Development and assessment of gastroretentive sustained release captopril tablets
- Authors: Mukozhiwa, Samantha Yolanda
- Date: 2014-04-11
- Subjects: Captopril , Drug delivery systems , Drugs Controlled release , Cardiovascular system Diseases , Cardiovascular agents , Angiotensin converting enzyme Inhibitors
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480301 , vital:78427
- Description: Cardiovascular diseases (CVD) are the leading cause of death worldwide and global projections predict that the number of deaths due to CVD will continue to increase over the next 17 years [1]. With the growing burden of CVD the design and development of formulations that optimise the delivery of existing therapeutic molecules may be an approach to improving the management of patients with CVD. Captopril (CPT) is an angiotensin converting enzyme (ACE) inhibitor used for the routine management of hypertension, cardiac failure and diabetic nephropathy [2-4]. However it has a relatively short half-life and typical therapeutic dosing regimens require multiple dosing [2]. CPT is a potential candidate for sustained oral drug delivery, however its poor stability profile and high water solubility present significant formulation challenges. CPT exhibits optimal stability at pH < 4 and is unstable in the alkaline environment of intestinal fluids [5]. A sustained release gastroretentive formulation is therefore proposed as an approach that may improve the in vivo stability of CPT in addition to slowly releasing the molecule at a desired rate that may also minimize the occurrence of drug-related adverse effects. A Capillary Zone Electrophoresis (CZE) method for the quantitation of CPT in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. The CZE method was found to have the necessary linearity, accuracy, precision, sensitivity and specificity for the analysis of CPT in pharmaceutical formulations. Preformulation studies were conducted as part of the preparative work required to manufacture high quality, stable gastroretentive sustained release CPT tablets. The experiments conducted were tailored for the development of CPT sustained release tablets using direct compression manufacture and included an analysis of particle size and shape, powder flow properties and CPT-excipient compatibility studies. The results revealed that there was no definite evidence of interactions between CPT and the excipients to be used to manufacture CPT tablets, and CPT formulations were developed using these excipients. A direct compression procedure was selected for tablet manufacture due to apparent simplicity and to avoid unnecessary exposure of CPT to the heat and moisture that would be encountered if a wet granulation manufacturing process was used. A numerical optimisation approach was used to predict a formulation composition that would produce minimal CPT release initially, a short floating lag time (FLT) and maximum CPT release after 12 hours of dissolution testing. The effect of increasing the agitation speed of USP Apparatus 2 on the release of CPT from the optimised formulation was also investigated. The results revealed that changing the speed of the paddle had only a relatively small impact on the in vitro release behaviour of CPT from the tablets. The optimised formulation was subjected to additional testing in an attempt to investigate the effects of pH and osmolarity on the swelling and erosion characteristics of the dosage form. It was important to evaluate the effects of pH and osmolarity from the perspective of the solubility and stability of CPT. The results generated from swelling studies revealed that the swelling characteristics of the proposed formulation were not significantly altered by a change in pH and osmolarity of the test medium and this is probably due to the non-ionic nature of HPMC. In addition, the results revealed that the solubility and/or stability of CPT in different dissolution media did not affect the water uptake and swelling of the tablet matrices. The results revealed the erosion rate constants were low and suggest that although polymer erosion does occur, the role of this phenomenon in the release of CPT may not be as significant as that of diffusion. The release kinetics of CPT from the tablets was established by fitting in vitro release data to several mathematical models. The in vitro release data were best described using the Korsmeyer-Peppas model and values of release exponent (n) suggest that the majority of the tablets exhibited an anomalous CPT transport mechanism. The short-term stability of the optimised formulation was established by undertaking stability studies at 25°/60% RH and 40°/75% RH. The results revealed that there was no significant change in appearance and physicochemical properties of the tablets over 60 days. In conclusion, gastroretentive sustained release CPT tablets with the potential for further development and optimisation have been successfully developed and assessed in these studies. A basis is thus provided for further development of this technology. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, 2014
- Full Text:
- Date Issued: 2014-04-11
- Authors: Mukozhiwa, Samantha Yolanda
- Date: 2014-04-11
- Subjects: Captopril , Drug delivery systems , Drugs Controlled release , Cardiovascular system Diseases , Cardiovascular agents , Angiotensin converting enzyme Inhibitors
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480301 , vital:78427
- Description: Cardiovascular diseases (CVD) are the leading cause of death worldwide and global projections predict that the number of deaths due to CVD will continue to increase over the next 17 years [1]. With the growing burden of CVD the design and development of formulations that optimise the delivery of existing therapeutic molecules may be an approach to improving the management of patients with CVD. Captopril (CPT) is an angiotensin converting enzyme (ACE) inhibitor used for the routine management of hypertension, cardiac failure and diabetic nephropathy [2-4]. However it has a relatively short half-life and typical therapeutic dosing regimens require multiple dosing [2]. CPT is a potential candidate for sustained oral drug delivery, however its poor stability profile and high water solubility present significant formulation challenges. CPT exhibits optimal stability at pH < 4 and is unstable in the alkaline environment of intestinal fluids [5]. A sustained release gastroretentive formulation is therefore proposed as an approach that may improve the in vivo stability of CPT in addition to slowly releasing the molecule at a desired rate that may also minimize the occurrence of drug-related adverse effects. A Capillary Zone Electrophoresis (CZE) method for the quantitation of CPT in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. The CZE method was found to have the necessary linearity, accuracy, precision, sensitivity and specificity for the analysis of CPT in pharmaceutical formulations. Preformulation studies were conducted as part of the preparative work required to manufacture high quality, stable gastroretentive sustained release CPT tablets. The experiments conducted were tailored for the development of CPT sustained release tablets using direct compression manufacture and included an analysis of particle size and shape, powder flow properties and CPT-excipient compatibility studies. The results revealed that there was no definite evidence of interactions between CPT and the excipients to be used to manufacture CPT tablets, and CPT formulations were developed using these excipients. A direct compression procedure was selected for tablet manufacture due to apparent simplicity and to avoid unnecessary exposure of CPT to the heat and moisture that would be encountered if a wet granulation manufacturing process was used. A numerical optimisation approach was used to predict a formulation composition that would produce minimal CPT release initially, a short floating lag time (FLT) and maximum CPT release after 12 hours of dissolution testing. The effect of increasing the agitation speed of USP Apparatus 2 on the release of CPT from the optimised formulation was also investigated. The results revealed that changing the speed of the paddle had only a relatively small impact on the in vitro release behaviour of CPT from the tablets. The optimised formulation was subjected to additional testing in an attempt to investigate the effects of pH and osmolarity on the swelling and erosion characteristics of the dosage form. It was important to evaluate the effects of pH and osmolarity from the perspective of the solubility and stability of CPT. The results generated from swelling studies revealed that the swelling characteristics of the proposed formulation were not significantly altered by a change in pH and osmolarity of the test medium and this is probably due to the non-ionic nature of HPMC. In addition, the results revealed that the solubility and/or stability of CPT in different dissolution media did not affect the water uptake and swelling of the tablet matrices. The results revealed the erosion rate constants were low and suggest that although polymer erosion does occur, the role of this phenomenon in the release of CPT may not be as significant as that of diffusion. The release kinetics of CPT from the tablets was established by fitting in vitro release data to several mathematical models. The in vitro release data were best described using the Korsmeyer-Peppas model and values of release exponent (n) suggest that the majority of the tablets exhibited an anomalous CPT transport mechanism. The short-term stability of the optimised formulation was established by undertaking stability studies at 25°/60% RH and 40°/75% RH. The results revealed that there was no significant change in appearance and physicochemical properties of the tablets over 60 days. In conclusion, gastroretentive sustained release CPT tablets with the potential for further development and optimisation have been successfully developed and assessed in these studies. A basis is thus provided for further development of this technology. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, 2014
- Full Text:
- Date Issued: 2014-04-11
Lived bodies: women’s experience of sex and gender
- Authors: Lothian, Julie-Anne
- Date: 2014-04-11
- Subjects: Lived body , Human body Sociological aspects , Women Sociological aspects , Sex role , Gender
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/69445 , vital:29538
- Description: This thesis will discuss the category of women, as a social group, through a phenomenological understanding of women’s subjective experiences. In arguing for the phenomenological perspective of the lived body, I show the ways in which other conceptions of women’s embodied subjectivity ultimately fail to provide comprehensive accounts of the lived experience of being a woman. I begin with an investigation into how biological determinists hypothesise women’s bodies as sexed. I then move to respond to Judith Butler’s poststructuralist feminist account of the gendered body. Finally, I argue that the embodied experience of being a woman is best explained as an ambiguous relationship between socially constructed expectations of femininity and biological materiality. , Thesis (MA) -- Faculty of Humanities, Political and International Studies, 2014
- Full Text:
- Date Issued: 2014-04-11
- Authors: Lothian, Julie-Anne
- Date: 2014-04-11
- Subjects: Lived body , Human body Sociological aspects , Women Sociological aspects , Sex role , Gender
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/69445 , vital:29538
- Description: This thesis will discuss the category of women, as a social group, through a phenomenological understanding of women’s subjective experiences. In arguing for the phenomenological perspective of the lived body, I show the ways in which other conceptions of women’s embodied subjectivity ultimately fail to provide comprehensive accounts of the lived experience of being a woman. I begin with an investigation into how biological determinists hypothesise women’s bodies as sexed. I then move to respond to Judith Butler’s poststructuralist feminist account of the gendered body. Finally, I argue that the embodied experience of being a woman is best explained as an ambiguous relationship between socially constructed expectations of femininity and biological materiality. , Thesis (MA) -- Faculty of Humanities, Political and International Studies, 2014
- Full Text:
- Date Issued: 2014-04-11
Sorption and emulsion liquid membranes in the remediation of metal processing waste water effluents using rhodium, trioctylamine and trihexylamine as a model
- Authors: Moyo, Francis
- Date: 2014-04-11
- Subjects: Liquid membranes , Rhodium , Trioctylamine , Trihexylamine , Emulsions (Pharmacy) , Sorption
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480289 , vital:78426
- Description: Two optimised ELMs were prepared with the diluent always being 30 % solution of toluene in kerosene. The first ELM contained 30.000 g/L (w/v) polyisobutylene, 10.870 g/L (m/v) of trioctyl amine and 51.001 g/L (m/v) of SPAN 80. The other optimised ELM was composed of 20.000 g/l of polyisobutylene, 10.268 g/l trioctyl amine and 50.024 g/l of SPAN 80. The stripping phase was always 2 M HNO3 and the mixing ratios of organic phase to stripping phase were 1:1 and 2:1. The t-test was used to test for the difference between the mean micro-droplet sizes had a p-value of 0.3018 at 5 % level of significance, i.e. there was no statistically the mean micro-droplet size of the optimised ELMs. Demulsification was performed with polyethylene glycol with molecular weight of 400 g/mol at 50 ± 1 °C for 24 hours. The volumetric ratio of treated side-stream and the ELM was 5:1 and 98.7 to 108 % of the initial Rh amount was recovered in the stripping phase after chemical demulsification. Major carryover of the diluent components into the stripping phase observed was from trioctyl amine, toluene and polyethylene glycol was observed. The final spent side-stream should not be discharged into the environment based on the acute Daphnia pulex toxicity test. For sorption studies, the specific surface area of kaolin was 18.21 0.8 m2 g-1 and loss on ignition was 0.0086 0.004 %. Removal efficiencies of trioctyl amine for 10 g of kaolin and particle size 65-100 μm and 101-400 μm were 18.1 % and 17.5 % respectively while sorption capacities were 0.92 g/g and 0.88 g/g respectively. The removal efficiency of 20 g of kaolin was 35.8 % and 33.3 % and sorption capacities were 0.93 g/g and 0.87 g/g respectively. For particle sizes 101-400 μm, the R2 values obtained for Freundlich and Langmuir were 0.9757 and 0.9819 respectively. The n and Kf for Freundlich isotherm were 1.086 and 2.622. Removal efficiency for trihexyl amine for particle size 101-400 μm and 65-100 μm was 28.5 % and 29.3 % respectively while sorption capacities were 0.73 g/g and 0.75 g/g respectively. The R2 values obtained for Freundlich and Langmuir for particle sizes 101-400 μm were 0.957 and 0.989 respectively. The n and Kf for Freundlich isotherm were 1.307 and 2.151 respectively. These results suggest that kaolinite could potentially be used in remediation of metal wastewaters containing hydrophobic extractants. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, 2014
- Full Text:
- Date Issued: 2014-04-11
- Authors: Moyo, Francis
- Date: 2014-04-11
- Subjects: Liquid membranes , Rhodium , Trioctylamine , Trihexylamine , Emulsions (Pharmacy) , Sorption
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480289 , vital:78426
- Description: Two optimised ELMs were prepared with the diluent always being 30 % solution of toluene in kerosene. The first ELM contained 30.000 g/L (w/v) polyisobutylene, 10.870 g/L (m/v) of trioctyl amine and 51.001 g/L (m/v) of SPAN 80. The other optimised ELM was composed of 20.000 g/l of polyisobutylene, 10.268 g/l trioctyl amine and 50.024 g/l of SPAN 80. The stripping phase was always 2 M HNO3 and the mixing ratios of organic phase to stripping phase were 1:1 and 2:1. The t-test was used to test for the difference between the mean micro-droplet sizes had a p-value of 0.3018 at 5 % level of significance, i.e. there was no statistically the mean micro-droplet size of the optimised ELMs. Demulsification was performed with polyethylene glycol with molecular weight of 400 g/mol at 50 ± 1 °C for 24 hours. The volumetric ratio of treated side-stream and the ELM was 5:1 and 98.7 to 108 % of the initial Rh amount was recovered in the stripping phase after chemical demulsification. Major carryover of the diluent components into the stripping phase observed was from trioctyl amine, toluene and polyethylene glycol was observed. The final spent side-stream should not be discharged into the environment based on the acute Daphnia pulex toxicity test. For sorption studies, the specific surface area of kaolin was 18.21 0.8 m2 g-1 and loss on ignition was 0.0086 0.004 %. Removal efficiencies of trioctyl amine for 10 g of kaolin and particle size 65-100 μm and 101-400 μm were 18.1 % and 17.5 % respectively while sorption capacities were 0.92 g/g and 0.88 g/g respectively. The removal efficiency of 20 g of kaolin was 35.8 % and 33.3 % and sorption capacities were 0.93 g/g and 0.87 g/g respectively. For particle sizes 101-400 μm, the R2 values obtained for Freundlich and Langmuir were 0.9757 and 0.9819 respectively. The n and Kf for Freundlich isotherm were 1.086 and 2.622. Removal efficiency for trihexyl amine for particle size 101-400 μm and 65-100 μm was 28.5 % and 29.3 % respectively while sorption capacities were 0.73 g/g and 0.75 g/g respectively. The R2 values obtained for Freundlich and Langmuir for particle sizes 101-400 μm were 0.957 and 0.989 respectively. The n and Kf for Freundlich isotherm were 1.307 and 2.151 respectively. These results suggest that kaolinite could potentially be used in remediation of metal wastewaters containing hydrophobic extractants. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, 2014
- Full Text:
- Date Issued: 2014-04-11
“Pragmatic yet principled”: an assessment of Botswana’s foreign policy record as a small state
- Authors: Mahupela, Kabelo Moganegi
- Date: 2014-04-11
- Subjects: Constructivism (Philosophy) , Botswana Foreign relations , States, Small Economic conditions , States, Small Politics and government , Africa Politics and government , Africa Foreign relations
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480278 , vital:78425
- Description: International Relations (IR) theory has traditionally downplayed the capabilities of small states, focusing rather on how the behaviour of large powers dictates interactions of actors within an anarchic arena. This has been very much the case for the realist/neorealist and to a very large extent neoliberal canons of IR, which privilege the structure of the international environment ahead of the agency of actors. As such, the foreign policy analysis of smaller powers in IR – and especially that of African countries – has been marginalised to the periphery. In response to these oversights, constructivism has posited a set of theories in which state identities and interests are determined by an inter-subjective interactive process that gives meaning to the material world. These set of theories also point out that norms can constrain and indeed energise state behaviour in a socially constructed world. This has thus opened up a space within which small state foreign policy behaviour can be analysed – whether it is through conference diplomacy, negotiation skills or idiosyncratic behaviour predicated upon elite ideas and identities. This thesis draws upon the above framework to assess a number of foreign policy choices embarked upon by Botswana in which she has leveraged herself vis-à-vis more powerful actors. The study looks at how Botswana managed to break out of its hostage station within Southern Africa during apartheid, at a time when Gaborone was surrounded by unfavourable white minority rule (in South Africa, Rhodesia, Angola and Mozambique). The study also evaluates Botswana‟s leveraging of her favourable image perception amongst powerful actors, as well as her negotiation proficiency in managing to punch above her weight and obtain favourable outcomes – thereby mitigating the desperate economic conditions she had inherited from colonialism. In a time where much of Southern Africa (and indeed the continent as a whole) disregard and actively disrupt normative imperatives related to democracy, human rights and the rule of law, the thesis also assesses Botswana‟s principled foreign policy posture. Through these chapters, it will be demonstrated that Botswana is an example of a state that has managed to use a careful combination of pragmatism and principle to show that African small states can indeed exercise agency. , Thesis (MA) -- Faculty of Humanities, Political and International Studies, 2014
- Full Text:
- Date Issued: 2014-04-11
- Authors: Mahupela, Kabelo Moganegi
- Date: 2014-04-11
- Subjects: Constructivism (Philosophy) , Botswana Foreign relations , States, Small Economic conditions , States, Small Politics and government , Africa Politics and government , Africa Foreign relations
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480278 , vital:78425
- Description: International Relations (IR) theory has traditionally downplayed the capabilities of small states, focusing rather on how the behaviour of large powers dictates interactions of actors within an anarchic arena. This has been very much the case for the realist/neorealist and to a very large extent neoliberal canons of IR, which privilege the structure of the international environment ahead of the agency of actors. As such, the foreign policy analysis of smaller powers in IR – and especially that of African countries – has been marginalised to the periphery. In response to these oversights, constructivism has posited a set of theories in which state identities and interests are determined by an inter-subjective interactive process that gives meaning to the material world. These set of theories also point out that norms can constrain and indeed energise state behaviour in a socially constructed world. This has thus opened up a space within which small state foreign policy behaviour can be analysed – whether it is through conference diplomacy, negotiation skills or idiosyncratic behaviour predicated upon elite ideas and identities. This thesis draws upon the above framework to assess a number of foreign policy choices embarked upon by Botswana in which she has leveraged herself vis-à-vis more powerful actors. The study looks at how Botswana managed to break out of its hostage station within Southern Africa during apartheid, at a time when Gaborone was surrounded by unfavourable white minority rule (in South Africa, Rhodesia, Angola and Mozambique). The study also evaluates Botswana‟s leveraging of her favourable image perception amongst powerful actors, as well as her negotiation proficiency in managing to punch above her weight and obtain favourable outcomes – thereby mitigating the desperate economic conditions she had inherited from colonialism. In a time where much of Southern Africa (and indeed the continent as a whole) disregard and actively disrupt normative imperatives related to democracy, human rights and the rule of law, the thesis also assesses Botswana‟s principled foreign policy posture. Through these chapters, it will be demonstrated that Botswana is an example of a state that has managed to use a careful combination of pragmatism and principle to show that African small states can indeed exercise agency. , Thesis (MA) -- Faculty of Humanities, Political and International Studies, 2014
- Full Text:
- Date Issued: 2014-04-11
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