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10 Ergebnisse
Bereich: Suchergebnisse
Publikation Not the usual suspects. Alternative surfactants for biopharmaceuticals(American Chemical Society, 2023) Brosig, Sebastian; Cucuzza, Stefano; Serno, Tim; Bechtold-Peters, Karoline; Buecheler, Jakob; Zivec, Matej; Germershaus, Oliver; Gallou, Fabrice01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Controlled, localized delivery of macromolecular drugs through composite design and matrix modification(11/2018) Germershaus, Oliver06 - PräsentationPublikation Matrix Metalloprotease Triggered Bioresponsive Drug Delivery Systems–Design, Synthesis and Application(Elsevier, 10/2018) Nultsch, Kira; Germershaus, OliverEngineering of drug delivery systems has evolved in recent decades from comparably simple designs that merely controlled drug release to complex, often multistage systems that respond to multiple biological or environmental stimuli. Matrix metalloproteases (MMPs) are a family of proteolytic enzymes that are involved in numerous physiologic and pathophysiologic processes, including cancer. Therefore, these enzymes represent highly relevant targets for the development of novel bioresponsive drug delivery systems. The first part of this review summarizes major developments of the various types of MMP responsive drug delivery systems that have been achieved in the last decade and highlights promising strategies. The selection and incorporation of MMP sensitive elements into drug delivery systems as well as the interaction between MMP, drug delivery system and drug require additional scrutiny to avoid common pitfalls. Thus, the second part of this review focusses on strategies for successful selection and incorporation of MMP sensitive elements and on important design parameters related to the drug delivery system and the drug. This review will therefore provide a broad overview of successful MMP-sensitive drug delivery system designs and will inform about important design criteria for novel systems.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Methods To Determine the Silicone Oil Layer Thickness in Sprayed-On Siliconized Syringes(Parenteral Drug Association, 05/2018) Loosli, Viviane; Germershaus, Oliver; Steinberg, Henrik; Dreher, Sascha; Grauschopf, Ulla; Funke, StephanieThe silicone lubricant layer in prefilled syringes has been investigated with regards to siliconization process performance, prefilled syringe functionality, and drug product attributes, such as subvisible particle levels, in several studies in the past. However, adequate methods to characterize the silicone oil layer thickness and distribution are limited, and systematic evaluation is missing. In this study, white light interferometry was evaluated to close this gap in method understanding. White light interferometry demonstrated a good accuracy of 93-99% for MgF2 coated, curved standards covering a thickness range of 115-473 nm. Thickness measurements for sprayed-on siliconized prefilled syringes with different representative silicone oil distribution patterns (homogeneous, pronounced siliconization at flange or needle side, respectively) showed high instrument (0.5%) and analyst precision (4.1%). Different white light interferometry instrument parameters (autofocus, protective shield, syringe barrel dimensions input, type of non-siliconized syringe used as base reference) had no significant impact on the measured average layer thickness. The obtained values from white light interferometry applying a fully developed method (12 radial lines, 50 mm measurement distance, 50 measurements points) were in agreement with orthogonal results from combined white and laser interferometry and 3D-laser scanning microscopy. The investigated syringe batches (lot A and B) exhibited comparable longitudinal silicone oil layer thicknesses ranging from 170-190 nm to 90-100 nm from flange to tip and homogeneously distributed silicone layers over the syringe barrel circumference (110- 135 nm). Empty break-loose (4-4.5 N) and gliding forces (2-2.5 N) were comparably low for both analyzed syringe lots. A silicone oil layer thickness of 100-200 nm was thus sufficient for adequate functionality in this particular study. Filling the syringe with a surrogate solution including short-term exposure and emptying did not significantly influence the silicone oil layer at the investigated silicone level. It thus appears reasonable to use this approach to characterize silicone oil layers in filled syringes over time. The developed method characterizes non-destructively the layer thickness and distribution of silicone oil in empty syringes and provides fast access to reliable results. The gained information can be further used to support optimization of siliconization processes and increase the understanding of syringe functionality.LAY ABSTRACT: Silicone oil layers as lubricant are required to ensure functionality of prefilled syringes. Methods evaluating these layers are limited, and systematic evaluation is missing. The aim of this study was to develop and assess white light interferometry as an analytical method to characterize sprayed-on silicone oil layers in 1 mL prefilled syringes. White light interferometry showed a good accuracy (93-99%) as well as instrument and analyst precision (0.5% and 4.1%, respectively). Different applied instrument parameters had no significant impact on the measured layer thickness. The obtained values from white light interferometry applying a fully developed method concurred with orthogonal results from 3D-laser scanning microscopy and combined white light and laser interferometry. The average layer thicknesses in two investigated syringe lots gradually decreased from 170-190 nm at the flange to 100-90 nm at the needle side. The silicone layers were homogeneously distributed over the syringe barrel circumference (110-135 nm) for both lots. Empty break-loose (4-4.5 N) and gliding forces (2-2.5 N) were comparably low for both analyzed syringe lots. Syringe filling with a surrogate solution, including short-term exposure and emptying, did not significantly affect the silicone oil layer. The developed, non-destructive method provided reliable results to characterize the silicone oil layer thickness and distribution in empty siliconized syringes. This information can be further used to support optimization of siliconization processes and increase understanding of syringe functionality.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Container Closure Integrity Testing of Prefilled Syringes,(Elsevier, 08/2018) Pelaez, Sarah; Mahler, Hanns-Christian; Koulov, Atanas; Singh, Satish K.; Germershaus, Oliver; Mathaes, RomanPrefilled syringes (PFSs) are increasingly preferred over vials as container closure systems (CCSs) for injectable drug products when facilitated or self-administration is required. However, PFSs are more complex compared to CCSs consisting of vial, rubber stopper, and crimp cap. Container closure integrity (CCI) assurance and verification has been a specific challenge for PFSs as they feature several sealing areas. A comprehensive understanding of the CCS is necessary for an appropriate CCI assessment as well as for packaging development and qualification. A comprehensive CCI assessment of 6 different PFSs from 3 different manufacturers (including 1 polymeric PFS) was conducted using helium leak testing. PFS components were manipulated to systematically assess the contribution of the different sealing areas to CCI, namely rigid needle shield (RNS)/needle, RNS/tip cone, and the individual ribs of a syringe plunger. The polymeric PFS required an equilibrium measurement for accurate container closure integrity testing. The different sealing areas and a single plunger rib were shown to provide adequate CCI. Acceptable tip cap movement until the point of CCI failure was estimated. The assessment of acceptable tip cap movement demonstrated the importance of considering the RNS/tip cone seal design to ensure CCI of the PFS upon post assembly possesses and shipment.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Surface modification of nanofibrous matrices via layer-by-layer functionalized silk assembly for mitigating the foreign body reaction(Elsevier, 05/2018) Qian, Yuna; Li, Linhao; Song, Yang; Dong, Lili; Chen, Peixing; Li, Xiaoming; Cai, Kaiyong; Germershaus, Oliver; Li, Yang; Fan, YuboThe inherent hydrophobicity and large surface area of electrospun synthetic polymeric scaffolds often cause non-specific protein adsorption, thereby influencing macrophage functions and eventually leading to fibrosis at the tissue-scaffold interface. This work reports fabrication of silk fibroin (SF)-functionalized electrospun polycaprolactone (PCL) fibers by single-component layer-by-layer assembly and decorate the SF with heparin disaccharide (HD), resulting in the non-covalent binding of interleukin-4 (IL-4) with the capacity to modulate macrophage polarization. A modified SF derivative was obtained by diazonium coupling and then covalently bonded with HD via click chemistry to eventually bind IL-4 efficiently and maintain its bioactivity. In vitro studies showed that IL-4 surface-functionalized nanofibrous scaffolds promoted polarization to M2 macrophages in the short-term. Importantly, in a murine subcutaneous implantation model, we found that promoting transient shifts in macrophage polarization at early stage can significantly inhibit the extent of the late foreign body reactions. Furthermore, the results of a transcriptomic profiling showed that MARK, PI3K, JNK and NF-κB signaling pathways played an important role in regulating the macrophage phenotypes in the SF/HD/IL-4-functionalized fibers. Our results suggest that such a strategy offers a new approach for utilizing biological agent surface functionalization to modulate the foreign body reaction to nanofibrous scaffolds.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Effects of Silk Degumming Process on Physicochemical, Tensile, and Optical Properties of Regenerated Silk Fibroin(Wiley, 09/2018) Nutsch, Kira; Bast, Livia K.; Näf, Muriel; El Yakhlifi, Salima; Bruns, Nico; Germershaus, OliverSericin removal from silk (degumming) affects material characteristics of silk fibroin (SF). Sodium carbonate is most commonly used for degumming, but numerous alternative methods are available. Herein, a systematic comparison of degumming methods is provided. Sodium carbonate, sodium oleate, trypsin, and ionic liquid are used, and materials are characterized regarding mass loss, SF content, molecular integrity of SF, refractive index, and tensile properties. Complete degumming is achieved within 30 min of using sodium carbonate, but results in significant reduction of molecular weight, shift toward less acidic charge variants, and reduction of yield‐ and rupture force. Sodium oleate and trypsin are inefficient and negatively affect tensile properties, while ionic liquid shows good efficiency and marginal degradation of SF but also reduced yield‐ and rupture force. Refractive index is not affected by degumming. These results allow rational selection of the degumming method and tuning of SF properties for biomedical applications.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Application of natural and semi-synthetic polymers for the delivery of sensitive drugs(Taylor & Francis, 02/2015) Germershaus, Oliver; Lühmann, Tessa; Rybak, Jascha-Nikolai; Ritzer, Jennifer; Meinel, LorenzAbstract This review summarises recent developments in the application of natural and semi-synthetic polymers for the delivery of sensitive drugs. Peptides, proteins and nucleic acids are drugs of increasing relevance potentially offering treatment options in indications with high unmet medical need. However, these drugs are characterised by high molecular weight, high sensitivity to enzymatic degradation, unfavourable pharmacokinetics and often require targetting to specific cell types or cellular compartments. To successfully transform these drug molecules into efficacious therapies, advanced drug delivery systems must be developed that protect the drug, control drug release to improve pharmacokinetics and allow efficient targetting. Synthetic, semi-synthetic or natural polymers or inorganic materials are frequently used for the development of drug delivery systems. Considering factors such as biocompatibility, biodegradability, solvent-free processing and availability from renewable resources, natural and semi-synthetic polymers are often advantageous compared to synthetic alternatives. On the other hand, material heterogeneity and purity of natural materials are concerns that need to be addressed. In this review, authors focus on frequently used biopolymers such as polysaccharides like chitosan and hyaluronan and proteins like silk fibroin (SF) and collagen and their semi-synthetic derivatives. Special emphasis will be put on material properties of such polymers rendering them suitable for drug delivery purposes and allow tight control to assure product quality and proper release characteristics. Natural polymers are frequently synthetically modified to alter or improve their characteristics. Such semi-synthetic derivatives and their advantages and disadvantages are critically discussed. Furthermore, the biocompatibility of natural materials and their derivatives is discussed.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Influence of salt type and ionic strength on self-assembly of dextran sulfate-ciprofloxacin nanoplexes(Elsevier, 2015) Kutscher, Marika; Cheow, Wean Sin; Werner, Vera; Lorenz, Udo; Ohlsen, Knut; Meinel, Lorenz; Hadinoto, Kunn; Germershaus, OliverWe evaluated an analytical setup to identify optimal preparation conditions for nanoplex formation of small molecule drugs and polyelectrolytes using ciprofloxacin (CIP) and dextran sulfate (DS) as model compounds. The suitability of isothermal titration calorimetry (ITC) as a screening tool for rational formulation optimization was assessed. Besides ITC, static and dynamic light scattering, zeta potential measurements and scanning electron microscopy were applied to analyze the influence of different salt types and ionic strengths on CIP/DS nanoplex formation. The addition of low amounts of salt, especially 0.1M NaCl, improved the formation of CIP/DS nanoplexes. The presence of low amounts of salt led to smaller and more numerous particles of higher uniformity but had no influence on the release of CIP from nanoplexes. Furthermore, the molar range, within which efficient complexation was achieved, was broader in the presence of 0.1M NaCl than in the absence of salt with overall comparable complexation efficiency. Importantly, binding affinity correlated with particle shape and morphology, potentially enabling optimization of critical quality attributes based on ITC data. Altogether, ITC along with supplemental methods is a versatile screening tool for the evaluation of nanoplex formulation conditions regarding mixing ratio, salt type and ionic strength.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Simple and rapid high performance liquid chromatography method for the determination of polidocanol as bulk product and in pharmaceutical polymer matrices using charged aerosol detection(Elsevier, 02/2015) Ilko, David; Puhl, Sebastian; Meinel, Lorenz; Germershaus, Oliver; Holzgrabe, UlrikeCurrently, neither the European nor the United States Pharmacopoeia provide a method for the determination of polidocanol (PD) content despite the fact that PD, besides being an excipient, is also used as an active pharmaceutical ingredient. We therefore developed a method where the PD content was determined using a Kinetex C18 column operated at 40°C with water-acetonitrile (15:85, v/v) as mobile phase. A Corona(®) charged aerosol detector was employed for the detection of PD that is lacking a suitable UV chromophore. The method was fully validated. Additionally, the method was applied for the determination of PD release from a pharmaceutical polymer matrix consisting of poly-ɛ-caprolactone and poly(lactic-co-glycolic acid) and PD.01A - Beitrag in wissenschaftlicher Zeitschrift