Electronic Theses and Dissertations (Masters)

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Browsing Electronic Theses and Dissertations (Masters) by Author "Kumar, Pradeep"

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    Design and evaluation of a non-opioid tripartite release tablet for chronic inflammatory pain
    (University of the Witwatersrand, Johannesburg, 2024) Mazarura, Kundai Roselyn; Van Eyk, Armorel; Choonara, Yahya E.; Kumar, Pradeep
    Formulation-based approaches towards curbing the prescription opioid crisis include the discovery and development of non-opioid analgesics such as the novel benzyloxy- cyclopentyladenosine (BnOCPA). A more expedited approach involves the development of combinatorial systems of already existing non-addicting analgesics to tap into unexplored synergistic potentials. Despite the recent advances in drug delivery systems, tablets still hold the position of being the most widely used oral dosage form, particularly in the management of chronic ailments; it is cost-effective, non-invasive, and does not require administration expertise. Challenges in the production of complex geometry combinatorial, multi-drug tablets remain to some extent enigmatic to pharmaceutical researchers, hence the steady paradigm shift from traditional compression to 3-dimensional printing. Although it is superior in multiple aspects, the technique is still in its nascent stages with limited information on regulatory guidelines. Therefore, the aim of this work was to design and develop a non-opioid tripartite controlled- release tablet for efficient chronic inflammatory pain management. Because adherence to adjunct gastroprotective agents (GPAs) in non-steroidal anti-inflammatory drugs (NSAIDs) users has been established to be suboptimal, esomeprazole magnesium trihydrate (ESM) was added to the drug delivery system (DDS). The rationale behind the design was based on inherent drug properties, target release sites, desired therapeutic effects, and allowance for drug release manipulation, therefore a tablet was assembled, constituting an immediate- release top layer formulation of 250 mg paracetamol (PAR) for an early onset of analgesia; a cup layer for the delayed and retarded release of 100 mg of diclofenac sodium (DS) and 250 mg of PAR in tandem, and lastly a core containing a press-coated 20 mg ESM pill. A reproducible and efficient Reverse-Phase High-Performance Liquid Chromatographic (RP-HPLC) method was developed and validated for the simultaneous detection of the APIs over the concentration ranges studied. Deleterious drug-excipient incompatibilities were ruled out through pre-formulation investigations by FTIR, DSC, and TGA analyses. Combining both wet and dry granulation methodologies; the chosen formulation and polymers (7.5% hydroxypropyl methylcellulose (HPMC) K15M, 25.3% eudagrit L (EL) 100-55, and 10.5% croscarmellose sodium (CCS)), while considering the quality target product profiles (QTPPs), critical process parameters (CPP), and critical material attributes (CMAs), resulted in the development of a pragmatic tablet delivering fifty percent of the PAR dosage in the initial 30 minutes, with a cumulative release of 95.0% ± 0.08% and 94.9% ±3.87% for DS and ESM, respectively. Through in-process quality control tests, the validity of the manufacturing process was confirmed, with all results falling within pharmacopeial specifications. The release mechanism of PAR and DS from the cup after the 2-hour mark distinctly followed the Hixson-Crowell model where the geometrical characteristic of the cup was maintained with surface erosion. Visuals from scanning electron microscopy (SEM) analysis obtained prior to and during dissolution, confirmed hydration gravimetric analysis results as well as bulk and surface erosion mechanisms. The obtained ex vivo analysis results showed retarded permeation rates of the tabletted APIs compared to the APIs in their pure state. Therefore, it is imperative to consider improving the existing models employed for ex-vivo permeability studies of tableted formulations, with a particular focus on exploring the impact of excipients/polymers on drug permeation
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    Targeted nanosystems for tuberculosis pericarditis interventions
    (University of the Witwatersrand, Johannesburg, 2024) Ayodele, Simisola Ayobami; Kumar, Pradeep; Choonara, Yahya Essop
    Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. It presents as the second most lethal infectious disease after HIV/AIDS. The presence of resistance and immune-compromising disease favors the disease in maintaining its footing in the health care burden despite various anti-TB drugs. The main factors contributing to resistance and difficulty in treating disease include prolonged treatment duration (at least 6 months) and severe toxicity, which further leads to patient non-compliance, and thus a ripple effect leading to therapeutic non-efficacy. The efficacy of new regimens demonstrates that targeting host factors concomitantly with the Mycobacterium tuberculosis (M.tb) strain is urgently required. Due to the huge expenses and time required of up to 20 years for new drug research and development, drug repurposing may be the most economical, circumspective, and conveniently faster journey to embark on. Host-directed therapy (HDT) will dampen the burden of the disease by acting as an immunomodulator, allowing it to defend the body against antibiotic-resistant pathogens whilst minimizing the possibility of developing new resistance to susceptible drugs. Repurposed drugs in TB act as host-directed therapies, acclimatizing the host immune cell to the presence of TB, improving its antimicrobial activity and time taken to get rid of the disease, whilst minimizing inflammation and tissue damage. Anti-TB drugs incorporated in nanosystems may reduce side effects by delivering the drug selectively into infection reservoirs such as macrophages, which may assist in clearing the TB bacilli faster and reducing the duration of therapy. Tuberculosis pericarditis (TBP) is a type of extrapulmonary tuberculosis caused by the retrograde lymphatic spread of the bacilli from lymph nodes. TBP is known to have a high burden in southern Africa due to the high prevalence of HIV and its contribution to TBP. Traditional anti-TB drugs have poor permeation across the pericardium, making TBP a difficult disease to treat with high mortality. Rapid HPLC methods were initially established for the detection and quantification of isoniazid and pyrazinamide at a physiological pH (pH 7.4). These methods were subsequently used for the detection and quantification of both compounds in the ex vivo pericardium studies. Although both drugs diffused across the pericardium, only isoniazid has anti-tubercular effects at physiological pH. Both drugs permeated across the pericardium at pH 7.4, but only isoniazid has anti-tubercular effects at this pH. Bedaquiline is known to shorten the duration of therapy but has limitations e.g., poor solubility and adverse effects such as prolongation of QT interval, causing careful use and close monitoring of its adverse effects and possible drug interactions. In this study, bedaquiline was incorporated into an inherently targeted nanosystem made of mannan (host-directed therapy) for improved permeation of the drug across the pericardium. The bedaquiline-loaded mannan-chitosan oligosaccharide lactate nanoparticles were prepared by a one-step ionic gelation probe sonication method. A PermeGear 7-in-line flow-through system was used for the ex vivo diffusion studies across porcine and human pericardium. The nano gel was loaded into the donor compartment. Phosphate buffer saline (pH 7.4 with 0.2% sodium lauryl sulphate) was pumped through the receptor compartments at 1.5 ml.h-1 (37 °C). Samples were collected every 2 h for 24 h and analyzed via HPLC. Bedaquiline loaded nanoparticles with particle size and potential of 192.4 nm and 40.5 mV, respectively, were synthesised. The chitosan-mannan bedaquiline loaded nanoparticles had an encapsulation efficacy of 98.7% and drug loading of 0.6%. Diffusion data of bedaquiline in the nanosystem indicated a flux of 2.889 and 2.346 μg.cm - 2. min -1 for porcine and human pericardium, respectively, as compared to 0.991 μg.cm-2.min-1 and 1.1578 μg.cm-2.min-1 for isoniazid and pyrazinamide, respectively. The permeation of the nanosystem indicated a consistent and linear diffusion pattern across both porcine and human pericardium, additionally approving the porcine pericardium as a great comparable tissue to human tissue for pericardial studies. The nanosystem, therefore, presents an exceptional direction for the treatment of tuberculosis pericarditis with prospectively minimized systemic side effects and host-directed therapy