Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole

AbstractThis study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance

Synthese und Evaluierung von selektiven Hemmstoffen der Aldosteronsynthase (CYP11B2) vom Typ Naphthaline und Dihydronaphthaline zur Behandlung von Herzinsuffizienz und Myokardfibrose

The aim of this work was to design and synthesize potent and highly selective CYP11B2 inhibitors, which could be used for the treatment of congestive heart failure and myocardial fibrosis. We have synthesized different heteroaryl substituted naphthalenes, dihydronaphthalenes and indenes. The compounds were tested for inhibitory activity towards human CYP11B2 and the active inhibitors were also tested towards CYP11B1 to obtain information about selectivity. Selectivity towards other steroidogenic CYP enzymes, CYP19 and CYP17, was evaluated as well. The best naphthalene compound was the 3-(6-methoxy-2-naphthyl)pyridine 21 (IC50 CYP11B2 = 6 nM) with a selectivity factor of 263. The 6-methoxy dihydronaphthalene 53 showed the best potency (IC50 CYP11B2 = 2 nM) in the dihydronaphthalene class of compounds; the 5-methoxy indene 52 was very active (IC50 CYP11B2 = 4 nM) and had an exceptional selectivity factor of 1421, displaying the best selectivity profile described until now. Docking and molecular dynamics studies using the homology modelled CYP11B2 protein model were performed to explain some very interesting structure-activity relationships. The potent and selective compounds were tested in adult male rats after stimulation with ACTH. Permeability screening using Caco-2 cells, metabolic stability studies with rat liver microsomes and pharmacokinetic profiling were performed as well.Das Ziel dieser Arbeit war das Design und die Synthese potenter und hochselektiver CYP11B2 Inhibitoren, potentielle Therapeutika zur Behandlung von Herzinsuffizienz und Myokardfibrose. Verschiedene Heteroaryl-substituierte Naphthaline, Dihydronaphthaline und Indene wurden hergestellt. Die Verbindungen wurden auf Hemmaktivität gegenüber menschlichem CYP11B2 getestet und die aktiven Inhibitoren wurden ebenfalls gegenüber CYP11B1 evaluiert, um Informationen über die Selektivität zu erhalten. Selektivität gegenüber anderen steroidogenen CYP Enzymen, CYP19 und CYP17, wurde ebenfalls ermittelt. Die beste Naphthalin Verbindung war das 3-(6-Methoxy-2-naphthyl)pyridin 21 (IC50 CYP11B2 = 6 nM), das einen Selektivitätsfaktor von 263 aufwies. Das 6-Methoxy-Dihydronaphthalin 53 zeigte die beste Potenz (IC50 CYP11B2 = 2 nM); das 5-Methoxy-Inden 52, war sehr aktiv (IC50 CYP11B2 = 4 nM) und hatte einen extrem hohen Selektivitätsfaktor von 1421. Diese Verbindung ist somit die selektivste Verbindung, die bislang entwickelt wurde. Docking und Moleküldynamikstudien wurden mit einer Homologie modellierten CYP11B2 Proteinstruktur durchgeführt, um einige der interessanten Strukturwirkungsbeziehungen zu erklären. Die potenten und selektiven Hemmstoffe 21 und 53 wurden an erwachsenen männlichen Ratten nach Stimulation mit ACTH getestet. Ein Permeabilitätsscreening unter Verwendung von CaCo-2-Zellen, Studien zum Metabolismus mit Rattenlebermikrosomen und pharmacokinetischen Profiling wurden auch durchgeführt

Molecular control over colloidal assembly

Contemporary chemical and material engineering often takes inspiration from nature, targeting for example strong yet light materials and materials composed of highly ordered domains at multiple different lengthscales for fundamental science and applications in e.g. sensing, catalysis, coating technology, and delivery. The preparation of such hierarchically structured functional materials through guided bottom-up assembly of synthetic building blocks requires a high level of control over their synthesis, interactions and assembly pathways. In this perspective we showcase recent work demonstrating how molecular control can be exploited to direct colloidal assembly into responsive materials with mechanical, optical or electrical properties that can be adjusted post-synthesis with external cues

Discordant Supramolecular Fibres Reversibly Depolymerised by Temperature and Light

Synthetic stimuli responsive supramolecular polymers attract increasing interest for their ability to mimic the unique properties of natural assemblies. Here we focus on the well-studied benzene-1,3,5-tricarboxamide (BTA) motif, and substitute it with two (S)-3,7-dimethyloctyl groups and an azobenzene photoswitch. We demonstrate the UV (λ=365 nm) induced depolymerisation of the helical hydrogen-bonded polymers in methylcyclohexane (MCH) through circular dichroism and UV-vis spectroscopy in dilute solution (15 μm), and NMR and iPAINT super-resolution microscopy in concentrated solution (300 μm). The superstructure can be regenerated after thermal depolymerization, whilst repeated depolymerisation can be reversed without degradation by irradiating at λ=455 nm. Molecular dynamics simulations show that the most energetically favourable configuration for these polymers in MCH is a left-handed helical network of hydrogen-bonds between the BTA cores surrounded by two right-handed helices of azobenzenes. The responsiveness to two orthogonal triggers across a broad concentration range holds promise for use in, for example, photo-responsive gelation

Vlaamse en Nederlandse burgemeesters in volle crisis(s)t(r)ijd

Hoe hebben Vlaamse en Nederlandse burgemeesters de eerste maanden van de coronacrisis ervaren? Om dat te achterhalen, zoomen we eerst in op het lokale bestuurssysteem waarbinnen burgemeesters opereren. Dat systeem verschilt tussen de lage landen vanuit functioneel, territoriaal en politiek perspectief. Een grondige documentenanalyse en een reeks interviews leren ons echter dat de positie en speelruimte van burgemeesters veeleer gelijkend is in volle corona(s)t(r)ijd. Zowel in Vlaanderen als Nederland wordt de crisisbesluitvorming gecentraliseerd. Burgemeesters maakten er dan ook snel een stevige verschuiving door in termen van (1) macht en autoriteit (respectievelijk naar de provinciegouverneur en het federale niveau en naar de regioburgemeester en het nationale niveau); (2) taken (prioriteren van crisismanagement over andere taken); en (3) rollen (toegenomen belang voor uitvoerende rol met impact op rol als burgervader/burgermoeder). Ze getuigen steevast van veel flexibiliteit en vindingrijkheid in deze uitzonderlijke situatie. En daarmee toont onze bijdrage dat Vlaamse en Nederlandse burgemeesters, en bij verlenging lokale besturen, vandaag onmisbaar zijn ter aanpak van een crisis, ook al reikt die hun eigen grenzen ver voorbij

The Belgian and Dutch response to COVID-19 : change and stability in the mayors’ position

How did Belgian and Dutch mayors experience their own role and that of local government during the first few months of the COVID-19 outbreak? This question was addressed by drawing on three analytical perspectives (functional, territorial, and political) on local government systems and using a qualitative case study design. Interestingly, the position and leeway of Belgian and Dutch mayors did not differ that much during the first crisis months. The type of virus and scope of the outbreak necessitated a centralised approach. Consequently, the decisions were made at the national level and mayors focused primarily on implementing these central measures. Moreover, Belgian and Dutch mayors experienced a similar shift in terms of (1) power and authority (respectively to the provincial governor and the national level and to the regional mayor and the national level); (2) tasks (prioritising crisis management over other tasks); and (3) roles (increasing importance of their executive role while lamenting the effects of COVID-19 on their social role vis-à-vis their citizens)

An Azobenzene-Based Single-Component Supramolecular Polymer Responsive to Multiple Stimuli in Water

One of the most appealing features of supramolecular assemblies is their ability to respond to external stimuli due to their noncovalent nature. This provides the opportunity to gain control over their size, morphology, and chemical properties and is key toward some of their applications. However, the design of supramolecular systems able to respond to multiple stimuli in a controlled fashion is still challenging. Here we report the synthesis and characterization of a novel discotic molecule, which self-assembles in water into a single-component supramolecular polymer that responds to multiple independent stimuli. The building block of such an assembly is a C3-symmetric monomer, consisting of a benzene-1,3,5-tricarboxamide core conjugated to a series of natural and non-natural functional amino acids. This design allows the use of rapid and efficient solid-phase synthesis methods and the modular implementation of different functionalities. The discotic monomer incorporates a hydrophobic azobenzene moiety, an octaethylene glycol chain, and a C-terminal lysine. Each of these blocks was chosen for two reasons: to drive the self-assembly in water by a combination of H-bonding and hydrophobicity and to impart specific responsiveness. With a combination of microscopy and spectroscopy techniques, we demonstrate self-assembly in water and responsiveness to temperature, light, pH, and ionic strength. This work shows the potential to integrate independent mechanisms for controlling self-assembly in a single-component supramolecular polymer by the rational monomer design and paves the way toward the use of multiresponsive systems in water

An Azobenzene-Based Single-Component Supramolecular Polymer Responsive to Multiple Stimuli in Water

One of the most appealing features of supramolecular assemblies is their ability to respond to external stimuli due to their noncovalent nature. This provides the opportunity to gain control over their size, morphology, and chemical properties and is key toward some of their applications. However, the design of supramolecular systems able to respond to multiple stimuli in a controlled fashion is still challenging. Here we report the synthesis and characterization of a novel discotic molecule, which self-assembles in water into a single-component supramolecular polymer that responds to multiple independent stimuli. The building block of such an assembly is a C3-symmetric monomer, consisting of a benzene-1,3,5-tricarboxamide core conjugated to a series of natural and non-natural functional amino acids. This design allows the use of rapid and efficient solid-phase synthesis methods and the modular implementation of different functionalities. The discotic monomer incorporates a hydrophobic azobenzene moiety, an octaethylene glycol chain, and a C-terminal lysine. Each of these blocks was chosen for two reasons: to drive the self-assembly in water by a combination of H-bonding and hydrophobicity and to impart specific responsiveness. With a combination of microscopy and spectroscopy techniques, we demonstrate self-assembly in water and responsiveness to temperature, light, pH, and ionic strength. This work shows the potential to integrate independent mechanisms for controlling self-assembly in a single-component supramolecular polymer by the rational monomer design and paves the way toward the use of multiresponsive systems in water

Engineered living materials based on adhesin-mediated trapping of programmable cells

Engineered living materials have the potential for wide-ranging applications such as biosensing and treatment of diseases. Programmable cells provide the functional basis for living materials; however, their release into the environment raises numerous biosafety concerns. Current designs that limit the release of genetically engineered cells typically involve the fabrication of multilayer hybrid materials with submicrometer porous matrices. Nevertheless the stringent physical barriers limit the diffusion of macromolecules and therefore the repertoire of molecules available for actuation in response to communication signals between cells and their environment. Here, we engineer a novel living material entitled "Platform for Adhesin-mediated Trapping of Cells in Hydrogels" (PATCH). This technology is based on engineered E. coli that displays an adhesion protein derived from an Antarctic bacterium with a high affinity for glucose. The adhesin stably anchors E. coli in dextran-based hydrogels with large pore diameters (10-100 μm) and reduces the leakage of bacteria into the environment by up to 100-fold. As an application of PATCH, we engineered E. coli to secrete the bacteriocin lysostaphin which specifically kills Staphyloccocus aureus with low probability of raising antibiotic resistance. We demonstrated that living materials containing this lysostaphin-secreting E. coli inhibit the growth of S. aureus, including the strain resistant to methicillin (MRSA). Our tunable platform allows stable integration of programmable cells in dextran-based hydrogels without compromising free diffusion of macromolecules and could have potential applications in biotechnology and biomedicine.

Engineered Living Materials Based on Adhesin-Mediated Trapping of Programmable Cells

Engineered living materials have the potential for wide-ranging applications such as biosensing and treatment of diseases. Programmable cells provide the functional basis for living materials; however, their release into the environment raises numerous biosafety concerns. Current designs that limit the release of genetically engineered cells typically involve the fabrication of multilayer hybrid materials with submicrometer porous matrices. Nevertheless the stringent physical barriers limit the diffusion of macromolecules and therefore the repertoire of molecules available for actuation in response to communication signals between cells and their environment. Here, we engineer a novel living material entitled "Platform for Adhesin-mediated Trapping of Cells in Hydrogels" (PATCH). This technology is based on engineered E. coli that displays an adhesion protein derived from an Antarctic bacterium with a high affinity for glucose. The adhesin stably anchors E. coli in dextran-based hydrogels with large pore diameters (10-100 μm) and reduces the leakage of bacteria into the environment by up to 100-fold. As an application of PATCH, we engineered E. coli to secrete the bacteriocin lysostaphin which specifically kills Staphyloccocus aureus with low probability of raising antibiotic resistance. We demonstrated that living materials containing this lysostaphin-secreting E. coli inhibit the growth of S. aureus, including the strain resistant to methicillin (MRSA). Our tunable platform allows stable integration of programmable cells in dextran-based hydrogels without compromising free diffusion of macromolecules and could have potential applications in biotechnology and biomedicine