another preparation, sometimes leading to particle coalescence and enlargement. Such unwanted effects can lead to fat embolism syndrome after intravenous application. This study describes the physical stability of 5 commercially available propofol preparations mixed with sufentanil citrate solutions. METHODS: Two common markers of emulsion stability were used in this study; namely, the zeta potential and size distribution of the emulsion droplets. Both were measured using dynamic light scattering. The data for the pure propofol preparations and their mixtures with sufentanil citrate solution were compared. RESULTS: The absolute value of zeta potential decreased in 4 of the 5 propofol preparations after they had been mixed with sufentanil citrate. This effect indicates a lowering of repulsive interactions between the emulsion droplets. Although this phenomenon tends to cause agglomeration, none of the studied mixtures displayed a substantial increase in droplet size within 24 hours of blending. However, our long-term stability study revealed the instability of some of the propofol-sufentanil samples. Two of the 5 studied mixtures displayed a continual increase in particle size. The same 2 preparations showed the greatest reductions in the absolute value of zeta potential, thereby confirming the correlation of both measurement methods. The increase in particle size was more distinct in the samples stored at higher temperatures and with higher sufentanil concentrations. CONCLUSIONS: To ensure the microbial stability of an emulsion infusion preparation, clinical regulations require that such preparations should be applied to patients within 12 hours of opening. In this respect, we can confirm that during this period, none of the studied propofol-sufentanil mixtures displayed any physical instability that could lead to particle enlargement; thus, fat embolism should not be a risk after their intravenous application. However, our long-term stability study revealed differences between commercially available preparations containing the same active ingredient; some of the mixtures showed an increase in particle size and polydispersity over a longer period. Although our results should not be generalized beyond the particular propofol-sufentanil preparations and concentrations studied here, they do suggest that, as a general principle, a compatibility study should be performed for any preparation before the first intravenous application to exclude the risk of droplet aggregation.

Effect of lipid nanoparticle formulations on skin delivery of a lipophilic substance.

The aim of this study was to follow the skin penetration of a model lipophilic compound (Nile red) delivered by nanoparticulate carriers, the so-called lipid nanocapsules. The nanocapsules consisting of an oil core stabilized by amixture of surfactants were prepared by the phase inversion temperature method. Varying the particle composition (the oil/surfactant ratio) nanoparticles of different size were prepared and characterized. The penetration profile of Nile red delivered into the porcine skin by the nanoparticles compared to non-particulate samples was determined using fluorescence microscopy combined with a novel, statistically robust quantitative image analysis method. This study demonstrated that lipid nanoparticles promoted the skin penetration of encapsulated Nile red in comparison with all the non-particulate samples. Nile red delivered by the lipid-based nanoparticles was able to diffuse across the stratum corneum and partition itself uniformly in the epidermis. No relationship between Nile red penetration into the skin and the particle size was found. Moreover, the presence of sodium chloride in the water phase had a negative impact on the Nile red penetration into the skin. The results indicate that the physico-chemical circumstances of the nanoparticulate formulation play the major role in the penetration of lipophilic substances into the skin.

Nanocrystals for dermal penetration enhancement - Effect of concentration and underlying mechanisms using curcumin as model.

Nanocrystals have received considerable attention in dermal application due to their ability to enhance delivery to the skin and overcome bioavailability issues caused by poor water and oil drug solubility. The objective of this study was to investigate the effect of nanocrystals on the mechanism of penetration behavior of curcumin as a model drug. Curcumin nanocrystals were produced by the smartCrystals® process, i.e. bead milling followed by high pressure homogenization. The mean particle size of the curcumin crystals was about 200nm. Stabilization was performed with alkyl polyglycoside surfactants. The distribution of curcumin within the skin was determined in vitro on cross-sections of porcine skin and visualized by fluorescent microscopy. The skin penetration profile was analyzed for the curcumin nanosuspension with decreasing concentrations (2%, 0.2%, 0.02% and 0.002% by weight) and compared to nanocrystals in a viscous hydroxypropylcellulose (HPC) gel. This study demonstrated there was minor difference between low viscous nanosuspension and the gel, but low viscosity seemed to favor skin penetration. Localization of curcumin was observed in the hair follicles, also contributing to skin uptake. Looking at the penetration of curcumin from formulations with decreasing nanocrystal concentration, formulations with 2%, 0.2% and 0.02% showed a similar penetration profile, whereas a significantly weaker fluorescence was observed in the case of a formulation containing 0.002% of curcumin nanocrystals. In this study we have shown that curcumin nanocrystals prepared by the smartCrystal® process are promising carriers in dermal application and furthermore, we identified the ideal concentration of 0.02% nanocrystals in dermal formulations. The comprehensive study of decreasing curcumin concentration in formulations revealed that the saturation solubility (Cs) is not the only determining factor for the penetration. A new mechanism based also on the concentration of the nanocrystals on skin surface was proposed.

Freeze-drying as a preserving preparation technique for in vitro testing of human skin.

In vitro testing of drugs with excised human skin is a valuable prerequisite for clinical studies. However, the analysis of excised human skin presents several obstacles. Ongoing drug diffusion, microbial growth and changes in hydration state influence the results of drug penetration studies. In this work, we evaluate freeze-drying as a preserving preparation method for skin samples to overcome these obstacles. We analyse excised human skin before and after freeze-drying and compare these results with human skin in vivo. Based on comprehensive thermal and spectroscopic analysis, we demonstrate comparability to in vivo conditions and exclude significant changes within the skin samples due to freeze-drying. Furthermore, we show that freeze-drying after skin incubation with drugs prevents growth of drug crystals on the skin surface due to drying effects. In conclusion, we introduce freeze-drying as a preserving preparation technique for in vitro testing of human skin.