A self-emulsifying delivery system loaded with efavirenz: The case for flax-seed oil
- Authors: Mazonde, Priveledge
- Date: 2021-10-29
- Subjects: Drug delivery systems , Linseed oil , Antiretroviral agents , HIV (Viruses) , Drug carriers (Pharmacy) , Solubility , High performance liquid chromatography , Efavirenz
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/192944 , vital:45283
- Description: The feasibility of incorporating efavirenz (EFV), an antiretroviral agent against HIV into a lipid-based self-emulsifying drug delivery system (SEDDS) containing vegetable oils was investigated. EFV has poor aqueous solubility and is classified under the Biopharmaceutical Classification System (BCS) as a class II compound with highly permeability, its aqueous solubility is less than 10 mg/ml and is defined as a practically insoluble compound with a consequent poor bioavailability of approximately 40%, and erratic dissolution behaviour. SEDDS formulations have been shown to improve the aqueous solubility and consequently the bioavailability of BCS II compounds such as EFV. EFV is a first line antiviral agent used in combination with other agents in antiretroviral therapy (ART). Among the number of NNRTIs approved for use in HIV treatment, EFV is one of the most commonly prescribed drug. Statistical methods and Design of Experiments (DoE) using Response Surface Methodology (RSM), specifically a Central Composite Design (CCD), were used to facilitate the development of a reversed-phase high performance liquid chromatographic (HPLC) method for the quantitation of EFV during formulation product and process development studies. A rapid, accurate, precise and sensitive HPLC method with ultraviolet (UV) detection was developed, optimised and validated for the in-vitro analysis of EFV in a total run time under 10 minutes for the elution of both EFV and loratidine which was used as the internal standard (IS). The method was then successfully applied to the determination of EFV in commercially available tablets. Excipient screening was undertaken using solubility studies and revealed that EFV had highest solubility in flaxseed oil in comparison to soybean, macadamia, grapeseed, sunflower and olive oils. The non-ionic Tween® 80 and Span® 20 were selected as surfactant and co-surfactant, respectively with ethanol co-solvent as they exhibited improved miscibility with co-solvent. Pre-formulation studies were undertaken to investigate the compatibility of the API with excipients and to identify a nano-emulsion region and other emulsion types using pseudoternary phase diagrams. The phase behaviour of crude cold pressed flaxseed oil with the selected non-ionic surfactants revealed an area within pseudo-ternary phase diagrams for different surfactant-mixtures formed gels/semisolid structures which can be exploited for other drug delivery strategies that require such properties. Fourier transform infrared spectroscopy (FT-IR), powder x-ray diffraction (XRD) and Raman spectroscopy were used to identify and assess the compatibility of EFV with chosen excipients. 2 A reduction in the peak intensity was observed for EFV when combined with each hydrophobic/lipid excipient evaluated revealing that there was a marked reduction in the crystallinity of the EFV. A decrease in crystallinity in comparison with the bulk API may indicate that EFV were amorphous or sequestered in a molecular dispersion and exhibited an increased solubility for the molecule. Flaxseed oil was used as the oil phase in studies for the optimization of surfactant mixtures undertaken using DoE, specifically a D-optimal mixtures design with the flaxseed oil content set at 10% m/m was performed. Solutions from the desired optimization function were produced based on desirability and five nanoemulsion formulations were produced and characterized in terms of in vitro release of efavirenz, drug loading capacity, Zeta Potential, droplet sizes and polydispersity index (PDI). Kinetically stable nanoemulsions containing 10% m/m flaxseed oil were successfully manufactured and assessed. Droplet sizes ranged between 156 and 225 nm, Zeta Potential between −24 and −41 mV and all formulations were found to be monodisperse with polydispersity indices ≤ 0.487. SEDDS formulations of EFV in nano-sized carriers were developed and optimised, in vitro drug release varied with varying amounts of ethanol in the formulation producing formulations that exhibited differently modulated drug in-vitro release profiles that may be further manipulated for better performance and therapeutic outcomes in terms of solubility and possibly bioavailability of EFV when delivered using SEDDS rather than using tablets which in turn may lead to better therapeutic outcomes for patients with HIV. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2021
- Full Text:
- Date Issued: 2021-10-29
- Authors: Mazonde, Priveledge
- Date: 2021-10-29
- Subjects: Drug delivery systems , Linseed oil , Antiretroviral agents , HIV (Viruses) , Drug carriers (Pharmacy) , Solubility , High performance liquid chromatography , Efavirenz
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/192944 , vital:45283
- Description: The feasibility of incorporating efavirenz (EFV), an antiretroviral agent against HIV into a lipid-based self-emulsifying drug delivery system (SEDDS) containing vegetable oils was investigated. EFV has poor aqueous solubility and is classified under the Biopharmaceutical Classification System (BCS) as a class II compound with highly permeability, its aqueous solubility is less than 10 mg/ml and is defined as a practically insoluble compound with a consequent poor bioavailability of approximately 40%, and erratic dissolution behaviour. SEDDS formulations have been shown to improve the aqueous solubility and consequently the bioavailability of BCS II compounds such as EFV. EFV is a first line antiviral agent used in combination with other agents in antiretroviral therapy (ART). Among the number of NNRTIs approved for use in HIV treatment, EFV is one of the most commonly prescribed drug. Statistical methods and Design of Experiments (DoE) using Response Surface Methodology (RSM), specifically a Central Composite Design (CCD), were used to facilitate the development of a reversed-phase high performance liquid chromatographic (HPLC) method for the quantitation of EFV during formulation product and process development studies. A rapid, accurate, precise and sensitive HPLC method with ultraviolet (UV) detection was developed, optimised and validated for the in-vitro analysis of EFV in a total run time under 10 minutes for the elution of both EFV and loratidine which was used as the internal standard (IS). The method was then successfully applied to the determination of EFV in commercially available tablets. Excipient screening was undertaken using solubility studies and revealed that EFV had highest solubility in flaxseed oil in comparison to soybean, macadamia, grapeseed, sunflower and olive oils. The non-ionic Tween® 80 and Span® 20 were selected as surfactant and co-surfactant, respectively with ethanol co-solvent as they exhibited improved miscibility with co-solvent. Pre-formulation studies were undertaken to investigate the compatibility of the API with excipients and to identify a nano-emulsion region and other emulsion types using pseudoternary phase diagrams. The phase behaviour of crude cold pressed flaxseed oil with the selected non-ionic surfactants revealed an area within pseudo-ternary phase diagrams for different surfactant-mixtures formed gels/semisolid structures which can be exploited for other drug delivery strategies that require such properties. Fourier transform infrared spectroscopy (FT-IR), powder x-ray diffraction (XRD) and Raman spectroscopy were used to identify and assess the compatibility of EFV with chosen excipients. 2 A reduction in the peak intensity was observed for EFV when combined with each hydrophobic/lipid excipient evaluated revealing that there was a marked reduction in the crystallinity of the EFV. A decrease in crystallinity in comparison with the bulk API may indicate that EFV were amorphous or sequestered in a molecular dispersion and exhibited an increased solubility for the molecule. Flaxseed oil was used as the oil phase in studies for the optimization of surfactant mixtures undertaken using DoE, specifically a D-optimal mixtures design with the flaxseed oil content set at 10% m/m was performed. Solutions from the desired optimization function were produced based on desirability and five nanoemulsion formulations were produced and characterized in terms of in vitro release of efavirenz, drug loading capacity, Zeta Potential, droplet sizes and polydispersity index (PDI). Kinetically stable nanoemulsions containing 10% m/m flaxseed oil were successfully manufactured and assessed. Droplet sizes ranged between 156 and 225 nm, Zeta Potential between −24 and −41 mV and all formulations were found to be monodisperse with polydispersity indices ≤ 0.487. SEDDS formulations of EFV in nano-sized carriers were developed and optimised, in vitro drug release varied with varying amounts of ethanol in the formulation producing formulations that exhibited differently modulated drug in-vitro release profiles that may be further manipulated for better performance and therapeutic outcomes in terms of solubility and possibly bioavailability of EFV when delivered using SEDDS rather than using tablets which in turn may lead to better therapeutic outcomes for patients with HIV. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2021
- Full Text:
- Date Issued: 2021-10-29
Development and assessment of gastric-retentive sustained release metronidazole microcapsules
- Authors: Makan, Anjana
- Date: 2017
- Subjects: Metronidazole , Drug delivery systems , Helicobacter pylori , High performance liquid chromatography , Gas chromatography , Drugs , Drugs Controlled release
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59240 , vital:27491
- Description: Helicobacter pylori is one of the most common pathogenic bacterial infections and is the leading cause of gastritis, gastroduodenal ulcer disease and gastric cancers. Studies have revealed the prevalence of Helicobacter pylori is high in many countries around the globe. Although Helicobacter pylori is highly sensitive to antimicrobial agents in vitro the clinical eradication rate of the disease is still low. The instability of API at gastric pH, low concentration of API in the gastric mucosa and short gastric residence times are the main reasons for poor eradication rates. The high prevalence rate of this disease necessitates the design and development of gastric-retentive site specific oral dosage forms for the optimized delivery of existing therapeutic molecules and may be an approach to improving the eradication rate of Helicobacter pylori. Metronidazole (MTZ) is a 5-nitroimidazole derivative that exhibits antibiotic and antiprotozoal activity. MTZ is used in combination with other compounds for the treatment of Helicobacter pylori in peptic ulcer disease. MTZ is a potential candidate for inclusion in a sustained release gastric-retentive delivery system that acts in the stomach and since it is unstable in the intestinal/colonic environment enhancing gastric residence time would be a therapeutic advantage. MTZ is a cost-effective therapy that exhibits good anti-microbial activity and has a favourable pharmacokinetic profile. A sustained release gastric-retentive formulation is therefore proposed as an approach to enhance the local delivery of MTZ and improve treatment outcomes for patients infected with Helicobacter pylori. A stability indicating Reversed-Phase High Performance Liquid Chromatography (RP- HPLC) method for the quantitation of MTZ in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. The RP-HPLC method was found to be linear, accurate, precise, sensitive, selective, and was applied to the analysis of MTZ in commercially available medicines. Preformulation studies were conducted as preparative work prior to manufacture gastric- retentive sustained release MTZ microcapsules. The experiments conducted were tailored for the development of sustained release MTZ microcapsules using a solvent evaporation method. The particle size and shape of the microcapsules was investigated using Scanning Electron Microscopy (SEM). MTZ- excipient compatibility studies were performed using Fourier Transform Infra-red Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD). The results revealed that no definite interaction between MTZ and intended excipients to be used for manufacture of MTZ formulations occurred. A solvent evaporation procedure was used for the manufacture of MTZ microcapsules. Preliminary formulations were manufactured using two different grades of Methocel® at various levels. In addition the impact of processing parameters on performance was also investigated. The formulations were assessed in terms of in vitro release, buoyancy, yield, encapsulation efficiency and microcapsule size. Formulation optimisation was undertaken using a CCD approach and numerical optimisation was used to predict an optimised formulation composition that would produce minimal initial MTZ release, maximum MTZ release at 12 hours and maximum buoyancy, encapsulation efficiency and yield. The kinetics of MTZ release from microcapsules was established by fitting in vitro release data to different mathematical models. Higuchi model and first-order model appeared to best fit the data as majority of the formulation batches had highest R2 values for these models. Short-term stability assessment of the optimised formulation was established by undertaking stability studies at 25°C/60% RH and 40°C/75%RH. No significant changes in any of the CQA were observed over 30 days of stability testing. A gas chromatographic (GC) method was developed and validated for the quantitation of residual acetone and n-hexane. The optimised formulation contained 213.60 ppm/g acetone and 25.23 ppm/g n-hexane which are well below the limits set for residual solvents. In conclusion, gastric-retentive sustained release MTZ microcapsules with potential for further development and optimisation have been successfully developed and assessed in these studies. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2017
- Full Text:
- Date Issued: 2017
- Authors: Makan, Anjana
- Date: 2017
- Subjects: Metronidazole , Drug delivery systems , Helicobacter pylori , High performance liquid chromatography , Gas chromatography , Drugs , Drugs Controlled release
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59240 , vital:27491
- Description: Helicobacter pylori is one of the most common pathogenic bacterial infections and is the leading cause of gastritis, gastroduodenal ulcer disease and gastric cancers. Studies have revealed the prevalence of Helicobacter pylori is high in many countries around the globe. Although Helicobacter pylori is highly sensitive to antimicrobial agents in vitro the clinical eradication rate of the disease is still low. The instability of API at gastric pH, low concentration of API in the gastric mucosa and short gastric residence times are the main reasons for poor eradication rates. The high prevalence rate of this disease necessitates the design and development of gastric-retentive site specific oral dosage forms for the optimized delivery of existing therapeutic molecules and may be an approach to improving the eradication rate of Helicobacter pylori. Metronidazole (MTZ) is a 5-nitroimidazole derivative that exhibits antibiotic and antiprotozoal activity. MTZ is used in combination with other compounds for the treatment of Helicobacter pylori in peptic ulcer disease. MTZ is a potential candidate for inclusion in a sustained release gastric-retentive delivery system that acts in the stomach and since it is unstable in the intestinal/colonic environment enhancing gastric residence time would be a therapeutic advantage. MTZ is a cost-effective therapy that exhibits good anti-microbial activity and has a favourable pharmacokinetic profile. A sustained release gastric-retentive formulation is therefore proposed as an approach to enhance the local delivery of MTZ and improve treatment outcomes for patients infected with Helicobacter pylori. A stability indicating Reversed-Phase High Performance Liquid Chromatography (RP- HPLC) method for the quantitation of MTZ in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. The RP-HPLC method was found to be linear, accurate, precise, sensitive, selective, and was applied to the analysis of MTZ in commercially available medicines. Preformulation studies were conducted as preparative work prior to manufacture gastric- retentive sustained release MTZ microcapsules. The experiments conducted were tailored for the development of sustained release MTZ microcapsules using a solvent evaporation method. The particle size and shape of the microcapsules was investigated using Scanning Electron Microscopy (SEM). MTZ- excipient compatibility studies were performed using Fourier Transform Infra-red Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD). The results revealed that no definite interaction between MTZ and intended excipients to be used for manufacture of MTZ formulations occurred. A solvent evaporation procedure was used for the manufacture of MTZ microcapsules. Preliminary formulations were manufactured using two different grades of Methocel® at various levels. In addition the impact of processing parameters on performance was also investigated. The formulations were assessed in terms of in vitro release, buoyancy, yield, encapsulation efficiency and microcapsule size. Formulation optimisation was undertaken using a CCD approach and numerical optimisation was used to predict an optimised formulation composition that would produce minimal initial MTZ release, maximum MTZ release at 12 hours and maximum buoyancy, encapsulation efficiency and yield. The kinetics of MTZ release from microcapsules was established by fitting in vitro release data to different mathematical models. Higuchi model and first-order model appeared to best fit the data as majority of the formulation batches had highest R2 values for these models. Short-term stability assessment of the optimised formulation was established by undertaking stability studies at 25°C/60% RH and 40°C/75%RH. No significant changes in any of the CQA were observed over 30 days of stability testing. A gas chromatographic (GC) method was developed and validated for the quantitation of residual acetone and n-hexane. The optimised formulation contained 213.60 ppm/g acetone and 25.23 ppm/g n-hexane which are well below the limits set for residual solvents. In conclusion, gastric-retentive sustained release MTZ microcapsules with potential for further development and optimisation have been successfully developed and assessed in these studies. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2017
- Full Text:
- Date Issued: 2017
In vitro release of ketoprofen from proprietary and extemporaneously manufactured gels
- Tettey-Amlalo, Ralph Nii Okai
- Authors: Tettey-Amlalo, Ralph Nii Okai
- Date: 2005
- Subjects: Transdermal medication , Drug delivery systems , High performance liquid chromatography , Nonsteroidal anti-inflammatory agents , Rheumatoid arthritis -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3797 , http://hdl.handle.net/10962/d1003275 , Transdermal medication , Drug delivery systems , High performance liquid chromatography , Nonsteroidal anti-inflammatory agents , Rheumatoid arthritis -- Treatment
- Description: Ketoprofen is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of ketoprofen can cause gastric irritation and adverse renal effects. Transdermal delivery of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug concentrations at the site of administration. The release of ketoprofen from proprietary gel products from three different countries was evaluated by comparing the in vitro release profiles. Twenty extemporaneously prepared ketoprofen gel formulations using Carbopol® polymers were manufactured. The effect of polymer, drug concentration, pH and solvent systems on the in vitro release of ketoprofen from these formulations were investigated. The gels were evaluated for drug content and pH. The release of the drug from all the formulations obeyed the Higuchi principle. Two static FDA approved diffusion cells, namely the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell, were compared by measuring the in vitro release rate of ketoprofen from all the gel formulations through a synthetic silicone membrane. High-performance liquid chromatography and ultraviolet spectrophotometric analytical techniques were both used for the analysis of ketoprofen. The validated methods were employed for the determination of ketoprofen in the sample solutions taken from the receptor fluid. Two of the three proprietary products registered under the same manufacturing license exhibited similar results whereas the third product differed significantly. Among the variables investigated, the vehicle pH and solvent composition were found have the most significant effect on the in vitro release of ketoprofen from Carbopol® polymers. The different grades of Carbopol® polymers showed statistically significantly different release kinetics with respect to lag time. When evaluating the proprietary products, both the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell were deemed adequate although higher profiles were generally obtained from the European Pharmacopoeia diffusion cells. Smoother diffusion profiles were obtained from samples analysed by high-performance liquid chromatography than by ultraviolet spectrophotometry in both diffusion cells. Sample solutions taken from Franz diffusion cells and analysed by ultraviolet spectrophotometry also produced smooth diffusion profiles. Erratic and higher diffusion profiles were observed with samples taken from the European Pharmacopoeia diffusion cell and analysed by ultraviolet spectrophotometry. The choice of diffusion cells and analytical procedure in product development must be weighed against the relatively poor reproducibility as observed with the European Pharmacopoeia diffusion cell.
- Full Text:
- Date Issued: 2005
- Authors: Tettey-Amlalo, Ralph Nii Okai
- Date: 2005
- Subjects: Transdermal medication , Drug delivery systems , High performance liquid chromatography , Nonsteroidal anti-inflammatory agents , Rheumatoid arthritis -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3797 , http://hdl.handle.net/10962/d1003275 , Transdermal medication , Drug delivery systems , High performance liquid chromatography , Nonsteroidal anti-inflammatory agents , Rheumatoid arthritis -- Treatment
- Description: Ketoprofen is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of ketoprofen can cause gastric irritation and adverse renal effects. Transdermal delivery of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug concentrations at the site of administration. The release of ketoprofen from proprietary gel products from three different countries was evaluated by comparing the in vitro release profiles. Twenty extemporaneously prepared ketoprofen gel formulations using Carbopol® polymers were manufactured. The effect of polymer, drug concentration, pH and solvent systems on the in vitro release of ketoprofen from these formulations were investigated. The gels were evaluated for drug content and pH. The release of the drug from all the formulations obeyed the Higuchi principle. Two static FDA approved diffusion cells, namely the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell, were compared by measuring the in vitro release rate of ketoprofen from all the gel formulations through a synthetic silicone membrane. High-performance liquid chromatography and ultraviolet spectrophotometric analytical techniques were both used for the analysis of ketoprofen. The validated methods were employed for the determination of ketoprofen in the sample solutions taken from the receptor fluid. Two of the three proprietary products registered under the same manufacturing license exhibited similar results whereas the third product differed significantly. Among the variables investigated, the vehicle pH and solvent composition were found have the most significant effect on the in vitro release of ketoprofen from Carbopol® polymers. The different grades of Carbopol® polymers showed statistically significantly different release kinetics with respect to lag time. When evaluating the proprietary products, both the modified Franz diffusion cell and the European Pharmacopoeia diffusion cell were deemed adequate although higher profiles were generally obtained from the European Pharmacopoeia diffusion cells. Smoother diffusion profiles were obtained from samples analysed by high-performance liquid chromatography than by ultraviolet spectrophotometry in both diffusion cells. Sample solutions taken from Franz diffusion cells and analysed by ultraviolet spectrophotometry also produced smooth diffusion profiles. Erratic and higher diffusion profiles were observed with samples taken from the European Pharmacopoeia diffusion cell and analysed by ultraviolet spectrophotometry. The choice of diffusion cells and analytical procedure in product development must be weighed against the relatively poor reproducibility as observed with the European Pharmacopoeia diffusion cell.
- Full Text:
- Date Issued: 2005
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