A medicinal chemistry study in nitrogen containing heterocycles
- Authors: Lunga, Mayibongwe Junior
- Date: 2018
- Subjects: Indole , Tetrazoles , Antimalarials , Heat shock proteins , Plasmodium falciparum
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63521 , vital:28430
- Description: Heterocyclic structures have found extensive utility in the field of medicinal chemistry, as prominent regions of pharmacophores resulting in numerous drug treatments for many diseases. Accordingly, in this project we explored the respective antimalarial and anticancer activity exhibited by compounds featuring nitrogen containing indole and tetrazole heterocycles respectively. This thesis therefore comprises of two distinct parts. Part 1. Following the development of resistance towards traditional antimalarial therapy such as chloroquine and emerging resistance towards artemisinin combination therapies, the WHO reported the urgent need for new, effective drugs and identification of new drug targets to combat the Plasmodium falciparum parasite. In 2015 the parasite was the cause of 429 000 deaths, the majority occurring in the sub-Saharan region of Africa. This highlights the failing effectiveness of vector control strategies, reiterating the need to develop alternative control and treatment strategies. In response to this need we wanted to expand and further describe the SAR of the indole based series, indolyl-3-ethanone-α- thioethers, previously synthesized in our laboratory. These compounds were found to exhibit antimalarial activity with compounds 2.26 and 2.27 exhibiting activity against P. falciparum 3D7 in the nanomolar range. Based on these compounds we synthesized compounds 3.21 and 3.24 – 3.32 following a three step reaction pathway. Our results in this study, indicate that compound 3.28, a pnitrothiophenol analogue of 2.27 was the most active of the compounds we synthesized and furthermore was superior in activity against Plasmodium compared to 2.27. This result indicated that the presence of p-NO2 is important in enhancing anti-plasmodial activity. Comparing compounds 3.25 and 3.26 with an oxygen on the ether bridge to compounds 3.29 and 3.30 with a sulfur, we observed an increase in hydrophilicity coupled to a decrease in anti-plasmodial activity in the compounds, thus, highlighting the importance of sulfur for enhanced activity. Furthermore, we investigated bioisosteric replacement of the 5-chloro substituent present in hit compounds 2.27 and 3.28, with an electron withdrawing nitrile (3.27) and electron donating methyl (3.29) and methoxy (3.31) substituents. These substituents decreased anti-plasmodial activity, confirming that a chlorine substituent is optimal for biological activity. This study furthered our understanding of the SAR of indolyl-3-ethanone-α- thioethers for the development of potent anti-plasmodial lead compounds. Part 2. Triple negative breast cancer (TNBC), which disproportionately affects women of sub-Saharan Africa, is unresponsive to hormone-based therapies. This emergence presents a population of patients devoid of effective drug treatment, signaling the urgent need to develop new effective therapies with novel drug targets. Therefore, we identified our target in TNBC cells as the protein-protein interaction between the co-chaperones HOP and HSP90. We reasoned that a disruption of this interaction would ultimately result in cancer cell death via the degradation of essential oncogenic client proteins. Following a fragment screening campaign, which identified several acid and tetrazole containing hits (4.56 – 4.58) which bound to HOP, with low anticancer activity, we sought to develop synthetic methodology to elaborate our fragment hits synthesizing tetrazole containing fragments to target TNBC cell lines. We therefore proceeded to synthesize a range of multi substituted fragments (4.59 – 4.63), utilizing a nitrile (4.66) to access tetrazoles via 1,3-cycloaddition and an acid by nitrile hydrolysis. We successfully synthesized the tetrazole and acid fragments which are currently undergoing characterization for activity against TNBC. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
- Authors: Lunga, Mayibongwe Junior
- Date: 2018
- Subjects: Indole , Tetrazoles , Antimalarials , Heat shock proteins , Plasmodium falciparum
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63521 , vital:28430
- Description: Heterocyclic structures have found extensive utility in the field of medicinal chemistry, as prominent regions of pharmacophores resulting in numerous drug treatments for many diseases. Accordingly, in this project we explored the respective antimalarial and anticancer activity exhibited by compounds featuring nitrogen containing indole and tetrazole heterocycles respectively. This thesis therefore comprises of two distinct parts. Part 1. Following the development of resistance towards traditional antimalarial therapy such as chloroquine and emerging resistance towards artemisinin combination therapies, the WHO reported the urgent need for new, effective drugs and identification of new drug targets to combat the Plasmodium falciparum parasite. In 2015 the parasite was the cause of 429 000 deaths, the majority occurring in the sub-Saharan region of Africa. This highlights the failing effectiveness of vector control strategies, reiterating the need to develop alternative control and treatment strategies. In response to this need we wanted to expand and further describe the SAR of the indole based series, indolyl-3-ethanone-α- thioethers, previously synthesized in our laboratory. These compounds were found to exhibit antimalarial activity with compounds 2.26 and 2.27 exhibiting activity against P. falciparum 3D7 in the nanomolar range. Based on these compounds we synthesized compounds 3.21 and 3.24 – 3.32 following a three step reaction pathway. Our results in this study, indicate that compound 3.28, a pnitrothiophenol analogue of 2.27 was the most active of the compounds we synthesized and furthermore was superior in activity against Plasmodium compared to 2.27. This result indicated that the presence of p-NO2 is important in enhancing anti-plasmodial activity. Comparing compounds 3.25 and 3.26 with an oxygen on the ether bridge to compounds 3.29 and 3.30 with a sulfur, we observed an increase in hydrophilicity coupled to a decrease in anti-plasmodial activity in the compounds, thus, highlighting the importance of sulfur for enhanced activity. Furthermore, we investigated bioisosteric replacement of the 5-chloro substituent present in hit compounds 2.27 and 3.28, with an electron withdrawing nitrile (3.27) and electron donating methyl (3.29) and methoxy (3.31) substituents. These substituents decreased anti-plasmodial activity, confirming that a chlorine substituent is optimal for biological activity. This study furthered our understanding of the SAR of indolyl-3-ethanone-α- thioethers for the development of potent anti-plasmodial lead compounds. Part 2. Triple negative breast cancer (TNBC), which disproportionately affects women of sub-Saharan Africa, is unresponsive to hormone-based therapies. This emergence presents a population of patients devoid of effective drug treatment, signaling the urgent need to develop new effective therapies with novel drug targets. Therefore, we identified our target in TNBC cells as the protein-protein interaction between the co-chaperones HOP and HSP90. We reasoned that a disruption of this interaction would ultimately result in cancer cell death via the degradation of essential oncogenic client proteins. Following a fragment screening campaign, which identified several acid and tetrazole containing hits (4.56 – 4.58) which bound to HOP, with low anticancer activity, we sought to develop synthetic methodology to elaborate our fragment hits synthesizing tetrazole containing fragments to target TNBC cell lines. We therefore proceeded to synthesize a range of multi substituted fragments (4.59 – 4.63), utilizing a nitrile (4.66) to access tetrazoles via 1,3-cycloaddition and an acid by nitrile hydrolysis. We successfully synthesized the tetrazole and acid fragments which are currently undergoing characterization for activity against TNBC. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
Assessment of pharmaceutical equivalence of topical cream products containing hydrocortisone acetate using in vitro release testing (IVRT)
- Mudyahoto, Nyengeterai Amanda
- Authors: Mudyahoto, Nyengeterai Amanda
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63384 , vital:28404
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Mudyahoto, Nyengeterai Amanda
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63384 , vital:28404
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
Development and assessment of a smart thermosetting intranasal hydrogel for lamotrigine
- Authors: Melamane, Siyabonga
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62975 , vital:28349
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Melamane, Siyabonga
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62975 , vital:28349
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
Development and assessment of gastroretentive sustained release captopril micro-balloons
- Authors: Oridota, Omoyosola Omolola
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63491 , vital:28419
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Oridota, Omoyosola Omolola
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63491 , vital:28419
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
Development and validation of a health literacy measure for limited literacy public sector patients in South Africa
- Authors: Marimwe, Chipiwa
- Date: 2018
- Subjects: Health literacy -- South Africa , Patient education -- South Africa , Communication in medicine -- South Africa , Health literacy -- Social aspects -- South Africa , Poor -- Medical care -- South Africa , Analysis of variance , Multidimensional Screener of Functional Health Literacy (MSFHL)
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62661 , vital:28227
- Description: The growing complexity of healthcare demands greater patient involvement and skills to navigate this complex system. It has therefore become increasingly important to identify individuals with inadequate health literacy, by using efficient, short and reliable measures for doing so. Most research on the development and validation of health literacy tests has been conducted in high-income countries, with very little reported from low-and middle-income countries (LMICs). Existing health literacy measures have come under scrutiny for their lack of cultural sensitivity, bias towards certain population groups and failure to acknowledge health literacy as a multidimensional concept. These measures usually have limited application in LMICs due to the significantly different structuring of healthcare systems, they overlook the extreme discrepancies in educational levels, and rely too heavily on the ability to read health information. No health literacy data for South Africa are available, and only a few health literacy-based research papers have been published in this country. The aim of the study was to develop and validate a health literacy measure that is contextually and culturally appropriate to measure health literacy in limited literacy public sector patients in South Africa. An Item Bank of 30 questions was developed with the input of a diverse expert consultant panel, and included skills-based and self-reported questions which ensured cultural, contextual and educational level appropriateness. The Information and Support for Health Actions Questionnaire (ISHA-Q) is a health literacy measure developed to assess health literacy for LMICs which includes 14 core scales. These were useful in ensuring coverage of a range of health literacy constructs within the Item Bank. The 30 questions were then allocated to one of three health literacy domains: Procedural knowledge, Factual knowledge and Access to healthcare, health services and social support. Ethical approval for the study was obtained. The questions were translated into isiXhosa and underwent pilot testing. Following pilot testing, 120 isiXhosa first-language speakers, at least 18 years old, who attended public sector facilities and had a maximum 12 years of education were recruited from a primary healthcare clinic in Grahamstown. An interpreter was trained and he participated in all interviews. A questionnaire was used to collect data on the 30-question Item Bank. The Multidimensional Screener of Functional Health Literacy (MSFHL) was used as the primary comparator.The second phase of the study involved the refinement of the 30 questions in the Item Bank, which involved a multi-stage process. Data were analysed statistically using t-test, correlations, chi-square and ANOVA tests at a 5% level of significance, in order to identify problematic questions. Item Response Theory was used to ascertain difficulty and discriminatory ability of the questions. Each question was further subjected to in-depth interrogation by a panel of healthcare professionals to ensure that questions were supported by the conceptual framework and the definitions of health literacy adopted for this study. The number of questions was reduced from 30 to 12, and formed the new Health Literacy Test - Limited Literacy (HELT-LL). To validate the HELT-LL, 210 patients with the same inclusion criteria as previously noted, were recruited from four primary healthcare clinics in the Eastern Cape Province. Individual interviews were conducted with the assistance of the interpreter to collect sociodemographic data as well as data from the HELT-LL, the primary comparator (MSFHL), and a secondary comparator which was a South African modified version of the Newest Vital Sign (NVS-SA). The HELT-LL was re-administered to 40 patients in a follow-up interview two weeks later. The HELT-LL categorised only 17.6% of the patients as having adequate health literacy, just over a third with inadequate health literacy, and the majority with marginal health literacy. Questions in the cognitively demanding Procedural knowledge domain were the most poorly answered, with a mean score of 48.6±24.9%. Patients had great difficulty performing the basic numeric tasks in this domain. The overall mean score for the HELT-LL was 52.8±18.4%, compared with the more cognitively demanding NVS-SA with a mean of 28.6±21.1%, and clearly illustrated the impact of the strategy to include in the HELT-LL a variety of questions with differing cognitive load. The MSFHL, which is based on demographic characteristics and perceived difficulties with reading and writing, had an overall mean score of 44.4±26.2%. Demographic characteristics including age, education and English literacy, were found to be good predictors of limited health literacy, with significant correlations being found between these variables and the mean HELT-LL score. An acceptable value for Cronbach’s alpha, excellent test-retest reliability and excellent concurrent validity show that the HELT-LL is a valid and reliable measure of health literacy in our target population. As there is a paucity of health literacy research emanating from developing countries, this study presents a significant contribution to literature. It is the first study to report the development and validation of a health literacy measure to address the dearth of available health literacy measures applicable for South Africa. If implemented for use in clinical settings and for research purposes, it could provide valuable South African health literacy data which could inform the development of interventions focusing on improving health literacy and health outcomes.
- Full Text:
- Date Issued: 2018
- Authors: Marimwe, Chipiwa
- Date: 2018
- Subjects: Health literacy -- South Africa , Patient education -- South Africa , Communication in medicine -- South Africa , Health literacy -- Social aspects -- South Africa , Poor -- Medical care -- South Africa , Analysis of variance , Multidimensional Screener of Functional Health Literacy (MSFHL)
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62661 , vital:28227
- Description: The growing complexity of healthcare demands greater patient involvement and skills to navigate this complex system. It has therefore become increasingly important to identify individuals with inadequate health literacy, by using efficient, short and reliable measures for doing so. Most research on the development and validation of health literacy tests has been conducted in high-income countries, with very little reported from low-and middle-income countries (LMICs). Existing health literacy measures have come under scrutiny for their lack of cultural sensitivity, bias towards certain population groups and failure to acknowledge health literacy as a multidimensional concept. These measures usually have limited application in LMICs due to the significantly different structuring of healthcare systems, they overlook the extreme discrepancies in educational levels, and rely too heavily on the ability to read health information. No health literacy data for South Africa are available, and only a few health literacy-based research papers have been published in this country. The aim of the study was to develop and validate a health literacy measure that is contextually and culturally appropriate to measure health literacy in limited literacy public sector patients in South Africa. An Item Bank of 30 questions was developed with the input of a diverse expert consultant panel, and included skills-based and self-reported questions which ensured cultural, contextual and educational level appropriateness. The Information and Support for Health Actions Questionnaire (ISHA-Q) is a health literacy measure developed to assess health literacy for LMICs which includes 14 core scales. These were useful in ensuring coverage of a range of health literacy constructs within the Item Bank. The 30 questions were then allocated to one of three health literacy domains: Procedural knowledge, Factual knowledge and Access to healthcare, health services and social support. Ethical approval for the study was obtained. The questions were translated into isiXhosa and underwent pilot testing. Following pilot testing, 120 isiXhosa first-language speakers, at least 18 years old, who attended public sector facilities and had a maximum 12 years of education were recruited from a primary healthcare clinic in Grahamstown. An interpreter was trained and he participated in all interviews. A questionnaire was used to collect data on the 30-question Item Bank. The Multidimensional Screener of Functional Health Literacy (MSFHL) was used as the primary comparator.The second phase of the study involved the refinement of the 30 questions in the Item Bank, which involved a multi-stage process. Data were analysed statistically using t-test, correlations, chi-square and ANOVA tests at a 5% level of significance, in order to identify problematic questions. Item Response Theory was used to ascertain difficulty and discriminatory ability of the questions. Each question was further subjected to in-depth interrogation by a panel of healthcare professionals to ensure that questions were supported by the conceptual framework and the definitions of health literacy adopted for this study. The number of questions was reduced from 30 to 12, and formed the new Health Literacy Test - Limited Literacy (HELT-LL). To validate the HELT-LL, 210 patients with the same inclusion criteria as previously noted, were recruited from four primary healthcare clinics in the Eastern Cape Province. Individual interviews were conducted with the assistance of the interpreter to collect sociodemographic data as well as data from the HELT-LL, the primary comparator (MSFHL), and a secondary comparator which was a South African modified version of the Newest Vital Sign (NVS-SA). The HELT-LL was re-administered to 40 patients in a follow-up interview two weeks later. The HELT-LL categorised only 17.6% of the patients as having adequate health literacy, just over a third with inadequate health literacy, and the majority with marginal health literacy. Questions in the cognitively demanding Procedural knowledge domain were the most poorly answered, with a mean score of 48.6±24.9%. Patients had great difficulty performing the basic numeric tasks in this domain. The overall mean score for the HELT-LL was 52.8±18.4%, compared with the more cognitively demanding NVS-SA with a mean of 28.6±21.1%, and clearly illustrated the impact of the strategy to include in the HELT-LL a variety of questions with differing cognitive load. The MSFHL, which is based on demographic characteristics and perceived difficulties with reading and writing, had an overall mean score of 44.4±26.2%. Demographic characteristics including age, education and English literacy, were found to be good predictors of limited health literacy, with significant correlations being found between these variables and the mean HELT-LL score. An acceptable value for Cronbach’s alpha, excellent test-retest reliability and excellent concurrent validity show that the HELT-LL is a valid and reliable measure of health literacy in our target population. As there is a paucity of health literacy research emanating from developing countries, this study presents a significant contribution to literature. It is the first study to report the development and validation of a health literacy measure to address the dearth of available health literacy measures applicable for South Africa. If implemented for use in clinical settings and for research purposes, it could provide valuable South African health literacy data which could inform the development of interventions focusing on improving health literacy and health outcomes.
- Full Text:
- Date Issued: 2018
Evaluating metabolism-induced toxicity using a non-hepatic cell line
- Authors: Weyers, Carli
- Date: 2018
- Subjects: Cytochrome P-450 , Drugs Metabolism , Drugs Design
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/61950 , vital:28087
- Description: The drug discovery pipeline is a complicated process taking roughly 15 years to complete, costing in excess of $1 billion per new chemical entity. It has been estimated that for every 100, 000 promising hit or lead compounds, only one will make it onto the market due to numerous drug candidates being discarded because of many complications. One such complication is metabolism-induced toxicity. Accordingly, an early understanding of the metabolism of any new chemical entity is becoming an integral part of the pipeline. In order to explore this, various methods have been developed including in silico and in vitro techniques. One such method involves performing cell viability assays on human liver cancer cell lines, which overexpress specific metabolic cytochrome P450 enzymes. If a toxic metabolite is produced it would result in reduced cell viability of the transformed cell line in comparison to a control. Since the liver is the primary site of metabolism in the human body, we were curious as to the extent to which background metabolism may play a role in the degree to which toxic metabolites would be produced in these cell lines. The aim of this project, therefore, was to establish if a non-hepatic cell-based system which overexpresses CYP3A4 could be used to detect the metabolism and any subsequent toxicity of compounds which have been reported to be substrates of the CYP450 enzyme. The HEK293 cell line was stably transfected with a plasmid vector for human CYP3A4 to create a model overexpression system for our metabolism studies. The activity of the enzyme was confirmed using the substrate, 7-benzyloxy-4-trifluoromethyl-coumarin. Subsequently, cytotoxicity testing was done on four known pharmaceuticals reported to generate toxic metabolites in hepatic cell-based assays. In silico metabolic predictions on the four known compounds were performed and compared to the results of published literature. Finally, the metabolism of one compound was studied using a combination of high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) in order to detect predicted metabolites. We observed no change in cellular toxicity nor did we detect the formation of metabolites, even though the overexpressed CYP3A4 enzyme was active. The results suggest that caution should be taken when interpreting the results of cell-based metabolism studies, and background metabolism may play a significant role in the data. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
- Authors: Weyers, Carli
- Date: 2018
- Subjects: Cytochrome P-450 , Drugs Metabolism , Drugs Design
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/61950 , vital:28087
- Description: The drug discovery pipeline is a complicated process taking roughly 15 years to complete, costing in excess of $1 billion per new chemical entity. It has been estimated that for every 100, 000 promising hit or lead compounds, only one will make it onto the market due to numerous drug candidates being discarded because of many complications. One such complication is metabolism-induced toxicity. Accordingly, an early understanding of the metabolism of any new chemical entity is becoming an integral part of the pipeline. In order to explore this, various methods have been developed including in silico and in vitro techniques. One such method involves performing cell viability assays on human liver cancer cell lines, which overexpress specific metabolic cytochrome P450 enzymes. If a toxic metabolite is produced it would result in reduced cell viability of the transformed cell line in comparison to a control. Since the liver is the primary site of metabolism in the human body, we were curious as to the extent to which background metabolism may play a role in the degree to which toxic metabolites would be produced in these cell lines. The aim of this project, therefore, was to establish if a non-hepatic cell-based system which overexpresses CYP3A4 could be used to detect the metabolism and any subsequent toxicity of compounds which have been reported to be substrates of the CYP450 enzyme. The HEK293 cell line was stably transfected with a plasmid vector for human CYP3A4 to create a model overexpression system for our metabolism studies. The activity of the enzyme was confirmed using the substrate, 7-benzyloxy-4-trifluoromethyl-coumarin. Subsequently, cytotoxicity testing was done on four known pharmaceuticals reported to generate toxic metabolites in hepatic cell-based assays. In silico metabolic predictions on the four known compounds were performed and compared to the results of published literature. Finally, the metabolism of one compound was studied using a combination of high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) in order to detect predicted metabolites. We observed no change in cellular toxicity nor did we detect the formation of metabolites, even though the overexpressed CYP3A4 enzyme was active. The results suggest that caution should be taken when interpreting the results of cell-based metabolism studies, and background metabolism may play a significant role in the data. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
Exploring para-thiophenols to expand the SAR of antimalarial 3-indolylethanones
- Authors: Chisango, Ruramai Lissa
- Date: 2018
- Subjects: Antimalarials , Malaria Chemotherapy , Thiols , Plasmodium falciparum , Blood-brain barrier
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63515 , vital:28428
- Description: According to the WHO, malaria is responsible for over half a million deaths annually especially in populations from disadvantaged settings. Although there has been a documented improvement in the mortality rates, malaria has proved to be a global emergency. Mostly affecting the poor population, this disease is perpetuating a vicious cycle of poverty in the developing world as current preventive measures are not adequate unless adopted in addition to effective treatment. However, there has been a worldwide increase in resistance to available treatment which presents a need for novel, affordable treatment. A study conducted in our laboratory identified two hit thiophenol containing compounds 2.24 and 2.25. These molecules provided initial insight into the SAR and potential pharmacophore of this class of compounds. We decided to further explore these compounds by making bioisosteric replacements to optimize the structure as we monitor the effect of these modifications on the anti-plasmodial activity. The synthetic pathway to form the target compounds of our study comprised of three steps which were initiated by the Friedel-Crafts acetylation of the indoles resulting in compounds 3.5 - 3.7. A bromination step followed which yielded the -bromo ketones (3.8 - 3.11). Some of the thiophenols (3.14 and 3.16) were not readily available in our laboratory and so were synthesized for the final synthetic step. This step involved the nucleophilic displacement of the -bromine to generate the -aryl substituted 3-indolylethanones (3.17 - 3.27). The thioethers displayed improved antimalarial activity from 2.24 and 2.25 against the chloroquine sensitive 3D7 Plasmodium falciparum strain. In addition, these compounds were non-toxic against HeLa cells which indicated this potential novel class of antimalarials is selective for the malaria parasite as hypothesized in the previous study conducted in our laboratory. In an attempt to predict the bioavailability of some of our compounds, in silico studies were conducted revealing that these compounds could be passively absorbed by the gastrointestinal tract, a positive result for bioavailability purposes. However, results from these studies indicate that modifications of these compounds would be necessary to allow for permeation through the blood brain barrier (BBB) for instances when the patient has cerebral malaria. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
- Authors: Chisango, Ruramai Lissa
- Date: 2018
- Subjects: Antimalarials , Malaria Chemotherapy , Thiols , Plasmodium falciparum , Blood-brain barrier
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63515 , vital:28428
- Description: According to the WHO, malaria is responsible for over half a million deaths annually especially in populations from disadvantaged settings. Although there has been a documented improvement in the mortality rates, malaria has proved to be a global emergency. Mostly affecting the poor population, this disease is perpetuating a vicious cycle of poverty in the developing world as current preventive measures are not adequate unless adopted in addition to effective treatment. However, there has been a worldwide increase in resistance to available treatment which presents a need for novel, affordable treatment. A study conducted in our laboratory identified two hit thiophenol containing compounds 2.24 and 2.25. These molecules provided initial insight into the SAR and potential pharmacophore of this class of compounds. We decided to further explore these compounds by making bioisosteric replacements to optimize the structure as we monitor the effect of these modifications on the anti-plasmodial activity. The synthetic pathway to form the target compounds of our study comprised of three steps which were initiated by the Friedel-Crafts acetylation of the indoles resulting in compounds 3.5 - 3.7. A bromination step followed which yielded the -bromo ketones (3.8 - 3.11). Some of the thiophenols (3.14 and 3.16) were not readily available in our laboratory and so were synthesized for the final synthetic step. This step involved the nucleophilic displacement of the -bromine to generate the -aryl substituted 3-indolylethanones (3.17 - 3.27). The thioethers displayed improved antimalarial activity from 2.24 and 2.25 against the chloroquine sensitive 3D7 Plasmodium falciparum strain. In addition, these compounds were non-toxic against HeLa cells which indicated this potential novel class of antimalarials is selective for the malaria parasite as hypothesized in the previous study conducted in our laboratory. In an attempt to predict the bioavailability of some of our compounds, in silico studies were conducted revealing that these compounds could be passively absorbed by the gastrointestinal tract, a positive result for bioavailability purposes. However, results from these studies indicate that modifications of these compounds would be necessary to allow for permeation through the blood brain barrier (BBB) for instances when the patient has cerebral malaria. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
Formulation, characterisation and optimisation of self-nanoemulsifying drug delivery systems (SNEDDS) loaded with artemether and lumefantrine
- Authors: Mudyahoto, Tsitsi
- Date: 2018
- Subjects: Uncatalogued
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63503 , vital:28422
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Mudyahoto, Tsitsi
- Date: 2018
- Subjects: Uncatalogued
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63503 , vital:28422
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
Investigating the influence of ring substitution on indole hydrogen bonding, with amino acids
- Authors: Nel, Donovan
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63509 , vital:28426
- Description: Expected release date-April 2019
- Full Text: false
- Date Issued: 2018
- Authors: Nel, Donovan
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63509 , vital:28426
- Description: Expected release date-April 2019
- Full Text: false
- Date Issued: 2018
Medicine use in swallowing-impaired patients: Pharmacists’ knowledge, practice and information needs
- Authors: Masilamoney, Mehrusha
- Date: 2018
- Subjects: Deglutition disorders , Drugs -- Administration , Oral medication -- Administration , Pharmacists -- Practice , South African Pharmacy Council
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/61940 , vital:28086
- Description: Dysphagia, or swallowing impairment, is a growing problem that affects 13.5% of the general population. The ability to swallow is essential for patients taking oral medicines, so this presents a challenge for swallowing-impaired (SI) patients as tablets and capsules will usually require modification prior to ingestion. Pharmacists should play a central role in advising SI patients about their medicine use, as well as problems that may impact on safety, adherence and therapeutic outcome. However, little is known about pharmacists’ level of knowledge, their practice and their information needs when dealing with SI patients and their use of medicines. The aim of this study was to investigate pharmacist knowledge, practice and information needs relating to the support of SI patients and their medicine-related needs. The study design included both quantitative and qualitative methods. A quantitative questionnaire was developed to collect data on the knowledge, practice and information needs of pharmacists and was piloted in 10 pharmacists, which resulted in minor modifications. The questionnaire was converted to a web-based survey and emailed to all pharmacists registered with the South African Pharmacy Council. Two knowledge scores were generated by summating correct responses: knowledge of dysphagia (KOD) and knowledge of medicine use (KOMU) in SI patients. Correlation analysis was used to investigate the strength of the relationship between specific variables with KOD and KOMU using the Pearson correlation coefficient. Qualitative semi-structured interviews were conducted with pharmacists from community, hospital and primary healthcare clinics in both a small town and a major metropole. The aim was to gain deeper understanding of issues arising from the survey, and to explore preferences for topic-specific information materials. All interviews were audio-recorded and transcribed verbatim. Thematic analysis was used to analyse the data. A total of 439 pharmacists responded to the survey, with 67% being females.The mean KOD score out of a maximum score of 10 was 6.1 ± 1.8. KOD was inadequate (<5) in just over one-third (37.8%) of pharmacists. The mean KOMU score achieved (maximum score 17) was 9.4 ± 2.0, with inadequate knowledge (<10) being established in just over two-thirds of pharmacists (70.8%). Age, length of registration as a pharmacist, and years of practice in a setting with direct patient interaction were significantly but weakly correlated with KOMU, whereas KOD showed no significant association with these variables. Qualification significantly influenced both KOD and KOMU; the highest group with adequate knowledge had either a Masters or a PharmD degree. Fewer than half the pharmacists (44%) never ask patients about their swallowing ability, and most (86%) reported no knowledge of locally available viscosity enhancers. Almost all pharmacists were interested in receiving information materials on assisting SI patients with their medicine use. Three major themes emerged from the semi-structured interviews. Pharmacists recognised their knowledge deficit and felt that lack of both undergraduate training and formal training during practice, as well as limited exposure to SI patients, were contributing factors. Barriers to their practice with SI patients included lack of time, lack of institutional support and lack of easily accessible references on the pharmacists’ role in supporting medicine use in SI patients. Lastly, most pharmacists were not prepared to take ownership of medicine-related problems in SI patients and had conflicting opinions of the pharmacists’ role, usually shifting the responsibility of medicine use in SI patients to nurses. This is the first study to investigate pharmacist knowledge of medicine use in SI patients. The findings indicate that pharmacists do not have the requisite knowledge when dealing with SI patients and their medicine-taking issues despite being the most highly trained healthcare professionals in this field. Lack of undergraduate training, in-house training and limited exposure to SI patients were reported to contribute to poor knowledge. Current practice revealed that there appears to be poor communication among different healthcare professionals, pharmacists were reluctant to work with and/or train nurses on appropriate medicine use in SI patients, and there appeared to be ambiguity surrounding the role of a pharmacist. This research identified that pharmacists regard this topic to be highly relevant to their everyday practice and are keen to receive more information and training relating to this area of study. Information materials were designed and will be made accessible to all pharmacists registered in South Africa.
- Full Text:
- Date Issued: 2018
Medicine use in swallowing-impaired patients: Pharmacists’ knowledge, practice and information needs
- Authors: Masilamoney, Mehrusha
- Date: 2018
- Subjects: Deglutition disorders , Drugs -- Administration , Oral medication -- Administration , Pharmacists -- Practice , South African Pharmacy Council
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/61940 , vital:28086
- Description: Dysphagia, or swallowing impairment, is a growing problem that affects 13.5% of the general population. The ability to swallow is essential for patients taking oral medicines, so this presents a challenge for swallowing-impaired (SI) patients as tablets and capsules will usually require modification prior to ingestion. Pharmacists should play a central role in advising SI patients about their medicine use, as well as problems that may impact on safety, adherence and therapeutic outcome. However, little is known about pharmacists’ level of knowledge, their practice and their information needs when dealing with SI patients and their use of medicines. The aim of this study was to investigate pharmacist knowledge, practice and information needs relating to the support of SI patients and their medicine-related needs. The study design included both quantitative and qualitative methods. A quantitative questionnaire was developed to collect data on the knowledge, practice and information needs of pharmacists and was piloted in 10 pharmacists, which resulted in minor modifications. The questionnaire was converted to a web-based survey and emailed to all pharmacists registered with the South African Pharmacy Council. Two knowledge scores were generated by summating correct responses: knowledge of dysphagia (KOD) and knowledge of medicine use (KOMU) in SI patients. Correlation analysis was used to investigate the strength of the relationship between specific variables with KOD and KOMU using the Pearson correlation coefficient. Qualitative semi-structured interviews were conducted with pharmacists from community, hospital and primary healthcare clinics in both a small town and a major metropole. The aim was to gain deeper understanding of issues arising from the survey, and to explore preferences for topic-specific information materials. All interviews were audio-recorded and transcribed verbatim. Thematic analysis was used to analyse the data. A total of 439 pharmacists responded to the survey, with 67% being females.The mean KOD score out of a maximum score of 10 was 6.1 ± 1.8. KOD was inadequate (<5) in just over one-third (37.8%) of pharmacists. The mean KOMU score achieved (maximum score 17) was 9.4 ± 2.0, with inadequate knowledge (<10) being established in just over two-thirds of pharmacists (70.8%). Age, length of registration as a pharmacist, and years of practice in a setting with direct patient interaction were significantly but weakly correlated with KOMU, whereas KOD showed no significant association with these variables. Qualification significantly influenced both KOD and KOMU; the highest group with adequate knowledge had either a Masters or a PharmD degree. Fewer than half the pharmacists (44%) never ask patients about their swallowing ability, and most (86%) reported no knowledge of locally available viscosity enhancers. Almost all pharmacists were interested in receiving information materials on assisting SI patients with their medicine use. Three major themes emerged from the semi-structured interviews. Pharmacists recognised their knowledge deficit and felt that lack of both undergraduate training and formal training during practice, as well as limited exposure to SI patients, were contributing factors. Barriers to their practice with SI patients included lack of time, lack of institutional support and lack of easily accessible references on the pharmacists’ role in supporting medicine use in SI patients. Lastly, most pharmacists were not prepared to take ownership of medicine-related problems in SI patients and had conflicting opinions of the pharmacists’ role, usually shifting the responsibility of medicine use in SI patients to nurses. This is the first study to investigate pharmacist knowledge of medicine use in SI patients. The findings indicate that pharmacists do not have the requisite knowledge when dealing with SI patients and their medicine-taking issues despite being the most highly trained healthcare professionals in this field. Lack of undergraduate training, in-house training and limited exposure to SI patients were reported to contribute to poor knowledge. Current practice revealed that there appears to be poor communication among different healthcare professionals, pharmacists were reluctant to work with and/or train nurses on appropriate medicine use in SI patients, and there appeared to be ambiguity surrounding the role of a pharmacist. This research identified that pharmacists regard this topic to be highly relevant to their everyday practice and are keen to receive more information and training relating to this area of study. Information materials were designed and will be made accessible to all pharmacists registered in South Africa.
- Full Text:
- Date Issued: 2018
The development, manufacture and assessment of solid dispersions of gliclazide
- Authors: Govere, Grace Shalom
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63390 , vital:28405
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Govere, Grace Shalom
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/63390 , vital:28405
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
The development, manufacture and evaluation of a selfmicro-emulsifying drug delivery system for efavirenz
- Musakana, Tanyaradzwa Gracious
- Authors: Musakana, Tanyaradzwa Gracious
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62643 , vital:28223
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
- Authors: Musakana, Tanyaradzwa Gracious
- Date: 2018
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62643 , vital:28223
- Description: Expected release date-April 2020
- Full Text:
- Date Issued: 2018
The development, manufacture and evaluation of sustained release gastric-resistant isoniazid and gastroretentive microporous rifampicin microspheres
- Authors: Mwila, Chiluba
- Date: 2018
- Subjects: Biodegradation , Microspheres (Pharmacy) , Drug delivery systems , Rifampin , Isoniazid
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/63497 , vital:28421 , DOI 10.21504/10962/63497
- Description: According to the World Health Organization Global Tuberculosis (TB) 2017 Report, there were an estimated 10.4 million new TB cases worldwide of which, in 2016, 65 % occurred in men, 28.1 % in women and 6.9 % in children. TB is the ninth leading cause of death globally and is the leading cause due to an infectious organism surpassing HIV/AIDS. Treatment is long-term and the use of a combination of medicines is required for success. The concern related to the use of fixed dose combination products for the treatment of TB is the issue of low bioavailability of rifampicin observed from a number of fixed dose combination (FDC) formulations. The hydrolysis of rifampicin, in acidic media, to form insoluble 3-formyl rifamycin SV contributes to poor bioavailability of rifampicin. The degradation of rifampicin to form this poorly absorbed compound is accelerated in the presence of isoniazid via the reversible formation of isonicotinyl hydrazone is a further factor contributing to the poor bioavailability of rifampicin. Therefore, the development of a novel drug delivery technology that prevents interactions between rifampicin and isoniazid in an acidic medium is required. A Box Behnken design was successfully used for the optimisation of a rapid and accurate stability-indicating gradient elution RP-HPLC method for the simultaneous analysis of isoniazid, pyrazinamide and rifampicin. The method was validated using ICH guidelines and the results indicate it can be used for the rapid analysis of commercially available TB FDC formulations containing the active pharmaceutical ingredients, API. The method is precise, sensitive and has the necessary selectivity for use during formulation development and optimisation studies for a combination of rifampicin, isoniazid and pyrazinamide. Initially formulation activities were undertaken with rifampicin and isoniazid for the development of an approach to enhance the effective delivery of these compounds. The characterisation of rifampicin and isoniazid was undertaken using spectroscopic, thermal and microscopic analysis. The studies revealed that the compounds are crystalline and exhibit distinct characteristic sharp peaks in X-ray diffractograms and Differential Scanning Calorimetry thermograms. The thermograms, 13C Nuclear Magnetic Resonance and Fourier Transform Infrared spectroscopy results identified that rifampicin occurs as the form II polymorph however, as there are no significant biopharmaceutic differences between the polymorphic forms of rifampicin this information was used for identification purposes only. The results were used as baseline data for comparative purposes to monitor changes that may occur when rifampicin and isoniazid are used in formulation development, dosage form manufacture and characterisation activities for a FDC technology designed to deliver both compounds simultaneously. Hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and Eudragit® L100 polymers were successfully used for manufacture of isoniazid loaded gastric-resistant sustained release microspheres using an o/o solvent emulsification and evaporation approach. A Hybrid experimental design was used to investigate the influence of input variables viz., homogenisation speed and amount of HPMC-AS and Eudragit® L100 on gastric-resistance, INH release and encapsulation efficiency. The approach of using coating polymers viz., HPMC-AS and Eudragit® L100, to manufacture gastric resistant sustained release microspheres of isoniazid is unique and was efficient for preventing the release of isoniazid in an acidic environment. Only 0.523 % isoniazid was released from the optimised formulation after 2 h exposure to pH 1.2 0.1 M HCl suggesting there is also the possibility of minimising the accelerated degradation of rifampicin that occurs in the presence of isoniazid in acidic media. The microspheres also exhibited sustained release properties without burst release in pH 6.8 0.1 M phosphate buffer as < 5 % isoniazid was released at 0.5 h and only 11 % isoniazid was released at 2 h. The release of isoniazid was sustained over the entire period of dissolution testing with > 85 % isoniazid released at 24 h, implying that the majority of encapsulated isoniazid would be available for absorption. The manufacturing process resulted in the production of hard spherical particles and particle size analysis revealed that the microspheres ranged between 415.76 ± 76.93 μm and 903.35 ± 197.10 μm in diameter. The microspheres exhibited excellent flow properties attributed to the spherical nature of particles. Carr‟s index (CI) was 4.934 ± 0.775 % and the Hausner ratio (HR) was 1.148 ± 0.033 indicating good packability of the microspheres that would help in achieving weight and content uniformity of capsule dosage units. The manufacturing process however produced a low % yield suggesting that scale up difficulties may be encountered. However the high encapsulation efficiency observed may counter the challenges associated with the low yield. The DSC thermograms and FT Raman spectra of 1:1 mixtures of isoniazid, excipients and the microspheres did not reveal any potential detrimental interactions. Microporous floating sustained release microspheres for the delivery of rifampicin in the stomach have been successfully manufactured using emulsification and a diffusion/evaporation process. A novel approach using solvent mixture of acetone and dichloromethane that has not been reported for the manufacture of rifampicin microspheres was successfully used and resulted in the formation of a stable emulsion and the manufacture of rifampicin-loaded microspheres with uniform characteristics. In addition the manufacturing process was shorter than most other reported methods. A Box-Behnken experimental design was successfully used to study the influence of ethylcellulose, Eudragit® RLPO and d-glucose content on the floating properties, encapsulation efficiency and % yield of microspheres. The optimised formulation did not yield desired floating characteristics as the % buoyancy was low and floating lag times were high. The optimised formulation was modified by addition of NaHCO3 to increase the % buoyancy and reduce the floating lag time. Rifampicin release from the microspheres of the modified batch was 87.10 % at 12 h and the microspheres exhibited a % buoyancy of 87.66 ± 1.28 % (n = 6) and floating lag time of 15 ± 3.2 (n = 6) seconds. The microspheres remained buoyant for up to 12 h and an encapsulation efficiency of 88.26 ± 1.25 % was achieved. SEM images of microspheres following exposure to dissolution fluid revealed that the microspheres had numerous pores on their surface. The mean particle size distribution ranged between 423.19 ± 121.86 μm to 620.07 ± 102.67 μm. The microspheres exhibited similar flow characteristics to isoniazid microspheres with a CI of 1.422 ± 0.074 %, and HR of 1.034 ± 0.002. The excellent flow characteristics indicate that filling of the microspheres into hard gelatin capsules was unlikely to pose a challenge in respect of producing a product with uniform content. Rifampicin-excipient compatibility studies did not reveal any potential or significant interactions suggesting that the excipients used for the manufacture of the microspheres were compatible, although long term stability studies would be required to ascertain this is, indeed the case. The microporous floating sustained release microspheres manufactured in these studies has the potential to increase the bioavailability of rifampicin as they may be retained in the stomach where the solubility of rifampicin is high and from which absorption is best achieved. The degradation of rifampicin after 12 h dissolution testing in pH 1.2 0.1 M HCl in the presence of isoniazid gastric-resistant sustained release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be overcome by encapsulation of both active pharmaceutical ingredients in a manner that ensure release in different segments of the gastrointestinal tract. The use of sustained release microporous gastroretentive rifampicin microspheres in combination with sustained release isoniazid gastric-resistant microspheres revealed that accelerated degradation of rifampicin in the presence of isoniazid is reduced significantly when using this approach and a FDC of rifampicin and isoniazid microspheres has the potential to improve the bioavailability of rifampicin thereby enhancing therapeutic outcomes. In vivo studies would be required to confirm the potential benefits of using this approach to deliver rifampicin in combination with isoniazid. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
- Authors: Mwila, Chiluba
- Date: 2018
- Subjects: Biodegradation , Microspheres (Pharmacy) , Drug delivery systems , Rifampin , Isoniazid
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/63497 , vital:28421 , DOI 10.21504/10962/63497
- Description: According to the World Health Organization Global Tuberculosis (TB) 2017 Report, there were an estimated 10.4 million new TB cases worldwide of which, in 2016, 65 % occurred in men, 28.1 % in women and 6.9 % in children. TB is the ninth leading cause of death globally and is the leading cause due to an infectious organism surpassing HIV/AIDS. Treatment is long-term and the use of a combination of medicines is required for success. The concern related to the use of fixed dose combination products for the treatment of TB is the issue of low bioavailability of rifampicin observed from a number of fixed dose combination (FDC) formulations. The hydrolysis of rifampicin, in acidic media, to form insoluble 3-formyl rifamycin SV contributes to poor bioavailability of rifampicin. The degradation of rifampicin to form this poorly absorbed compound is accelerated in the presence of isoniazid via the reversible formation of isonicotinyl hydrazone is a further factor contributing to the poor bioavailability of rifampicin. Therefore, the development of a novel drug delivery technology that prevents interactions between rifampicin and isoniazid in an acidic medium is required. A Box Behnken design was successfully used for the optimisation of a rapid and accurate stability-indicating gradient elution RP-HPLC method for the simultaneous analysis of isoniazid, pyrazinamide and rifampicin. The method was validated using ICH guidelines and the results indicate it can be used for the rapid analysis of commercially available TB FDC formulations containing the active pharmaceutical ingredients, API. The method is precise, sensitive and has the necessary selectivity for use during formulation development and optimisation studies for a combination of rifampicin, isoniazid and pyrazinamide. Initially formulation activities were undertaken with rifampicin and isoniazid for the development of an approach to enhance the effective delivery of these compounds. The characterisation of rifampicin and isoniazid was undertaken using spectroscopic, thermal and microscopic analysis. The studies revealed that the compounds are crystalline and exhibit distinct characteristic sharp peaks in X-ray diffractograms and Differential Scanning Calorimetry thermograms. The thermograms, 13C Nuclear Magnetic Resonance and Fourier Transform Infrared spectroscopy results identified that rifampicin occurs as the form II polymorph however, as there are no significant biopharmaceutic differences between the polymorphic forms of rifampicin this information was used for identification purposes only. The results were used as baseline data for comparative purposes to monitor changes that may occur when rifampicin and isoniazid are used in formulation development, dosage form manufacture and characterisation activities for a FDC technology designed to deliver both compounds simultaneously. Hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and Eudragit® L100 polymers were successfully used for manufacture of isoniazid loaded gastric-resistant sustained release microspheres using an o/o solvent emulsification and evaporation approach. A Hybrid experimental design was used to investigate the influence of input variables viz., homogenisation speed and amount of HPMC-AS and Eudragit® L100 on gastric-resistance, INH release and encapsulation efficiency. The approach of using coating polymers viz., HPMC-AS and Eudragit® L100, to manufacture gastric resistant sustained release microspheres of isoniazid is unique and was efficient for preventing the release of isoniazid in an acidic environment. Only 0.523 % isoniazid was released from the optimised formulation after 2 h exposure to pH 1.2 0.1 M HCl suggesting there is also the possibility of minimising the accelerated degradation of rifampicin that occurs in the presence of isoniazid in acidic media. The microspheres also exhibited sustained release properties without burst release in pH 6.8 0.1 M phosphate buffer as < 5 % isoniazid was released at 0.5 h and only 11 % isoniazid was released at 2 h. The release of isoniazid was sustained over the entire period of dissolution testing with > 85 % isoniazid released at 24 h, implying that the majority of encapsulated isoniazid would be available for absorption. The manufacturing process resulted in the production of hard spherical particles and particle size analysis revealed that the microspheres ranged between 415.76 ± 76.93 μm and 903.35 ± 197.10 μm in diameter. The microspheres exhibited excellent flow properties attributed to the spherical nature of particles. Carr‟s index (CI) was 4.934 ± 0.775 % and the Hausner ratio (HR) was 1.148 ± 0.033 indicating good packability of the microspheres that would help in achieving weight and content uniformity of capsule dosage units. The manufacturing process however produced a low % yield suggesting that scale up difficulties may be encountered. However the high encapsulation efficiency observed may counter the challenges associated with the low yield. The DSC thermograms and FT Raman spectra of 1:1 mixtures of isoniazid, excipients and the microspheres did not reveal any potential detrimental interactions. Microporous floating sustained release microspheres for the delivery of rifampicin in the stomach have been successfully manufactured using emulsification and a diffusion/evaporation process. A novel approach using solvent mixture of acetone and dichloromethane that has not been reported for the manufacture of rifampicin microspheres was successfully used and resulted in the formation of a stable emulsion and the manufacture of rifampicin-loaded microspheres with uniform characteristics. In addition the manufacturing process was shorter than most other reported methods. A Box-Behnken experimental design was successfully used to study the influence of ethylcellulose, Eudragit® RLPO and d-glucose content on the floating properties, encapsulation efficiency and % yield of microspheres. The optimised formulation did not yield desired floating characteristics as the % buoyancy was low and floating lag times were high. The optimised formulation was modified by addition of NaHCO3 to increase the % buoyancy and reduce the floating lag time. Rifampicin release from the microspheres of the modified batch was 87.10 % at 12 h and the microspheres exhibited a % buoyancy of 87.66 ± 1.28 % (n = 6) and floating lag time of 15 ± 3.2 (n = 6) seconds. The microspheres remained buoyant for up to 12 h and an encapsulation efficiency of 88.26 ± 1.25 % was achieved. SEM images of microspheres following exposure to dissolution fluid revealed that the microspheres had numerous pores on their surface. The mean particle size distribution ranged between 423.19 ± 121.86 μm to 620.07 ± 102.67 μm. The microspheres exhibited similar flow characteristics to isoniazid microspheres with a CI of 1.422 ± 0.074 %, and HR of 1.034 ± 0.002. The excellent flow characteristics indicate that filling of the microspheres into hard gelatin capsules was unlikely to pose a challenge in respect of producing a product with uniform content. Rifampicin-excipient compatibility studies did not reveal any potential or significant interactions suggesting that the excipients used for the manufacture of the microspheres were compatible, although long term stability studies would be required to ascertain this is, indeed the case. The microporous floating sustained release microspheres manufactured in these studies has the potential to increase the bioavailability of rifampicin as they may be retained in the stomach where the solubility of rifampicin is high and from which absorption is best achieved. The degradation of rifampicin after 12 h dissolution testing in pH 1.2 0.1 M HCl in the presence of isoniazid gastric-resistant sustained release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be overcome by encapsulation of both active pharmaceutical ingredients in a manner that ensure release in different segments of the gastrointestinal tract. The use of sustained release microporous gastroretentive rifampicin microspheres in combination with sustained release isoniazid gastric-resistant microspheres revealed that accelerated degradation of rifampicin in the presence of isoniazid is reduced significantly when using this approach and a FDC of rifampicin and isoniazid microspheres has the potential to improve the bioavailability of rifampicin thereby enhancing therapeutic outcomes. In vivo studies would be required to confirm the potential benefits of using this approach to deliver rifampicin in combination with isoniazid. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
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