Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.769037
Title: Drug-excipient interaction investigation using calorimetry and related techniques
Author: Swaine, Tanya
ISNI:       0000 0004 7656 4777
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2018
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Abstract:
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.
Supervisor: Waters, Laura ; Parkes, Gareth Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.769037  DOI: Not available
Keywords: R Medicine (General)
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