@article{GuentzelSchillingHanioetal.2020, author = {G{\"u}ntzel, Paul and Schilling, Klaus and Hanio, Simon and Schlauersbach, Jonas and Schollmayer, Curd and Meinel, Lorenz and Holzgrabe, Ulrike}, title = {Bioinspired Ion Pairs Transforming Papaverine into a Protic Ionic Liquid and Salts}, series = {ACS Omega}, volume = {5}, journal = {ACS Omega}, number = {30}, doi = {10.1021/acsomega.0c02630}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230265}, pages = {19202-19209}, year = {2020}, abstract = {Microbial, mammalian, and plant cells produce and contain secondary metabolites, which typically are soluble in water to prevent cell damage by crystallization. The formation of ion pairs, for example, with carboxylic acids or mineral acids, is a natural blueprint to maintain basic metabolites in solution. Here, we aim at showing whether the mostly large carboxylates form soluble protic ionic liquids (PILs) with the basic natural product papaverine resulting in enhanced aqueous solubility. The obtained PILs were characterized by H-1-N-15 HMBC nuclear magnetic resonance (NMR) and in the solid state using X-ray powder diffraction, differential scanning calorimetry, and dissolution measurements. Furthermore, their supramolecular pattern in aqueous solution was studied by means of potentiometric and photometrical solubility, NMR aggregation assay, dynamic light scattering, zeta potential, and viscosity measurements. Thereby, we identified the naturally occurring carboxylic acids, citric acid, malic acid, and tartaric acid, as being appropriate counterions for papaverine and which will facilitate the formation of PILs with their beneficial characteristics, like the improved dissolution rate and enhanced apparent solubility.}, language = {en} } @article{SchlauersbachHanioLenzetal.2021, author = {Schlauersbach, Jonas and Hanio, Simon and Lenz, Bettina and Vemulapalli, Sahithya P. B. and Griesinger, Christian and P{\"o}ppler, Ann-Christin and Harlacher, Cornelius and Galli, Bruno and Meinel, Lorenz}, title = {Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection}, series = {Journal of Controlled Release}, volume = {330}, journal = {Journal of Controlled Release}, edition = {Accepted Version}, doi = {10.1016/j.jconrel.2020.12.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296957}, pages = {36-48}, year = {2021}, abstract = {Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection.}, language = {en} } @article{SchlauersbachHanioRaschigetal.2022, author = {Schlauersbach, Jonas and Hanio, Simon and Raschig, Martina and Lenz, Bettina and Scherf-Cavel, Oliver and Meinel, Lorenz}, title = {Bile and excipient interactions directing drug pharmacokinetics in rats}, series = {European Journal of Pharmaceutics and Biopharmaceutics}, volume = {178}, journal = {European Journal of Pharmaceutics and Biopharmaceutics}, edition = {accepted version}, doi = {10.1016/j.ejpb.2022.07.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296969}, pages = {65-68}, year = {2022}, abstract = {Bile solubilization plays a major role in the absorption of poorly water-soluble drugs. Excipients used in oral drug formulations impact bile-colloidal properties and their molecular interactions. Polymer-induced changes of bile colloids, e.g., by Eudragit E, reduced the flux of the bile interacting drug Perphenazine whereas bile non-interacting Metoprolol was not impacted. This study corroborates these in vitro findings in rats. Eudragit E significantly reduced systemic availability of Perphenazine but not Metoprolol compared to the oral administrations without polymer. This study confirms the necessity to carefully select polymers for bile interacting drugs whereas non-bile interacting drugs are more robust in terms of excipient choice for formulation. The perspective of bile interaction may introduce interesting biopharmaceutical leverage for better performing oral formulations of tomorrow.}, language = {en} } @article{PoepplerLuebtowSchlauersbachetal.2019, author = {P{\"o}ppler, Ann-Christin and L{\"u}btow, Michael M. and Schlauersbach, Jonas and Wiest, Johannes and Meinel, Lorenz and Luxenhofer, Robert}, title = {Strukturmodell von Polymermizellen in Abh{\"a}ngigkeit von der Curcumin-Beladung mithilfe von Festk{\"o}rper-NMR-Spektroskopie}, series = {Angewandte Chemie}, volume = {131}, journal = {Angewandte Chemie}, number = {51}, doi = {10.1002/ange.201908914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212513}, pages = {18712-18718}, year = {2019}, abstract = {Detaillierte Einblicke in die Struktur von mit Wirkstoffen beladenen Polymermizellen sind rar, aber wichtig um gezielt optimierte Transportsysteme entwickeln zu k{\"o}nnen. Wir konnten beobachten, dass eine Erh{\"o}hung der Curcumin-Beladung von Triblockcopolymeren auf Basis von Poly(2-oxazolinen) und Poly(2-oxazinen) schlechtere Aufl{\"o}sungseigenschaften nach sich zieht. Mitthilfe von Festk{\"o}rper-NMR-Spektroskopie und komplement{\"a}ren Techniken ist es m{\"o}glich, ein ladungsabh{\"a}ngiges Strukturmodell auf molekularer Ebene zu erstellen, das eine Erkl{\"a}rung f{\"u}r die beobachteten Unterschiede liefert. Dabei belegen die {\"A}nderungen der chemischen Verschiebungen und Kreuzsignale in 2D-NMR-Experimenten die Beteiligung des hydrophoben Polymerblocks an der Koordination der Curcumin-Molek{\"u}le, w{\"a}hrend bei h{\"o}herer Beladung auch eine zunehmende Wechselwirkung mit dem hydrophilen Polymerblock beobachtet wird. Letztere k{\"o}nnte elementar f{\"u}r die Stabilisierung von ultrahochbeladenen Polymermizellen sowie das Design von verbesserten Wirkstofftransportsystemen sein.}, language = {de} } @article{PoepplerLuebtowSchlauersbachetal.2019, author = {P{\"o}ppler, Ann-Christin and L{\"u}btow, Michael M. and Schlauersbach, Jonas and Wiest, Johannes and Meinel, Lorenz and Luxenhofer, Robert}, title = {Loading dependent Structural Model of Polymeric Micelles Encapsulating Curcumin by Solid-State NMR Spectroscopy}, series = {Angewandte Chemie International Edition}, volume = {58}, journal = {Angewandte Chemie International Edition}, number = {51}, doi = {10.1002/anie.201908914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206705}, pages = {18540-18546}, year = {2019}, abstract = {Detailed insight into the internal structure of drug-loaded polymeric micelles is scarce, but important for developing optimized delivery systems. We observed that an increase in the curcumin loading of triblock copolymers based on poly(2-oxazolines) and poly(2-oxazines) results in poorer dissolution properties. Using solid-state NMR spectroscopy and complementary tools we propose a loading-dependent structural model on the molecular level that provides an explanation for these pronounced differences. Changes in the chemical shifts and cross-peaks in 2D NMR experiments give evidence for the involvement of the hydrophobic polymer block in the curcumin coordination at low loadings, while at higher loadings an increase in the interaction with the hydrophilic polymer blocks is observed. The involvement of the hydrophilic compartment may be critical for ultrahigh-loaded polymer micelles and can help to rationalize specific polymer modifications to improve the performance of similar drug delivery systems.}, language = {en} } @phdthesis{Schlauersbach2023, author = {Schlauersbach, Jonas}, title = {The bile-drug-excipient interplay}, doi = {10.25972/OPUS-29653}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296537}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {The bile system in vertebrates is an evolutionary conserved endogenous solubilization system for hydrophobic fats and poorly water-soluble vitamins. Bile pours out from the gallbladder through the common bile duct into the duodenum triggered by cholecystokinin. Cholecystokinin is released from enteroendocrine cells after food intake. The small intestine is also the absorption site of many orally administered drugs. Most emerging drug candidates belong to the class of poorly water-soluble drugs (PWSDs). Like hydrophobic vitamins, these PWSDs might as well be solubilized by bile. Therefore, this natural system is of high interest for drug formulation strategies. Simulated intestinal fluids containing bile salts (e.g., taurocholate TC) and phospholipids (e.g., lecithin L) have been widely applied over the last decade to approximate the behavior of PWSDs in the intestine. Solubilization by bile can enhance the oral absorption of PWSDs being at least in part responsible for the positive "food effect". The dissolution rate of PWSDs can be also enhanced by the presence of bile. Furthermore, some PWSDs profit from supersaturation stabilization by bile salts. Some excipients solubilizing PWSDs seemed to be promising candidates for drug formulation when investigated in vitro without bile. When tested in vivo, these excipients reduced the bioavailability of drugs. However, these observations have been hardly examined on a molecular level and general links between bile interaction in vitro and bioavailability are still missing. This thesis investigated the interplay of bile, PWSDs, and excipients on a molecular level, providing formulation scientists a blueprint for rational formulation design taking bile/PWSD/excipient/ interaction into account. The first chapter focus on an in silico 1H nuclear magnetic resonance (NMR) spectroscopy-based algorithm for bile/drug interaction prediction. Chapter II to IV report the impact of excipients on bioavailability of PWSDs interacting with bile. At last, we summarized helpful in vitro methods for drug formulation excipient choice harnessing biopharmaceutic solubilization in chapter V. Chapter I applies 1H NMR studies with bile and drugs on a large scale for quantitative structure-property relationship analysis. 141 drugs were tested in simulated intestinal media by 1H NMR. Drug aryl-proton signal shifts were correlated to in silico calculated molecular 2D descriptors. The probability of a drug interacting with bile was dependent on its polarizability and lipophilicity, whereas interaction with lipids in simulated intestinal media components was dependent on molecular symmetry, lipophilicity, hydrogen bond acceptor capability, and aromaticity. The probability of a drug to interact with bile was predictive for a positive food effect. This algorithm might help in the future to identify a bile and lipid interacting drug a priori. Chapter II investigates the impact of excipients on bile and free drug fraction. Three different interaction patterns for excipients were observed. The first pattern defined excipients that interacted with bile and irreversibly bound bile. Therefore, the free drug fraction of bile interacting drugs increased. The second pattern categorized excipients that formed new colloidal entities with bile which had a high affinity to bile interacting drugs. These colloids trapped the drug and decreased the free drug fraction. The last excipient pattern described excipients that formed supramolecular structures in coexistence with bile and had no impact on the free drug fraction. These effects were only observed for drugs interacting with bile (Perphenazine and Imatinib). Metoprolol's free drug fraction, a compound not interacting with bile, was unaffected by bile or bile/excipient interaction. We hypothesized that bile/excipient interactions may reduce the bioavailability of bile interacting drugs. Chapter III addresses the hypothesis from chapter II. A pharmacokinetic study in rats revealed that the absorption of Perphenazine was reduced by bile interacting excipients due to bile/excipient interaction. The simultaneous administration of excipient patterns I and II did not further reduce or enhance Perphenazine absorption. Conversely, the absorption of Metoprolol was not impacted by excipients. This reinforced the hypothesis, that drugs interacting with bile should not be formulated with excipients also interacting with bile. Chapter IV further elaborates which in vitro methods using simulated intestinal fluids are predictive for a drug's pharmacokinetic profile. The PWSD Naporafenib was analyzed in vitro with simulated intestinal fluids and in presence of excipients regarding solubility, supersaturation, and free drug fraction. Naporafenib showed a strong interaction with TC/L from simulated bile. Assays with TC/L, but not without identified one excipient as possibly bioavailability reducing, one as supersaturation destabilizing, and the last as bile not interacting and supersaturation stabilizing excipient. A pharmacokinetic study in beagle dogs outlined and confirmed the in vitro predictions. The Appendix summarizes in vivo predictive methods as presented in chapter I to IV and rationalizes experimental design paving the way towards a biopharmaceutic excipient screening. The first presented preliminary decision tree is transformed into a step-by-step instruction. The presented decision matrix might serve as a blueprint for processes in early phase drug formulation development. In summary, this thesis describes how a drug can be defined as bile interacting or non-interacting and gives a guide as well how to rate the impact of excipients on bile. We showed in two in vivo studies that bile/excipient interaction reduced the bioavailability of bile interacting drugs, while bile non-interacting drugs were not affected. We pointed out that the bile solubilization system must be incorporated during drug formulation design. Simulated gastrointestinal fluids offer a well-established platform studying the fate of drugs and excipients in vivo. Therefore, rational implementation of biopharmaceutic drug and excipient screening steers towards efficacy of oral PWSD formulation design.}, subject = {Solubilisation}, language = {en} }