Browsing by Author "Choonara, Yahya E."

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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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    Design and synthesis of a nanocapsule system for transdermal delivery of lignocaine across the skin
    (University of the Witwatersrand, Johannesburg, 2024) Makha, Lerato Mathabelo; Choonara, Yahya E.; Ubanako, Philemon; Makhathini, Sifiso
    Pain is a major health problem that is caused by an emotional and sensory experience due to injury of tissues and can be differentiated as acute or chronic. Pain protects humans by assisting in making us aware that there is body injury or potentially damaging situations. If acute pain is not treated correctly, it can lead to chronic pain. Pain can be treated by several classes of medications including analgesics, Non-steroidal Anti-inflammatory drugs (NSAIDs), opioids, anti-depressants, and local anaesthetics. These medicines are administered orally. Although this is the preferred route of administration, it has many inherent limitations that can negatively impact the drug's desired pharmacological effects. Since the skin is the most convenient and accessible region for medication administration, innovative delivery techniques like Transdermal Drug Delivery Systems (TDDS) have been developed to circumvent the drawbacks of traditional drug delivery routes. This method has displayed fewer side effects experienced with conventional oral medications like gastric irritation and first-pass hepatic metabolism causing low blood concentration of the drug leading to low therapeutic effect. Nonetheless, the stratum corneum (SC), the skin's outermost layer, functions as a strong barrier to prevent most medications from penetrating the skin. Much attention has been paid to the use of nanocarriers as a transdermal delivery system of different accessible pharmaceuticals through the SC with the potential to have local or systemic effects to treat various disorders (Alexander et al., 2012). The purpose of this report was to synthesize Lignocaine (LIG)-loaded nanocapsules to evaluate their potential to transport LIG across the skin for increased effectiveness and fewer side effects. Lignocaine-loaded nanocapsules (LIG-PLGA-PC) were prepared by employing the solvent displacement technique. Aqueous phase consisted of 200 mg of Tween® 80 in 30 ml of purified water. The mixture was ultrasonicated for few minutes then put under electronic magnetic agitation. Organic phase was prepared by dissolving 125 mg of PLGA, 250 mg of PC and 30 mg of LIG in 5 ml of chloroform. Under probe sonication, organic phase was added drop wise to the aqueous phase and was allowed to stir overnight to remove the organic solvent. The formulated nanosystem was then frozen and lyophilized (FreeZone® 2,5, Labconco®, Kansas City, MS, USA) at -80 °C for 48 hours to yield a powder and analyzed using different analytical techniques. Four samples were prepared with three samples having a drug loaded in the organic phase. The fourth sample was blank, without the drug in the organic phase. The synthesised nanoparticles were characterized using Scanning Electron Microscopy (SEM), zetasizer, Ultraviolet (UV) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and Thermogravimetric Analysis (TGA). SEM clarified the configuration of the surface and shape of the nanocapsules by beaming electrons that interacted with the sample's atoms to produce three-dimensional surface topography. Using the zeta-sizer, the size of nanoparticles was found to be around 139.8 nm and a polydispersity index (PDI) of 0.182 a while the zeta potential was -48,2 mV. A drug entrapment efficacy (DEE) percentage of 72 % was achieved. LIG release studies showed a sustained release over a 24-hour period. The FTIR spectral evaluation of drug loaded sample showed a vibration at 3000–2800 cm−1 indicating a N-H stretch, and 1750-1735 cm−1 presented with a C=O stretching group. At 1250–1020 cm−1 there is a C-N stretching confirming the presence of an amine group. Thermogravimetric Analysis (TGA) thermal studies indicated that the LIG nanoparticulate structure increased the thermal stability of LIG. To investigate the biocompatibility of the nanoformulation, immortalized human keratinocytes (HaCaT) were treated with LIG-PLGA-PC copolymeric nanocapsules and an MTT (3-(4,5- dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay was conducted to evaluate the cytotoxicity of the treatments. Absorbance values were measured at 570 nm employing a Thermo Lab systems Multiskan MK3 microplate reader. From the cytotoxicity study conducted, at 48-hour, LIG-PLGA-PC nano formulation showed increased cell viability of 102, 103, and 110 % for 6,25 μg/ml, 3,125 μg/ml, 1,5625 μg/ml concentrations respectively. The blank nanocapsule showed a cell viability of 99, 98 and 100 % at concentrations of 6,25 μg/ml, 3,125 μg/ml, and 1,5625 μg/ml. The HaCaT cell micrographs showed cell proliferation on the drug loaded as well as plain drug figures. This can be confirmed by the MTT assay that the nanoformulation was non-cytotoxic with predicted biocompatibility. The combined experiments and findings of the LIG-PLGA-PC nanocapsule synthesis demonstrated that further studies and investigations are required to show that these nanoparticles can be used as a possible formulation for TDDS medication delivery of LIG for pain treatment.
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    Novel Design and Analysis of an Oral Cannabidiol (Cbd) Therapeutic Delivery System for Pain Management
    (University of the Witwatersrand, Johannesburg, 2023-11) Khan-Flear, Faryal; Adeyemi, Samson A.; Kondiah, Pierre P. D.; Choonara, Yahya E.
    Cannabidiol (CBD) is a non-psychoactive cannabinoid used for its antinociceptive, analgesic and anti-inflammatory properties in chronic pain. The endocannabinoid system (ECS) influences CBD: receptor binding to generate or regulate antinociceptive responses, producing centrally acting analgesia predominantly through Cannabinoid receptor 1 (CB1) abundant in the brain and spinal cord. In contrast, Cannabinoid receptor 2 (CB2) modulates inflammatory responses in immune system cells and tissues. Most oral medications can have inefficient absorption ability and insufficient therapeutic bioavailability due to the solubility of active ingredients and dosage form dissolution. Although the high lipophilicity of CBD enables it to cross the blood-brain barrier (BBB), which prevents the entry of most systematically administered drugs, the oil-soluble CBD is poorly soluble in water, resulting in erratic, incomplete absorption and poor drug bioavailability, preventing therapeutic doses from reaching specific receptors and regions in the brain. Directly ingested CBD also undergoes hepatic and intestinal metabolism, further contributing to therapeutic insufficiencies. Lipid-Based Drug Delivery Systems (LBDDS) can circumvent the drug's hysicochemical properties and the body's protective biological barriers to enhance drug-receptor interaction and elicit a biological response. Lipid combinations in self-emulsifying lipid formulations (SELF) create liposome nanocarriers that entrap and release CBD, providing a non-invasive, transitory, regionally selective delivery method. Nanoliposomes restrict therapeutic delivery to targeted areas, minimizing systemic toxicity and improving drug bioavailability. Manipulating the physical, chemical, and mechanical aspects of nano-liposomes and the material properties of their constituents concerning human anatomy and physiology can help or hinder therapeutic efficiency, drug safety, and delivery. Most therapeutic nanoliposome designs fall within 50–100 nm, facilitating passive transport across the BBB enabling drug receptor binding at brain and spinal cord receptor sites. Modulator uptake and interactions with host cells, enhanced uptake by target cells, and limits accumulation in specific tissues. Nanoliposomes smaller than 100 nm also extend blood circulation by evading renal, hepatic, and immunogenic sequestration and clearance by the mononuclear phagocyte system (MPS), the reticuloendothelial system (RES), opsonization, modulator uptake and interactions with host cells, limited accumulation in specific tissues, low uptake by target cells. This experiment used established system predictors such as HLB and LogP values, Poulton's Lipid Classification System (LCS), Biopharmaceutics Classification System (BCS), Lipinski's Rule of 5 (Ro5), FBDD Rule of 3 (Ro3), Biopharmaceutics Drug Disposition Classification System (BDDCS) to evaluate the critical quality attributes of two optimized formulations able to deliver CBD to the brain and spinal cord. Both formulations consisted of a phospholipid (soy lecithin), unmodified vegetable oils (coconut, olive/castor oil), surfactants (Span 80 and Tween 20), and a cosolvent (ethyl acetate) in the same ratios with the same ingredients, except that the olive oil in one formulation replaced castor oil in the other. These formulations molecularly dispersed CBD in the polymeric matrix of an unstable amorphous solid dispersion (ASD), improving drug solubility and bioavailability compared to crystalline forms. Thermodynamically unstable ASD must be assessed for quality, stability, and resilience to design helpful dosage forms. Both optimized validation batches successfully encapsulated CBD in liposomes in the eutectic ASD mixtures, as reflected in Fourier transform infrared spectroscopy (FTIR) spectrograms and the Differential scanning calorimetry (DSC). The olive oil-containing formulation produced self-micro-emulsifying drug delivery system (SMEDDS). At the same time, the castor oil preparation formed a self-nano-emulsifying drug delivery system (SNEDDS), accounting for the differences in particle size, size distribution, zeta potential, rheology, morphology, drug release and cell culture analysis. The differences arose due to the oils' unique fatty acid composition and chemistry. Drug release test results of each formulation loaded in hydroxypropyl methylcellulose (HPMC) capsules showed good timing for capsule dissolution and a burst release preceding sustained release over 48 hours. Drug release test results established cell viability in culture studies. The positive cell proliferation indicated that the CBD concentrations released by both formulations were non-toxic to mouse embryonic fibroblasts (NIH/3T3) and human embryonic kidney epithelial cell (HEK 293) cultures. Although both formulations yielded favourable results, the analysis indicated that the castor oil formulation was more robust and, therefore, suitable as a nanocarrier for CBD.