Drug-Excipient Interaction Investigation using Calorimetry and Related Techniques

Beads loaded with drugs have been shown to be useful for drug delivery, yet only limited research has been undertaken on analysing drug-bead interactions and the behaviour of the resultant products. This study investigated specific drug-bead physicochemical parameters, such as factors affecting binding and subsequent drug release phenomena under conditions mimicking the clinic and the body. Isothermal titration calorimetry (ITC) was initially used to investigate interactions between a drug, doxorubicin (Dox) and a drug eluting bead (DEB), DC Bead™. Dox was titrated into polymer beads at various temperatures, concentrations, volumes, and pH’s of the drug and the polymer considered. Furthermore, washing the beads in acid prior to analysis displaced sodium ions which had previously interfered with the drug-bead interaction. Similar binding ratios were found with DC Bead™ to that of previously reported ultra-violet visible (UV-Vis) spectroscopic analysis of 0.90:1 bead binding sites to the drug. The technique was extended to evaluate a range of drugs with DC Bead™ such as Mitoxantrone (Mit), Irinotecan (Iri), Topotecan (Top), in addition to other types (DC Bead Lumi™, LifePearl™, Tandem™ and HepaSphere™) and sizes of beads (from 60 to 700 nm). The thermodynamic information collected suggests that interactions were significantly greater in DC Bead™ than the competitor product LifePearl™. Mit-DC Bead™ was the only drug which bound to two bead sites per drug molecule, consequently half the concentration of drug was required for bead saturation. Alternatively, Iri-DC Bead™ and Top-DC Bead™ involved two drug sites depending on the experimental pH, however this encompassed partial binding to each site resulting in ratios similar to that of Dox. The open-loop flow-through elution method determined drug elution with different parameters such as packing material, flow rate, salt concentration, eluent type and bead volume. Rate of elution increased with a decrease in bead size, as a result of a larger surface area to volume ratio. DC Bead™ and DC Bead LUMI™ fully eluted Dox at a range of concentrations, however Tandem™ only eluted ~80 % of the drug, possibly due to drug permanently bound to the beads. Initially DC Bead™ had a higher concentration of drug released in comparison to the slower more sustained release of DC Bead LUMI™ and Tandem™, and Iri was found to elute much faster than Dox. The method achieved flow rates of 0.1 mL/min, close to that of an embolised vessel. At these slow flow rates LifePearl™ was found to have similar characteristics to DC Bead™, which correlated well with the acquired ITC data. Three-dimensional microscopy (3DM) and hot stage microscopy (HSM) supported the view that bead swelling effects changed the elution profile. It was also evident that DC Bead™, DC Bead LUMI™ and Lifepearl™ homogenously loaded and completely eluted, whereas Tandem™ heterogeneously loaded did not fully elute. HepaSphere™ images indicated significant aggregation and fragmentation. Investigation of the drug in vitro could be used to predict elution characteristics in vivo, with potential implications for product development and quality assurance. In summary, knowledge of the drug-bead interactions facilitated a deeper understanding of drug-bead binding to be attained using ITC and drug-bead release accomplished with a method of elution. These methods developed will undoubtedly assist in developing optimum treatment options

A calorimetric investigation of doxorubicin-polymer bead interactions

Isothermal titration calorimetry (ITC) was utilised to investigate suitability of the technique to determine the stoichiometry and thermodynamics of the interactions that occur between a commonly used chemotherapeutic drug, namely doxorubicin, and a polymer bead-based drug delivery embolisation system (DC Bead™). Six temperatures were selected for drug-polymer titrations (293 to 313 K) and in all cases an initially exothermic signal reverted to an endothermic response upon the saturation of the beads with drug. From these experiments, and subsequent calculations, the molar ratio of drug to SO3- (polymer) was found to be 0.4:1 at all temperatures studied. Enthalpic data was calculated from the raw ITC data with an average enthalpy of drug-polymer binding of – 14.8 kJmol-1 at 293 K through to – 19.4 kJmol-1 at 313 K implying the process is enthalpically-driven yet only affected by an increase in experimental temperature to a limited extent whereby an increase in experimental temperature results in a small increase in the negativity in change in enthalpy recorded. The application of ITC in this study (with its unique ability to monitor real-time interactions and facilitate stoichiometric calculations) resolves the lack of knowledge regarding the thermodynamics of this specific drug-polymer interaction. This study confirms that ITC is not only useful for this specific system, but also highlights the potential use of ITC for more general studies in this area

Evaluation of ion exchange processes in drug-eluting embolization beads by use of an improved flow-through elution method.

n improved method for evaluating drug release behaviour of drug-eluting embolization beads (DEBs) was developed utilizing an open-loop flow-through system, in which the beads were packed into an occlusive mass within the system and extracted with a flowing elution medium over time. Glass beads were introduced into the beads mass in order to ensure laminar flow, reduce dead volume and improve reproducibility by compensating for swelling phenomena. The effects of glass bead ratio, elution medium flow rate and ion concentration, DEB size and drug concentration and drug type (doxorubicin and irinotecan) were evaluated using DEB composed of a sulfonate-modified polyvinyl alcohol hydrogel (DC Bead™) as the test article. The rate and amount of drug elution from the packed beads was affected by flow rate, the bead size and initial loading dose. The raw data from the concentration profile analysis provided valuable information to reveal the drug elution behaviour akin to the pharmacokinetic data observed for embolized beads (yielding in vitro Cmax and tmax data) which was complementary to the normal cumulative data obtained. A good correlation with historical reported in vivo data validated the usefulness of the method for predicting in vivo drug elution behaviour

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

TRY plant trait database - enhanced coverage and open access

10.1111/gcb.14904GLOBAL CHANGE BIOLOGY261119-18