Development and validation of an alternative disturbed skin model by mechanical abrasion to study drug penetration.

Pharmaceuticals and cosmetics for dermal application are usually tested on healthy skin, although the primary permeation barrier, the stratum corneum, is often impaired by skin diseases or small skin lesions, especially on the hands. These skin conditions can considerably influence the permeation of chemicals and drugs. Furthermore, risk assessment for example of nanoparticles should be performed under various skin conditions to reflect the true circumstances. Therefore, an alternative and reproducible method for a high throughput of skin samples with impaired skin barrier was developed and verified by skin permeation studies (25 h) of caffeine, sorbic acid and testosterone compared to healthy (untreated) and tape-stripped skin. Skin barrier disruption was controlled by TEWL measurement. Skin permeation of the three substances was increased in tape-stripped and abraded skin compared to untreated skin due to the reduced barrier integrity. Enhancement of drug uptake was highest for the most hydrophilic substance, caffeine, followed by sorbic acid and lipophilic testosterone. No significant difference in drug uptake studies was observed between the new abrasion method with an aluminum-coated sponge and the tape-stripping method. The obtained results demonstrate that this abrasion method is an alternative way to achieve a disturbed skin barrier for drug and chemical uptake studies.

Drug release and skin penetration from solid lipid nanoparticles and a base cream: a systematic approach from a comparison of three glucocorticoids.

Solid lipid nanoparticles (SLNs) can enhance drug penetration into the skin, yet the mechanism of the improved transport is not known in full. To unravel the influence of the drug-particle interaction on penetration enhancement, 3 glucocorticoids (GCs), prednisolone (PD), the diester prednicarbate (PC) and the monoester betamethasone 17-valerate (BMV), varying in structure and lipophilicity, were loaded onto SLNs. Theoretical permeability coefficients (cm/s) of the agents rank BMV (-6.38) ≥ PC (-6.57) > PD (-7.30). GC-particle interaction, drug release and skin penetration were investigated including a conventional oil-in-water cream for reference. Both with SLN and cream, PD release was clearly superior to PC release which exceeded BMV release. With the cream, the rank order did not change when studying skin penetration, and skin penetration is thus predominantly influenced by drug release. Yet, the penetration profile for the GCs loaded onto SLNs completely changed, and differences between the steroids were almost lost. Thus, SLNs influence skin penetration by an intrinsic mechanism linked to a specific interaction of the drug-carrier complex and the skin surface, which becomes possible by the lipid nature and nanosize of the carrier and appears not to be derived by testing drug release. Interestingly, PC and PD uptake from SLN even resulted in epidermal targeting. Thus, SLNs are not only able to improve skin penetration of topically applied drugs, but may also be of particular interest when specifically aiming to influence epidermal dysfunction.

Interaction of drug-carrier systems with targets--a study using atomic force microscopy.

To learn about the interaction between drug agents and nanoparticular carrier systems, the physical analytical methods of parelectric, electron spin and fluorescence spectroscopy have proven helpful tools to yield descriptive models of such complex systems. For a deeper understanding of drug absorption from body surfaces and drug distribution into the tissues, however, the lack of knowledge about the interaction between such agents and membranes on different levels is a severe drawback. This gap can be closed by the application of atomic force microscopy at normal temperatures and under the admission of liquid surroundings. Moreover, this method allows the inspection of such system-membrane interactions in dependence on time. We studied membrane topography in liquid and gel-phase mixtures, structural changes of membranes during their destruction by aqueous peptide solutions as well as the stability of the membranes exposed to surfactants of increasing concentration and to lipid nanoparticles (solid lipid nanoparticles, nanostructured lipid carriers). For future modelling we can describe the geometry of lipid nanoparticles as well.

Development of multiple W/O/W emulsions as dermal carrier system for oligonucleotides: effect of additives on emulsion stability.

Multiple water-in-oil-in-water (W/O/W) emulsions are of major interest as potential skin delivery systems for water-soluble drugs like oligonucleotides due to their distinct encapsulation properties. However, multiple emulsions are highly sensitive in terms of variations of the individual components. The presence of osmotic active ingredients in the inner water phase is crucial for the generation of stable multiple emulsions. In order to stabilize the emulsions the influence of NaCl, MgSO(4), glucose and glycine and two cellulose derivatives was investigated. Briefly, multiple W/O/W emulsions using Span 80 as a lipophilic emulsifier and different hydrophilic emulsifiers (PEG-40/50 stearate, steareth-20 and polysorbate 80) were prepared. Stability of the emulsions was analyzed over a period of time using rheological measurements, droplet size observations and conductivity analysis. In this study we show that additives strongly influence the properties stability of multiple emulsions. By increasing the concentration of the osmotic active ingredients, smaller multiple droplets are formed and the viscosity is significantly increased. The thickening agents resulted in a slightly improved stability. The most promising emulsions were chosen and further evaluated for their suitability and compatibility to incorporate a DNAzyme oligonucleotide as active pharmaceutical ingredient.

In vitro skin absorption and drug release - a comparison of six commercial prednicarbate preparations for topical use.

Reconstructed human epidermis is a useful tool for in vitro skin absorption studies of chemical compounds. If this may hold true also for topical dermatics, we investigated the glucocorticoid prednicarbate applied by two sets (innovator and generic) of cream, ointment and fatty ointment using the commercially available EpiDerm model. Moreover, stability and local tolerability of the preparations as well as drug release were studied, to estimate an influence on prednicarbate absorption and metabolism. While release ranked in the order cream

Interaction of drug molecules with carrier systems as studied by parelectric spectroscopy and electron spin resonance.

According to recent investigations of nanoparticular carrier systems the mode of drug-particle interaction appears to influence drug penetration into the skin. For a more detailed insight into the molecular structure of drug loaded particles the two independent analytical methods, namely the parelectric spectroscopy (PS) and the electron spin resonance (ESR) have been applied to 4,5,5,-trimethyl-1-yloxy-3-imidazoline-2-spiro-3'-(5'()-cholestane) as a model drug. Spectra have been analyzed in dependence on the concentration of the spin label. Changes in the concentration-dependent dipole mobility and dipole density given by PS and the concentration-dependent rotational correlation time (ESR) which are a measure of the vicinity of carrier and/or the surfactant and guest molecule were studied with cholestane-labeled solid lipid nanoparticles (SLN), nanoparticular lipid carriers (NLC) and nanoemulsions (NE). The spin probes were attached to the SLN surface which consists of two distinct sub-compartments: the rim and the flat surface of the disk-like shapes. The shape could be observed by freeze-fraction electron microscopy. Spin probes, however, were incorporated into the carrier matrix in the cases of NLC and NE. Results of PS are verified by ESR which allows a more detailed insight. Taking the results together a detailed new model of 'drug'-particle interaction could be established.