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A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs Johannesburg, 2014 / Aim The first step in a wet granulation process is dry mixing. This step has the objective of ensuring that all the raw materials are mixed such that the end product is homogeneous. Dry mixing in a high shear mixer instead of a blender saves cost. However, the mixing parameters have not been well researched. Dry mixing parameters that are currently used, have been established through experience, trial and error and in-process testing. Alexander and Muzzio (2006) confirms this by stating that there are currently no mathematical techniques to predict blending behaviour of granular components without prior experimental work; therefore, blending studies start with a small-scale, try-itand- see approach. Even though they are referring to blending, the same is also true for dry mixing. Both processes are the mixing of powders. Therefore the aim of this research was to develop parameters for dry mixing, based on experimental work. Methods Using a Saral rapid mixer and wet granulator (Saral Engineering Company, India), experiments were performed according to a 24 two-level Plackett-Burman Design method, to determine the effects of different blades (mixer/impeller and chopper) speeds and mixing times on the homogeneity of the mixtures containing different ratios of two powders that have different densities and particle sizes. One of the powders mixed, was enalapril maleate. This was chosen as it can be assayed. Samples were taken from the bowl and tested for assay. The mix for a specific experiment is homogeneous if the results of all 7 assayed samples are within 10 % of the target % w/w value and the % Relative Standard Deviation (% RSD) of the 7 results is less than or equal to 5,0 %. The outcome was being measured in % RSD. A lower % RSD indicates a more homogeneous mix. The parameters developed, will be beneficial to pharmaceutical companies as it can assist them to improve accuracy, consistency and quality of granular mixes. The experimental method used can serve as an example for future experiments. Results The results indicated that impeller blade mixing speed and mixing time are the two factors that have the biggest impact on the homogeneity of a mix in a high shear mixer. Chopper blade speed was also found to be significant, but less than the above two parameters mentioned. Optimal parameters were predicted. Conclusion As there are many parameters to be controlled during dry mixing in a high shear mixer, a statistical design method is suitable to establish the parameters that would have the most impact on the end result. Statistically it was found that mixing speed of the main impeller and chopper blades and overall mixing time are the three factors that have the biggest impact on the homogeneity of a mixture. The mixing time and impeller blade speed have proven to be more significant than the chopper blade speed. Concentration was found to be insignificant. For our experiments and for the specific granulator used the following optimal parameters could be deduced: Impeller blade set at 191 rpm, chopper blade set at 2002 rpm and mixing time set at 3.01 minutes.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Doctor of Philosophy / Alzheimer’s disease (AD) is the most prevalent and progressive neurodegenerative disorder (ND). It is characterized by a progressive decline of cognitive function, complete loss of memory, deterioration of visual capacity and the inability to function independently. According to the World Health Organization (WHO) it is estimated that about 26 million people suffer with AD worldwide. Although the etiology of AD is not fully understood, the aggregation of β-amyloidal (A) peptides that are associated with the formation of extracellular neurotoxin senile plaques and neurofibrillary tangles comprising hyperphosphorylated tau proteins have been recognized as the primary constituents that play a crucial role in AD. Several potential neurotherapeutic agents that can improve the management of AD such as metal chelators and alkaloid drugs have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Metal chelators [e.g. histidine, Ethylenediaminetetraacetic acid (EDTA) and zinc acetate (ZnAc)] are the main therapy used for modulating Aβ peptide aggregation with biological metals (such as zinc and copper ions) which is associated with promoting neurotoxicity in AD. While alkaloid drugs, such as donepezil, galantamine and rivastigmine, are used to inhibit the enzyme acetylcholinesterase (AChE); memantine is used to block the N-methyl-D-aspartate (NMDA) receptors associated with pathological activation. Despite the availability of these indispensable drugs, the clinical utility of these drugs is hampered by their poor retention and difficulty in bypassing the highly restrictive Blood Brain Barrier (BBB). Therefore this study aimed at developing novel nanoliposomes (NLPs) surface-engineered with chelating and synthetic peptides that are capable of crossing the BBB thus improving delivery efficacy and modulating the extracellular neurotoxicity associated with β-Amyloid aggregates of AD. Furthermore, since this system was designed for a chronic condition, a temporary depot-based polymeric system was integrated for further enhancement of the liposomal half-life, storage and prolonged drug delivery over a period of 50 days. The surface-engineered NLPs produced were spherical in shape, 100-149±28nm ~ size, with a zeta potential range of -9.59 to -37.3mV and a polydispersity index (PdI) of 0.02-0.2. A Box-Behnken experimental design was employed for maximizing the ligand coupling efficiency (40-78%) and drug entrapment efficiency (DEE) that ranged from 42-79%. The optimized peptide-based ligand NLP formulation showed sustained drug release (30% of drug released within 48 hours). Chelating ligands on the surface of NLPs showed 50-68% modulation of neurotoxicity on PC12 neuronal cells induced by ZnAβ (1-42) or CuAβ (1-42) aggregates. When drug-loaded functionalized NLPs were embedded within the temporal hydrophilic hydrogel network/scaffold as an implantable nano-enabled bio-robotic intracranial device (BICD), the physicomechanical and physicochemical dynamics showed improvement of liposomal structure such as the stability, and homogeneity in distribution of the liposomes within the internal core of the hydrogel networks and post-lyophilized scaffold. In vitro studies in simulated cerebrospinal fluid (CSF) showed prolonged release behavior of the drug-loaded functionalized NLPs from the BICD with 50-70% released over 50 days. Scanning Electron Microscopy (SEM) and confocal microscopy confirmed intact liposomal structures within the temporal polymeric scaffold/depot post-fixation and post-lyophilization. Ex vivo studies confirmed cell proliferation and a low level of lactate dehydrogenase (LDH), which is associated with cell membrane damage/injury, after PC12 neuronal cells were exposed to the BICD. In addition, when PC12 neuronal cells were exposed to the BICD high accumulation of galantamine (GAL) into these PC12 neuronal cells was observed post-cultivation. This outcome indicated that the released drug-loaded functionalized NLPs from the BICD were still in their intact form and capable of serving as bio-robotic markers for the delivery of GAL into the neuronal cells in response to AD. Furthermore, intracellular activity validated that the synthetic peptide has the potency for targeted delivery of the drug-loaded NLPs post-release of the BICD in ex vivo studies. Overall, results from this study revealed that the BICD device had superior cytocompatibility and may be suitable for application as a prolonged and targeted delivery system for GAL into neuronal cells to treat AD.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2016 / Oral drug delivery is acknowledged by many as the idyllic method of drug delivery due to its versatility and convenience of administration. Nevertheless, the bioavailability of drugs delivered via the oral route remains disputed. Classically, conventional marketed drug delivery systems release drugs in inconstant and unpredictable manners, leading to sub-therapeutic and in some cases toxic drug doses. Consequently, patient compliance is compromised, in turn having an effect on the success of the therapeutic intervention in question. One such limitation occurs in the treatment of Schizophrenia, with patients unable to comply with treatment due to multiple administration requirements. Sulpiride, an antipsychotic agent, displays notable efficiency in reducing both positive and negative symptoms of Schizophrenia. However, sulpiride has a low bioavailability and thus therapy requires the use of large doses, and hence multiple administrations. In addition, a large percentage of Schizophrenic patients present with concomitant mood disorders, namely ‘Schizoaffective’ disorder, which further necessitates the use of mood stabilizing agents. As a result, patients end up with a huge pill burden and are unable to comply with therapy and this leads to reduced clinical outcomes. A dual layered, xerogel-bioadhesive intestinal patch drug delivery system (ODLS) was thus designed, formulated, and evaluated for the site-specific delivery of two bioactives in the treatment of Schizophrenia with concomitant mood disorders in a time controlled-idiosyncratic manner. Ultimately easing compliance to complicated treatment regimens, enhancing bioavailability and improving patient compliance. The ODLS essentially comprises of a bi-layered tablet, layer one comprised of a sustained release semi-interpenetrating polymer network (s-IPN) xerogel and a layer two of embedded pulsatile release bioadhesive intestinal patches, with the system as a whole enteric coated for protection. Intestinal patches encompassed in layer two are fabricated of a backing layer, a drug loaded layer, a mucoadhesive layer, and a mucus cleaving layer. The ODLS employs a combination of sustained and pulsatile drug release mechanisms, in addition to intestinal retentive mechanisms. Furthermore, the system physically protects the drug delivery system from acidic or proteolytic degradation within the human gastro-intestinal tract. The present study utilized the use of bioadhesion for site-specific and gastro retentive drug delivery, with crosslinking being employed for rate-modulated drug delivery. Sulpiride and sodium valproate were selected as model drugs for the sustained release xerogel layer and the pulsatile bioadhesive patch layer respectively in this study as sulpiride is an antipsychotic with low bioavailability yet good antipsychotic activity and sodium valproate is the mainstay drug treatment for mood disorders in schizophrenia. Therefore, sulpiride would profit from the sustained release as it would improve bioavailability and hence patient compliance, whereas sodium valproate would benefit from the pulsatile release so as to avoid the well-known resistance to therapy due to prolonged exposure to drug. Thus these drugs would gain benefit from the site-specific controlled drug delivery offered by the ODLS. The primary aim of the sustained release s-IPN xerogel was to ensure delayed release of drug over 24 hours thus decreasing the need for multiple administrations and to maintain a steady state drug concentration. Film casting, a versatile technique was utilized in the fabrication of polymeric films to develop the bioadhesive intestinal patches. Preliminary in vitro investigations led to identification of a combination of polymers and crosslinking agent best suited to develop the system. A central composite design was employed for system optimization. The xerogel layer demonstrated that zero-order drug release was achieved after the crosslinking procedure. Delayed drug release fundamentally decreases the number of doses required daily and thus patient compliance and clinical efficacy is improved. The pulsatile release layer displayed distinct triphasic drug release after assembly of the intestinal patches, pulsatile release of drugs fundamentally reduced resistance to drug therapy as well as reducing pill burden. Furthermore, in vitro analysis of the ODLS showed that the xerogel layer behaved superiorly in terms of controlling drug delivery in a site-specific and prolonged fashion in comparison to a marketed gold standard. There exists no gold standard for pulsatile delivery of sodium valproate hence the pulsatile layer was tested against the marketed standard administered as a single dose. In vitro findings were substantiated by in vivo analysis in a white pig model. Results indicated that the systemic bioavailability of sulpiride was higher than the gold standard and drug release was prolonged in a zero-order fashion over 24 hours. Sodium valproate released in a triphasic manner over 24 hours thus reducing the risk of treatment resistance and decreased pill burden. To summarize, the ODLS was able to overcome the many challenges associated with oral drug delivery in schizoaffective disorder, by simplification of complicated treatment regimens, and hence improving bioavailability of drug delivery orally. The benefits associated with oral drug delivery have evidently been exploited by the present study, producing a versatile drug delivery system which can successfully deliver two bioactives simultaneously via individualistic release patterns, thus treating both conditions with a single oral dosage form with a single daily administration. / MT2016

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Thesis (M.Pharm.)--University of the Witwatersrand, Faculty of Health Sciences, 2011.

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A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science in Medicine 2015 / The dissertation aims to discuss the disulphide and thiol chemistry for use in drug delivery. In particular it focuses on the use of the modified native ovalbumin polymer as a vehicle for the thiol containing captopril. The binding capabilities of thiols expand the area in which peptides and proteins can be used as potential therapeutic drug carriers. It is important that drug delivery systems enhance drug storage stability and in vivo particle stability while delivering the drug efficiently. As part of the developing novel drug delivery systems, thiol-based chemical reactions are distinctive role players in stabilizing disulphide bioconjugated nanostructures for use as efficient drug carrier vehicles in vivo. A review of the current approaches for designing, optimizing and functionalizing nanostructures and conjugates by thiol chemistry modifications was explored. Captopril (Cp) is an Angiotensin-Converting Enzyme (ACE) inhibitor, which acts as an anti-hypertensive, structurally contains a free reactive thiol that binds variably via the thiol/disulphide reaction. A single dose of captopril can regulate hypertension for up to eight hours and the duration of the antihypertensive action of a single dose of 35-75 mg would be taken at 8 hour intervals for 24 hours. Hence the necessities in developing a sustained controlled release ovalbumin carrier system to maintain relatively constant blood pressure levels for 24 hours. The research focused on the construction, characterization and optimization of the thiol conjugated complex for sustained oral drug delivery. The thiol/disulphide-functionalized captopril-ovalbumin conjugate complex was assessed in terms of the structural characteristics and the thiol-disulphide covalent substitution reaction. For analysis of the conjugation complex, the Fourier Transmission IR-spectroscopy (FTIR), H+ NMR and Differential Scanning Calorimetry (DSC) was performed and used to confirm conjugation. Preliminary studies focused on a comparative study of sodium alginate, polyvinyl alcohol and hydroxypropylmethylcellulose hydrogel formulations for the release testing and drug entrapment of the ovalbumin-captopril conjugate complex. Utilizing this data, a series of process variables were used to achieve an optimized formulation through a Box- Behnken statistical design. Furthermore the drug release profiles of the optimised formulation were then analyzed in vitro and in vivo. The captopril released from the formulation was high with a cumulative release of 82%. In vivo analysis was the final testing to verify the validity of the ovalbumin-captopril conjugate complex encapsulated in sodium alginate and utilized a pig model. Ultra Performance Liquid Chromatography (UPLC) blood analysis revealed increased blood levels of captopril (Cmax Cp=33.2ng/mL) in relation to conventional dosage forms validating prolonged (24 hour) site-specific release and increased bioavailability. In conclusion, our validated method was successfully applied to the pharmacokinetic studies of captopril in the blood plasma samples.