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Lipid nanocarriers : a novel approach to delivering ophthalmic clarithromycin

- Makoni, Pedzisai Anotida

  • Authors: Makoni, Pedzisai Anotida
  • Date: 2021
  • Subjects: Clarithromycin , Nanomedicine , Nanostructures , Antibiotics , Eye -- Diseases -- Treatment , Ocular pharmacology , Ophthalmic drugs , Karatitis -- Chemotherapy
  • Language: English
  • Type: text , Thesis , Doctoral , PhD
  • Identifier: http://hdl.handle.net/10962/171678 , vital:42109 , 10.21504/10962/171678
  • Description: The feasibility of incorporating clarithromycin (CLA) into innovative solid lipid nanoparticles (SLN) and nanostructured lipi d carriers (NLC) using hot emulsification ultrasonication (HEUS) was investigated. This approach was investigated in an attempt to address the shortcomings associated with the use of lyophilized parenteral formulations administered via the ocular route suc h as toxic reactions, intolerance and patient discomfort due to frequent insti llation of topical solutions of CLA. In particular, sustained release approaches to delivery may enhance precorneal retention, increase ocular availability and permit dose reduction or use of a longer dosing frequency when treating ocular non - tuberculous m ycobacterial (NTM) keratitis infections. This approach may potentially improve the delivery of CLA to the eye, thereby addressing some or all of the unmet clinical needs described vide infra . Prior to initiating pre - formulation, formulation development a nd optimization studies of CLA - loaded SLN and/or NLC, Design of Experiments (DoE), specifically a Central Composite Design (CCD) was used in conjunction with Response Surface Methodology (RSM) to develop and optimize a suitable method for the quantitative determination of CLA in pharmaceutical formulations and for monitoring CLA release from SLN and/or NLC in vitro . A simple, accurate, precise, sensitive and stability - indicating reversed phase - high performance liquid chromatography (RP - HPLC) method with ele ctrochemical (EC) detection was developed, validated and optimized for the in vitro analysis of CLA loaded SLN and/or NLC formulations. Pre - formulation studies were undertaken to investigate the thermal stability of CLA and bulk lipids to facilitate the s election of lipid excipients for the manufacture of nanocarriers in addition to establishing compatibility of CLA with the excipients. It was established that CLA was thermostable up to a temperature of approximately 300 °C thereby indicating that HEUS cou ld be used for the manufacture of CLA - loaded SLN and/or NLC. Lipid screening revealed that CLA i s, in general, poorly soluble in solid and liquid lipids however a combination of stearic acid (SA) and Transcutol ® HP (THP) exhibited the best dissolution pote ntial for CLA of all lipids tested . Stearic acid appears to exist as polymorphic form B prior to exposure to heat however occurs as the form C polymorph following heating at 85 °C for one hour. The best ratio for the mixture of SA and THP for the manufactu re of CLA - NLC ii was an 80:20 ( w/w ) ratio of SA: THP as the two lipids are miscible in this ratio and exhibited the greatest dissolution potential for CLA. Furthermore, an investigation of binary mixtures of CLA/SA and SA/Transcutol ® HP, in addition to eutect ic mixtures of CLA, SA and Transcutol ® HP, revealed no obvious interaction between CLA and the lipids selected for the production of the nanocarriers. Due to the relatively high solubility of CLA in THP in comparison to SA, NLC are likely to exhibit a hig her loading capacity (LC) and encapsulation efficiency (EE) for CLA than SLN. Consequently the feasibility of incorporating CLA (10% w/w ) into NLC was investigated and evaluation of the production of SLN was not undertaken as the production of these might not result in the manufacture of a delivery technology with a high EE and LC for CLA. Tween ® 20 was used as the surfactant as it is readily available, exhibits little or no cytotoxicity and is relatively cheap. Polyethylene glycol (PEG) was used as a coati ng polymer to impart muco - adhesive properties the formulated CLA - NLC. Response surface methodology (RSM) in conjunction with DoE, specifically a Box - Behnken Design (BBD) used as a screening design was used to identify a formulation composition which would produce a product that would meet the pre - defined target critical quality attributes (CQA) for the nanoparticles viz. particle size (PS) in the nano - range, polydispersity index (PDI) < 0.5, Zeta Potential (ZP) ≥ ± 30 mV, and EE > 80%. The formulation composition identified was subsequently used for the optimization of the manufacturing parameters viz. sonication time and amplitude, using a Central Composite Design (CCD) . The LC and EE, in vitro CLA release, cytotoxicity, osmolarity, pH, degree of crystallinity and lipid modification, elemental analysis and surface morphology of the optimized batch was investigated and mon itored to ensure that CLA - loaded NLC, of the desirable quality, had been produced. On the day of manufacture the mean PS and PDI of the optimized CLA - loaded NLC formulation adjusted to physiological osmolarity (250 – 450 mOsm/kg) was 461.9 ± 40.16 nm and 0. 523 ± 0.104, respectively. The ZP for the optimized NLC generated on the day of manufacture using HPLC grade water as the dispersion medium was - 20.5 ± 4.82 mV. The pH and osmolarity of the optimized CLA - loaded NLC formulation was 7.76 ± 0.01 and 316 ± iii 2 m Osm/Kg, respectively and the EE was 88.62 ± 0.23 %. The optimized NLC exhibited a decreased crystallinity in comparison to the bulk lipid materials. DSC, WAXS and FT - IR revealed that CLA was molecularly dispersed in the nanocarriers. The optimized CLA - load ed NLC exhibited muco - adhesive properties, when tested under stationary conditions using laser doppler anemometry (LDA). The optimized formulation also exhibited sustained release of CLA over 24 hours during in vitro release testing and CLA release was bes t described using the Baker - Lonsdale model . The cumulative % CLA released over 24 hours was 56.13 ± 0.23% and mass balance analysis revealed 41.38 ± 0.02% CLA had been retained in the NLC. In vitro cytotoxicity testing revealed that the optimized CLA - NLC w ere less cytotoxic to HeLa cells when compared to CLA alone and further confirmed that the lipids and excipients used in these studies were of GRAS status . Stability studies revealed that the EE reduced over 28 days by 14.42% and 5.14% when stored at 4 °C and 22 °C , respectively. In addition, the particle size increased from the nm to μm range for samples stored at 22 °C. The findings are a good starting point but require further optimization to ensure prolongation of stability. In addition , the technology requires additional developmental studies and a powder for reconstitution for use as a single - dose considered as single dose packaging may be a solution to the compromised formulation stability observed in these studies. The CLA - NLC produced in these stu dies exhibit sound product attributes which serve as a useful foundation for the novel delivery of antibiotics to the eye. The results suggest that the optimized NLC have the potential to enhance precorneal retention and increase ocular availability of CLA , which in turn may be useful to reduce the required dose and dosing frequency when administering CLA as a reconstituted solution to treat susceptible organisms that infect ocular tissues.
  • Full Text:
  • Date Issued: 2021

Synthesis of novel heterocyclic systems as potential inhibitors of HIV-1 enzymes

- Sekgota, Khethobole Cassius

  • Authors: Sekgota, Khethobole Cassius
  • Date: 2020
  • Subjects: Protease inhibitors , Heterocyclic compounds , HIV (Viruses) , Quinoline , Amides , Nuclear magnetic resonance , Antiretroviral agents , AIDS vaccines , Nitrobenzaldehyde , Propylphosphonic acid anhydride
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: http://hdl.handle.net/10962/146502 , vital:38531
  • Description: This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores.
  • Full Text:
  • Date Issued: 2020

The international community’s implementation of the Responsibility to Protect (R2P) Principle: a Comparative Study of Sudan and Libya

- Nizeimana, John Bosco

  • Authors: Nizeimana, John Bosco
  • Date: 2020
  • Subjects: Responsibility to protect (International law) , Humanitarian intervention -- Libya , Libya -- Foreign relations -- 1969- , Libya -- Politics and government -- 1969- , Humanitarian intervention -- Sudan , Sudan -- Foreign relations , Sudan -- Politics and government -- 1985-
  • Language: English
  • Type: text , Thesis , Doctoral , PhD
  • Identifier: http://hdl.handle.net/10962/162631 , vital:40962
  • Description: In the history of international relations, the adoption of the R2P principle in 2005 was widely understood to be a break-through in the international community’s efforts to respond to massive human rights violations and atrocities. Despite this, the international community’s implementation of the R2P has been widely contested, including in relation to its application in Sudan and Libya. There is agreement in the literature that, in both cases, the implementation of the R2P failed to achieve its intended purpose of protecting civilian populations. This thesis addresses the question of why the R2P failed in Sudan and Libya. Most explanations concerning the failure of the R2P in Sudan and Libya tend to focus on the politics of big power countries. The study argues that the failure to implement the R2P is related to the interactions between regional organisations and the international community (global organisations like UN) in attempting to solve large-scale human rights violent conflict. The study is firmly embedded in scholarly debates about humanitarian intervention so as to demonstrate the fact that this study is part of efforts to advance knowledge of scholarly debates on humanitarian intervention in this contemporary world order. The study combines a case study approach and qualitative research approach to achieve a nuanced understanding of the reason why the R2P failed in Sudan and Libya. The study relied on the use of documentary reviews and in-depth interviews of experts to collect data which was analysed using critical discourse analysis. The thesis demonstrated that the implementation of the R2P was characterised by a breakdown of the relationship between regional actors like the AU and global institutions like the UN. This breakdown contributed to the failure of the R2P in Sudan and Libya. The lack of financial and operational capacity for rapid deployment, the internal divisions with the AU, and the lack of political will within the AU members states were also cited as obstacles to the realisation of the R2P efforts in Sudan. To establish in-depth knowledge the study revealed other factors related to the politics of big power countries and how they played a part in the failure of the R2P in Sudan and Libya. Among these factors include implementation inconsistencies, the ICC factor, the absence of UNSC consensus in the response over Darfur and Libya, and the veto power factor and its implications in the efforts of the international community in both cases. This study also showed that the implementation of the R2P may not work effectively if left only to international actors to implement. Regional and sub-regional actors are important stakeholders of the R2P, and their interactions with the international community in actualising the implmementation of the R2P on the ground are essential. The manner in which the R2P was applied in Sudan and Libya is an indication its implementation requires improved interaction between regional actors and the international community at all level of collaboration including at global, regional and sub-regional level. This can build a strong foundation to drive the effective implementation of the R2P in future interventions. The findings of this thesis will significantly improve the available literature on the reason why the R2P failed in Sudan and Libya, particularly by paying much attention to the role of regional and sub-regional actors.
  • Full Text:
  • Date Issued: 2020

If you strike a woman: an analysis of how women are represented in political cartoons of South Africa’s Women’s Day, 2009-2017

- Levin, Bianca

  • Authors: Levin, Bianca
  • Date: 2019
  • Subjects: Caricatures and cartoons -- South Africa , Women in mass media -- South Africa , Political cartoons -- South Africa
  • Language: English
  • Type: text , Thesis , Masters , MA
  • Identifier: http://hdl.handle.net/10962/92661 , vital:30731
  • Description: On 7 August 2017, two days prior to South Africa’s National Women’s Day, video footage of a representative of the State, Mduduzi Manana, beating up a woman went viral. This marred the Women’s Day celebrations of that year, as it became clear to the public that the he was not going to be punished. As important political commentators, cartoonists used Manana’s actions as an opportunity to depict the violence women face, even in a month dedicated to women. In these cartoons, Manana became the face of a patriarchal system, one which has deeply affected the quality of life for women who, to date, cannot claim their Constitutional rights. This thesis is interested in the mini-narratives of such cartoons, ones which offer a view on the status of South African women. Through this qualitative study, a textual analysis in the spirit of Critical Discourse Analysis of seven selected cartoons leads to a discussion of what their representations of women means for gender justice. What this research shows is that the representations that cartoons offer of the position of women in South Africa are complex. These cartoons articulate that South Africa has a long way to go to reach equality and gender justice. In order for gender justice to be realised, the representation of women needs to evolve into one which recognises women’s plight but does not relegate them to the state of victimhood.
  • Full Text:
  • Date Issued: 2019

A critical evaluation of local level responses to mine closure in the Northwestern KwaZulu-Natal coal belt region, South Africa

- Buthelezi, Mbekezeli Simphiwe

  • Authors: Buthelezi, Mbekezeli Simphiwe
  • Date: 2004
  • Subjects: Reconstruction and Development Programme (South Africa) , Deindustrialization -- Economic aspects--South Africa -- KwaZulu-Natal , Coal mines and mining -- South Africa -- KwaZulu-Natal , Economic development -- South Africa -- KwaZulu-Natal , Community development -- South Africa -- KwaZulu-Natal , Rural industries -- South Africa -- KwaZulu-Natal , Rural development -- South Africa , Local government -- South Africa -- KwaZulu-Natal , Labor supply -- South Africa -- KwaZulu-Natal , Rural development projects -- South Africa -- KwaZulu-Natal -- Citizen participation , KwaZulu-Natal (South Africa) -- Social conditions , KwaZulu-Natal (South Africa) -- Economic conditions , KwaZulu-Natal (South Africa) -- Economic policy , South Africa -- Economic policy
  • Language: English
  • Type: Thesis , Masters , MA
  • Identifier: vital:4822 , http://hdl.handle.net/10962/d1005497 , Reconstruction and Development Programme (South Africa) , Deindustrialization -- Economic aspects--South Africa -- KwaZulu-Natal , Coal mines and mining -- South Africa -- KwaZulu-Natal , Economic development -- South Africa -- KwaZulu-Natal , Community development -- South Africa -- KwaZulu-Natal , Rural industries -- South Africa -- KwaZulu-Natal , Rural development -- South Africa , Local government -- South Africa -- KwaZulu-Natal , Labor supply -- South Africa -- KwaZulu-Natal , Rural development projects -- South Africa -- KwaZulu-Natal -- Citizen participation , KwaZulu-Natal (South Africa) -- Social conditions , KwaZulu-Natal (South Africa) -- Economic conditions , KwaZulu-Natal (South Africa) -- Economic policy , South Africa -- Economic policy
  • Description: The de-industrialisation process that was a common feature of North America and Western Europe in the 1970s, through into the 1980s has become an observable feature in African countries and South Africa in particular in the last two decades. Globally, hard hit areas include those associated with the early Industrial Revolution characterised by mass production and the agglomeration of iron and steel, coal and textile industries. General changes in the global market, especially the falling demand for extractive heavy minerals like coal and gold have also affected many countries region and localities. In the case of South Mrica, the previous high economic dependence on mined minerals like coal and gold has resulted in many once prosperous mining regions of the country being reduced to a shadow of their former selves. The worst affected areas in South Africa are those of the Klerksdorp Goldfields in the North West Province and Free State Goldfields, with the latter alone losing 100,000 jobs during the 1990s. This trend has also been acute in the coal-mining industry of the KwaZulu-Natal province since the late 1970s. The firms that had grown in the shadow of the major mining company supplyipg machinery, or who processed the semi-manufactured product are also severely affected by the closing down and restructuring in the mining and iron industries. These industries have often been forced to close down because of a break in the vital connections they developed with these mining industries. Such localised economic crisis has encouraged the universal trend towards the devolution of developmental responsibilities to the local governments and other local stakeholders to - empower them to respond to these changes. This study investigated the local economic initiatives which have been undertaken in the three municipalities of north-western KwaZulu Natal i.e. Utrecht, Dundee and Dannhauser to respond to the closures which have taken place in the mining industry of this region, which used to be among the most prosperous coal mining regions of South Africa. Using their new developmental mandate the local governments, in partnership with the communities and other external interveners have tried to respond to these localised economic crisis and also indirectly to the general poverty and underdevelopment, which characterises this region of KwaZulu-Natal. The effects of apartheid policies, and previous discriminatory rural development policies in, particular, and the Regional Industrial Development policy, which was intensively applied in the 1980s by the pre-1994 government regime, have further compounded the magnitude of the challenge. The lack of capacity in some municipalities has constrained successful implementation of Local Economic Development has led to some communities acting alone to face their situation with or without external intervention.
  • Full Text:
  • Date Issued: 2004

Poetic situation in the poetry of John Crowe Ransom

- Driver, Dorothy

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