Development of a protocol for extracting and quantifying the concentration of thiafentanil in blesbok (Damaliscus pygargus phillipsi) matrices 72-74 hours post administration
- Authors: Webber, Judith Tracy
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/164738 , vital:41159
- Description: Thesis (MSc)--Rhodes University, Faculty of Science, Chemistry, 2020
- Full Text:
- Authors: Webber, Judith Tracy
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/164738 , vital:41159
- Description: Thesis (MSc)--Rhodes University, Faculty of Science, Chemistry, 2020
- Full Text:
Formulation and evaluation of liposomal films for buccal delivery of antiretroviral drug
- Authors: Okafor, Nnamdi Ikemefuna
- Date: 2020
- Subjects: Liposomes , Highly active antiretroviral therapy , Antiretroviral agents , HIV infections -- Prevention
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117161 , vital:34485
- Description: The human immune deficiency virus (HIV) infection has been ranked as one of the most devastating microbial infections in the world. This status is a result of the HIV rapid genetic variation, which limits discovery of a vaccine. Use application of antiretroviral therapy (ARVT) in treatment of the disease caused by the HIV infection (known as acquired immunodeficiency syndrome, HIV-AIDS) is frequently compromised by several factors such as the low bioavailability and severe adverse effects associated with the existing antiretroviral drugs (ARVDs). This underlines the need for controlling the pharmacokinetics profiles of ARVD using effective vehicles that can modify drug biodistribution. The same is true for many other conditions, where delivery systems can determine the success or failure of treatment by controlling pharmacokinetic and dynamic properties. The mucosal linings of the oral cavities in addition offer adorable route of administration for systematic drug delivery, improving drug therapeutic performance and often preferred by clinicians and patients. Liposomes are tiny spherical sacs of phospholipid molecules enclosing water droplets, formed (artificially) to carry drugs or other substances into the tissues by crossing and targeting to specific organelles. This work therefore focused on preparation of liposomes and liposomal buccal films (BFs) for potential buccal delivery of efavirenz, an ARVD model endowed with poor solubility and several side effects. The liposomes were prepared by thin film hydration method using crude soybean lecithin (CL) and cholesterol. Efavirenz loaded liposomes were evaluated for particle size, Zeta potential (ZP), morphology, encapsulation efficiency (EE%) and release kinetics studies. The physiochemical properties of the liposomes were also evaluated using Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), energy dispersity spectroscopy (EDS), and Fourier transform infrared (FTIR), while the formulation with the best encapsulation efficiency was used as the solvent medium for the buccal film formation. The buccal films were prepared using solvent casting method, where the liposomal suspension was used as the dispersing medium. The films were optimized for physical properties (thickness, weight variation and folding endurance) using digital Vernier calliper and digital weighing balance. The physiochemical properties of the selected BFs films made of Carbopol (CP) and its combination with Pluronic F127 (PF127) were further characterized using XRD, DSC, FTIR, Transmission Electron Microscopy (TEM), EDS and Scanning Electron Microscopy (SEM). The permeation study of the selected BFs was investigated using Franz diffusion cell. The BFs composed of CP alone or its combination with PF127 demonstrated much better bio-adhesive properties than the films made of other polymers (like Hydroxyl propyl methyl cellulose, HPMC) alone or in combination with PF127. The developed liposome formulation showed high encapsulation 98.8 ± 0.01 % in CL to cholesterol mass ratio of 1:1 and total lipid to drug mass ratio of 2:1. The average particle size 104.82 ± 2.29 nm and Zeta potential -50.33 ± 0.95 mV of these liposomes were found to be attractive for targeted delivery to the HIV infected cells. The CP based BFs (without and with PF127) exhibited good film thickness 0.88 ± 0.10 and 0.76 ± 0.14 mm, with weight uniformity 68.22 ± 1.04 and 86.28 ± 2. 16 mg, satisfactory flexibility values 258 and 321, and slightly acidic pH 6.43 ± 0.76 and 6.32 ± 0.01. The swelling percentage was found to be 50 % for CP film alone and 78 % for CP film with PF127. The cumulative amount of drug that permeated through the buccal epithelium over 24 hours was about 66 % from CP film alone and 75 % from CP film with PF127. Since no evidence of the liposomal encapsulation of EFV have been reported to our knowledge, we find the insights from the present study valuable as a set of preliminary data to encourage further investigations of the encapsulation and delivery of EFV like antiretrovirals for enhanced solubility, site targeting and prolonged release using crude soybean lecithin and mucoadhesive polymers, which holds some added economical values as naturally occurring lipid and polymeric mixtures as a promising delivery systems for buccal delivery of ARVDs.
- Full Text:
- Authors: Okafor, Nnamdi Ikemefuna
- Date: 2020
- Subjects: Liposomes , Highly active antiretroviral therapy , Antiretroviral agents , HIV infections -- Prevention
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117161 , vital:34485
- Description: The human immune deficiency virus (HIV) infection has been ranked as one of the most devastating microbial infections in the world. This status is a result of the HIV rapid genetic variation, which limits discovery of a vaccine. Use application of antiretroviral therapy (ARVT) in treatment of the disease caused by the HIV infection (known as acquired immunodeficiency syndrome, HIV-AIDS) is frequently compromised by several factors such as the low bioavailability and severe adverse effects associated with the existing antiretroviral drugs (ARVDs). This underlines the need for controlling the pharmacokinetics profiles of ARVD using effective vehicles that can modify drug biodistribution. The same is true for many other conditions, where delivery systems can determine the success or failure of treatment by controlling pharmacokinetic and dynamic properties. The mucosal linings of the oral cavities in addition offer adorable route of administration for systematic drug delivery, improving drug therapeutic performance and often preferred by clinicians and patients. Liposomes are tiny spherical sacs of phospholipid molecules enclosing water droplets, formed (artificially) to carry drugs or other substances into the tissues by crossing and targeting to specific organelles. This work therefore focused on preparation of liposomes and liposomal buccal films (BFs) for potential buccal delivery of efavirenz, an ARVD model endowed with poor solubility and several side effects. The liposomes were prepared by thin film hydration method using crude soybean lecithin (CL) and cholesterol. Efavirenz loaded liposomes were evaluated for particle size, Zeta potential (ZP), morphology, encapsulation efficiency (EE%) and release kinetics studies. The physiochemical properties of the liposomes were also evaluated using Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), energy dispersity spectroscopy (EDS), and Fourier transform infrared (FTIR), while the formulation with the best encapsulation efficiency was used as the solvent medium for the buccal film formation. The buccal films were prepared using solvent casting method, where the liposomal suspension was used as the dispersing medium. The films were optimized for physical properties (thickness, weight variation and folding endurance) using digital Vernier calliper and digital weighing balance. The physiochemical properties of the selected BFs films made of Carbopol (CP) and its combination with Pluronic F127 (PF127) were further characterized using XRD, DSC, FTIR, Transmission Electron Microscopy (TEM), EDS and Scanning Electron Microscopy (SEM). The permeation study of the selected BFs was investigated using Franz diffusion cell. The BFs composed of CP alone or its combination with PF127 demonstrated much better bio-adhesive properties than the films made of other polymers (like Hydroxyl propyl methyl cellulose, HPMC) alone or in combination with PF127. The developed liposome formulation showed high encapsulation 98.8 ± 0.01 % in CL to cholesterol mass ratio of 1:1 and total lipid to drug mass ratio of 2:1. The average particle size 104.82 ± 2.29 nm and Zeta potential -50.33 ± 0.95 mV of these liposomes were found to be attractive for targeted delivery to the HIV infected cells. The CP based BFs (without and with PF127) exhibited good film thickness 0.88 ± 0.10 and 0.76 ± 0.14 mm, with weight uniformity 68.22 ± 1.04 and 86.28 ± 2. 16 mg, satisfactory flexibility values 258 and 321, and slightly acidic pH 6.43 ± 0.76 and 6.32 ± 0.01. The swelling percentage was found to be 50 % for CP film alone and 78 % for CP film with PF127. The cumulative amount of drug that permeated through the buccal epithelium over 24 hours was about 66 % from CP film alone and 75 % from CP film with PF127. Since no evidence of the liposomal encapsulation of EFV have been reported to our knowledge, we find the insights from the present study valuable as a set of preliminary data to encourage further investigations of the encapsulation and delivery of EFV like antiretrovirals for enhanced solubility, site targeting and prolonged release using crude soybean lecithin and mucoadhesive polymers, which holds some added economical values as naturally occurring lipid and polymeric mixtures as a promising delivery systems for buccal delivery of ARVDs.
- Full Text:
Investigating cannabinoids and endocannabinoid receptors as drug targets for pain and inflammation
- Authors: Marwarwa, Sinobomi Zamachi
- Date: 2020
- Subjects: Cannabinoids , Cannabinoids Receptors , Inflammation Alternative treatment , Pain Alternative treatment , Drug targeting
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/164468 , vital:41121
- Description: Cannabinoids and the endocannabinoid system have been studied in the past decades but have yet to be fully understood. An insight into interactions that occur between cannabinoid compounds and their receptors is important for understanding the cannabinoids and the endocannabinoid system. Cannabinoids are natural products found in some cannabis plants, and they have similar effects to endocannabinoids, which are chemicals in the body that are involved many aspects of health from appetite, memory, and movement to pain, inflammation and response to cancer. Cannabinoids have a high impact on the treatment of pain and inflammation, they show different antinociceptive mechanisms to existing drugs like opioids, also, they have antimigraine properties better than those achieved by aspirin. The CB1 and CB2 human receptors have been the most studied cannabinoid receptors. In this project, we used a combination of mass-spectrometry to generate plausible chemical fragments and computational techniques to assess the binding of these fragments to these two main CB receptors. CB1 was adapted from the protein data bank (PBD), file 5U09 and the CB2 model was predicted using the hierarchical protocol I-TASSER, starting from the amino acid sequence in UniProt (P34972 CNR2_HUMAN). The proposed active site for CB1 was reported in a publication accompanying the 5U09 PDB model, which was originally generated with a pre-existing ligand in the active site. However, CB2 had to be built from a homology model and the active site determined using a combination of I-TASSER, Maestro, and CASTp the more favourable binding energies were determined by CASTp, leading to the use of the CASTp coordinates as default for docking in the CB2 human receptor. The molecular docking of cannabinoids THC, CBD, CBDV, CBG and CBN on both the CB1 and CB2 proteins was performed to identify the amino acids that interact with these compounds at their active sites. This would provide a guide to a future fragment-based drug discovery (FBDD) synthesis project. The docking in this work showed adequate accuracy with binding energies between -8.23 kcal/mol and -9.97 kcal/mol for CB1 and between -6.78 kcal/mol and -7.74 kcal/mol for CB2. An observation made was that binding energies of the CB1 human receptor docking were higher than those of the CB2 human receptor, which could support the widely held belief that CB1 is more important in cannabinoid interactions. The cannabinoids were then subjected to collision-induced dissociation to produce fragment structures predicted in chapter 2. These hypothetical fragments were docked in the CB1 and CB2 human receptor, the general trend again being the binding energies for the CB1 receptor was again around 10% higher than those of the CB2 receptor. As expected, larger fragments tended to have better binding, with the fragment proposed from m/z 259 with binding energies -9.62 kcal/mol in CB1 and -6.26 kcal/mol. Those fragments with significant lipophilic side chains or some aromatic moiety also showed good binding or around -6.00 kcal/mol, similar to the intact cannabinoids. In our case, this fragment was proposed from m/z 223 with binding energies -7.71 kcal/mol in CB1 and -6.5 kcal/mol in CB2. The results from the fragment dockings were favourable in that they have binding affinities lower than -6.0 kcal/mol which is good enough for the structures to be leads in the creation of fragment libraries. The docking was performed with Autodock 1.5.6 and data visualization with a discovery studio. , Thesis (MSc) -- Faculty of Science, Chemistry, 2020
- Full Text:
- Authors: Marwarwa, Sinobomi Zamachi
- Date: 2020
- Subjects: Cannabinoids , Cannabinoids Receptors , Inflammation Alternative treatment , Pain Alternative treatment , Drug targeting
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/164468 , vital:41121
- Description: Cannabinoids and the endocannabinoid system have been studied in the past decades but have yet to be fully understood. An insight into interactions that occur between cannabinoid compounds and their receptors is important for understanding the cannabinoids and the endocannabinoid system. Cannabinoids are natural products found in some cannabis plants, and they have similar effects to endocannabinoids, which are chemicals in the body that are involved many aspects of health from appetite, memory, and movement to pain, inflammation and response to cancer. Cannabinoids have a high impact on the treatment of pain and inflammation, they show different antinociceptive mechanisms to existing drugs like opioids, also, they have antimigraine properties better than those achieved by aspirin. The CB1 and CB2 human receptors have been the most studied cannabinoid receptors. In this project, we used a combination of mass-spectrometry to generate plausible chemical fragments and computational techniques to assess the binding of these fragments to these two main CB receptors. CB1 was adapted from the protein data bank (PBD), file 5U09 and the CB2 model was predicted using the hierarchical protocol I-TASSER, starting from the amino acid sequence in UniProt (P34972 CNR2_HUMAN). The proposed active site for CB1 was reported in a publication accompanying the 5U09 PDB model, which was originally generated with a pre-existing ligand in the active site. However, CB2 had to be built from a homology model and the active site determined using a combination of I-TASSER, Maestro, and CASTp the more favourable binding energies were determined by CASTp, leading to the use of the CASTp coordinates as default for docking in the CB2 human receptor. The molecular docking of cannabinoids THC, CBD, CBDV, CBG and CBN on both the CB1 and CB2 proteins was performed to identify the amino acids that interact with these compounds at their active sites. This would provide a guide to a future fragment-based drug discovery (FBDD) synthesis project. The docking in this work showed adequate accuracy with binding energies between -8.23 kcal/mol and -9.97 kcal/mol for CB1 and between -6.78 kcal/mol and -7.74 kcal/mol for CB2. An observation made was that binding energies of the CB1 human receptor docking were higher than those of the CB2 human receptor, which could support the widely held belief that CB1 is more important in cannabinoid interactions. The cannabinoids were then subjected to collision-induced dissociation to produce fragment structures predicted in chapter 2. These hypothetical fragments were docked in the CB1 and CB2 human receptor, the general trend again being the binding energies for the CB1 receptor was again around 10% higher than those of the CB2 receptor. As expected, larger fragments tended to have better binding, with the fragment proposed from m/z 259 with binding energies -9.62 kcal/mol in CB1 and -6.26 kcal/mol. Those fragments with significant lipophilic side chains or some aromatic moiety also showed good binding or around -6.00 kcal/mol, similar to the intact cannabinoids. In our case, this fragment was proposed from m/z 223 with binding energies -7.71 kcal/mol in CB1 and -6.5 kcal/mol in CB2. The results from the fragment dockings were favourable in that they have binding affinities lower than -6.0 kcal/mol which is good enough for the structures to be leads in the creation of fragment libraries. The docking was performed with Autodock 1.5.6 and data visualization with a discovery studio. , Thesis (MSc) -- Faculty of Science, Chemistry, 2020
- Full Text:
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