Thesis (MTech. degree in Pharmaceutical Sciences)--Tshwane University of Technology, 2010. / Investigates the absorption enchancing properties of N-trimethyl chitosan chloride (TMC) and monocaprin (MC), individually and in combination, on the permeability of insulin across the Caco-2 intestinal epothelial cell line.

D. Tech. Polymer Technology. / Addresses the aim of generating new knowledge on: 1) the effect of supercritical CO2 on H-bond behaviour between polymers, and on 2) drug-loaded interpolymer complex preparation in supercritical CO2.

M. Tech. Pharmaceutical Sciences. / Aims to design, evaluate and optimize an extended release matrix tablet of Nicotinic acid using natural polymers to match the in-vitro dissolution profile of Niaspan.

Polymeric biomaterials have become ubiquitous in modern medical devices. ‘Smart’ materials, materials that respond to external stimuli, have been of particular interest for biomedical applications such as drug delivery. Poly(n-isopropylacrylamide) (pNIPAAm) is the best studied thermally responsive, biocompatible, ‘smart’ polymer and has been integrated into many potential drug delivery devices; however, the architectural design of the polymer in these devices is often overlooked. My research focus was the exploration of pNIPAAm architecture for biological applications. Two new biomaterials were synthesized as a result. Architectural modification of linear pNIPAAm was used to synthesize a well-defined homopolymer pNIPAAm with a sharp transition slightly above normal body temperature under isotonic conditions. This polymer required a combination of polymerization and control techniques including controlled radical polymerization, hydrogen bond induced tacticity, and end-group manipulation. The synthesis of this polymer opened up a variety of biomedical possibilities, one of which is the use of these polymers in a novel hydrogel system. Through the use of the controlled linear pNIPAAm synthesized through chain architectural modification, hydrogels with physiological transition temperatures were also synthesized. These hydrogels showed greater shrinking properties than traditional hydrogels synthesized in the same manner and showed physiological mechanical properties. Highly branched pNIPAAm was also optimized for biological applications. In this case, the branching reduced the efficacy of end-groups in transition temperature modification but increased the efficacy of certain copolymers. The resulting biomaterial was incorporated into a nanoparticle drug delivery system. By combining gold nanoparticles with highly branched pNIPAAm, which was designed to entrap small molecule drugs, a hybrid system was synthesized where heating of the nanoparticle through surface plasmon resonance can trigger drug release from the pNIPAAm. This system proved to be easy to synthesize, effective in loading, and controlled in release. As shown from the applications, architectural control of pNIPAAm can open up new possibilities with this polymer for biomedical applications. Small structural changes can lead to significant changes in the bulk properties of the polymer and should be considered in future pNIPAAm based medical devices.

The aim of the present study was to formulate oral modified release matrices of diclofenac sodium, using the Eudragit® polymers. In addition to the formulation processes, numerous variables had to be investigated, which included dissolution variables, formulation variables, and processing variables. The application of the tabletting technique as well as the use of Eudragit® polymers to modify the release of diclofenac sodium is motivated at the outset. A comprehensive review of modified drug release, the use of the tabletting methodologies and the application of Eudragit® polymers are presented. In-process quality control tests as well as the mechanisms and interpretation of the dissolution process are outlined. Diclofenac sodium, a potent nonsteroidal anti-inflammatory drug, was used in the present study, hence a brief review of this drug is also presented. The direct compression as well as the wet granulation tabletting methods were investigated. The major limitation of the direct compression method was found to be the lack of suitable flow properties of the powder blend. The wet granulation technique however, was successfully employed to prepare various diclofenac sodium Eudragit® matrix tablets. All tablets were prepared to contain 100 mg diclofenac sodium. The optimisation process was shown to be an integral procedure in influencing the matrix characteristics. In addition, it was shown that drug release was significantly influenced by different types and concentrations of Eudragit® polymers. A specific formulation was selected to investigate the integrity of the matrices produced by the wet granulation technique. The drug release profile of a commercially available modified release preparation containing diclofenac sodium viz. Veltex® 100 CR (reference standard) was also obtained. A comparison of the drug release profiles of Veltex® 100 CR capsules and the selected formulation showed them to be markedly dissimilar. Hence, a strong motivation is provided for rationalising the selection of the particular formulation in the present study, that was shown to release diclofenac sodium optimally. The selected formulation was prepared using a combination of the Eudragit® RL and Eudragit® RS polymers. In vitro dissolution studies on the selected as well as various other formulations demonstrated the wet granulation method to be both predictable and reproducible. However, absolute drug release independency of dissolution methods, media and agitation rates was unattainable. Furthermore, drug release was shown to be pH dependent. The selected formula was subjected to certain formulation and processing variables. An increase in the concentrations of lactose and starch was shown to increase drug release. Different types of diluents were also shown to influence drug release from the tablets. The method of incorporation of the lubricant, magnesium stearate, was investigated. Compression studies demonstrated the susceptibility of the tablets to changes in drug release behaviour and morphological characteristics as the hardness was varied. X-ray diffraction studies demonstrated that the processes of granulation and compression did not promote any atomic rearrangement of the drug and Eudragit® polymers. Scanning electron microscopy was useful in investigating the integrity and surface morphology of newly formulated as well as stored samples, while energy dispersive x-ray microprobe analysis adequately revealed the elemental composition of the tablets. The selected formulation was shown to be stable at room temperature (21 ±1°C) and low temperature (5± 1°C), while storage at 37°C with 80% relative humidity and 40°C demonstrated significantly decreased drug release behaviour during short term (3 months) stability testing. Tablet hardness evaluated during the stability testing showed that there were virtually no differences in tablet hardness between the room temperature and low temperature samples, while tablets stored at 37°C with 80% relative humidity and 40°C hardened considerably. However, tablet potencies and the moisture content of the samples were not significantly influenced during the storage period. In addition to usual observations and mathematical manipulation, some of the data generated from this study were also evaluated statistically. / Thesis (M.Sc.)-University of Durban-Westville, 1998.

The motivation for the present study is systematically presented and the aims and objectives of the study are clearly defined. A comprehensive review on modified release drug delivery has been presented to provide the basis for the meltable aqueous dispersion technique as an approach to the formulation of a multiple-unit oral modified release drug delivery system. In addition, a brief discussion on the theory of dissolution testing and the mechanisms and interpretation of the dissolution process has been presented. Naproxen sodium, a potent non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic activity employed in the study, has been briefly discussed. In the present study, the coacervation phase separation technique utilizing ethylcellulose was initially investigated but proved unsuccessful in producing a formulation displaying suitable drug release characteristics. Subsequently, the meltable aqueous dispersion technique utilizing cetostearyl alcohol was successfully employed to formulate a multipleunit modified release naproxen sodium preparation containing 550 mg of naproxen sodium. The use of cetosteary!alcohol, as·a·retarding material, generated modified ·drug release characteristics as a function of its content. Magnesium stearate (anti-tackiness agent) and Span 20 and Tween 60· (surfactants) were incorporated in the formulation to optimize particle size and sphericity. The influence. of various formulation variables on drug release characteristics were investigated: An optimized formulation displaying a desirable modified release profile of naproxen sodium was achieved employing a 1:1 ratio of naproxen sodium:cetostearyl alcohol, 2% m/m .. .. magnesium stearate, and 1%m/m Span 20 dispersed in a liquid manufacturing vehicle of pH 0.6 containing 2% m/m Tween 60. In vitro dissolution studies on the selected formulation showed drug release to be predictable and reproducible, dependent on the dissolution method, agitation rate, and the pH of the dissolution media (i.e. pH-dependent drug release). The density of the microspheres was shown to decrease as the concentration of cetostearyl alcohol increased whilst the mean specific surface area increased with increasing concentrations of cetostearyl alcohol. Differential scanning calorimetric studies reveals a change in the thermograms which is suggestive of eutectic formation. Scanning electron microscopy proved useful in evaluating the integrity and surface morphology of the microspheres as well as in elucidating the drug release characteristics of the formulation. Energy dispersive x-ray microprobe analysis revealed the elemental composition of the microspheres to be a composite of the pure ingredients. X-ray mapping and the line scan depicted the homogenous distribution of drug within the microspheres and confirmed that the formulation is a matrix-type modified release I' preparation. Stability studies were performed on the selected formulation at room temperature (21 :t 1°C), 40°C, 37°C with 80% relative humidity, and at low temperature (5 :t 1°C). The shelf-life of the selected formulation was determined to be 1.29 years. Applying the data to five different kinetic models to investigate the drug release mechanisms showed that first order and cube-root release characteristics were exhibited by the microspheres. / Thesis (M.Sc.)--University of Durban-Westville, 1997.

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable drug release rates on chemotherapeutic efficacy. Block copolymer micelles, spherical nanoassemblies with a core-shell structure, are widely used in recent research. Micelles for this study were engineered to release a model drug (doxorubicin: DOX) at differential rates under acidic conditions, corresponding to tumor tissue (pH < 7). Three specific aims were pursued: to develop drug carriers capable of tuning drug release rates; to determine activity of developed carriers in vitro; and to elucidate effects of tunable drug release rates in vivo. Block copolymers with covalently linked DOX were synthesized and self-associated, forming micelles. Drug binding linkers (glycine, aminobenzoate, or hydrazide) were used to tune release of DOX. Micelles were characterized to determine physicochemical properties such as particle size, drug entrapment yields, and drug release parameters. Characterization revealed that drug release profiles were modulated by interchanging drug binding linkers. Micelles were evaluated in vitro to elucidate the effect of tunable drug release. Micelles delivered drugs at a slower, prolonged rate compared to free DOX. Cytotoxicity and cellular internalization analysis revealed that by slowing release rates, micelles kill cells more efficiently. Biodistribution studies showed that micelles decrease DOX accumulation in peripheral tissue while increasing the maximum tolerated dose. Antitumor activity studies verified that micelles with slower release rates better suppressed tumor growth. This further confirms that release rates play a key role in chemotherapeutic efficacy. Therefore, this thesis provides better insights into the effects of tunable drug release in tumors, leading the way for improved chemotherapy treatments in the future.

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Tuberculosis (TB) is an infectious, deadly disease, caused by Mycobacterium tuberculosis (M.tb). In 2010, there were 8,8 million incident cases of TB globally. South Africa currently has the third highest TB incident cases worldwide. In an attempt to address the challenges facing TB chemotherapy, among which frequent dosing and long duration of therapy resulting in poor patient compliance, a novel poly(DL-lactic-co-glycolic) acid (PLGA) nanoparticulate drug delivery system (DDS) encapsulating anti-TB drugs was developed. It is hypothesised that this nanoparticulate DDS will address the challenges mentioned by enabling decreased dosing frequency, shortening duration of therapy and minimising adverse side effects. Therefore, favourable modification of pharmacodynamic (PD) and pharmacokinetic (PK) properties of the conventional anti-TB drugs was demonstrated. Furthermore, the nanoparticles will provide a platform for drug delivery to macrophages that serve as hosts for M.tb. The study design was based on determining specific physicochemical properties of the nanoparticulate DDS to elucidate the hypothesis. Spray-dried PLGA nanoparticles were prepared using the double emulsion solvent evaporation technique. In vivo analysis of macrophage uptake and possible immunological response in mice were evaluated. In vitro protein-binding assays of PLGA nanoparticles encapsulating anti-TB drugs isoniazid (INH) and rifampicin (RIF) were performed with subsequent in vivo tissue distribution assays to support protein-binding data generated. Finally, PK/PD analyses were conducted to evaluate the effect of nanoencapsulation on the anti-TB drugs. These involved in vitro assays to determine if sufficient drug was released from the nanoparticles to exhibit minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). Furthermore, in vivo drug distribution and drug release kinetics assays of encapsulated RIF, INH, pyrazinamide (PZA) and ethambutol (ETB) in a mouse model were performed. The results confirmed that the PLGA nanoparticles (<250 nm, low positive zeta potential) were taken up by macrophages in vivo with no significant immunological effect. Furthermore the nanoparticles were present in the brain, heart, kidneys, lungs, liver and spleen for up to 7 days following once-off oral dosing at 13.23± 0.11%, 16.81± 0.11%, 54.89± 0.95%, 15.61± 1.15%, 48.48± 2.28% and 5.73± 0.21%, respectively. This was further confirmed by drug analysis demonstrating the presence of INH, RIF and ETB at different time points up to 7 days in the lungs, kidneys, liver and spleen. However, PZA was not detected. Nanoencapsulated RIF and INH exhibited MICs and MBCs in vitro over 14 days and these drugs were also observed in plasma for up to 7 days post once-off oral dosing. ETB and PZA were observed up to 3 days. From the results generated, it can be concluded that the nanoparticles were taken up by macrophages without eliciting an immune response. This provides a platform for drug delivery to specific sites. Furthermore, the nanoparticulate DDS exhibited sustained drug release in vitro and in vivo over a number of days above the MIC for the drugs analysed. Sustained drug distribution was also observed. It can therefore be concluded that the hypothesised reduction in dose frequency and duration of therapy for this DDS is a possibility / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies. To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of levodopa, resulting in significantly normalised motor function. A permanent system for long-term levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary. To conclude, pharmacokinetics of levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.