Saudi Cultural Missions Theses & Dissertations
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Item Restricted Optimization of Antibiotic-Loaded Liposomes for Inhalation to Improve Lung Infection Treatment(Queen's University Belfast, 2025-05) AlHamood, Noura; Vicky, Kett; Deirdre, GilpinCystic fibrosis (CF) and bronchiectasis (BE) are chronic respiratory disorders marked by airway inflammation, mucus obstruction, and recurrent bacterial infections that worsen disease progression. Oral antibiotics, the standard treatment for CF and BE infections, can lead to systemic side effects and antibiotic resistance. Pulmonary delivery of antibiotics offers a localized approach to minimize these issues. Also, inhaled antimicrobial liposomal formulations could offer several advantages over systemic administration, such as enhancing drug concentration directly in the airways, minimizing systemic side effects, and enabling prolonged drug release. This project focuses on manufacturing and optimization of formulations for the pulmonary delivery of apramycin-loaded liposomes in dry powder form with desirable physicochemical characteristics such as: size (< 150 nm), zeta potential (> 50 mV), polydispersity index (PDI) (≤ 0.3), encapsulation efficiency (EE) (>50% ), powder particle sizes (≤ 5 μm), glass transition (Tg) (>50 °C) and water content (≤ 3%) of the final dried powder apramycin products. Initially, Spray-drying parameters were optimized to produce liposomal formulations with small particle size (<150 nm), narrow size distribution (PDI ≤ 0.3), high EE > 50%, positive zeta potential (>30 mV), and respirable particle size (≤5 μm). Subsequently, the composition of the liposomes was optimized to develop an affordable and effective dry powder formulation for pulmonary delivery. The results show that formulation containing D-α tocopherol polyethylene glycol 1000 succinate (TPGS) consistently demonstrated better size and EE compared to those with poloxamer 407, which showed significant size increases post-spray drying. The formulations containing dimethyldioctadecylammonium bromide (DDAB) and TPGS exhibited desirable properties. Stability testing showed that the product remained stable for 24 weeks at 20°C but degraded at higher temperatures of 40 °C with 75 % humidity. Both formulations demonstrated comparable antibacterial efficacy against clinical isolates of Mycobacterium avium complex (MAC) and Pseudomonas aeruginosa (P. aeruginosa), maintaining consistent antimicrobial activity across the isolates. Additionally, the liposomal formulations showed minimal cytotoxicity, with over 80% cell viability at all tested concentrations, confirming their biocompatibility. Reducing the DDAB content to half its amount improved cost-effectiveness while maintaining liposome stability. A freeze-dried formulation was also developed to deliver the liposomes hydrated with apramycin for nebulization. Freeze-drying, with trehalose as a cryoprotectant, minimized water content, preserved a high Tg > 50°C, and enhanced long-term stability. Stability testing of freeze-dried formulations rehydrated into liquid form showed that those stored at 2°C exhibited a low degree of aggregation and performed better than those stored at 20°C. Transitioning from liquid to powder form further improved stability, reducing risks of aggregation and drug leakage. Powder formulations stored at both 2°C and 20°C demonstrated significantly enhanced stability, underscoring their suitability for pulmonary delivery. Finally, this work has demonstrated that inhalable liposomal antibiotic formulations could potentially serve as a novel therapeutic approach for treating lung infections associated with respiratory diseases.15 0Item Restricted Development of Liposomal Inhaled Antibiotic Formulations to Target Pulmonary Infection(Queen’s University Belfast, 2024) Alhamod, Mona; Kett, Vicky; Tunney, MichaelThe lungs of people with cystic fibrosis, bronchiectasis and chronic obstructive pulmonary disease are susceptible to bacterial infection which is difficult to eliminate; this results in repeated and prolonged antimicrobial treatment that is frequently associated with systemic side effects. Inhaled antimicrobial liposomal formulations present a promising alternative to systemic administration. They offer several potential advantages, including enhanced drug concentration in the airways, minimized systemic side effects, and sustained drug release. This thesis focuses on the encapsulation of vancomycin and rifampicin into liposomes using a liposomal composition of soy-phosphatidylcholine (SPS), dimethyldioctadecylammonium bromide (DDAB), and D-α tocopherol polyethylene glycol 1000 succinate (TPGS). Vancomycin was successfully encapsulated into liposomes using two methods; Thin film hydration (TFH) and organic free solvent (OSF) with high EE%. Spray drying and freeze drying converted the formulation into a dry powder suitable for inhalation, with both techniques producing particles of appropriate size, low water content %, and high Tg. The dried liposomal vancomycin demonstrated controlled in vitro release. Stability testing showed that the product remained stable for 24 weeks at 20°C but degraded at higher temperatures 40 °C with 75 % humidity. The efficacy of liposomal vancomycin was comparable to that of free vancomycin when tested against Staphylococcus aureus and MRSA isolates. The results indicate that both free and liposomal vancomycin have antimicrobial effects, and liposomal vancomycin exhibits a higher antimicrobial effect against some clinical isolates tested. Furthermore, the TFH method was employed to load rifampicin into liposomes. The resulting liposomal rifampicin was converted into a powder form using mini spray drying. During this process, key formulation characteristics such as particle size, PDI, surface charge, and encapsulation efficiency and morphology were investigated. The findings indicated that trehalose-based formulations produced spherical particles with properties suitable for inhalation, although further optimization was needed due to slightly larger liposomes sizes and PDI. Subsequently, a nano spray-drying technique was used, resulting in smaller, positively charged liposomes with favourable powder characteristics. In addition, rifampicin-loaded liposomes reduced both the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for most clinical isolates of Nontuberculous Mycobacteria (NTM), indicating enhanced antibacterial efficacy. In time kill assays, liposomal rifampicin exhibited greater bactericidal and bacteriostatic activity against most isolates tested compared to free rifampicin. The liposomal formulation was able to more effectively target intracellular bacteria within macrophages compared to the free drug. Furthermore, the liposomal formulation was found to have no toxic effects on common lung cell lines at concentrations up to 512 µg/ml of rifampicin and vancomycin. This work has demonstrated that inhalable liposomal antibiotic formulations could potentially serve as a promising new therapeutic option for treating lung infections associated with respiratory diseases.15 0