Saudi Cultural Missions Theses & Dissertations
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Item Restricted Improving Pharmacokinetic Modelling Through Improved Prediction of Intestinal Drug Absorption(University College London, 2024) Alharthi, Bashayr; Sorthouse, DavidIntestinal permeability (Peff) is a critical determinant of drug absorption and plays a pivotal role in the accuracy of Physiologically Based Pharmacokinetic (PBPK) models, which are essential for drug development and regulatory approval. Accurate prediction of Peff is vital for optimizing these models, enhancing bioavailability predictions, and reducing the reliance on extensive in vivo testing, thereby accelerating the drug development process. In this study, a machine learning (ML) model was developed to predict Peff using a small and complex dataset derived from pharmacokinetic studies. Given the dataset’s limitations, including its small size and inherent variability, traditional ML approaches were insufficient. To address these challenges, data augmentation (DA) techniques, particularly synthetic data generation, were employed to enhance the training data, thereby improving the model’s predictive performance. The suitability of the augmented data was evaluated by comparing model performance on synthetic versus real data. The study further explored the benefits and limitations of data augmentation, demonstrating its potential to address small dataset issues in pharmacokinetic modelling. Model interpretation was also conducted to understand the relationships between the target (Peff) and feature variables, offering insights into the key factors influencing the model’s predictions. This research underscores the value of data augmentation in enhancing the predictive power of ML models for PBPK applications and lays the groundwork for future work focused on optimizing data augmentation strategies and refining model interpretability.16 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 0Item Restricted Three Dimensional Printed Immunomodulatory Scaffolds with Controlled Drug Release for Bone Regeneration(Saudi Digital Library, 2023-10-24) Majrashi, Majed; Yang, Jing; Ghaemmaghami, AmirLarge bone defects pose significant challenges in orthopaedic surgery, necessitating the exploration of innovative repair technologies beyond traditional treatments like autografts, allografts, and synthetic substitutes, each fraught with specific challenges. Tissue engineering and regenerative medicine have emerged as promising fields, employing bioactive materials, growth factors, and cellular components to emulate natural bone properties and functions. Notably, additive manufacturing techniques contribute to these advancements by customising 3D-printed scaffolds enhancing patient-specific treatments. Recent studies underscore the significant influence of immune responses in bone regeneration, an area still in its infancy. Particularly, the modulation of immune reactions through specialised biomaterials and the strategic delivery of anti-inflammatory agents like dexamethasone present a novel approach to support bone healing processes, avoiding the systemic side effects of traditional drug administration. In this thesis, novel inks were developed to sustain the release of dexamethasone from a 3D-printed scaffold to modulate the immune response and osteogenesis. Excipients with surfactant properties, including the poloxamers F127, F68, L31, sorbitan monooleate Span80, and sucrose acetate isobutyrate (SAIB), were added to PCL to test their ability to sustain drug release. All these inks were fabricated into scaffolds by using direct ink writing 3D printing technique. The fabricated scaffolds were then characterised by SEM, DSC, FTIR, and ToF-SIMS. Macrophages and mesenchymal stem cells (MSCs) were cocultured to investigate the effects of the controlled release of dexamethasone on the modulation of macrophage polarisation and osteogenic differentiation of MSCs. Notably, blending PCL with 40% wt/wt (SAIB) has improved dexamethasone-cyclodextrin dispersal and facilitated a sustained 35-day release dominated by first-ordered and Higuchi models. In this modified environment, investigations into macrophage-mesenchymal stem cell (MSC) interactions revealed that controlled dexamethasone release significantly influenced macrophage behaviour and MSC osteogenic differentiation. M1 macrophages boosted early alkaline phosphatase production (ALP) at (7 days), while later stages (21 days) saw dexamethasone's predominance. Bone morphogenic protein-2 (BMP-2) was significantly increased at day 21; meanwhile, interleukin-6 (IL-6) decreased at the same time. Moreover, the released dexamethasone switched the phenotype of macrophages from M1 to M2 at day 21, evidenced by the increased level of mannose receptor and decreased expression of calprotectin receptor. These results offer new insight into macrophage-MSC cross-talk and demonstrate the potential of drug-release scaffolds to modulate inflammation and enhance bone regeneration.21 0