Fabrication and characterization of ciprofloxacin loaded niosomes for transtympanic delivery
- Authors: Mhlanga, Asavela
- Date: 2022-04-06
- Subjects: Drug delivery systems , Liposomes , Ciprofloxacin , Quinolone antibacterial agents , Drug carriers (Pharmacy) , Drug stability , Lamellarity , Niosomes
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290715 , vital:56777
- Description: Ciprofloxacin (CPH) is a broad-spectrum antibiotic used to treat bone, joint, and skin infections. It is commercially available as an extended-release tablet and as a cream dosage form. CPH is a bactericidal active pharmaceutical ingredient (API) of the fluoroquinolone drug class. It inhibits deoxyribonucleic acid (DNA) replication by inhibiting bacterial DNA topoisomerase and DNA gyrase enzymes. Common adverse effects include nausea, vomiting, unusual fatigue, pale skin, and may increase the risk of tendinitis, which could be a major concern. CPH is, according to the Biopharmaceutics Classification System (BCS), classified as a BCS class IV drug exhibiting low oral bioavailability, low solubility, and intestinal permeability. CPH was chosen as a good candidate for the study because of its stability in solutions, its low molecular weight (331.4 g/mol), and its moderate lipophilicity (log P = 0.28) [16]. The use of conventional ear drops in the ear is effective, avoids hepatic first metabolism and extensive protein binding and may reduce adverse effects as a low dose may be used to achieve a therapeutic effect. However, conventional ear drops and oral antibiotics have a long onset of action and have to be taken/applied in short intervals. For convenience and assurance of a long residence time in the ear, CPH may be delivered by using a niosomal formulation, a liquid at room temperature, to allow administration into the ear without the need to constantly apply the ear drops for long periods of time. A simple, rapid, precise, accurate, reproducible, and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method using ultraviolet (UV) detection for the quantitation of CPH was developed and optimized using a central composite design (CCD). The method was validated using International Conference on Harmonisation (ICH) guidelines and was found to be linear, precise, accurate, and specific for the analysis of CPH. Since the method is specific, it was used to quantify CPH in commercial and experimental formulations and monitor CPH released during in-vitro release testing. The compatibility of CPH and potential excipients was investigated during preformulation studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) to identify and select suitable excipients for use during formulation development activities. No apparent interactions were evident between CPH, and the excipients tested. The probe sonication method was used to manufacture CPH loaded niosomes using different surfactants/surfactant combinations, and a combination of Tween® 80: sodium lauryl sulfate (SLS) was found to be the best composition in terms of both entrapment efficiency and Zeta potential. The limits for the independent input variables used for the manufacture included amplitude, sonication time, and amount of cholesterol were determined. Design of experiments (DOE) was used to design the study. The input variables investigated included amplitude, amount of cholesterol, and sonication time. The output or responses monitored included Zeta potential, vesicle size, polydispersity index (PDI), and entrapment efficiency. Non-ionic surfactant systems are predominantly stabilized by steric stabilization, and there is only a minor electrostatic element from adsorbed hydroxyl ions. With the inclusion of SLS it is to be expected that Zeta potential will be a contributing factor. DOE using Box-Behnken design (BBD) and response surface methodology (RSM) in addition to Artificial Neural Networks (ANN) were used for the optimization of the formulation. The optimized formulation had a composition of 1 g cholesterol, 1 g of Tween® 80, 1 g of SLS and was prepared at an amplitude of 11.294 % with a sonication time of 3.304 minutes. The formulation exhibited zero-order release kinetics and had an average pH of 7.45. The formulation was stored at 4 ℃ and 25 ℃ and was assessed for vesicle size, entrapment efficiency, Zeta potential, colour, lamellarity, and PDI every 7 days for 4 weeks. The lead formulation stored at 4 ℃ was more stable than the formulation at 25 ℃ in terms of entrapment efficiency, PDI and vesicle size during the 4-week period. CPH loaded niosomes for transtympanic delivery in the treatment of otitis media were developed and optimized. The technology exhibits sustained release of CPH and has the potential for further development and optimization. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2022
- Full Text:
- Date Issued: 2022-04-06
- Authors: Mhlanga, Asavela
- Date: 2022-04-06
- Subjects: Drug delivery systems , Liposomes , Ciprofloxacin , Quinolone antibacterial agents , Drug carriers (Pharmacy) , Drug stability , Lamellarity , Niosomes
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290715 , vital:56777
- Description: Ciprofloxacin (CPH) is a broad-spectrum antibiotic used to treat bone, joint, and skin infections. It is commercially available as an extended-release tablet and as a cream dosage form. CPH is a bactericidal active pharmaceutical ingredient (API) of the fluoroquinolone drug class. It inhibits deoxyribonucleic acid (DNA) replication by inhibiting bacterial DNA topoisomerase and DNA gyrase enzymes. Common adverse effects include nausea, vomiting, unusual fatigue, pale skin, and may increase the risk of tendinitis, which could be a major concern. CPH is, according to the Biopharmaceutics Classification System (BCS), classified as a BCS class IV drug exhibiting low oral bioavailability, low solubility, and intestinal permeability. CPH was chosen as a good candidate for the study because of its stability in solutions, its low molecular weight (331.4 g/mol), and its moderate lipophilicity (log P = 0.28) [16]. The use of conventional ear drops in the ear is effective, avoids hepatic first metabolism and extensive protein binding and may reduce adverse effects as a low dose may be used to achieve a therapeutic effect. However, conventional ear drops and oral antibiotics have a long onset of action and have to be taken/applied in short intervals. For convenience and assurance of a long residence time in the ear, CPH may be delivered by using a niosomal formulation, a liquid at room temperature, to allow administration into the ear without the need to constantly apply the ear drops for long periods of time. A simple, rapid, precise, accurate, reproducible, and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method using ultraviolet (UV) detection for the quantitation of CPH was developed and optimized using a central composite design (CCD). The method was validated using International Conference on Harmonisation (ICH) guidelines and was found to be linear, precise, accurate, and specific for the analysis of CPH. Since the method is specific, it was used to quantify CPH in commercial and experimental formulations and monitor CPH released during in-vitro release testing. The compatibility of CPH and potential excipients was investigated during preformulation studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) to identify and select suitable excipients for use during formulation development activities. No apparent interactions were evident between CPH, and the excipients tested. The probe sonication method was used to manufacture CPH loaded niosomes using different surfactants/surfactant combinations, and a combination of Tween® 80: sodium lauryl sulfate (SLS) was found to be the best composition in terms of both entrapment efficiency and Zeta potential. The limits for the independent input variables used for the manufacture included amplitude, sonication time, and amount of cholesterol were determined. Design of experiments (DOE) was used to design the study. The input variables investigated included amplitude, amount of cholesterol, and sonication time. The output or responses monitored included Zeta potential, vesicle size, polydispersity index (PDI), and entrapment efficiency. Non-ionic surfactant systems are predominantly stabilized by steric stabilization, and there is only a minor electrostatic element from adsorbed hydroxyl ions. With the inclusion of SLS it is to be expected that Zeta potential will be a contributing factor. DOE using Box-Behnken design (BBD) and response surface methodology (RSM) in addition to Artificial Neural Networks (ANN) were used for the optimization of the formulation. The optimized formulation had a composition of 1 g cholesterol, 1 g of Tween® 80, 1 g of SLS and was prepared at an amplitude of 11.294 % with a sonication time of 3.304 minutes. The formulation exhibited zero-order release kinetics and had an average pH of 7.45. The formulation was stored at 4 ℃ and 25 ℃ and was assessed for vesicle size, entrapment efficiency, Zeta potential, colour, lamellarity, and PDI every 7 days for 4 weeks. The lead formulation stored at 4 ℃ was more stable than the formulation at 25 ℃ in terms of entrapment efficiency, PDI and vesicle size during the 4-week period. CPH loaded niosomes for transtympanic delivery in the treatment of otitis media were developed and optimized. The technology exhibits sustained release of CPH and has the potential for further development and optimization. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2022
- Full Text:
- Date Issued: 2022-04-06
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
Formulation development, manufacture and evaluation of hydralazine hydrochloride microspheres
- Kangausaru, Shakemore Tinashe
- Authors: Kangausaru, Shakemore Tinashe
- Date: 2017
- Subjects: Hydralazine , Microspheres , Drugs Controlled release , Drugs Design , Drug development , Hypertension Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59220 , vital:27482
- Description: Despite improvements in its detection and treatment since the 1970s, hypertension is the most common and important risk factor for cardiovascular diseases. Hypertension is a chronic condition often underdiagnosed and/or inadequately treated in Sub-Saharan Africa. Recent survey results illustrate that the condition continues to contribute significantly to mortality and morbidity in adults and that it is poorly controlled in clinical practice. Hydralazine (HYD) is used either alone or in combination for the management of chronic hypertension, chronic cardiac failure and hypertensive crises. Due to its short plasma half-life of between 2 to 4 hours, HYD is normally administered two to four times daily, therefore making it a potential candidate for inclusion in sustained release formulations. The formulation of sustained release microsphere dosage forms may be useful to improve patient adherence and to achieve predictable and optimised therapeutic plasma concentrations. A stability indicating reversed-phase high performance liquid chromatography (RP-HPLC) method for the quantitation of HYD in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. UV/Vis detection method was selected as HYD contains an ultraviolet light-absorbing chromophore. The method was validated with respect to linearity and range, limits of quantitation (LOQ) and detection (LOD), accuracy, precision, sensitivity, selectivity and specificity as per International Conference on Harmonisation (ICH) guidelines. The method was applied to commercially available HYD tablets. No interfering peaks were observed from excipients used in the commercially available tablets. Preformulation studies were conducted to ensure the manufacture of high quality, stable sustained release HYD microspheres. The results revealed that there was an interaction between HYD and Carbopol® 971P, therefore Carbopol® polymers were not included during formulation studies. HYD was found to be compatible with Methocel® K100LV, Eudragit® RS PO and Avicel® 101 and HYD formulations were developed and optimised using these excipients. An oil-in-oil (o/o) solvent evaporation technique was selected for the manufacture of HYD microspheres due to its simplicity and to avoid exposure of HYD to moisture that could have been encountered if a water-in-oil (w/o) manufacturing process was used. The selection of o/o solvent evaporation technique was also based on the hydrophilicity of HYD and the polymers selected. Different grades of Methocel® and Eudragit® were selected to evaluate their effect on encapsulation efficiency (EE), in vitro release and microparticle shape and morphology. The best combination of these polymers which resulted in the desired EE, in vitro release, microparticle shape and size were then selected for formulation optimisation. A numerical optimisation approach was used to predict a formulation composition that would produce minimal HYD release initially and maximum HYD release after 12 hours of dissolution testing. The release kinetics of HYD from the manufactured microspheres were established by fitting in vitro release data to several mathematical models. The in vitro release data for the optimised formulations was best described using Higuchi model. The short-term stability of the optimised formulations was established by undertaking stability studies at 4°C, 25 °C/60 % RH and 40 °C/75 % RH. The results revealed that there was no significant change in appearance and physicochemical properties of the microspheres over a period of one month. However, long-term stability studies would be required to determine the shelf-life of the formulations. In addition, a gas chromatographic (GC) method was selected for determining residual amounts of acetone and n-hexane in the optimised formulations. GC methods were developed and optimised by evaluation of process parameters. System suitability testing was performed with respect to resolution, theoretical number of plates and selectivity. Method validation was performed with respect to linearity, range, inter- and intra-day precision, retention time (Rt) precision, limit of quantitation (LOQ) and detection (LOD). A solvent extraction method was used to analyse residual solvents in the optimised formulations. The drying process was sufficient in evaporating acetone and n-hexane from the optimised formulations. Solvent evaporation technique has been successfully used in the manufacture of HYD microspheres. The microspheres have potential for further development, scale up formulation studies and long-term stability studies. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2017
- Full Text:
- Date Issued: 2017
- Authors: Kangausaru, Shakemore Tinashe
- Date: 2017
- Subjects: Hydralazine , Microspheres , Drugs Controlled release , Drugs Design , Drug development , Hypertension Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59220 , vital:27482
- Description: Despite improvements in its detection and treatment since the 1970s, hypertension is the most common and important risk factor for cardiovascular diseases. Hypertension is a chronic condition often underdiagnosed and/or inadequately treated in Sub-Saharan Africa. Recent survey results illustrate that the condition continues to contribute significantly to mortality and morbidity in adults and that it is poorly controlled in clinical practice. Hydralazine (HYD) is used either alone or in combination for the management of chronic hypertension, chronic cardiac failure and hypertensive crises. Due to its short plasma half-life of between 2 to 4 hours, HYD is normally administered two to four times daily, therefore making it a potential candidate for inclusion in sustained release formulations. The formulation of sustained release microsphere dosage forms may be useful to improve patient adherence and to achieve predictable and optimised therapeutic plasma concentrations. A stability indicating reversed-phase high performance liquid chromatography (RP-HPLC) method for the quantitation of HYD in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. UV/Vis detection method was selected as HYD contains an ultraviolet light-absorbing chromophore. The method was validated with respect to linearity and range, limits of quantitation (LOQ) and detection (LOD), accuracy, precision, sensitivity, selectivity and specificity as per International Conference on Harmonisation (ICH) guidelines. The method was applied to commercially available HYD tablets. No interfering peaks were observed from excipients used in the commercially available tablets. Preformulation studies were conducted to ensure the manufacture of high quality, stable sustained release HYD microspheres. The results revealed that there was an interaction between HYD and Carbopol® 971P, therefore Carbopol® polymers were not included during formulation studies. HYD was found to be compatible with Methocel® K100LV, Eudragit® RS PO and Avicel® 101 and HYD formulations were developed and optimised using these excipients. An oil-in-oil (o/o) solvent evaporation technique was selected for the manufacture of HYD microspheres due to its simplicity and to avoid exposure of HYD to moisture that could have been encountered if a water-in-oil (w/o) manufacturing process was used. The selection of o/o solvent evaporation technique was also based on the hydrophilicity of HYD and the polymers selected. Different grades of Methocel® and Eudragit® were selected to evaluate their effect on encapsulation efficiency (EE), in vitro release and microparticle shape and morphology. The best combination of these polymers which resulted in the desired EE, in vitro release, microparticle shape and size were then selected for formulation optimisation. A numerical optimisation approach was used to predict a formulation composition that would produce minimal HYD release initially and maximum HYD release after 12 hours of dissolution testing. The release kinetics of HYD from the manufactured microspheres were established by fitting in vitro release data to several mathematical models. The in vitro release data for the optimised formulations was best described using Higuchi model. The short-term stability of the optimised formulations was established by undertaking stability studies at 4°C, 25 °C/60 % RH and 40 °C/75 % RH. The results revealed that there was no significant change in appearance and physicochemical properties of the microspheres over a period of one month. However, long-term stability studies would be required to determine the shelf-life of the formulations. In addition, a gas chromatographic (GC) method was selected for determining residual amounts of acetone and n-hexane in the optimised formulations. GC methods were developed and optimised by evaluation of process parameters. System suitability testing was performed with respect to resolution, theoretical number of plates and selectivity. Method validation was performed with respect to linearity, range, inter- and intra-day precision, retention time (Rt) precision, limit of quantitation (LOQ) and detection (LOD). A solvent extraction method was used to analyse residual solvents in the optimised formulations. The drying process was sufficient in evaporating acetone and n-hexane from the optimised formulations. Solvent evaporation technique has been successfully used in the manufacture of HYD microspheres. The microspheres have potential for further development, scale up formulation studies and long-term stability studies. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2017
- Full Text:
- Date Issued: 2017
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