Probing the molecular interactions between pharmaceutical polymeric carriers and bile salts in simulated gastrointestinal fluids using NMR spectroscopy

Abstract

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 surfaceactive 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.

Bile salts in digestion and transport of lipids

“…At higher BS concentrations, mixed micelles are formed and two types of complexes are formed: the copolymer-rich or the BSrich. This behaviour at higher BS concentration resembles the one reported above for nonionic surfactants by Vinarov et al [80], and for HPMC [58].…”

“…The BE aggregates formed at a physiological concentration dissociated in the presence of both types of HPMC. A more recent NMR study has proved interactions between a model BS, NaTC, and HPMC in simulated intestinal media [58]. Interactions between the BS and HPMC molecules were favoured in the simulated intestinal media mimicking the fasted state (lower BS concentrations) and might be driven by hydrophobic forces.…”

Mechanisms of Interactions between Bile Acids and Plant Compounds—A Review

“…To elucidate the nature of molecular interactions, a variety of structural techniques can be used. These include nuclear magnetic resonance (NMR) methods to study chemical shift changes in bile salt resonances as a function of the concentration of digested plant compounds [55][56][57]. Additionally, small-angle X-ray and/or neutron scattering, microcalorimetry, surface plasmon resonance analysis, and molecular docking experiments can be performed to elucidate binding stoichiometry and energetics of interactions [58,59].…”

Physiology and Physical Chemistry of Bile Acids

“…Polymeric carriers for the oral administration of drugs are expected to interact with BAs, which may affect the drug solubilization and absorption. With this motivation, the interaction in mixtures of sodium taurocholate and widely used hydrophilic model polymers such as hydroxypropyl methylcellulose and polyvinylpyrrolidone, was investigated, revealing that the formation of mixed BA/polymer aggregates occurs in the mixtures, which could significantly affect the drug solubilization in the gut when hydrophilic polymers are used as dispersant [144].…”