PharmBioTec GmbH

Saarbrücken, Germany

PharmBioTec GmbH

Saarbrücken, Germany
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Seif S.,Saarland University | Seif S.,PharmBioTec GmbH | Franzen L.,Saarland University | Windbergs M.,Saarland University | And 2 more authors.
International Journal of Pharmaceutics | Year: 2015

For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing. In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters. Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization. ©2014 Elsevier B.V. All rights reserved.

Planz V.,Helmholtz Center for Infection Research | Lehr C.-M.,Saarland University | Windbergs M.,PharmBioTec GmbH
Journal of Controlled Release | Year: 2016

For preclinical testing of novel therapeutics, predictive in vitro models of the human skin are required to assess efficacy, absorption and safety. Simple as well as more sophisticated three-dimensional organotypic models of the human skin emerged as versatile and powerful tools simulating healthy as well as diseased skin states. Besides addressing the demands of research and industry, such models serve as valid alternative to animal testing. Recently, the acceptance of several models by regulatory authorities corroborates their role as important building block for preclinical development. However, valid assessment of readout parameters derived from these models requires suitable analytical techniques. Standard analytical methods are mostly destructive and limited regarding in-depth investigation on molecular level. The combination of adequate in vitro models with modern non-invasive analytical modalities bears a great potential to address important skin drug delivery related questions. Topics of interest are for instance the assessment of repeated dosing effects and xenobiotic biotransformation, which cannot be analyzed by destructive techniques. This review provides a comprehensive overview of current in vitro skin models differing in functional complexity and mimicking healthy as well as diseased skin states. Further, benefits and limitations regarding analytical evaluation of efficacy, absorption and safety of novel drug carrier systems applied to such models are discussed along with a prospective view of anticipated future directions. In addition, emerging non-invasive imaging modalities are introduced and their significance and potential to advance current knowledge in the field of skin drug delivery is explored. © 2016 Elsevier B.V.

Kann B.,Saarland University | Windbergs M.,Saarland University | Windbergs M.,Helmholtz Institute for Pharmaceutical Research Saarland | Windbergs M.,PharmBioTec GmbH
AAPS Journal | Year: 2013

Confocal Raman microscopy is an analytical technique with a steadily increasing impact in the field of pharmaceutics as the instrumental setup allows for nondestructive visualization of component distribution within drug delivery systems. Here, the attention is mainly focused on classic solid carrier systems like tablets, pellets, or extrudates. Due to the opacity of these systems, Raman analysis is restricted either to exterior surfaces or cross sections. As Raman spectra are only recorded from one focal plane at a time, the sample is usually altered to create a smooth and even surface. However, this manipulation can lead to misinterpretation of the analytical results. Here, we present a trendsetting approach to overcome these analytical pitfalls with a combination of confocal Raman microscopy and optical profilometry. By acquiring a topography profile of the sample area of interest prior to Raman spectroscopy, the profile height information allowed to level the focal plane to the sample surface for each spectrum acquisition. We first demonstrated the basic principle of this complementary approach in a case study using a tilted silica wafer. In a second step, we successfully adapted the two techniques to investigate an extrudate and a lyophilisate as two exemplary solid drug carrier systems. Component distribution analysis with the novel analytical approach was neither hampered by the curvature of the cylindrical extrudate nor the highly structured surface of the lyophilisate. Therefore, the combined analytical approach bears a great potential to be implemented in diversified fields of pharmaceutical sciences. © 2013 American Association of Pharmaceutical Scientists.

Franzen L.,Saarland University | Mathes C.,Saarland University | Hansen S.,Saarland University | Hansen S.,Helmholtz Center for Infection Research | And 4 more authors.
Journal of Biomedical Optics | Year: 2013

Hair follicles have recently gained a lot of interest for dermal drug delivery. They provide facilitated penetration into the skin and a high potential to serve as a drug depot. In this area of research, excised pig ear is a widely accepted in vitro model to evaluate penetration of drug delivery into hair follicles. However, a comparison of human and porcine follicles in terms of chemical composition has not been performed so far. In this study, we applied confocal Raman microscopy as a chemically selective imaging technique to compare human and porcine follicle composition and to visualize component distribution within follicle cross-sections. Based on the evaluation of human and porcine Raman spectra optical similarity for both species was successfully confirmed. Furthermore, cyanoacrylate skin surface biopsies, which are generally used to determine the extent of follicular penetration, were imaged by a novel complementary analytical approach combining confocal Raman microscopy and optical profilometry. This all-encompassing analysis allows investigation of intactness and component distribution of the excised hair bulb in three dimensions. Confocal Raman microscopy shows a high potential as a noninvasive and chemically selective technique for the analysis of trans-follicular drug delivery. © 2013 SPIE.

Schmitt C.,Saarland University | Kail D.,PharmBioTec GmbH | Mariano M.,Saarland University | Empting M.,Helmholtz Institute For Pharmazeutische Forschung Saarland | And 5 more authors.
PLoS ONE | Year: 2014

The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions. © 2014 Schmitt et al.

Franzen L.,Saarland University | Windbergs M.,Saarland University | Windbergs M.,Helmholtz Center for Infection Research | Windbergs M.,PharmBioTec GmbH | And 2 more authors.
Skin Pharmacology and Physiology | Year: 2012

To perform accurate tape-stripping measurements and to control for site-specific and interindividual differences the amount of stratum corneum (SC) removed by each tape and the total SC thickness must be known. The purpose of this study was to evaluate the use of near-infrared (NIR) densitometry at λ = 850 nm for in situ determination of the total SC thickness. Quantitative tape stripping was performed on pig ear skin. The amount of SC removed by each tape was measured by NIR densitometry and by microprotein assay. Derived from the linear correlation between both measurements, a conversion factor was calculated that relates the individual NIR densitometry readings to the thickness of the SC on the corresponding tape (lSC-tape [μm] = (abs.850 - abs.850(blank))/23.9). The total SC thickness was determined based on the accumulated values of all tapes applied in quantitative tape stripping and compared to the values obtained from microscopic cross sections of biopsies. The total SC thickness was correctly determined by infrared densitometry independent of storage time and conditions (4°C up to 24 h; -21°C up to 3 months) in comparison with the standard histological evaluation. Copyright © 2012 S. Karger AG, Basel.

Gross P.C.,PharmBioTec GmbH | Burkart S.C.,PharmBioTec GmbH | Burkart S.C.,Saarland University | Muller R.,PharmBioTec GmbH | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

Purification and quality control of therapeutic peptides is often performed by one single method, RP-HPLC. As usage of an orthogonal technique is highly advisable for quality assurance, capillary electrophoresis (CE) employing a coated capillary coupled via a sheathless interface to a mass spectrometer was applied in parallel. The basic therapeutic peptide aviptadil served as a model substance to study the impurity profiles revealing 15 detectable impurities using CE-MS, two were detected by an appropriate nanoRP-HPLC-MS method. None of the impurities detected by CE were observed in LC and vice versa. The LOD in CE-MS was determined in the base peak electropherogram at ~1. fmol, a value 2500 times smaller than the LOD found in nanoRP-HPLC-MS (3. pmol). In nanoRP-HPLC-MS only 0.2% of the extrapolated CE-MS signal for a 25. ng aviptadil load was observed. We conclude that both, the LOD as well as the impurity profile of aviptadil, as analyzed by nanoRP-HPLC are influenced by both, the ligand-derivatized silica matrix and the flow-rate. Peptides may disappear completely and their variable emergence may lead to the determination of incorrect ratios as present in the sample. © 2013 .

Franzen L.,Saarland University | Windbergs M.,Saarland University | Windbergs M.,Helmholtz Center for Infection Research | Windbergs M.,PharmBioTec GmbH
Journal of Raman Spectroscopy | Year: 2014

The opportunity of label-free and non-destructive detection of substances inside human skin by confocal Raman microscopy represents a novel approach for investigating drug penetration and permeation. Several studies already introduced confocal Raman microscopy for depth profiling in skin; however, the reported results show high deviations. Thus, analysis of the spectral variability of human skin itself is a necessary prerequisite for systematic quantitative investigations of drug penetration and permeation by confocal Raman microscopy. In our work, we acquired Raman depth profiles from excised human skin samples after abdominal plastic surgery and investigated the absolute intensity fluctuation of four major skin derived Raman peaks. The results prove the expected high variability in spectral intensity, but we could not detect dissimilarities between different skin donors. A detailed analysis of the major endogenous skin components revealed differences in spatial distribution which consequently affects their individual applicability as reference peaks for relative depth profiling. Furthermore, we discovered an increase in signal variability in deeper stratum corneum layers, which has to be considered in future substance depth profiling investigations. In addition, we discovered an exponential decay of the Raman signal for all major skin components accounting for signal attenuation inside biological tissue. Based on this mathematical description, quantitative follow-up of substances in human skin can be realized. All in all, the results of this study elucidate the necessity of substantial understanding of endogenous spectral characteristics inside human skin as essential prerequisite for rational depth profiling of substances in human skin. Copyright © 2013 John Wiley & Sons, Ltd.

Franzen L.,Saarland University | Anderski J.,Saarland University | Windbergs M.,Saarland University | Windbergs M.,Helmholtz Center for Infection Research | Windbergs M.,PharmBioTec GmbH
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2015

For rational development and evaluation of dermal drug delivery, the knowledge of rate and extent of substance penetration into the human skin is essential. However, current analytical procedures are destructive, labor intense and lack a defined spatial resolution. In this context, confocal Raman microscopy bares the potential to overcome current limitations in drug depth profiling. Confocal Raman microscopy already proved its suitability for the acquisition of qualitative penetration profiles, but a comprehensive investigation regarding its suitability for quantitative measurements inside the human skin is still missing. In this work, we present a systematic validation study to deploy confocal Raman microscopy for quantitative drug depth profiling in human skin. After we validated our Raman microscopic setup, we successfully established an experimental procedure that allows correlating the Raman signal of a model drug with its controlled concentration in human skin. To overcome current drawbacks in drug depth profiling, we evaluated different modes of peak correlation for quantitative Raman measurements and offer a suitable operating procedure for quantitative drug depth profiling in human skin. In conclusion, we successfully demonstrate the potential of confocal Raman microscopy for quantitative drug depth profiling in human skin as valuable alternative to destructive state-of-the-art techniques. © 2015 Elsevier B.V. All rights reserved.

Franzen L.,Saarland University | Windbergs M.,Saarland University | Windbergs M.,Helmholtz Center for Infection Research | Windbergs M.,PharmBioTec GmbH
Advanced Drug Delivery Reviews | Year: 2015

In the field of skin research, confocal Raman microscopy is an upcoming analytical technique. Substantial technical progress in design and performance of the individual setup components like detectors and lasers as well as the combination with confocal microscopy enables chemically selective and non-destructive sample analysis with high spatial resolution in three dimensions. Due to these advantages, the technique bears tremendous potential for diverse skin applications ranging from the analysis of physiological component distribution in skin tissue and the diagnosis of pathological states up to biopharmaceutical investigations such as drug penetration kinetics within the different tissue layers.This review provides a comprehensive introduction about the basic principles of Raman microscopy highlighting the advantages and considering the limitations of the technique for skin applications. Subsequently, an overview about skin research studies applying Raman spectroscopy is given comprising various in vitro as well as in vivo implementations. Furthermore, the future perspective and potential of Raman microscopy in the field of skin research are discussed. © 2015 Elsevier B.V.

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