Browsing by Author "Mazarura, Kundai Roselyn"

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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