Polymer-bile salts interaction and its impact on the solubilisation and intestinal uptake of poorly water-soluble drugs

I would like to thank my primary supervisor Dr. Sheng Qi for the invaluable support and encouragement received during my PhD time at UEA. Thanks also to my supervisors Prof. Peter Wilde and Prof. Duncan Craig for their help. I would also like to express my gratitude to Prof. Pete Belton, Dr. Francesca Baldelli Bombelli from the UEA School of Pharmacy for their precious scientific collaboration. Thanks to Dr. Patrick Gunning, Dr. Nicola Woodwards and Mr. Andrew Kirby, Dr. Paul Kroon and Mr. Mark Winterbone from the Institute of Food Research for their help with Nanosight, pendant drop and biological experiments. I would like to thank all the friends that have been part of my life in Norwich, for the happy times together and for being supportive when I mostly needed. A special thanks goes to Yohan for being a good friend and taking care of me as a brother. Thanks to my housemates Desirè and Hanae, for their friendship and their constant support. Thanks to Francesca and Alberto for all the laughes and their invaluable help and care. Thanks to Lorina, Elisabetta, Marcello, Antonella and Tiziana for being good friends during these years. Thanks to all the other friends from the schools of Pharmacy and Chemistry. I would also like to thank my friends from Italy, in particular Ilaria for being a constant presence and support in my life. Finally I would like to thank my family, my outstanding parents for their love, their encouragement and support. Thanks to my sister Flavia, for being the special sister she is

Probing the Molecular Interactions between Pharmaceutical Polymeric Carriers and Bile Salts in Simulated Gastrointestinal Fluids using NMR Spectroscopy

The number of poorly soluble new drugs is increasing and one of the effective ways to deliver such pharmaceutically active molecules is using hydrophilic polymers to form a solid dispersion. Bile salts play an important role in the solubilisation of poorly soluble compounds in the gut prior to absorption. When a poorly water-soluble drug is delivered using a hydrophilic polymer based solid dispersion oral formulation, it is still unclear whether there are any polymer-bile salt interactions, which may influence the drug dissolution and solubilisation. This study, using two widely used hydrophilic model polymers, Hydroxypropyl methylcellulose (HPMC) and polyvynilpirrolidone (PVP), and sodium taurocholate (NaTC) as the model bile salt, aims to investigate the interactions between the polymers and bile salts in simulated fed state (FeSSIF) and fasted state (FaSSIF) gut fluids. The nature of the interactions was characterised using a range of NMR techniques. The results revealed that the aggregation behaviour of NaTC in FaSSIF and FeSSIF is much more complex than in water. The addition of hydrophilic polymers led to the occurrences of NaTC-HPMC and NaTC-PVP aggregation. For both systems, pH and ionic strength strongly influenced the aggregation behavior, while the ion type played a less significant role. The outcome of this study enriched the understanding of the aggregation behaviour of bile salts and typical hydrophilic pharmaceutical polymers in bio-relevant media. Due to the highly surface-active behaviour of the bile salts, such aggregation behaviour is expected to play a role in drug solubilisation in the gut when the drug is delivered by hydrophilic polymer based dispersions

Halogenation dictates the architecture of amyloid peptide nanostructures

Amyloid peptides yield a plethora of interesting nanostructures though difficult to control. Here we report that depending on the number, position, and nature of the halogen atoms introduced into either one or both phenylalanine benzene rings of the amyloid β peptide-derived core-sequence KLVFF, four different architectures were obtained in a controlled manner. Our findings demonstrate that halogenation may develop as a general strategy to engineer amyloidal peptide self-assembly and obtain new amyloidal nanostructures

Hydrophobin-stabilized dispersions of PVDF nanoparticles in water

In this study, aqueous dispersions of partially crystalline PVDF nanoparticles (NPs) were obtained employing hydrophobin (HFB), an amphiphilic film-forming protein able to film hydrophobic surfaces. Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) analysis of PVDF-HFBII aqueous dispersions confirmed the HPBII ability to film PVDF hydrophobic NPs. Freeze-dried PVDF-HFBII bio-nanocomposites were shown to be effectively re-dispersible in water. An aqueous dispersion of PVDF NPs may have an impact on the applications of this polymer in the perspective of the development of environmentally friendly coating methods

Acid⋅⋅⋅amide supramolecular synthon for tuning amino acid-based hydrogels' properties

: Supramolecular hydrogels formed by the self-assembly of N-Fmoc-l-phenylalanine derivatives are gaining relevance for several applications in the materials and biomedical fields. In the challenging attempt to predict or tune their properties, we selected Fmoc-pentafluorophenylalanine (1) as a model efficient gelator, and studied its self-assembly in the presence of benzamide (2), a non-gelator able to form strong hydrogen bonds with the amino acid carboxylic group. Equimolar mixtures of 1 and 2 in organic solvents afforded a 1 : 1 co-crystal thanks to the formation of an acid⋅⋅⋅amide heterodimeric supramolecular synthon. The same synthon occurred in the transparent gels formed by mixing the two components in 1 : 1 ratio in aqueous media, as revealed by structural, spectroscopic, and thermal characterizations performed on both the co-crystal powder and the lyophilized hydrogel. These findings revealed the possibility of modulating the properties of amino acid-based hydrogels by involving the gelator in the formation of a co-crystal. Such a crystal engineering-based approach is shown also to be useful for the time-delayed release of suitable bioactive molecules, when involved as hydrogel coformers

L'unghia pigmentata

le unghie spesso appaiono pigmentate in parte o in tutte le sue componenti .Gli Autori esaminano le varie cause e sottolineano possibili diagnosi differenzial

Halogen bond-assisted self-assembly of gold nanoparticles in solution and on a planar surface

| openaire: EC/H2020/789815/EU//MINIRESHalogen bonding (XB) has been shown to be a powerful tool for promoting molecular self-assembly in different fields. The use of XB for noncovalent assembly of inorganic nanoparticles (NP) is, instead, quite limited, considering how extensively other interactions (i.e., electrostatic forces, hydrophobic effect, hydrogen bonding, etc.) have been exploited to modulate and program NP self-assembly. Here, we designed and synthesized XB-capable organic ligands that were efficiently used to functionalize the surface of gold NPs (AuNPs). XB-assisted AuNP self-assembly was attained in solution mixing AuNPs bearing XB-donor ligands with ditopic XB-acceptor molecules and AuNPs functionalized with XB-acceptor moieties. Likewise, a preliminary study of XB-driven adsorption of these AuNPs on surface was performed via Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D), used as an in situ tool for measuring mass changes upon XB-driven self-assembly.Peer reviewe

Interaction of polymers with bile salts - Impact on solubilisation and absorption of poorly water-soluble drugs

Formulating poorly soluble drugs with polymers in the form of solid dispersions has been widely used for improving drug dissolution. Endogenous surface-active species present in the gut, such as bile salts, lecithin and other phospholipids, have been shown to play a key role in facilitating lipids and poorly soluble drugs solubilisation in the gut. In this study, we examined the possible occurrence of interactions between a model bile salt, sodium taurocholate (NaTC), and model spray dried solid dispersions comprising piroxicam and Hydroxypropyl Methylcellulose (HPMC), a commonly used hydrophilic polymer for solid dispersion preparation. Solubility measurements revealed the good solubilisation effect of NaTC on the crystalline drug, which was enhanced by the addition of HPMC, and further boosted by the drug formulation into solid dispersion. The colloidal behaviour of the solid dispersions upon dissolution in biorelevant media, with and without NaTC, revealed the formation of NaTC-HPMC complexes and other mixed colloidal species. Cellular level drug absorption studies obtained using Caco-2 monolayers confirmed that the combination of drug being delivered by solid dispersion and the presence of bile salt and lecithin significantly contributed to the improved drug absorption. Together with the role of NaTC-HPMC complexes in assisting the drug solubilisation, our results also highlight the complex interplay between bile salts, excipients and drug absorption