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University of Birmingham
Glioblastoma (GBM) is an aggressive brain tumour with low survival rates. The blood-brain barrier (BBB) limits drug penetration into brain tissue, affecting the effectiveness of systemic chemotherapy. Localised drug delivery devices have emerged as a promising solution to address these limitations. This study focuses on developing and investigating biodegradable implantable devices to directly deliver chemotherapeutic drugs to brain tissue, reducing systemic administration and recurrence risk. Irinotecan (IRN) has shown success in clinical trials against GBM. However, large intravenous doses of IRN lead to severe systemic side effects. The study investigates the local delivery of IRN through implantable drug delivery devices to improve therapeutic outcomes while minimising adverse effects. The first study develops IRN-loaded poly(lactic-co-glycolic acid) (PLGA) implants using injection moulding (IM) and hot melt extrusion (HME) techniques. The study compared IM and HME implants, finding that HME implants showed better drug content uniformity and homogeneous drug distribution due to high shear mixing. Factors such as PLGA type, drug load, and implant size influenced drug release behaviour. HME implants exhibited slower drug release due to their denser matrix. Accelerated release studies showed both IM and HME implants had sustained release over seven days, with HME implants considered preferable based on drug content, stability, and distribution results. Pitavstatin (PTV) effectively slows tumour growth, but its limited BBB penetration suggests potential benefits of local administration. The second study involves the development of PTV-loaded PLGA implants using IM and HME techniques. Both IM and HME implants demonstrate an amorphous state of PTV. HME implants show higher drug content and uniformity due to homogeneous drug distribution facilitated by high shear mixing force, making them preferable over IM. In vitro drug release studies revealed slower drug release from HME implants due to denser matrices, and accelerated release studies confirmed sustained release over seven days for HME implants. In the third study, the high-performance liquid chromatography (HPLC) method was developed and validated for quantifying IRN and PTV in multi-layered implantable drug delivery devices. This method allowed precise drug release quantification, ensuring accurate safety and efficacy assessment of the devices. The final study involves the development of IRN-PTV-loaded PLGA implants as multi-layered devices using HME. The purpose of combining IRN and PTV in these implants is their synergistic effects against the GBM. The multi-layered implants were characterised using HPLC, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Raman spectroscopy. They demonstrated uniformity in size, weight, and drug content, validating the reliability of the HME technique. XRD and DSC analyses confirmed crystalline IRN in the IRN-PLGA layer and amorphous PTV in the PTV-PLGA layer, suggesting enhanced drug bioavailability and therapeutic effectiveness. Raman mapping reveals homogeneous drug distribution within the implants, ensuring consistent drug release. In vitro studies show biphasic drug release over seven days, characterised as non-Fickian behaviour by the Korsmeyer-Peppas model. This enhances our understanding of the release mechanism. This thesis presents advancements in implantable drug delivery devices for localised GBM treatment, offering valuable insights into formulation compositions and manufacturing techniques. Further research is necessary to assess in vivo performance and therapeutic efficacy.
Pharmacy, Drug Delivery, Pharmaceutical Science, Pharmaceutical Technology