Saudi Cultural Missions Theses & Dissertations
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Item Restricted Kinetic Parameters Estimation & Population Balanced Modelling (gFormulated) of Micro-Scale Mefenamic Acid in Ethyl Acetate Crystallisation(University of Strathclyde, 2018-11-07) Wan, Ghadeer Yousef; Brown, Cameron; Florence, AlastairMefenamic acid is an analgesic anti-inflammatory drug. It is commonly used for pain associated with menstruation. The crystallisation kinetics of mefenamic acid in ethyl acetate solvent was investigated. The experiments were carried out at small scales, using 1-5 ml vessels. These experiments were conducted in a high throughput reactor system (Crystalline instrument from Technobis). The experimental data was then used as the input for estimating the kinetic parameters. This methodology aims to obtain the sequential parameter estimation which is validated for the determination of the kinetic parameters of mefenamic acid in ethyl acetate. Another aim is to estimate the parameters of the following; primary, secondary nucleation, growth and agglomeration kinetics. Population balanced modelling (PBM) in the gFormulated products program (gPROMS) was used to predict the optimum parameters of kinetic growth and nucleation. The resulting crystallisation model has been able to obtain the quantiles d25, d50, d75 of particle size distribution, although, some errors and deviation in prediction might have arisen due to inaccurate measurements used. In this work, the comprehensive methodology proposed is intended to be an efficient estimation strategy for modelling mefenamic acid of crystallisation processes.41 0Item Restricted MANUFACTURING AND DEVELOPMENT OF IMPLANTABLE DRUG DELIVERY DEVICE FOR THE LOCALISED TREATMENT OF GLIOBLASTOMA(University of Birmingham, 2024-03-04) Wan, Ghadeer Yousef; McConville, ChristopherGlioblastoma (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.48 0Item Restricted Development of Local Drug Delivery Device for The Treatment of Pancreatic Cancer Resection Margin(University of Birmingham, 2024-02-02) Amin, Manna; McConville, ChristopherPancreatic cancer is a significant cause of cancer-related deaths worldwide, characterised by a 5-year survival rate that is notably low, typically ranging from 7-8%. Currently, the accepted norm for medical treatment is the surgical removal of the affected tissue, followed by administration of chemotherapy, particularly the highly potent one, FOLFIRINOX regimen. Due to the high toxicity associated with systemic delivery of FOLFIRINOX, and the intricate nature of the microenvironment of pancreatic cancer within the pancreas, there is a need for a more safer drug delivery method such as local delivery to treat the resection margin and prevent tumour recurrence. The study aimed at developing a local drug delivery device (Chemo Patch) composed of 3-dimensional printed catheter import part, a gelatine sponge and an ethylene vinyl acetate releasing membrane. Various sponges manufactured utilizing freeze-drying technique were prepared and characterized to ascertain the effects of gelatine concentration, blending with sodium alginate, and crosslinking with glutaraldehyde on the physical and mechanical properties of the sponges. The selection of the best sponge was based on its desirability, primarily determined by its mechanical properties. These properties are influenced by the characteristics of the control sponge, Gelfoam®. The results demonstrated that the dry Gelfoam® sponge had hardness value of 2.703Kg/mm2 ±35, whereas the hydrated sponge had 8.698 Kg/mm2 ±117.7. The dry Gelfoam® sponges had an elasticity ratio (the ratio between the force of retraction and the maximum force) of 78.71%±1.9, whereas hydrated sponges had 12.14%±1.7. The results showed that increasing gelatine content increases sponge hardness, with 1% and 2% lower than Gelfoam® sponge and 4% and 10% higher. Oppositely, an increase in gelatine concentration resulted in a decrease in the elasticity of the prepared sponges. This study examined how gelatine concentration and blending with sodium alginate affect precursor hydrogel rheology. The results revealed that as gelatine concentration increased, both viscoelastic moduli increased and that the storage modulus Gʹ dominated the loss modulus Gʺ, indicating more robust hydrogel behaviour. Similarly, as sodium alginate concentration increases, storage modulus G' surpasses loss modulus G", indicating a stronger hydrogel behaviour. The results demonstrated that for both dry and hydrated sponges, gelatine concentration increases hardness and decreases elasticity. Porosity and swelling ratio decrease as gelatine content increases. Similarly, with increasing the polymer blends concentration, the hardness increases, elasticity decreases, swelling ratio and porosity decrease. Also, for dry and hydrated sponges, glutaraldehyde concentration increases hardness and elasticity. Additionally, increased glutaraldehyde content decreases the porosity and swelling ratio. The optimum sponge was (4% gelatine, 4% sodium alginate, 0.5% glutaraldehyde), which was further characterised in comparison to Gelfoam®. The results revealed that a diverse pore structure in scanning electron microscopy for both sponges with an average pore size of 100μm. Raman mapping revealed non homogenous distribution for ironitican in both sponges. Fourier transform infrared spectroscopy analysis confirmed successful crosslinking with an Amide I shift peak associated with crosslinking. Differential scanning calorimetry showed a glass transition temperature of 125.24°C for the optimum sponge which was greater than Gelfoam® one (110°C). The hydrolysis degradation was more than 6 weeks for the optimum sponge, and the drug release exhibited a biphasic profile over 7 days. Linearity, range, accuracy, limit of detection, and limit of quantification validated the high liquid chromatography irinotican method. Ethylene vinyl acetate melt rheology was used to determine processing temperature for fused deposition three-dimensional printing chemo patch device. Melt rheology predicted a printing temperature of 84°C to 132°C, later confirmed by the greatest printed quality achieved at 120°C. A feasibility study tested two designs—square and oblong. The square-shaped device was 4 cm by 4 cm, while the elongated device was 15mm by 30mm and fits the cadaver pig’s surgical margin. After characterisation of different membranes in thickness, infill percentage, number and size of pores, the best one chosen was 1mm thickness and 75% infill based on drug release ,which was included as part of the Chemo Patch device. The three-dimensional printing parameters were, print speed 15 mm/s, print temperature 110 °C, build plate 55 °C, zig zag infill pattern, 120mm/sec travel speed, 35% flow rate, and 0.15mm layer height. Furthermore, the mechanical testing results indicated that the catheter attachment to Chemo Patch was satisfactory, and there was no evidence of any leakage from the walls of the device. Additionally, the in vitro FOLFIRINOX release was sustained over one week. The study's in vivo testing demonstrated that the Chemo Patch did not exhibit any significant incompatibility issues in the pig model. However, it was observed to elicit some immune response and fibrosis, which is a typical occurrence in implantable drug delivery devices. Furthermore, the study proved the effectiveness of the Chemo Patch device in delivering FOLFIRINOX locally in murine model, hence suppressing tumour growth.48 0Item Restricted Development of drug loaded cationic liposomes for pulmonary delivery(Saudi Digital Library, 2023-10-11) Alharbi, Sayer; Kett, VickyThe lower respiratory tract infections (LRTIs) represent a serious threat to human health, especially with the growing prevalence of antimicrobial resistance (AMR). Consequently, the demand for antibiotics with higher activity and better targeting is overwhelmingly increasing. The cationic liposomes composed of dimethyldioctadecylammoniumbromide (DDAB) and soy phosphatidylcholine (SPC) lipids with d-α-tocophyeryl polyethylene glycol succinate (TPGS) as an adjuvant, could have the potential to be effective drug delivery vehicles to deliver antibiotics to the infected sites via the pulmonary route. However, the current liposomal synthesis methods have some disadvantages such as the usage of organic solvents. So, this study aims to investigate an organic solvent free method (OSF) as a potential alternative for the thin film hydration method (TFH) for the preparation of drug loaded liposomes. In addition, this study aims to investigate the effects of DDAB and TPGS contents on the final characteristics of the proposed cationic liposomes formulation. Towards these aims, the hydrophilic apramycin (APR) and the hydrophobic rifampicin (RIF) were used as model drugs. The OSF method encompasses the manual trituration of the lipid components and mixing it with the aqueous phase. The loaded liposomes were characterised for particle size, surface charge, encapsulation efficiency, powder particle size, and thermal properties. The OSF prepared APR-loaded liposomes showed comparable characteristics to the TFH prepared APR-loaded liposomes. However, the RIF-loaded liposomes prepared by the OSF method showed poor characteristics in comparison with the TFH prepared. Indicating the suitability of the OSF method for the synthesis of APR-loaded liposomes and the unsuitability of the method to be used with RIF. These contradicting outcomes were linked to the differences in the aqueous solubility between the two drugs. DDAB and TPGS exerted no effects on the particle size of the liposomes. DDAB showed a proportional relationship with the liposomal surface charge of both drugs, which was linked to the cationic charge of DDAB. TPGS showed no effects on the encapsulation efficiency of APR, while increasing the TPGS content decreased the encapsulation efficiency of RIF. The decrease in RIF encapsulation was attributed to the reduction of the available space for hydrophobic drugs between the lipid bilayers due to the presence of TPGS. This study proposed a solvent free method for the preparation of APR-loaded liposomes, and it contributed to the knowledge about DDAB and TPGS effects on the liposomal formulation. Furthermore, this study recommended the exploration of other solvent free synthesis methods for the preparation of RIF-loaded liposomes.35 0