Listen
171 Ergebnisse
Ergebnisse nach Hochschule und Institut
Publikation Predictive computational models for assessing the impact of co-milling on drug dissolution(Elsevier, 07/2024) Pätzmann, Nicolas; O'Dwyer, Patrick J.; Beránek, Josef; Kuentz, Martin; Griffin, Brendan T.Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Comparison of protein-like model particles fabricated by micro 3D printing to established standard particles(Elsevier, 08/2024) Amara, Ilias; Germershaus, Oliver; Lentes, Christopher; Sass, Steffen; Youmto, Stephany Mamdjo; Stracke, Jan Olaf; Clemens-Hemmelmann, Mirjam; Assfalg, AnaceliaInnovative analytical instruments and development of new methods has provided a better understanding of protein particle formation in biopharmaceuticals but have also challenged the ability to obtain reproducible and reliable measurements. The need for protein-like particle standards mimicking the irregular shape, translucent nature and near-to-neutral buoyancy of protein particles remained one of the hot topics in the field of particle detection and characterization in biopharmaceutical formulations. An innovative protein-like particle model has been developed using two photo polymerization (2PP) printing allowing to fabricate irregularly shaped particles with similar properties as protein particles at precise size of 50 µm and 150 µm, representative of subvisible particles and visible particles, respectively. A study was conducted to compare the morphological, physical, and optical properties of artificially generated protein particles, polystyrene spheres, ETFE, and SU-8 particle standards, along with newly developed protein-like model particles manufactured using 2PP printing. Our results suggest that 2PP printing can be used to produce protein-like particle standards that might facilitate harmonization and standardization of subvisible and visible protein particle characterization across laboratories and organizations.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Computational support to explore ternary solid dispersions of challenging drugs using coformer and hydroxypropyl cellulose(American Chemical Society, 10.10.2024) Niederquell, Andreas; Herzig, Susanne; Schönenberger, Monica; Stoyanov, Edmont; Kuentz, MartinA majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for in silico evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the in silico screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Host cell protein networks as a novel co‐elution mechanism during protein. A chromatography(Wiley, 07.03.2024) Panikulam, Sherin; Hanke, Alexander; Kroener, Frieder; Karle, Anette; Anderka, Oliver; Villiger, Thomas; Lebesgue, NicolasHost cell proteins (HCPs) are process-related impurities of therapeutic proteins produced in for example, Chinese hamster ovary (CHO) cells. Protein A affinity chromatography is the initial capture step to purify monoclonal antibodies or Fc-based proteins and is most effective for HCP removal. Previously proposed mechanisms that contribute to co-purification of HCPs with the therapeutic protein are either HCP-drug association or leaching from chromatin heteroaggregates. In this study, we analyzed protein A eluates of 23 Fc-based proteins by LC-MS/MS to determine their HCP content. The analysis revealed a high degree of heterogeneity in the number of HCPs identified in the different protein A eluates. Among all identified HCPs, the majority co-eluted with less than three Fc-based proteins indicating a drug-specific co-purification for most HCPs. Only ten HCPs co-purified with over 50% of the 23 Fc-based proteins. A correlation analysis of HCPs identified across multiple protein A eluates revealed their co-elution as HCP groups. Functional annotation and protein interaction analysis confirmed that some HCP groups are associated with protein-protein interaction networks. Here, we propose an additional mechanism for HCP co-elution involving protein-protein interactions within functional networks. Our findings may help to guide cell line development and to refine downstream purification strategies.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Amorphous solid dispersion of a binary formulation with felodipine and HPMC for 3D printed floating tablets(Elsevier, 06/2024) Mora-Castaño, Gloria; Millán-Jiménez, Mónica; Niederquell, Andreas; Schönenberger, Monica; Shojaie, Fatemeh; Kuentz, Martin; Caraballo, IsidoroThis study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers(Elsevier, 09/2024) Thormann, Ursula; Marti, Selina; Lensmith, Elizabeth; Lanz, Michael; Herzig, Susanne; Naef, Reto; Imanidis, GeorgiosThe aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance in the home care setting and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels used as primary wound dressing on delivery was assessed. Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results. Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Developing an in vitro lipolysis model for real-time analysis of drug concentrations during digestion of lipid-based formulations(Elsevier, 03/2024) Ejskjær, Lotte; O'Dwyer, Patrick J.; Ryan, Callum D.; Holm, René; Kuentz, Martin; Box, Karl J.; Griffin, Brendan T.Understanding the effect of digestion on oral lipid-based drug formulations is a critical step in assessing the impact of the digestive process in the intestine on intraluminal drug concentrations. The classical pH-stat in vitro lipolysis technique has traditionally been applied, however, there is a need to explore the establishment of higher throughput small-scale methods. This study explores the use of alternative lipases with the aim of selecting digestion conditions that permit in-line UV detection for the determination of real-time drug concentrations. A range of immobilised and pre-dissolved lipases were assessed for digestion of lipid-based formulations and compared to digestion with the classical source of lipase, porcine pancreatin. Palatase® 20000 L, a purified liquid lipase, displayed comparable digestion kinetics to porcine pancreatin and drug concentration determined during digestion of a fenofibrate lipid-based formulation were similar between methods. In-line UV analysis using the MicroDISS ProfilerTM demonstrated that drug concentration could be monitored during one hour of dispersion and three hours of digestion for both a medium- and long-chain lipid-based formulations with corresponding results to that obtained from the classical lipolysis method. This method offers opportunities exploring the real-time dynamic drug concentration during dispersion and digestion of lipid-based formulations in a small-scale setup avoiding artifacts as a result of extensive sample preparation.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements(Nature, 09.10.2024) Raimondi, Federica; Siow, Kah Mun; Wrona, Dominik; Fuster-García, Carla; Pastukhov, Oleksandr; Schmitz, Michael; Bargsten, Katja; Kissling, Lucas; Swarts, Daan C.; Andrieux, Geoffroy; Cathomen, Toni; Modlich, Ute; Jinek, Martin; Siler, Ulrich; Reichenbach, JanineCRISPR-based genome editing of pseudogene-associated disorders, such as p47phox-deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the NCF1 gene and its pseudogenes, NCF1B and NCF1C, in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Water-mediated phase transformations of posaconazole. An intricate jungle of crystal forms(Elsevier, 04/2024) Guidetti, Matteo; Hilfiker, Rolf; Kuentz, Martin; Bauer-Brandl, Annette; Blatter, FritzPosaconazole is a broad-spectrum antifungal agent exhibiting rich polymorphism. Up to now, a total of fourteen different crystal forms have been reported, sometimes with an ambiguous nomenclature, but less is known about their properties and stability relationships. Investigating the solid-state of a drug compound is essential to identify the most stable form under working conditions and to prevent the risk of undesired solid-phase transformations under processing and storage. In this paper, we study posaconazole polymorphism by providing a description of its polymorphs, hydrates, and solvates. Powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), spectroscopic and thermal techniques were employed to characterize the different forms. In addition, the solid-phase transformations of posaconazole in aqueous suspensions were studied by means of Raman microscopy. Surprisingly, we found that Form S, the crystal form contained in the marketed oral suspension, is not the most stable form in water. Form S readily converts to a more stable hydrate, i.e. Form A, after storage in water for two weeks. In the commercial oral formulation the conversion between the two forms is prevented by the presence of polysorbate 80. Such insights into the stabilizing excipient effects beyond particle dispersion are critical to formulators.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation High loading of lipophilic compounds in mesoporous silica for improved solubility and dissolution performance(Elsevier, 04/2024) Brenner, Marvin Benedikt; Wüst, Matthias; Kuentz, Martin; Wagner, Karl G.Loading poorly soluble active pharmaceutical ingredients (API) into mesoporous silica can enable API stabilization in non-crystalline form, which leads to improved dissolution. This is particularly beneficial for highly lipophilic APIs (log D7.4 > 8) as these drugs often exhibit limited solubility in dispersion forming carrier polymers, resulting in low drug load and reduced solid state stability. To overcome this challenge, we loaded the highly lipophilic natural products coenzyme Q10 (CoQ10) and astaxanthin (ASX), as well as the synthetic APIs probucol (PB) and lumefantrine (LU) into the mesoporous silica carriers Syloid® XDP 3050 and Silsol® 6035. All formulations were physically stable in their non-crystalline form and drug loads of up to 50 % were achieved. At increasing drug loads, a marked increase in equilibrium solubility of the active ingredients in biorelevant medium was detected, leading to improved performance during biorelevant biphasic dissolution studies (BiPHa + ). Particularly the natural products CoQ10 and ASX showed substantial benefits from being loaded into mesoporous carrier particles and clearly outperformed currently available commercial formulations. Performance differences between the model compounds could be explained by in silico calculations of the mixing enthalpy for drug and silica in combination with an experimental chromatographic method to estimate molecular interactions.01A - Beitrag in wissenschaftlicher Zeitschrift