Tobias Blaschke

Nanoparticles for skin penetration enhancement--a comparison of a dendritic core-multishell-nanotransporter and solid lipid nanoparticles.

Nanosized particles are of growing interest for topical treatment of skin diseases to increase skin penetration of drugs and to reduce side effects. Effects of the particle structure and size were studied loading nile red to dendritic core-multishell (CMS) nanotransporters (20-30 nm) and solid lipid nanoparticles (SLNs, 150-170 nm). Interaction properties of CMS nanotransporters with the dye molecules--attachment to the carrier surface or incorporation in the carrier matrix--were studied by UV/Vis and parelectric spectroscopy. Pig skin penetration was studied ex vivo using a cream for reference. Interactions of SLN and skin were followed by scanning electron microscopy, internalisation of the particles by viable keratinocytes by laser scanning microscopy. Incorporating nile red into a stable dendritic nanoparticle matrix, dye amounts increased eightfold in the stratum corneum and 13-fold in the epidermis compared to the cream. Despite SLN degradation at the stratum corneum surface, SLN enhanced skin penetration less efficiently (3.8- and 6.3-fold). Viable human keratinocytes showed an internalisation of both nanocarriers. In conclusion, CMS nanotransporters can favour the penetration of a model dye into the skin even more than SLN which may reflect size effects.

Cyproterone acetate loading to lipid nanoparticles for topical acne treatment: particle characterisation and skin uptake.

PurposeTopical cyproterone acetate (CPA) treatment of skin diseases should reduce side effects currently excluding the use in males and demanding contraceptive measures in females. To improve skin penetration of the poorly absorbed drug, we intended to identify the active moiety and to load it to particulate carrier systems.Materials and MethodsCPA metabolism in human fibroblasts, keratinocytes and a sebocyte cell line as well as androgen receptor affinity of native CPA and the hydrolysis product cyproterone were determined. CPA 0.05% loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), a nanoemulsion and micropheres were characterized for drug-particle interaction and CPA absorption using human skin ex-vivo.ResultsNative CPA proved to be the active agent. Application of CPA attached to SLN increased skin penetration at least four-fold over the uptake from cream and nanoemulsion. Incorporation into the lipid matrix of NLC and microspheres resulted in a 2–3-fold increase in CPA absorption. Drug amounts within the dermis were low with all preparations. No difference was seen in the penetration into intact and stripped skin.ConclusionWith particulate systems topical CPA treatment may be an additional therapeutic option for acne and other diseases of the pilosebaceous unit.

CuBICA: independent component analysis by simultaneous third- and fourth-order cumulant diagonalization

CuBICA, which is an improved method for independent component analysis (ICA) based on the diagonalization of cumulant tensors is proposed. It is based on Comons algorithm, but it takes third- and fourth-order cumulant tensors into account simultaneously. The underlying contrast function is also mathematically much simpler and has a more intuitive interpretation. It is therefore easier to optimize and approximate. A comparison with Comons and three other ICA algorithms on different data sets demonstrates its performance.

Influences of opioids and nanoparticles on in vitro wound healing models

For efficient pain reduction in severe skin wounds, topical opioids may be a new option - given that wound healing is not impaired and the vehicle allows for slow opioid release, since long intervals of painful wound dressing changes are intended. We investigated the influence of opioids on the wound healing process via in vitro models, migration assay and scratch test. In fact, morphine, hydromorphone, fentanyl and buprenorphine increased the number of migrated HaCaT cells (spontaneously transformed keratinocytes) twofold. In the scratch test, morphine accelerated the closure of a monolayer wound (scratch). As possible slow release application forms are nanoparticulate systems like solid lipid nanoparticles (SLN) and dendritic core-multishell (CMS) nanotransporters, we evaluated the effect of unloaded nanoparticles on HaCaT cell migration, too. CMS nanotransporters did not inhibit migration, SLN even enhanced it (twofold). Applying morphine plus unloaded nanoparticles reduced morphine effects possibly due to uptake into CMS nanotransporters and adsorption to the surface of SLN. In contrast to SLN, TGF-beta1 was taken up by CMS nanotransporters, too. Both nanoparticles are tolerable by skin and eye as derived from Episkin-SM(TM) skin irritation test and HET-CAM assay. No acute toxic effects were observed either. In conclusion, opioids as well as the investigated nanoparticulate carriers conform the essential conditions for topical pain reduction.

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.

SLN for topical application in skin diseases--characterization of drug-carrier and carrier-target interactions.

The modes of drug-particle interactions considerably influence drug delivery by nanoparticulate carrier systems and drug penetration into the skin. The exact mechanism of the drug loading and its release are still ambiguous. Therefore, the loading process, the interaction of the agent and the lipid matrix of solid lipid nanoparticles (SLNs) as well as the uptake of the loaded agent by skin lipids were analysed by electron spin resonance (ESR) and parelectric spectroscopy (PS) using spin probes (TEMPO, TEMPOL, and CAT-1) as model drugs differing in their lipophilicity. The spin probes were closely attached to the particles lipid surface (TEMPO) or located in the layers of the surfactant (CAT-1), respectively. Furthermore, two distinct sub-compartments on the SLN were found. To simulate the processes at the phase boundary SLN dispersion/skin, skin lipid mixtures were prepared and the transfer process of the spin labels was followed by ESR tomography. Transfer rates were related to the lipophilicity of the spin probe, the lipid mixture and the applied pharmaceutical formulation, SLN dispersion and aqueous solution, respectively. In particular, SLN accelerated in particular the distribution of the lipophilic agents.

Independent Slow Feature Analysis and Nonlinear Blind Source Separation

In the linear case, statistical independence is a sufficient criterion for performing blind source separation. In the nonlinear case, however, it leaves an ambiguity in the solutions that has to be resolved by additional criteria. Here we argue that temporal slowness complements statistical independence well and that a combination of the two leads to unique solutions of the nonlinear blind source separation problem. The algorithm we present is a combination of second-order independent component analysis and slow feature analysis and is referred to as independent slow feature analysis. Its performance is demonstrated on nonlinearly mixed music data. We conclude that slowness is indeed a useful complement to statistical independence but that time-delayed second-order moments are only a weak measure of statistical independence.

What Is the Relation Between Slow Feature Analysis and Independent Component Analysis

We present an analytical comparison between linear slow feature analysis and second-order independent component analysis, and show that in the case of one time delay, the two approaches are equivalent. We also consider the case of several time delays and discuss two possible extensions of slow feature analysis.

Improving Topical Non-Melanoma Skin Cancer Treatment: In vitro Efficacy of a Novel Guanosine-Analog Phosphonate

Actinic keratosis, a frequent carcinoma in situ of non-melanoma skin cancer (NMSC), can transform into life-threatening cutaneous squamous cell carcinoma. Current treatment is limited due to low complete clearance rates and asks for novel therapeutic concepts; the novel purine nucleotide analogue OxBu may be an option. In order to enhance skin penetration, solid lipid nanoparticles (SLN, 136-156 nm) were produced with an OxBu entrapment efficiency of 96.5 ± 0.1%. For improved preclinical evaluation, we combined tissue engineering with clinically used keratin-18 quantification. Three doses of 10-3 mol/l OxBu, dissolved in phosphate-buffered saline as well as loaded to SLN, were effective on reconstructed NMSC. Tumour response and apoptosis induction were evaluated by an increase in caspase-cleaved fragment of keratin-18, caspase-7 activation as well as by reduced expression of matrix metallopeptidase-2 and Ki-67. OxBu efficacy was superior to equimolar 5-fluorouracil solution, and thus the drug should be subjected to the next step in preclinical evaluation.

An Improved Cumulant Based Method for Independent Component Analysis

An improved method for independent component analysis based on the diagonalization of cumulant tensors is proposed. It is based on Comons algorithm [1] but it takes third- and fourth-order cumulant tensors into account simultaneously. The underlying contrast function is also mathematically much simpler and has a more intuitive interpretation. It is therefore easier to optimize and approximate. A comparison with Comons algorithm, JADE [2] and FastICA [3] on different data sets demonstrates its performance.