Synthesis and biological evaluation of novel thiazole-based compounds
- Authors: Olawode, Emmanual Oladayo
- Date: 2016
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62955 , vital:28325
- Description: Thesis embargoed for one-year period. Expected date of release: April 2019
- Full Text:
- Date Issued: 2016
The development of captopril pellets using the principles of quality by design
- Authors: Veerubhotla, Hari Mani Krishna
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64769 , vital:28599
- Description: Expected release date-May 2018
- Full Text:
- Date Issued: 2016
An investigation into the feasibility of incorporating ketoconazole into solid lipid microparticles
- Authors: Jhundoo, Henusha Devi
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54701 , vital:26601
- Description: One of the major challenges of the oral administration of ketoconazole (KTZ), an inhibitor of sterol 14α demethylase, used in the management of systemic and topical mycoses in immuno-compromised and paediatric patients is the lack of availability of liquid dosage forms. In order to overcome this challenge, extemporaneous preparations have been manufactured by care-givers and health care providers by crushing or breaking solid oral dosage forms of KTZ and mixing with a vehicle to produce a liquid dosage form that can be swallowed by patients. However, the use of extemporaneous preparations may lead to under or over-dosing if the care-givers are not guided accordingly. Furthermore, the dearth of information on the stability of these KTZ-containing extemporaneous preparations may lead to ineffective antifungal therapy and complicate the problems of resistance as it is difficult to estimate the shelf-lives of these extemporaneous products under varying storage conditions due to the susceptibility of KTZ to chemical degradation. Therefore, there is a need for formulation scientists to develop novel drug delivery systems that avoid the need for extemporaneous preparations, possess well-established limits of stability and minimize the risks of systemic adverse effects to facilitate KTZ therapy. The use of solid lipid microparticles (SLM) as potential carriers for the oral administration of KTZ was investigated since solid lipid carriers are known to exhibit the advantages of traditional colloidal carriers. The research undertaken in these studies aimed to investigate the feasibility of developing and manufacturing solid lipid microparticles (SLM), using a simple micro-emulsion technique, as a carrier for KTZ. Prior to pre-formulation, formulation development and optimization studies of KTZ-loaded SLM, it was necessary to develop and validate an analytical method for the in vitro quantitation and characterization of KTZ in aqueous dispersions of SLM during development and assessment studies. An accurate, precise, specific and sensitive reversed-phase high performance liquid chromatographic (RP-HPLC) method coupled with UV detection at 206 nm was developed, optimized and validated for the analysis of KTZ in formulations. Formulation development studies were preceded by solubility studies of KTZ in different lipids. Labrafil® M2130 CS was found to exhibit the best solubilising potential for KTZ. Pre-formulation studies were also designed to determine the polymorphic behavior and the crystallinity of KTZ and Labrafil® M2130 CS that was used for subsequent manufacture of the solid lipid carriers. DSC and FTIR studies revealed that there were no changes in the crystallinity of KTZ or Labrafil® M2130 CS following exposure to a temperature of 60°C for 1 hour. In addition the potential for physicochemical interaction of KTZ with the lipid Labrafil® M2130 CS was investigated using DSC and FTIR and the results revealed that KTZ was molecularly dispersed in Labrafil® M2130 CS and that it is unlikely that KTZ would interact with the lipid. It was therefore established that KTZ and Labrafil® M2130 CS were thermo-stable at a temperature of 60°C and thus a micro-emulsion technique could be used to manufacture the KTZ-loaded SLM. Drug-free and KTZ-loaded SLM were prepared using a modified micro-emulsion technique that required the use of an Ultra-Turrax® homogenizer set at 24 000 rpm for 5 minutes followed by the use of the Erweka GmbH homogenizer. SLM were characterized in terms of particle size (PS), zeta potential (ZP), shape and surface morphology using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In addition drug loading capacity (DLC) and encapsulation efficiency (EE) of SLM for KTZ were assessed using RP-HPLC. Formulation development and optimization studies of KTZ-loaded SLM were initially aimed at selecting an emulsifying system that was able to stabilize the SLM in an aqueous dispersion. Successful formulations were selected based on their ability to remain physically stable on the day of manufacture. Pluronic® F68 used in combination with Lutrol® E40, Soluphor® P, Soluplus® produced unstable dispersions on the day of manufacture and these combinations were not investigated further. However, the formulation of a stable KTZ-loaded SLM dispersion was accomplished by use of a combination of Pluronic® F68, Tween 80 and sodium cholate as the surfactant system. Increasing amounts of Labrafil® M2130 CS resulted in the production of particles with low DLC and EE, a large PS and a relatively unchanged ZP. An optimum concentration of 10% w/v Labrafil® M2130 CS was selected to manufacture the KTZ-loaded SLM. Studies to determine the influence of KTZ loading on the quality of SLM revealed that concentrations of KTZ > 5% w/v led to a reduction in DLC and EE and an increase in PS with minimal impact on the ZP. Stability studies conducted at 25°C/65% RH and 40°C/75% RH for up to 30 days following manufacture revealed that batch SLM 15 manufactured using 10% w/v Labrafil® M2130 CS, 5% w/v KTZ and a combination of 4% w/v Pluronic® F-68, 2% w/v Tween 80 and 1% w/v sodium cholate produced the most stable dosage form when stored at 25°C/65% RH for up to 30 days. However, storage at 40°C/75% RH resulted in instability of the formulation. An aqueous dispersion of KTZ-loaded SLM has been developed and assessed and may offer an alternative to extemporaneous preparations used for KTZ therapy in paediatric and immuno-compromised patients.
- Full Text:
- Date Issued: 2015
Development and manufacture of sustained release captopril beads
- Authors: Mhaka, Farai Arthur
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54712 , vital:26602
- Description: Hypertension has a high mortality rate in developing countries such as South Africa. Although the prevention and control of hypertension is a health priority, efforts to decrease the global burden of hypertension and improve control over the condition are inadequate. The use of angiotensin converting enzyme (ACE) inhibitors such as captopril (CPT) have been effective for the management of hypertension when used as first line therapy alone or in combination. Commercially available immediate release dosage forms containing 12.5, 25 and 50 mg of CPT are administered two or three times a day to treat hypertension. CPT degrades in aqueous media with the sulfhydryl functional moiety responsible for adverse effects such as hypersensitivity, taste disturbances and/or presenting with a dry hacking cough. CPT has a short elimination half-life of between 1.6 and 1.9 hours, which means that the compound is a suitable candidate for inclusion in sustained release (SR) dosage forms. Manufacturing a SR dosage form of coated beads for twice daily dosing may reduce the incidence and intensity of undesirable adverse effects, improve the stability of CPT and improve patient adherence. A stability indicating reversed-phase high performance liquid chromatographic (RP-HPLC) method was developed and optimised using a central composite design approach. As part of this approach the interactive effects of input factors, viz. pH, methanol (MeOH) content and column temperature on retention time, were investigated to achieve a separation with well-resolved and symmetrical peaks for CPT and salicylic acid. The method was validated using ICH guidelines and was found to be simple, linear, precise, accurate, selective and rapid for the in vitro quantitation of CPT. The method was successfully applied for the analysis of both commercially available and test formulations. Preformulation studies were undertaken to establish the physical and chemical properties of CPT, excipients and dosage forms to ensure the production of stabile and bioavailable products. Powder blends were assessed for flow properties using angle of repose (AOR), and bulk and tapped density, which were subsequently used to calculate Carr’s Index (CI) and the Hausner ratio (HR). The addition of talc resulted in the most powder blends with AOR, CI and HR that were within a range indicative of satisfactory to good flow properties. The use of talc was necessary to ensure that blending prior to wet granulation and extrusion-spheronisation would produce homogenous powders. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FT-IR) were used for the identification and purity of CPT alone and 1:1 binary mixtures with excipients in an effort to establish if CPT was likely to undergo physical and/or chemical modification during production. The DSC thermograms for all CPT-excipient mixtures revealed the presence of a melting endotherm that was wider, occurring at 110.93 °C (Tpeak for pure CPT). The characteristic peaks for specific functional groups were present in the FT-IR spectra for powder mixtures, indicating the absence of incompatibilities. Dialysis studies were used to investigate if the ammonium oleate present in Surelease® E-7-19010 interacted with CPT. The results suggests that an interaction between CPT and Surelease® E-7-19010 during processing of CPT beads was unlikely to occur. Preliminary investigations reveal that Methocel® K100M, Methocel® E4M, Avicel® PH102, Eudragit® RS PO, Surelease® E-7-19010 and talc are compatible with CPT and could be used for the manufacture of SR CPT beads. CPT beads were manufactured using extrusion-spheronisation and coated using a fluidised bed drier fitted with a Wurster insert. The amount of granulating fluid, coating levels, curing time and formulation composition were varied to achieve CPT release with specific criteria to develop a preliminary formulation. The coated beads met all desired quality attributes in respect of micromeritic and flow properties, content uniformity and friability. Response Surface Methodology was used to further optimise the SR CPT formulation. The Plackett-Burman design was used for this process to produce an SR dosage form with desirable quality attributes achieved by altering formulation composition, extrusion-spheronisation variables and coating parameters. ANOVA data revealed significant responses for yield, aspect ratio, sphericity, coating efficiency and cumulative percent CPT released at 2 and 12 hours. Formulations in which the high molecular weight HPMC were used in increased concentrations resulted in the formation of a sticky wet mass and extrudate, resulting in a decrease in yield. The application of a permeable, but insoluble Surelease® coat onto the surface of the beads formed a barrier that complements the activity of the hydrophilic matrix in preventing rapid dissolution and retarding the release of CPT from the beads. The amount of CPT released over 12 hours revealed that increasing the Methocel® K100M content entrapped CPT and retained it more efficiently in the hydrated matrix, resulting in a slow rate of CPT release. In vitro release data were fitted to a number of models in an attempt to elucidate mechanistic aspects of transport processes specific to CPT from the coated bead formulations. The results of fitting data from optimised batches revealed that the goodness of fit based on the adjusted correlation coefficient ranged between 0.953 and 0.976 for the Higuchi model, indicating that diffusion is a predominant factor that controls CPT release from the coated beads. The results of fitting data to the Korsmeyer-Peppas model suggest that the mechanism of CPT release includes transport of the dissolution medium from the vessel reservoir into the core of the bead due to osmotic potential, dissolution of CPT, mass transfer of the dissolved CPT within the core, partitioning between the solution and polymeric film, mass transfer of dissolved CPT through the film to ultimately reach the bulk dissolution fluid. A SR CPT bead formulation that has potential for further development and optimisation for scaled-up production using RSM approaches and Design of Experiments such as CCD or Box-Behnken has been successfully developed and manufactured using extrusion, spheronisation and coating processes. Assessment of all batches of beads manufactured exhibited satisfactory to good flow properties and demonstrated SR profiles over 12 hours that met USP criteria for SR dosage forms.
- Full Text:
- Date Issued: 2015
Formulation, development and assessment of tenofovir disoproxil fumarate-loaded pellets
- Authors: Dube, Tawanda
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54690 , vital:26600
- Description: Tenofovir disoproxil fumarate (TDF) is a novel nucleotide analog reverse transcriptase inhibitor that is recommended by the WHO for use in first line treatment of HIV infections. Due to the high dose of TDF for anti-retroviral treatment the formulation of a pellet dosage form may improve patient adherence by incorporation of a large dose in a relatively small dosage form. TDF is currently only available in tablet form. A simple, sensitive, selective, rapid, accurate, precise, stability indicating reversed-phase HPLC method was developed and validated in accordance with ICH guidelines and was successfully used for the analysis of TDF raw material and pharmaceutical dosage forms. Preformulation studies included an investigation of TDF-excipient and excipient-excipient interactions with all materials that could potentially be used to produce extruded and spheronized pellets. Nuclear Magnetic Resonance spectroscopy (NMR), Infrared Spectroscopy (IR), Differential Scanning Colorimetry (DSC) and Thermogravimetric analysis were used for identification and purity testing of TDF and all excipients. DSC data revealed that no potential interactions between TDF and the excipients occurred suggesting that incompatibility reactions were unlikely during manufacture and storage. These findings were confirmed by IR analysis that revealed that no physical interaction was likely between any of the excipients used and TDF. DSC data also reveal the existence of the α and β-polymorphs of TDF as evidenced by two enthalpy changes observed on the resultant thermograms. The existence of two polymorphs is unlikely to result in incompatibility and was confirmed by IR analysis. The IR spectra reveal that all characteristic peaks for TDF were present in 1:1 binary mixtures. Therefore TDF is compatible with all excipients tested and thermal analysis confirmed the stability of TDF under manufacturing conditions. The temperature of degradation temperature established through DSC analysis confirmed that degradation during manufacture is unlikely as the temperature of manufacture is lower than that at which degradation occurs. Extrusion and spheronization were the processes used to manufacture TDF pellets as it is a simple and economic approach for production. The effects of extruder and spheronizer speed, amount of spheronization aid and diluents on the pellet size, shape, flow properties and TDF release characteristics were examined. In order to decrease the complexity of analysis and reduce the cost of development a Taguchi orthogonal array design of experiments was successfully applied to evaluate the impact of formulation variables on product characteristics and predict an optimized formulation with a minimum number of experiments. The use of Response Surface Methodology for the development and optimization of pharmaceutical systems, including the optimization of formulation composition, manufacturing processes and/or analytical methods is well established. However the application of RSM requires that accurate, precise and reproducible experimental conditions are used for the generation of reliable data and RSM use is limited due to sensitivity to experimental variability. The benefits of using RSM for formulation optimization include the fact that more than one variable can be investigated at a time and large amounts of information can be generated at the same time ensuring a more efficient process with respect to time and cost. An added advantage of this approach is that mathematical relationships can be generated for the models that are produced and provide formulation scientists with an indication of whether the effect(s) between factors are synergistic or antagonistic. There are several statistical design approaches that use RSM and a Taguchi orthogonal array design was selected for use in this optimization process as fewer experiments are required to generate data for the same number of factors to be investigated when compared to other statistical designs such as Central Composite (CCD) and Box-Behnken designs. The use of RSM clearly demonstrates the impact of different input variables on the % TDF released at 45 min and % TDF loaded into the particles. The amount of sorbitol and Kollidon® CL-M were the only significant variables that affected the % TDF released at 45 min and both excipients had an overall synergistic effect on the in vitro release of TDF. The prediction and manufacture of an optimized formulation led to the production of pellets that met predetermined specifications which was successfully achieved using RSM. The development of a TDF containing pellet dosage form has been achieved and the formulation, manufacture and characterization of the dosage form reveal that the product has the potential to be further developed.
- Full Text:
- Date Issued: 2015
Isolation and structure elucidation of halogenated metabolites from Portieria hornemannii and Portieria tripinnata
- Authors: Adam, Mohammed
- Date: 2015
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64674 , vital:28591
- Description: The red marine algal genus, Portieria, is known to produce a number of potent cytotoxic compounds with anticancer potential. The most important anticancer lead produced by this genus is the compound halomon. Unfortunately, the lack of sufficient quantities of this compound hampered its further development. Two Portieria species, Portieria hornemannii and Portieria tripinnata, are found along the South African coastline. Recent studies, based on DNA analysis, suggest that Portieria hornemannii may in fact be divided into several cryptic species. The current project is part of a larger study designed to investigate the use of secondary metabolites to identify new marine algal species. In this study 1H NMR profiles of the organic extracts of selected Portieria spp were compared in order to identify new species. Selected compounds were then isolated and characterised as potential chemotaxonomic markers. Four halogenated monoterpenes were isolated from Portieria hornemannii. Two of these were new compounds 4-(3-bromo-4-chloro-4-methylpentyl)-3-chlorofuran-2(5H)-one, which were isomers of each other. The two known compounds had been previously isolated from Portieria hornemannii samples off the Madagascar coast. These compounds could prove to be useful as chemotaxonomic marker compounds, as they have never been isolated from any other species of marine algae. Three known halogenated monoterpenes were isolated from Portieria tripinnata. These compounds had been previously isolated from different species of marine algae and therefore, could not serve as chemotaxonomic marker compounds for this species of marine alga. Further work needs to be done on Portieria tripinnata, with regards to its chemistry, as it is a species of marine algae that has not been previously researched.
- Full Text:
- Date Issued: 2015
Modification and application of the decentralised wastewater treatment technology for greywater treatment to reduce water needs
- Authors: Ngqwala, Nosiphiwe Patience
- Date: 2015
- Subjects: Uncatalogued
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/193509 , vital:45338
- Description: Water is a scarce resource that is being acknowledged as a limiting factor to further social- economic growth and development. Demand for freshwater is increasing with corresponding increases in human population, industrial and agricultural activities. Alternative sources, such as greywater and rainwater are often polluted. Though greywater can be used for non-potable purposes, such as irrigation, it still requires some measures of treatment to improve its quality. To improve on greywater quality to facilitate its reuse, decentralised wastewater treatment technologies carry a great potential as complementary and alternative means of wastewater management particularly in peri-urban areas. Five research goals are addressed in this thesis: (i) to monitor the performance of Fly Ash Lime Filter Tower (FLFT) in the treatment of greywater; (ii) to modify the Fly Ash Lime Filter Tower in the treatment of greywater in order to reduce the pH of the greywater, and improved on the reduction of chemical oxygen demand (COD) and coliform counts; (iii) to investigate the potential of the reuse of greywater for irrigation; (iv) to undertake a techno analysis of the FLFT system for commercial use; and (v) to evaluate the use of hydrogen-sulphide (H2S) test kit to monitor faecal contamination of various water sources using a multidisciplinary approach. The modification of the FLFT indicated good treatment efficiency, reducing the concentrations of COD, chlorides, nitrates, ammonia and sulphate by 82.6%, 60.4%, 72.9%, 60.5%, and 53.9%, respectively; while the average pH was at 8.3. Greywater contains nutrients that are beneficial to the growth of most plants. Growth variables included biomass, stem height, number of leaves and number of vegetables harvested. Soil analysis showed no effects of the treated greywater on soil physico-chemical and microbial quality with bulk density 2.0g/cm3, average pH 7.4, total phosphorus 0.16mg/L 8, faecal coliform 0.3 CFU/100 ml. The tomatoes had high biomass and dry weight (150 g; 33g) than beetroot (35 g; 15 g). Crops irrigated with greywater significantly grew faster compared with those irrigated with tap water. The community approach highlighted the value of knowledge management in greywater reuse. It highlighted the importance of creating an institutional knowledge in water management using the H2S kit. The techno-economic analysis was used to evaluate key factors and the activities that are relevant to develop a sustainable FLFT in order to gain insights into the possibility of developing, and incorporating a business model framework to support decision making in value creation and value capturing during the research and the scaling up of the system. By this, a long term perspective to accomplish sustainable FLFT service businesses can be achieved. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2015
- Full Text:
- Date Issued: 2015
Synthesis and biological evaluation of truncated sarganaphthoquinoic acid derivatives as Hsp90 inhibitors
- Authors: Chiwakata, Maynard T
- Date: 2015
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/64708 , vital:28594
- Description: Hsp90 inhibition has been at the centre of attention in current research due to the possibility of “cracking down” on the entire process leading to the development of malignant cancers. Small underlying principles common in all types of cancers have been determined that govern the transformation of normal human cells into cancerous cells, with all relying on the ATPase activity of Hsp90 protein. Hsp90 protein is therefore an attractive drug target that if successfully inhibited can result in the remission of cancer tumours by one form of treatment. To date, no Hsp90 inhibitor has been sanctioned for cancer treatment as most are still in clinical development. Our research was therefore inspired by reports that indicated the potential of quinones / naphthoquinones to act as Hsp90 inhibitors. Preliminary results of a few selected marine natural product quinone systems i.e. sargaquinoic acid (SQA) (2.47) and lapachol (3.6) showed moderate cytotoxicity and weak interactions with the Hsp90 molecular chaperone, and evidence suggested C-terminal binding of these molecules. No correlation has been determined yet between cytotoxicity and Hsp90 inhibition, hence we aimed to develop natural product inspired molecules that exhibit both cytotoxic and Hsp90 inhibition properties. Due to limited amounts of the natural product that can be acquired from natural sources, synthetic analogues were opted for. Isolation of a few selected quinones was conducted to have material that could be used in biological assays. For structural modifications, a series of truncated naphthoquinone systems were prepared adopting the sarganaphthoquinoic acid (3.5) scaffold. The naphthoquinones were prepared via Diels-Alder reactions of relevant benzoquinones with myrcene, followed by aromatization reactions using MnO2. Various alkyl and aryl amines were then coupled to the C-2/3 position of the naphthoquinone using Michael’s addition reactions. Tricyclic naphthoquinones were also synthesized from reactions with hypotaurine and citral. Design of the analogues incorporated functionalities from known Hsp90 inhibitors e.g. geldanamycin (2.28) and its analogues. Preliminary results obtained showed that coupling of naphthoquinones with aryl-amines resulted in the most cytotoxic compounds (4.14-4.19) with IC50 values as low as 0.3 μM against Hs578T breast cancer carcinoma (triple negative). Most of the alkyl amines (4.20-4.25) had IC50 values greater than 50 μM except for 4.20 and 4.21 that showed IC50 values of 7.6 μM and 2.6 μM respectively. Tricyclic naphthoquinones (4.28-4.29) showed moderate cytotoxic activity of approximately 10 μM. Hsp90 inhibition was assessed by client protein degradation assays, of which SQA (2.47), showed the best Hsp90 inhibition properties, followed by compound 4.20. The most cytotoxic arylamino-naphthoquinone (4.16) and tricyclic naphthoquinones (4.28-4.29) showed only moderate inhibition. None of the compounds led to Hsp70 induction, suggesting possible binding to the C-terminus of Hsp90. Interactions at the binding site were assessed by molecular docking studies and saturation transfer difference (STD) NMR. Docking studies were conducted on the N-terminus of Hsp90 and better binding was observed for arylamino naphthoquinones (4.14-4.19) than for other series of compounds. Unfortunately, the co-crystal structure for the C-terminus of Hsp90 is unavailable, hence docking study comparisons on both domains could not be conducted. However, STD NMR offered a platform to assess binding interactions between the naphthoquinones and the N- or C-terminal domains of Hsp90. However no interactions were observed at both the N- and C- termini of Hsp90 due to either weak binding of ligands to the protein or poor water solubility of the ligands. From these preliminary results, naphthoquinones bind to Hsp90 protein but conclusive remarks to which terminal domain they bind to could not be made. The best candidate from amongst the series of naphthoquinones prepared that showed moderate cytotoxicity and promising Hsp90 inhibition was compound 4.20. We therefore succeeded in developing a new series of naphthoquinones that possess moderate cytotoxicity and show Hsp90 inhibition.
- Full Text:
- Date Issued: 2015
The design and evaluation of targeted patient-centred health information to improve knowledge and behavioural outcomes in tuberculosis patients with limited literacy
- Authors: Patel, Sonal
- Date: 2015
- Subjects: Tuberculosis Patients , Health literacy , Patient education , Communication in medicine , Picture-writing
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/194071 , vital:45420 , DOI 10.21504/10962/194071
- Description: South Africa carries a significant TB burden as evidenced in the 2013 statistics which report 450 000 new active TB cases and 890 000 TB-related mortalities. For successful treatment outcomes, 90% adherence is necessary, but many patients prematurely discontinue treatment due to poor knowledge and understanding of their complex TB medicines. Patient education is pivotal in improving knowledge, health literacy and behavioural outcomes such as health information seeking, self-efficacy and adherence. In the under-resourced South African healthcare system, time and capacity to adequately counsel patients are limited. The value of written medicine information (WMI) to supplement the verbal information provided by healthcare professionals (HCPs) has been widely investigated but minimal South African research is available. Current WMI distributed in South Africa is mainly generated by pharmaceutical manufacturers and is complex, incomprehensible and undesirable to patients. TB-related WMI focuses mainly on the disease, with little information relating to TB medicines and their use. The overall aim of this project was to improve patient knowledge about their TB medicines through the use of a simple illustrated patient information leaflet (PIL). Objectives to achieve this aim included: investigation of the medicine information seeking behaviour (MISB) of long term patients attending public health sector facilities; the development and validation of a medicine literacy test (MLT) to identify patients with limited health literacy requiring additional support and counselling; the development and evaluation of a patient-centred illustrated PIL for first-line TB treatment; the assessment of self-efficacy and adherence using modified versions of the HIV Treatment Adherence Self-Efficacy Scale (HIV-ASES) and Morisky 8-item Medicine Adherence Scale (MMAS-8), respectively, and the investigation of the impact of the PIL on patient knowledge and these health-related behaviours. Six focus group discussions (FGDs) conducted in 34 isiXhosa-speaking patients with limited formal education taking long-term treatment explored themes related to information needs, information-seeking practices and awareness of and ability to utilize information sources. Codes were analysed and potential themes and subthemes were identified and refined. The findings of this study reflected a passive, disempowered patient due to both patient-related and systemic healthcare factors. Poor awareness of information sources, lack of health-related knowledge, stigma and lack of awareness of the importance of appropriate medicine-related knowledge contributed to a lack of information-seeking practice. Patients neither asked questions nor were encouraged to do so. All expressed an unmet need for information and a desire for receiving relevant, appropriate, written medicine-related information. Feedback from this phase of the study was used to inform the development of the targeted patientcentred PIL. A double-sided A4 PIL containing information about TB medicines was designed giving careful consideration to content, format and layout features. Twenty five pictograms were designed through a rigorous, iterative design process and were included in the PIL that was evaluated in a randomised control trial (RCT) conducted amongst 120 TB patients attending a high burden TB clinic in South Africa. Interviews were conducted in either isiXhosa or Afrikaans via a trained interpreter. Patients were randomly allocated to either a control (standard care) or an experimental group (standard care plus brief counselling using the PIL). Two interviews were conducted using a prepared questionnaire; one at baseline followed by a 4-week follow-up. Baseline data included demographics, medicine literacy test, health information sources, knowledge of TB medicines, self-reported adherence and self-efficacy. Data collected at the 4-week follow-up interview included TB knowledge, self-reported adherence, self-efficacy, opinion of TB medicine information and interpretation of pictograms. Data were analysed using t-test, correlations, chi-square and ANOVA tests at a 0.05 level of significance. The PIL was successful in improving patient knowledge of the disease, TB medicine-taking, side effects, drug-resistant TB and HIV and TB co-infection. At baseline, there was no significant difference in the overall mean percentage knowledge score between the control and experimental groups (p=0.074). At follow-up, the percentage knowledge score for the experimental group increased significantly from 59.0% to 84.6% (p<0.001) and showed a significantly higher score than the control group (p<0.001), displaying evidence of the impact of the PIL as a counselling tool on patient knowledge. The PIL generated a highly positive response in the experimental group who indicated that they had referred to the leaflet over the last month and that it had played an important role in improving their TB medicine-related knowledge. This was reflected in the experimental group knowledge score of greater than 80% for almost three quarters of the patients whereas only 14% in the control group achieved this score. Patients appreciated the inclusion of pictograms and strongly felt that they helped them to recall and understand the textual PIL content. The study found that patients want side effect information and, interestingly, did not perceive the presentation of side effects in pictorial form to constitute a risk factor for nonadherence. Use of the illustrated PIL (experimental group) resulted in a significant improvement in patient self-efficacy (p=0.002), but showed no effect on self-reported adherence (p=0.563). Neither self-efficacy nor adherence was influenced by gender, age or education. An education effect on knowledge was only observed in the control group at baseline. The newly developed MLT was shown to be a valid and reliable tool and a moderate, positive and significant correlation was noted between the MLT score and baseline TB medicine-related knowledge in both the control and experimental groups. As there is a paucity of studies investigating the influence of take-home written leaflets on TB medicine knowledge and on patient behaviour, this study represents a significant knowledge contribution. It is the first study to report the development and evaluation of a patient-centred PIL to address the dearth of available TB medicine information. The use of targeted user-friendly, illustrated information leaflets can be a valuable counselling aid to improve patient knowledge and self-efficacy, particularly among patients with limited literacy. However, careful consideration of the design and content, with input from the endusers at all stages of the process, will optimise its effectiveness. The proposed framework for the development and implementation of patient-centred health and medicines information in a developing country context presented in this thesis could be used as a theoretical basis for informing the development of effective information materials targeting other disease states. Local patients taking TB medicines identified nurses, WMI and media as their current sources of information but they expressed a strong desire to know more about their treatment. Targeted public health interventions that focus on medicine-taking information and behaviours and encourage patients to adopt a more active, questioning role in health consultations could improve health literacy and empower patients in their medicine-taking practices. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2015
- Full Text:
- Date Issued: 2015
The isolation, characterisation and chemotaxonomic significance of secondary metabolites from selected South African Laurencia spp. Rhodophyta
- Authors: Fakee, Jameel
- Date: 2015
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/64696 , vital:28593
- Description: Bioprospection of marine organisms as a potential source for lead drugs is becoming increasingly popular. The secondary metabolome of these organisms consists of structurally diverse molecules possessing unprecedented carbon skeletons, the biosynthesis of which occurs via complex metabolomic pathways driven by specialist enzymes. This structural novelty is highly influential on the favourable bioactivity these compounds display. A prominent example of such a compound is trabectedin marketed as Yondelis®. Registered for the treatment of soft tissue sarcomas, this marine drug was developed from extracts of the tunicate Ecteinascidia turbinata. South Africa is renowned for possessing a highly diverse marine biota including several endemic species of marine red algae belonging to the Laurencia sensu stricto genus, which falls within the Laurencia complex. Despite having a good reputation for fascinating secondary metabolites, the taxonomy of Laurencia natural products is proving challenging for reasons including the presence of cryptic species, as well as individual species displaying morphological variability. The aim of this study was thus to isolate secondary metabolites from various South African Laurencia spp. and subsequently assess their chemotaxonomic significance by analysis of a parallel plastid rbcL phylogeny study of Laurencia spp. This study reports the first phycochemical investigation into Laurencia natalensis Kylin, Laurencia cf. corymbosa J.Agardh, Laurencia complanata (Suhr) Kützing, Laurencia sodwaniensis Francis, Bolton, Mattio and Anderson submitted, Laurencia multiclavata Francis, Bolton, Mattio and Anderson submitted, and a South African specimen of Laurenciella marilzae Gil-Rodríguez, Sentíes, Díaz-Larrea, Cassano and M.T. Fujii (basionym: Laurencia marilzae) originally described from Spain. Additionally, the chemical profiles of previously explored species Laurencia flexuosa Kützing and Laurencia glomerata Kützing were re-investigated. The organic extracts of the above species afforded 31 compounds belonging to a wide array of structural classes including halo-chamigranes, linear C15 acetogenins, indole alkaloids, cuparanes and cyclic bromo-ethers. A new tri-cyclic keto-cuparane (4.4) was isolated from L.cf. corymbosa alongside the new cuparanes 4.1 and 4.7. Algoane (5.9), a unique marker compound isolated from L. natalensis, was previously only reported from a sea-hare. Such marker compounds which are exclusive to an individual algal species increase the ease of their subsequent identification. The feasibility of chemotaxonomy as an additional tool to classify Laurencia spp. Was established as broad predictions of a specimen’s phylogeny, based on representatives of its secondary metabolome, proved viable. The study specimens were shown to possess similar chemical profiles to their sister species e.g. L. complanata, L. sodwaniensis and L. multiclavata produced similar metabolites to their sister species as inferred by an rbcL phylogeny tree. Finally, a 1H NMR profiling study on the crude organic extracts of various Laurencia spp. generated distinctive, reproducible spectra, exposing the value of NMR spectroscopy as a rudimentary species discernment tool.
- Full Text:
- Date Issued: 2015
Adherence to antiretroviral therapy in children in Zimbabwe: a randomized control trial to validate a new self-reported adherence monitoring tool
- Authors: Mugore, Linnetie
- Date: 2014
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/54734 , vital:26607
- Description: Background: Among children taking antiretroviral therapy (ART), self-reports have been widely reported to over-estimate adherence levels. Pill count adherence levels are often lower than self-reported levels, with unannounced home pill count adherence being lower than facility based pill count adherence. There is often poor agreement between pill count adherence levels and those measured using other objective adherence measuring methods such as Medication Event Monitoring Systems (MEMS®), which is widely viewed as the gold standard for adherence measurement. Objectives: The aim of this study was to design and evaluate a new self-reported paediatric adherence monitoring tool, assess the feasibility of using pill count methods in monitoring adherence and identify challenges to reporting adherence among children on ART in rural and urban Zimbabwe. Methods A dual centre, superiority, parallel design RCT was conducted to evaluate the newly-developed visually- and verbally-cued „past 10 days‟ tool for the assessment of adherence in children on ART at two sites in Zimbabwe; Harare Central Children‟s Hospital in an urban setting, and Murambinda Mission Hospital, a rural site. Child-caregiver pairs presenting to one of these facilities for the child‟s review of ART and refill of the medication were recruited, signed informed consent obtained, and were randomised for self-reported adherence monitoring into either the experimental group („new 10-day tool‟) or the control group („PACTG-style‟ self-report tool). Data (demographic, socioeconomic, and reported adherence) were collected in individual interviews with child-caregiver pairs. Additional adherence monitoring methods used for both groups included the Morisky-8-Item Medication Adherence Scale (MMAS-8) and a facility based pill count. FGDs were held with groups of caregivers and groups of children ≥13 years of age to understand reasons for non-adherence as well as issues around reporting non-adherence. Superiority testing was conducted by comparing adherent proportions and their confidence intervals (95% CI). Further concurrent validity test was done using the Mann-Whitney U test to evaluate the relationship between the new tool and the MMAS-8 scores. Agreement between the child and caregiver reports of adherence was used as a test of reliability of the new tool using the kappa statistic. Socio-demographic, clinical and care-related factors associated with adherence were identified using reported adherence in both child and caregiver groups in a logistic regression model. Two pill count methods were assessed for feasibility using the proportions of children with complete data for calculating adherence levels, and their CI and a comparison of the two methods, a routinely-used method and one that incorporated the reported residual quantity (RRQ) of medication at last refill. Results : Analysis included 245 child-caregiver pairs, 123 in the experimental group and 122 in the control group. The median age for children was 9 years. In the experimental group, adherence by caregiver and child reports ranged from 94.3% - 98.4% and 78.4% - 96.1%, and those in the control group ranged from 89.2% - 97.5% and 71.2% - 98.1%, respectively. There was no significant difference between adherence levels in the two groups. Adherence levels measured by both the experimental and control tools were found to be associated with MMAS-8 adherence levels (p <0.05). Agreement between child- and caregiver-reported adherence was moderate though significant (kappa; 0.407, p <0.05). Only about half of the children had adequate data to compute pill counts. Proportions adherent at 95% cut-off were 39% by the „routine pill count‟ and 58% by the „Pill count RRQ‟. Being an orphan was associated with child reported-adherence whereas use of non-human reminders, having a maternal relative as a primary caregiver and knowledge of dose frequency, were all associated with caregiver-reported adherence. Major causes of non-adherence mentioned during the FGDs included interference of medication administration times with scheduling of routine socio-economic activities and lack of support from some non-biological caregivers. Reporting of non-adherence appeared to be hampered by perceptions of negative reactions by healthcare workers to these reports and by caregivers being unaware that the child missed some doses. Conclusions: The „new 10-day tool‟ was not shown to be superior to the „PACTG-style tool‟ in detecting non-adherence, however this new tool was found to be a valid and reliable adherence monitoring tool that included a moderately long recall period of 10 days, can be applied without the need for the respondent to remember names of individual medicines in the
- Full Text:
- Date Issued: 2014
Adolescent pregnancy: a community engaged participatory approach to design and implement an educational intervention
- Authors: Siruma, Amanda Tatenda
- Date: 2014
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54656 , vital:26597
- Description: Millennium Development Goal (MDG) 5 focuses on improving maternal health, due to global acknowledgment that no woman should have to die as a result of complications during pregnancy and childbirth. Adolescents have an increased risk of maternal death compared with older women. Adolescent pregnancy also poses a threat to the empowerment of young girls by mitigating their physical, educational, social, and economic development. In this context, maternal health promotion strategies which inclusively target adolescents are crucial, not only in improving maternal health outcomes, but also in optimising the overall transition of adolescent girls to adulthood. This study was a first time collaborative partnership of the Faculty of Pharmacy and Community Engagement Office of Rhodes University with the Angus Gillis Foundation (a non-profit community development organisation), and community participants of Glenmore and Ndwayana, two rural communities in the Eastern Cape. The aim of this study was to identify the maternal health issue of most concern to community participants and to design and implement an appropriate educational intervention for a suitable target group. During the baseline phase of this study, ten focus group discussions (FGDs) were conducted with 76 community stakeholders. Semi-structured interviews (SSIs) were conducted with two Sisters-in-Charge from each Primary Health Care (PHC) facility in the study setting. Data on the stock status of World Health Organization (WHO) identified lifesaving priority medicines for women’s health was also collected at both PHCs. Thereafter, pre- and posteducational interventions SSIs with female adolescent participants were conducted. The educational intervention was followed up with the development of a booklet on reproductive health. FGD participants identified adolescent pregnancy as the maternal health issue of most concern. They also highlighted challenges in service delivery of ambulance services for expectant mothers in urgent need of transportation to a referral hospital. A majority of preintervention SSI participants indicated coercion from both younger and older men as a factor influencing early sexual debut amongst adolescent girls in their communities. Despite availability in the PHCs, challenges in accessing contraceptives were highlighted by the participants. Additionally, a number of sexually active adolescent girls defaulted on their next allocated visit to the PHC due to myths regarding use of oral and injectable contraceptives. During the educational intervention sessions, participants recognised knowledge gaps regarding reproductive health issues and the influence of peer pressure as constraining factors in preventing adolescent pregnancy. During the post-intervention phase, participants highlighted that the educational intervention of this study had provided a forum to discuss ways of preventing adolescent pregnancy. The educational booklet developed is intended to serve as a resource tool of the educational programme on prevention of adolescent pregnancy, which is expected to be incorporated into the Angus Gillis Foundation’s existing ‘Positive Health’ Programme. The results of this study show that community-based participatory research facilitated the identification of the maternal health issue of most concern to these communities. Working synergistically with key stakeholders in designing and implementing an educational intervention for preventing adolescent pregnancy provides a good foundation for future up scaling and sustainability of this educational programme.
- Full Text:
- Date Issued: 2014
Development and assessment of sustained release stavudine loaded microparticles
- Authors: Zindove, Chiedza Cathrine
- Date: 2014
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54722 , vital:26603
- Description:
Stavudine (D4T) has been used as first line treatment for HIV/AIDS and is part of highly active anti retroviral treatment (HAART). It is an affordable medicine and its use is beneficial in resource limited settings. However D4T exhibits dose dependent side effects that may lead to non-adherence in patients. This study was undertaken to formulate, develop and manufacture a dosage form that could reduce dose dependent side effects by decreasing the dose of D4T but still exhibit antiretroviral (ARV) activity. The use of sustained release (SR) formulations of D4T that ensure constant levels of the D4T in the body would not only optimize therapy but also reduce the incidence of side effects thereby increasing patient adherence. SR microparticles containing 30mg D4T were manufactured and loaded into size 3 hard gelatine capsules prior to analysis. The D4T microparticles were manufactured by microencapsulation using non-aqueous oil-in-oil solvent evaporation approach. D4T-excipient, excipient-excipient interactions and D4T purity were assessed using Infrared Spectroscopy (IR), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Copolymers synthesized from acrylic and methacrylic acid esters viz., Eudragit® RSPO and S100 were used as rate retardant materials and the effect of microcrystalline cellulose (Avicel® PH102) on the microparticles was also investigated. Magnesium stearate was used as a droplet stabilizer and n-hexane was added to harden the microspheres formed in a liquid paraffin continuous phase. The microparticles were optimized using a Box Behnken design and Response Surface Methodology (RSM). The microparticles were characterized in terms of their flow properties and encapsulation efficiency (% EE), in addition to visualization of the surface morphology with Scanning Electron Microscopy. In vitro D4T release studies were performed using USP Apparatus III in media of different pH and the samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection that had been developed and optimized using a Central Composite Design (CCD). The method was validated according to ICH guidelines. The IR spectra and DSC thermographs revealed that D4T exhibited thermal stability and there was no evidence of D4T-excipient and excipient-excipient interactions. The microparticles that were produced were white, free flowing and were obtained in a high yield with high encapsulation efficiency. Scanning Electron Microscopy studies revealed that the microparticles were spherical and porous in nature. In vitro D4T release extended to 12 hours and the mechanism of release was established using model dependent methods by fitting the data to a Zero order, First order, Higuchi and Hixson Crowell model. It was observed that the mechanism of D4T release was diffusion-controlled and that the data was best fitted to the Higuchi model with correlation coefficients > 0.9. The release mechanism was confirmed using the Korsmeyer-Peppas model that revealed that most of the formulations exhibited anomalous transport kinetics with the release exponent, n, ranging from 0.5
- Full Text:
- Date Issued: 2014
Formulation, development and assessment of efavirenz-loaded lipid nanocarriers
- Authors: Makoni, Pedzisai Anotida
- Date: 2014
- Subjects: Nanomedicine , Drug delivery systems , Antiretroviral agents Psychotropic effects , AIDS dementia complex
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/209981 , vital:47448
- Description: The feasibility of incorporating efavirenz (EFV) into innovative solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) using the hot high-pressure homogenization (HHPH) technique was investigated in an attempt to address the shortcomings in therapy associated with the use of conventional dosage forms. The shortcomings include the unpalatable taste of API in solution, instability in the presence of light when in solution and psychiatric side effects of the API. In particular, sustained release approaches may reduce or limit the incidence of adverse psychiatric effects of EFV and alleviate Acquired Immune Deficiency Syndrome (AIDS)-related complications such as AIDS Dementia Complex (ADC) in patients, ultimately improving their quality of life. Prior to initiating pre-formulation, formulation development and optimization studies of EFV-loaded SLN and/or NLC, Response Surface Methodology (RSM) in conjunction with central composite design (CCD), was used to develop and validate suitable methods for the quantitative determination of EFV in pharmaceutical formulations and for monitoring EFV release from SLN and/or NLC in vitro. Simple, accurate, precise, sensitive and stabilityindicating reversed phase-high performance liquid chromatography (RP-HPLC) methods with UV and electrochemical (EC) detection were developed, validated and optimized for in vitro analysis of EFV in formulations. On the basis of risk-to-benefit ratio the RP-HPLC method with UV detection was selected as the most suitable for the quantitative determination of EFV in pharmaceutical formulations, and was applied to in vitro release studies of EFV from SLN and/or NLC. Pre-formulation studies were undertaken to investigate the thermal stability of EFV so as to facilitate the selection of lipid excipients for the manufacture of nanocarriers, and to establish their compatibility with EFV. It was found that EFV was thermostable up to a temperature of approximately 200°C, indicating that HHPH could be used for the manufacture of EFV-loaded SLN and/or NLC. Lipid screening revealed that EFV is highly soluble in solid and liquid lipids, with glyceryl monostearate and Transcutol® HP showing the best solubilizing potential for EFV. Glyceryl monostearate exists in a stable β-modification prior to exposure to heat, but exists in the α-polymorphic modification following exposure to heat. It was established that the addition of Transcutol® HP to glyceryl monostearate revealed the co-existence of the α- and β’-polymorphic modifications, thereby revealing the existence of the modifications in NLC produced from the optimum lipid combination. Furthermore, an investigation of binary mixtures of EFV/glyceryl monostearate and glyceryl monostearate/Transcutol® HP, in addition to eutectic mixtures of EFV, glyceryl monostearate and Transcutol® HP, revealed no interaction between EFV and the lipids selected for the production of the nanocarriers. Due to the significantly higher solubility of EFV in Transcutol® HP than in to glyceryl monostearate, NLC are most likely to have a higher LC and EE than SLN. In addition, the existence of both the α- and β’-polymorphic modifications in the binary mixture of the lipid implies that EFV expulsion on prolonged storage is unlikely to occur from NLC when compared to SLN. Consequently formulation development and optimization studies of SLN and NLC were performed to investigate the potential to deliver EFV from a novel technology with an appropriate LC and EE for EFV. Tween®80 was selected for use in these formulations as the use of this surfactant facilitates the targeting of nanocarriers to the CNS. RSM in conjunction with a Box-Behnken Design (BBD) was used to establish the effects of process variables, such as number of homogenization cycles and pressure, in addition to formulation variables such as amount of EFV and Tween®80 on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), visual assessment (VA) and release rate (RR) of EFV after 24 hours. In addition the LC and EE, degree of crystallinity and lipid modification, shape and surface morphology of the optimized batches were investigated to ensure that EFV-loaded SLN and NLC of desirable quality were produced. On the day of manufacture the mean PS and PDI of EFV-loaded SLN was 59.00 ± 23.16 nm and 0.382 ± 0.054 respectively. The mean PS and PDI of EFV-loaded NLC was 34.73 ± 0.7709 nm and 0.394 ± 0.027 respectively. The formulations were in the nanometer range and exhibited a narrow particle size distribution, as indicated by the PDI values. The ZP values for optimized SLN and NLC generated on the day of manufacture using HPLC grade water as the dispersion medium were -32.5 ± 4.99 mV and -22.4 ± 3.72 mV respectively. In addition the optimized batches of SLN and NLC revealed a decrease in crystallinity in comparison to bulk lipid material. DSC, WAXS and FT-IR revealed that EFV was molecularly dispersed in the nanocarriers. In addition EFV-loaded SLN existed in a single α-polymorphic form, whereas EFV-loaded NLC exhibited the co-existence of α- and β’-polymorphic forms. Generally SLN and NLC were spherically shaped when viewed under transmission electron microscopy (TEM) and scanning electron microscopy (SEM). On the day of manufacture the EE and LC of EFVloaded SLN was found to be 96.77 ± 0.453 % and 9.68 ± 1.772 % respectively. The EE and LC of EFV-loaded NLC was 99.93 ± 0.413 and 9.995 ± 0.672 respectively. The release profiles for the optimized formulations of SLN and NLC exhibited an initial burst release over the first 0-3 hours of testing, after which the release was sustained for up to 24 hours. The cumulative % EFV released over 24 hours was higher from SLN (91.5±3.423 %) than that observed for NLC (73.6±4.34 %). Stability studies performed for 8 weeks on the optimized batches of the SLN and the NLC were also conducted so as to ensure product quality. The formulations were assessed in terms of parameters considered benchmarks of stability, and included ZP, PS, PDI, LC and EE. Generally these parameters remained unchanged following storage for 8 weeks at 25°C/60% RH but showed considerable changes following storage for 8 weeks at 40°C/75% RH. These studies reveal that SLN and NLC when stored at 25°C/60% RH have the potential to be used as colloidal delivery systems for EFV that have the potential to protect EFV from photodegradation and sustain release into brain tissue. The latter will ultimately reduce or limit the incidence of adverse psychiatric effects and potentially alleviate AIDS-related complications such as ADC in patients with HIV/AIDS, ultimately improving their quality of life. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2014
- Full Text:
- Date Issued: 2014
The development and assessment of sustained release nevirapine tablets
- Authors: Mwila, Chiluba
- Date: 2013
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54667 , vital:26598
- Description: The use of antiretroviral (ARV) agents in the management of HIV/AIDS has significantly improved the lifestyle and wellbeing of patients. Despite the success that has been achieved with the use of ARV therapy, the occurrence of adverse effects and unpredictable bioavailability associated with most of these drugs remains a major concern. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in combination with other ARV compounds for the treatment of HIV-1 infections. It is also used for the prevention of mother to child transmission of the HIV-1 virus. NVP is a Biopharmaceutics Classification System (BCS) Class II compound. Although NVP exhibits good oral absorption, it induces self-metabolism leading to low and sometimes unpredictable bioavailability. NVP is commercially available as an immediate release and extended release dosage form, viz., Viramune® XR. Formulation of a generic sustained release (SR) dosage form for once daily dosing would result in delivery of constant amount of the drug to the circulation, reduce dose related adverse effects, improve patient compliance to medication and reduce the costs of therapy. A simple RP-HPLC method was developed and optimised using a central composite design approach. The method was validated using ICH guidelines and was found to be linear, precise, specific and accurate for the analysis of NVP both in bulk and dosage forms. Direct compression was used as the method of tablet manufacture. Different polymers were assessed for suitability as rate retarding polymers and included Methocel® K4M, Carbopol® 71G NF and Eudragit® RSPO. Powder blends were assessed for flow properties using the angle of repose, bulk and tapped density, Carr’s Compressibility index and Hausner’s ratio. The traditional approach of changing the amount of polymers and diluents systematically to achieve a desired NVP release profile was used for the development of a preliminary formulation. Response surface methodology was used for the optimisation of the formulation using a Box-Behnken quadratic design. Physical characteristics of the tablets such as thickness, weight, hardness, tensile strength and friability were assessed and the tablets passed Pharmacopoeial testing. NVP assay and content uniformity were assessed using a validated RP-HPLC method. Initially, USP Apparatus 2 was used to study NVP release over a 24 hour period and subsequently dissolution studies were performed using USP Apparatus 3 as it can be used to simulate GIT conditions. The dissolution profiles generated were used to determine the agitation rate for USP Apparatus 3 that would be equivalent to an agitation rate of 50 rpm when using USP Apparatus 2. The effect of the mesh screen pore size, buffer molarity strength and concentration of surfactant on NVP release were also investigated in order to select discriminatory dissolution test conditions for the test formulation. Dissolution profiles were compared to those of the commercially available Viramune® XR using the FDA recommended difference (f1) and similarity (f2) factors. The calculated values for f1 and f2 revealed that the dissolution profile for the optimised formulation that was identified was statistically similar to Viramune® XR. In vitro release data were fitted to different kinetic models to study the release kinetics of NVP. The overall mechanism of NVP release was best described using the Korsmeyer-Peppas diffusion exponent value, n. NVP release was found to be anomalous, implying that the release was influenced by a combination of diffusion, swelling and polymer chain relaxation. The Hixson-Crowell model revealed that there was constant change in surface area of the dosage form suggesting that erosion and swelling were significant factors affecting NVP release from the hydrophilic matrix technology. The release kinetics data were also used to design the optimised formulation. Tablets manufactured using the optimised formulation were subjected to water uptake and erosion studies and the results revealed that swelling and erosion occur simultaneously. The effects of pH and molarity on the swelling and erosion of the tablets were also investigated. The data suggest that increase in pH resulted in a slight increase in swelling while an increase in molarity did not have a significant effect on swelling. The change in pH did not have a significant effect on erosion while an increase in molarity strength resulted in a decrease in matrix erosion. The effect of HPMC grade on swelling, erosion and NVP release revealed that the grade of HPMC used had a significant effect on NVP release, with the release rate decreasing, swelling increasing and erosion decreasing as the viscosity of the HPMC grade increased. The effect of the particle size of MCC on NVP release was also studied by manufacturing tablets containing different grades of MCC and these studies revealed that particle size did not appear to have a significant effect on NVP release. Similarly the use of different types of lactose did not appear to have a significant impact on NVP release. In conclusion a sustained release NVP tablet formulation that has the potential for further development and optimisation has been developed, assessed and manufactured successfully and has been shown to exhibit similar dissolution behaviour to Viramune® XR, a commercially available NVP extended release product.
- Full Text:
- Date Issued: 2013
The design, synthesis and antiplasmodial activity of a series of halogenated fosmidomycin analogues and hybrid drugs
- Authors: Afolayan, Anthonia Folake
- Date: 2012
- Subjects: Uncatalogued
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/64370 , vital:28538
- Description: Malaria continues to be a devastating disease and a major cause of death in sub-Saharan Africa. With resistance against most of the available antimalarial drugs, there is a need for ongoing research and development of antimalarial agents. Fosmidomycin and its acetyl analogue FR900098 have been identified as potent inhibitors of Plasmodium falciparum, the causative agent of the most deadly form of malaria. Clinical trials of these agents have revealed poor absorption due to their high hydrophilicity. In the present studies the effect of halogenation of the acyl chain as well as the biological effect of extending the acyl sidechain was explored. This provided the basis on which fosmidomycin hybrids were designed to investigate the feasibility of hybrid extending into NADPH binding pocket. Synthesis of a series of halogenated FR900098 analogues was carried out in three stages. This included i) The introduction of the phosphonate group by reaction with 1,3dibromopropane in an Arbuzov reaction, ii) The introduction of a hydroxamate group by reaction of the propyl phosphonate by means of a nucleophilic substitution reaction with BocNHOBn and iii) The introduction of a halogenated acyl side chain on a protected fosmidomycin backbone. The synthesis of fosmidomycin-hybrids for which chloroquinefosmidomycin hybrids were used as the prototype, involved convergence of the two separately constructed moieties i.e. fosmidomycin and the quinoline moieties in a covalent linkage. The quinoline moiety was easily synthesized from the reaction of 4,7dichloroquinoline with 1,2-diamino ethane. The aminoquinoline so formed resulted in chloroquine-fosmidomycin hybrids 3.8 and 3.9 when reacted with halogenated FR900098 analogues. Antiplasmodial assays were conducted on the chloroquine-fosmidomycin hybrids and the halogenated fosmidomycin derivatives against the chloroquine resistant Gambian FCR-3 strain of P. falciparum. The most potent iodoacetyl fosmidomycin analogues 2.21 gave an IC50 value of 5.54 µM which is eight times more potent than the known antiplasmodial FR900098 which gave an IC50 value of 41.67 µM. All the halogenated FR900098 analogues showed better antiplasmodial activity than their non-halogenated derivatives. This indicated that the presence of halogens in the FR900098 analogues contributes to their biological Chapter 1 Literature review activity. The acetyl and propyl linked hybrids 3.8 and 3.9 showed potent antiplasmodial activity with IC50 values of 0.18 and 0.82 µM respectively. These were by far the most potent hybrids synthesized and provided leads for a new class of promising antimalarial agents. Preliminary E. coli DXR enzyme inhibition assays were carried out on the halogenated fosmidomycin analogues. The results showed good inhibition of the enzyme by the phosphonic acids of the chloroacetyl and chloropropyl analogues 2.1 and 2.2 respectively. Molecular modelling of the compounds on E. coli (PDB code: 2EGH) and P. falciparum (PDB code: 3AUA) DXR showed strong binding of the halogenated fosmidomycin analogues while the hybrids in the absence of docked NADPH showed minimum binding to the enzymes.
- Full Text:
- Date Issued: 2012