In vitro passage of ibuprofen through synthetic and biological membranes
- Authors: Purdon, Carryn Hamilton
- Date: 2001
- Subjects: Ibuprofen , Diffusion processes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3786 , http://hdl.handle.net/10962/d1003264 , Ibuprofen , Diffusion processes
- Description: Ibuprofen is a non-steroidal anti-inflammatory drug with three major types of effect: anti-inflammatory, analgesic and antipyretic. Ibuprofen may be administered in a number of different forms via the oral as well as the topical route. Published evidence suggests that topical, unlike oral, non-steroidal anti-inflammatory drugs are associated with few systemic side effects as plasma concentrations are low compared to oral therapy. In some countries it is particularly difficult to obtain human skin for in vitro experimentation and it is therefore important to have alternate biological or synthetic membranes which mimic human skin for diffusion experiments. Synthetic membranes serve as predictive models for topical drug release and in South Africa, shed snake skin is easily obtainable from the many snake parks present in the country. The FDA guidelines were considered when choosing the apparatus to be used in the comparative diffusion study on proprietary ibuprofen-containing topical preparations from three countries and the verification of the usefulness, or otherwise, of shed snake skin as a biological membrane for the assessment of the permeation of ibuprofen. Two diffusion techniques were considered appropriate for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing. One was the Franz diffusion cell, as modified by Keshary and Chien (88,169) and the other was the European Pharmacopoeia diffusion cell (187). High performance liquid chromatography was used as the analytical technique for the analysis of ibuprofen in aqueous solution using ultraviolet detection at 222 nm. The validated method was applied to the determination of the diffusion of ibuprofen from topical ibuprofen-containing formulations (gels, creams and mousse) through synthetic silicone membrane and shed snake skin biological membrane from four different species. In a study of fifteen topical ibuprofen-containing formulations (gels, creams and mousse) from three countries (South Africa, United Kingdom and France) it was found that there was a trend of products from two countries consistently exhibiting superior diffusion characteristics as well as products from the same two countries consistently exhibiting the lowest diffusion of ibuprofen. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses and peak integration values when drawing conclusions regarding comparative diffusion characteristics. Shed snake skin has been described as a 'model' membrane, i.e. a membrane which shows similar permeability to human stratum corneum. The results reported here show clearly that, for ibuprofen, the four species of snake produce shed skin with completely different diffusion characteristics when all other conditions are identical. It may well be that there is one particular species of snake which produces shed skin of identical permeability to human stratum corneum, but to describe shed snake skin in general as a model membrane seems incorrect. It is therefore important that if shed snake skin is used as a membrane, the species, skin site and orientation should be reported. The European Pharmacopoeia diffusion apparatus was judged to be the better of the two diffusion techniques assessed for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing using silicone membranes and for the measurement of the amount of ibuprofen diffusing across the ventral outside orientation of shed skin during in vitro testing, whereas the Franz diffusion apparatus was judged to be better for the measurement of the amount of ibuprofen diffusing across the dorsal outside orientation of shed skin during in vitro testing. However, the choice of this diffusion apparatus must be weighed against the relatively poor reproducibility as compared with the European Pharmacopoeia diffusion apparatus.
- Full Text:
- Date Issued: 2001
- Authors: Purdon, Carryn Hamilton
- Date: 2001
- Subjects: Ibuprofen , Diffusion processes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3786 , http://hdl.handle.net/10962/d1003264 , Ibuprofen , Diffusion processes
- Description: Ibuprofen is a non-steroidal anti-inflammatory drug with three major types of effect: anti-inflammatory, analgesic and antipyretic. Ibuprofen may be administered in a number of different forms via the oral as well as the topical route. Published evidence suggests that topical, unlike oral, non-steroidal anti-inflammatory drugs are associated with few systemic side effects as plasma concentrations are low compared to oral therapy. In some countries it is particularly difficult to obtain human skin for in vitro experimentation and it is therefore important to have alternate biological or synthetic membranes which mimic human skin for diffusion experiments. Synthetic membranes serve as predictive models for topical drug release and in South Africa, shed snake skin is easily obtainable from the many snake parks present in the country. The FDA guidelines were considered when choosing the apparatus to be used in the comparative diffusion study on proprietary ibuprofen-containing topical preparations from three countries and the verification of the usefulness, or otherwise, of shed snake skin as a biological membrane for the assessment of the permeation of ibuprofen. Two diffusion techniques were considered appropriate for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing. One was the Franz diffusion cell, as modified by Keshary and Chien (88,169) and the other was the European Pharmacopoeia diffusion cell (187). High performance liquid chromatography was used as the analytical technique for the analysis of ibuprofen in aqueous solution using ultraviolet detection at 222 nm. The validated method was applied to the determination of the diffusion of ibuprofen from topical ibuprofen-containing formulations (gels, creams and mousse) through synthetic silicone membrane and shed snake skin biological membrane from four different species. In a study of fifteen topical ibuprofen-containing formulations (gels, creams and mousse) from three countries (South Africa, United Kingdom and France) it was found that there was a trend of products from two countries consistently exhibiting superior diffusion characteristics as well as products from the same two countries consistently exhibiting the lowest diffusion of ibuprofen. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses and peak integration values when drawing conclusions regarding comparative diffusion characteristics. Shed snake skin has been described as a 'model' membrane, i.e. a membrane which shows similar permeability to human stratum corneum. The results reported here show clearly that, for ibuprofen, the four species of snake produce shed skin with completely different diffusion characteristics when all other conditions are identical. It may well be that there is one particular species of snake which produces shed skin of identical permeability to human stratum corneum, but to describe shed snake skin in general as a model membrane seems incorrect. It is therefore important that if shed snake skin is used as a membrane, the species, skin site and orientation should be reported. The European Pharmacopoeia diffusion apparatus was judged to be the better of the two diffusion techniques assessed for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing using silicone membranes and for the measurement of the amount of ibuprofen diffusing across the ventral outside orientation of shed skin during in vitro testing, whereas the Franz diffusion apparatus was judged to be better for the measurement of the amount of ibuprofen diffusing across the dorsal outside orientation of shed skin during in vitro testing. However, the choice of this diffusion apparatus must be weighed against the relatively poor reproducibility as compared with the European Pharmacopoeia diffusion apparatus.
- Full Text:
- Date Issued: 2001
Formulation and dissolution assessment of a novel repeat action tablet containing a decongestant and an antihistamine
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
An investigation into the possible neuroprotective role of melatonin in copper-loading
- Authors: Parmar, Paresh H
- Date: 2001
- Subjects: Melatonin , Copper , Nervous system -- Degeneration -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3783 , http://hdl.handle.net/10962/d1003261
- Description: Copper is an extremely toxic metal in biological systems and thus, its availability to the system, must be effectively and efficiently controlled. Copper is vital for life, as it is essential for critical enzymes in biological systems. It is free copper in the biological systems that is toxic, as free copper induces free radical generation, which disrupts lipid membranes, interacts with DNA causing mutations, and eventually leads to cell death. Wilson’s disease is a inherited copper disease, which results in hepatolenticular disease. Copper is unable to be excreted, and thus accumulates, eventually spilling over into the bloodstream from the liver, and “poisons” the patient. The Wilson’s disease patient leads a short life, due to neurological and hepatological problems. There is no cure for Wilson’s disease, only chelation therapy using potent chelators such as penicillamine and EDTA. Zinc, in high doses, can be used to compete with copper absorption. This has proved to be the only successful therapy at present. This study investigates the possible use of melatonin as a copper binder/chelator. Melatonin has been shown to interact with copper in vitro. By binding/chelating to copper, melatonin may inhibit copper-induced free radical generation, and thus prevent copper from interacting with DNA to cause mutations and act as a cytotoxin. In vivo studies on copper (2mg/kg) administered for 2-weeks and 6-weeks were carried out on Wistar rats. The potential of melatonin (12mg/kg) to prevent copper-induced cellular damage was investigated. The results indicate that melatonin does not protect the lipid membranes from copper-induced lipid peroxidation. In vitro investigations using 1mM, 5mM and 10mM copper and 5mM melatonin, show that melatonin prevents copper-induced lipid peroxidation at a copper concentration of 1mM (p<0.001). The 5mM and 10mM copper induces less lipid peroxidation, compared to the 1mM copper. It has been reported that metal ions, antioxidants and chelating agents can influence peroxide decomposition during the assay. Melatonin (5mM) administration does not significantly prevent copper-induced lipid peroxidation at 5mM and 10mM copper. It is possible that due to melatonin’s relatively low concentration, it is unable to inhibit lipid peroxidation induced by the copper. The chemical nature of the interaction between melatonin and copper was also investigated, using NMR, IR and electrochemistry techniques. The NMR and IR techniques show that melatonin coordinates with Cu²⁺ and not Cu¹⁺, at the carbonyl group of melatonin. The electrochemistry experiments using cyclic voltammetry and adsorptive stripping voltammetry, show that melatonin forms a strong bond with Cu¹⁺. Cu²⁺ prefers binding to oxygen, and that is clearly seen in the NMR and IR. Cu¹⁺ prefers binding to nitrogen and then oxygen, and this is seen in the electrochemistry, as Cu¹⁺ is forced to bind through one of the nitrogens on the melatonin. Previously, it has been shown that melatonin binds/chelates with Cu²⁺. Histochemical investigations show that copper administration for 2-weeks and 6-weeks, causes extensive mitochondrial damage in liver and kidney’s proximal convoluted tubule epithelium cells. Melatonin (12mg/kg) co-administration with copper for 2-weeks and 6-weeks did not significantly protect the mitochondria from copper-induced damage. Copper-specific stains (rhodanine, silver sulphide and rubeanic acid) were used to stain liver, brain and kidney tissue samples. Rhodanine and silver sulphide were equally sensitive in staining copper in the 2-week samples, but not at all in the 6-week samples. This could not be explained. Rubeanic acid was ineffective in all samples tested. Thus, it appears that specific copper stains cannot be used in making a definitive diagnosis in cases of copper overload, and that specific copper stains do not always correlate with a high concentration of copper present in tissues. Pineal organ culture was used to determine the effect of copper administration on pineal indole synthesis. Exogenous (³H) tryptophan was administered to the pineal organ cultures, and the level of (³H) pineal indoles synthesised, were measured. Pineals from 2-week and 6-week copper/melatonin treated animals exhibited paradoxical 5- methoxytryptophol (ML) levels, as compared to the 2-week and 6-week copper treated animals. The 2-week copper/melatonin administered animals, showed a decrease in the ML level (p<0.01), and the copper/melatonin administered for 6-weeks, showed an increase in the ML levels (p<0.01). This indicates that melatonin interacts with the HIOMT enzyme. Pineals from 6-week copper/melatonin treated animals, as compared to the 6-week copper treated animals, showed an increase in N-acetylserotonin levels. This indicates that melatonin prevents the inhibition of the NAT enzyme. The final experiment was to determine in vitro, the effect of Cu²⁺ and Cu¹⁺ administration, on mitochondrial electron transport chain. Rat liver homogenate was incubated with and solutions of Cu²⁺ (10mM) and Cu¹⁺ (10mM) and melatonin (10mM). Cu²⁺ administration caused an inhibition of the electron transport at t=0 and t=60, whereas Cu¹⁺ administration at t=0 caused an inhibition of electron transport, but at t=60, Cu¹⁺ administration stimulated electron transport. Melatonin administered with Cu²⁺, resulted in an inhibition of the electron transport chain at t=0 and t=60. The findings of this study indicate that melatonin might have a potentially beneficial effect in copper overloading, by binding/chelating copper.
- Full Text:
- Date Issued: 2001
- Authors: Parmar, Paresh H
- Date: 2001
- Subjects: Melatonin , Copper , Nervous system -- Degeneration -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3783 , http://hdl.handle.net/10962/d1003261
- Description: Copper is an extremely toxic metal in biological systems and thus, its availability to the system, must be effectively and efficiently controlled. Copper is vital for life, as it is essential for critical enzymes in biological systems. It is free copper in the biological systems that is toxic, as free copper induces free radical generation, which disrupts lipid membranes, interacts with DNA causing mutations, and eventually leads to cell death. Wilson’s disease is a inherited copper disease, which results in hepatolenticular disease. Copper is unable to be excreted, and thus accumulates, eventually spilling over into the bloodstream from the liver, and “poisons” the patient. The Wilson’s disease patient leads a short life, due to neurological and hepatological problems. There is no cure for Wilson’s disease, only chelation therapy using potent chelators such as penicillamine and EDTA. Zinc, in high doses, can be used to compete with copper absorption. This has proved to be the only successful therapy at present. This study investigates the possible use of melatonin as a copper binder/chelator. Melatonin has been shown to interact with copper in vitro. By binding/chelating to copper, melatonin may inhibit copper-induced free radical generation, and thus prevent copper from interacting with DNA to cause mutations and act as a cytotoxin. In vivo studies on copper (2mg/kg) administered for 2-weeks and 6-weeks were carried out on Wistar rats. The potential of melatonin (12mg/kg) to prevent copper-induced cellular damage was investigated. The results indicate that melatonin does not protect the lipid membranes from copper-induced lipid peroxidation. In vitro investigations using 1mM, 5mM and 10mM copper and 5mM melatonin, show that melatonin prevents copper-induced lipid peroxidation at a copper concentration of 1mM (p<0.001). The 5mM and 10mM copper induces less lipid peroxidation, compared to the 1mM copper. It has been reported that metal ions, antioxidants and chelating agents can influence peroxide decomposition during the assay. Melatonin (5mM) administration does not significantly prevent copper-induced lipid peroxidation at 5mM and 10mM copper. It is possible that due to melatonin’s relatively low concentration, it is unable to inhibit lipid peroxidation induced by the copper. The chemical nature of the interaction between melatonin and copper was also investigated, using NMR, IR and electrochemistry techniques. The NMR and IR techniques show that melatonin coordinates with Cu²⁺ and not Cu¹⁺, at the carbonyl group of melatonin. The electrochemistry experiments using cyclic voltammetry and adsorptive stripping voltammetry, show that melatonin forms a strong bond with Cu¹⁺. Cu²⁺ prefers binding to oxygen, and that is clearly seen in the NMR and IR. Cu¹⁺ prefers binding to nitrogen and then oxygen, and this is seen in the electrochemistry, as Cu¹⁺ is forced to bind through one of the nitrogens on the melatonin. Previously, it has been shown that melatonin binds/chelates with Cu²⁺. Histochemical investigations show that copper administration for 2-weeks and 6-weeks, causes extensive mitochondrial damage in liver and kidney’s proximal convoluted tubule epithelium cells. Melatonin (12mg/kg) co-administration with copper for 2-weeks and 6-weeks did not significantly protect the mitochondria from copper-induced damage. Copper-specific stains (rhodanine, silver sulphide and rubeanic acid) were used to stain liver, brain and kidney tissue samples. Rhodanine and silver sulphide were equally sensitive in staining copper in the 2-week samples, but not at all in the 6-week samples. This could not be explained. Rubeanic acid was ineffective in all samples tested. Thus, it appears that specific copper stains cannot be used in making a definitive diagnosis in cases of copper overload, and that specific copper stains do not always correlate with a high concentration of copper present in tissues. Pineal organ culture was used to determine the effect of copper administration on pineal indole synthesis. Exogenous (³H) tryptophan was administered to the pineal organ cultures, and the level of (³H) pineal indoles synthesised, were measured. Pineals from 2-week and 6-week copper/melatonin treated animals exhibited paradoxical 5- methoxytryptophol (ML) levels, as compared to the 2-week and 6-week copper treated animals. The 2-week copper/melatonin administered animals, showed a decrease in the ML level (p<0.01), and the copper/melatonin administered for 6-weeks, showed an increase in the ML levels (p<0.01). This indicates that melatonin interacts with the HIOMT enzyme. Pineals from 6-week copper/melatonin treated animals, as compared to the 6-week copper treated animals, showed an increase in N-acetylserotonin levels. This indicates that melatonin prevents the inhibition of the NAT enzyme. The final experiment was to determine in vitro, the effect of Cu²⁺ and Cu¹⁺ administration, on mitochondrial electron transport chain. Rat liver homogenate was incubated with and solutions of Cu²⁺ (10mM) and Cu¹⁺ (10mM) and melatonin (10mM). Cu²⁺ administration caused an inhibition of the electron transport at t=0 and t=60, whereas Cu¹⁺ administration at t=0 caused an inhibition of electron transport, but at t=60, Cu¹⁺ administration stimulated electron transport. Melatonin administered with Cu²⁺, resulted in an inhibition of the electron transport chain at t=0 and t=60. The findings of this study indicate that melatonin might have a potentially beneficial effect in copper overloading, by binding/chelating copper.
- Full Text:
- Date Issued: 2001
The influence of a methylated-β-Cyclodextrin on the solubility and photostability of midazolam in aqueous solution
- Authors: Lebete, Mosimotsana Leah
- Date: 2001 , 2013-04-26
- Subjects: Midazolam -- Solubility
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3823 , http://hdl.handle.net/10962/d1005923 , Midazolam -- Solubility
- Description: Midazolam, used clinically as an anticonvulsant, anxiolytic, muscle relaxant and sedative is a photolabile imidazo-benzodiazepine which is marketed under the trade names Dormicum® and Hypnovel® as tablets and injectables. Because of an aqueous solubility of < 0.1 mg/ml above pH 4, the preparation of aqueous dosage formulations near physiological pH, requires a solubilizer. The aim of this study was thus to prepare a 10 mg/ml midazolam aqueous solution for topical application using randomly-methylated-pcyclodextrin (RAMEB), considered to be a suitable candidate as a solubilizer because of its absorption enhancing properties, and to investigate its effect on both the solubility and the photostability of midazolam. Solubility studies of midazolam (excess of 15 mg/ml) in the presence of 0, 5,10,20, 30% m/v of RAMEB at pH 5.0 and pH 5.8 (phosphate buffer) were undertaken and the results analyzed using a UV method validated for linearity, accuracy, precision and specificity. A stability-indicating HPLC method was developed and validated (precision and accuracy, linearity, range, limit of quantitation, specificity, robustness and ruggedness) for application to kinetic photostability studies and the identification of photodegradants by LC-MS. Forced degradation studies were carried out at concentrations of 0.5 mg/ml of midazolam instead of the target concentration of 10 mg/ml because of the acceleratory effect of the decreased concentration on the rate of photodegradation. The solutions of midazolam with and without RAMEB were irradiated at 550 W/m² for 12 hrs in order to degrade the drug to ± 10% of the original concentration. The UV method proved to be valid in terms of linearity with a correlation coefficient of 0.9998, precise and accurate, and specific for the determination of midazolam in the presence of RAMEB. The results of the phase solubility studies indicated that desired solubility of 10 mg/ml was achieved with 30% m/v RAMEB at pH 5.0. RAMEB slightly decreased the photostability of midazolam, the rate constants being 0.137 and 0.154 hr⁻¹ in the absence and presence of RAMEB, respectively. LC-MS analysis revealed that one of the major photoproducts in the presence and absence of RAMEB was N-desalkylflurazepam, a starting material in the synthesis of midazolam. RAMEB inhibited formation of some photoproducts and introduced two new photoproducts, a dimer and an addition product. The difference in the nature of these photoproducts formed may be attributed to the ability of RAMEB to provide conformational control and to stabilize free radicals. Although RAMEB improved the solubility of midazolam to the target concentration, photostability is decreased with the presence of different photoproducts. These studies have however provided information on the overall photostability of midazolam, the identity of its photodegradants and the photodegradation pathway in the presence and absence of RAMEB, and may be used for further method development and validation for the analysis of aqueous dosage forms containing RAMEB as a solubilizer. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
- Authors: Lebete, Mosimotsana Leah
- Date: 2001 , 2013-04-26
- Subjects: Midazolam -- Solubility
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3823 , http://hdl.handle.net/10962/d1005923 , Midazolam -- Solubility
- Description: Midazolam, used clinically as an anticonvulsant, anxiolytic, muscle relaxant and sedative is a photolabile imidazo-benzodiazepine which is marketed under the trade names Dormicum® and Hypnovel® as tablets and injectables. Because of an aqueous solubility of < 0.1 mg/ml above pH 4, the preparation of aqueous dosage formulations near physiological pH, requires a solubilizer. The aim of this study was thus to prepare a 10 mg/ml midazolam aqueous solution for topical application using randomly-methylated-pcyclodextrin (RAMEB), considered to be a suitable candidate as a solubilizer because of its absorption enhancing properties, and to investigate its effect on both the solubility and the photostability of midazolam. Solubility studies of midazolam (excess of 15 mg/ml) in the presence of 0, 5,10,20, 30% m/v of RAMEB at pH 5.0 and pH 5.8 (phosphate buffer) were undertaken and the results analyzed using a UV method validated for linearity, accuracy, precision and specificity. A stability-indicating HPLC method was developed and validated (precision and accuracy, linearity, range, limit of quantitation, specificity, robustness and ruggedness) for application to kinetic photostability studies and the identification of photodegradants by LC-MS. Forced degradation studies were carried out at concentrations of 0.5 mg/ml of midazolam instead of the target concentration of 10 mg/ml because of the acceleratory effect of the decreased concentration on the rate of photodegradation. The solutions of midazolam with and without RAMEB were irradiated at 550 W/m² for 12 hrs in order to degrade the drug to ± 10% of the original concentration. The UV method proved to be valid in terms of linearity with a correlation coefficient of 0.9998, precise and accurate, and specific for the determination of midazolam in the presence of RAMEB. The results of the phase solubility studies indicated that desired solubility of 10 mg/ml was achieved with 30% m/v RAMEB at pH 5.0. RAMEB slightly decreased the photostability of midazolam, the rate constants being 0.137 and 0.154 hr⁻¹ in the absence and presence of RAMEB, respectively. LC-MS analysis revealed that one of the major photoproducts in the presence and absence of RAMEB was N-desalkylflurazepam, a starting material in the synthesis of midazolam. RAMEB inhibited formation of some photoproducts and introduced two new photoproducts, a dimer and an addition product. The difference in the nature of these photoproducts formed may be attributed to the ability of RAMEB to provide conformational control and to stabilize free radicals. Although RAMEB improved the solubility of midazolam to the target concentration, photostability is decreased with the presence of different photoproducts. These studies have however provided information on the overall photostability of midazolam, the identity of its photodegradants and the photodegradation pathway in the presence and absence of RAMEB, and may be used for further method development and validation for the analysis of aqueous dosage forms containing RAMEB as a solubilizer. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
Applicability of a health literacy test from the U.S. in a South African population
- Lecoko, Motlalepule Lebogang Elizabeth
- Authors: Lecoko, Motlalepule Lebogang Elizabeth
- Date: 2001 , 2013-04-29
- Subjects: Literacy , Literacy -- South Africa , Literacy -- Ability testing , Reading -- Ability testing
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3824 , http://hdl.handle.net/10962/d1005931 , Literacy , Literacy -- South Africa , Literacy -- Ability testing , Reading -- Ability testing
- Description: This thesis investigates the suitability and applicability of a health literacy test from the U.S. in a black, Xhosa-speaking, South African population. The concept of literacy is a controversial one which has been much debated, as it is not easy to classifY people as simply either literate or illiterate. As a result there are a number of definitions of literacy that vary with purpose and culture, but the most common one is that a person is literate if he/she can read and write. Estimating literacy from years of schooling is an inexpensive method but is also unreliable, since people generally read 3 to 5 grades below their stated educational level. This method affords little insight into the ability of patients to adequately function in a health care enviromnent, an ability which is referred to as functional health literacy. A number of health literacy tests such as the REALM (Rapid Estimate of Adult Literacy in Medicine) test have been developed to assess this skill. The REALM test is a word recognition test which places people into a relevant grade range estimate according to the number of words pronounced correctly. It appears to assume understanding of the word if the person is able to read that word correctly. In this project 125 black Xhosa-speaking respondents of varying educational levels who were literate in English were interviewed with the aid of an interpreter. Comprehensive demographic data were collected. Respondents were first asked to read all 66 words aloud during which time pronunciation was checked, and thereafter they were asked to explain each word. It was found that the ability to automatically decode and read the words did not necessarily guarantee comprehension of these words. Many of the words proved to be unfamiliar to the majority of the Xhosa respondents who were able to pronounce them correctly, but could not explain them. These tended to be phonetically transparent words which were therefore more accessible to the unfamiliar reader. This research has proven to be of great value in helping identify such words which should be substituted with simpler words for use in health information materials. A number of words could neither be pronounced nor understood by the population majority and, interestingly, a small group of words could not be pronounced but were satisfactorily explained by some respondents. The results showed an extremely poor correlation between the stated educational level and the REALM grade range estimate. This emphasizes the inappropriateness of years of formal schooling as an indicator of functional health literacy. The criteria were established for deciding cases in which the REALM test could be applied (or succeeds) and when it is inapplicable (or fails). It was found to be inapplicable in 41% of cases which clearly indicates that, in its current form, it is not a valid, reliable test to use in determining health literacy in this English second language population. It can, however, be used as a basis fur the development of a more appropriate test. Recommendations for future research direction are presented and an alternative structure for a health literacy test is suggested. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
- Authors: Lecoko, Motlalepule Lebogang Elizabeth
- Date: 2001 , 2013-04-29
- Subjects: Literacy , Literacy -- South Africa , Literacy -- Ability testing , Reading -- Ability testing
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3824 , http://hdl.handle.net/10962/d1005931 , Literacy , Literacy -- South Africa , Literacy -- Ability testing , Reading -- Ability testing
- Description: This thesis investigates the suitability and applicability of a health literacy test from the U.S. in a black, Xhosa-speaking, South African population. The concept of literacy is a controversial one which has been much debated, as it is not easy to classifY people as simply either literate or illiterate. As a result there are a number of definitions of literacy that vary with purpose and culture, but the most common one is that a person is literate if he/she can read and write. Estimating literacy from years of schooling is an inexpensive method but is also unreliable, since people generally read 3 to 5 grades below their stated educational level. This method affords little insight into the ability of patients to adequately function in a health care enviromnent, an ability which is referred to as functional health literacy. A number of health literacy tests such as the REALM (Rapid Estimate of Adult Literacy in Medicine) test have been developed to assess this skill. The REALM test is a word recognition test which places people into a relevant grade range estimate according to the number of words pronounced correctly. It appears to assume understanding of the word if the person is able to read that word correctly. In this project 125 black Xhosa-speaking respondents of varying educational levels who were literate in English were interviewed with the aid of an interpreter. Comprehensive demographic data were collected. Respondents were first asked to read all 66 words aloud during which time pronunciation was checked, and thereafter they were asked to explain each word. It was found that the ability to automatically decode and read the words did not necessarily guarantee comprehension of these words. Many of the words proved to be unfamiliar to the majority of the Xhosa respondents who were able to pronounce them correctly, but could not explain them. These tended to be phonetically transparent words which were therefore more accessible to the unfamiliar reader. This research has proven to be of great value in helping identify such words which should be substituted with simpler words for use in health information materials. A number of words could neither be pronounced nor understood by the population majority and, interestingly, a small group of words could not be pronounced but were satisfactorily explained by some respondents. The results showed an extremely poor correlation between the stated educational level and the REALM grade range estimate. This emphasizes the inappropriateness of years of formal schooling as an indicator of functional health literacy. The criteria were established for deciding cases in which the REALM test could be applied (or succeeds) and when it is inapplicable (or fails). It was found to be inapplicable in 41% of cases which clearly indicates that, in its current form, it is not a valid, reliable test to use in determining health literacy in this English second language population. It can, however, be used as a basis fur the development of a more appropriate test. Recommendations for future research direction are presented and an alternative structure for a health literacy test is suggested. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2001
The development and assessment of both a separate, once-daily modified release matrix formulation of metoprolol tartrate and a combination formulation with hydrochlorothiazide
- Authors: Arjun, Jessica
- Date: 2001
- Subjects: Metoprolol -- Controlled release , Chlorothiazide -- Controlled release , Diuretics , Hypertension -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3742 , http://hdl.handle.net/10962/d1003220 , Metoprolol -- Controlled release , Chlorothiazide -- Controlled release , Diuretics , Hypertension -- Treatment
- Description: The use of controlled release dosage forms has increased significantly in recent years as they result in increased patient compliance and higher therapeutic efficiency. This research focused on the development of a once daily dosage form that could be used for the treatment of hypertension. Both a separate sustained release dosage of metoprolol tartrate and a combination dosage form that included both an immediate release hydrochlorothiazide and a sustained release metoprolol component, were developed and evaluated. A matrix tablet, consisting of an ethylcellulose ranulation of metoprolol tartrate compressed into a hydrophilic hydroxypropyl methylcellulose polymer matrix, effectively sustained metoprolol release over a 22-hour experimental period. A multiparticulate combination dosage form that consisted of six coated mini matrix tablets of metoprolol and a powder blend of hydrochlorothiazide packed into a gelatin capsule, displayed zero order release kinetics for metoprolol release over 22 hours (r2=0.9946). The release of hydrochlorothiazide was found to be comparable to that of a commercially available product tested. Differential Scanning Calorimetry was used to identify possible incompatibilities between MPTA and excipients initially, and long term stability testing was used to assess to behaviour of the dosage form. Dissolution testing of the dosage forms was performed using USP Apparatus III, which was found to be more discriminating between the batches assessed. Dissolution curves were evaluated for similarity and difference using f1 and f2 fit factors. Samples were analyzed using a high performance liquid chromatographic method that was developed and validated for the simultaneous determination of the compounds of interest. Various factors influencing drug release from the developed dosage forms were assessed and recommendations for further optimization of the formulation are made. Factors evaluated included the quantity of granulating fluid, matrix polymer content, drug load and process variables, including drying time and compression force. The influence of various coating levels on drug release was assessed and none of the levels assessed were found to adequately retarded drug release over a 22-hour period. Combinations of tablets coated to different levels allowed for the successful development of a sustained release metoprolol component, which could be included into the combination dosage form.
- Full Text:
- Date Issued: 2001
- Authors: Arjun, Jessica
- Date: 2001
- Subjects: Metoprolol -- Controlled release , Chlorothiazide -- Controlled release , Diuretics , Hypertension -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3742 , http://hdl.handle.net/10962/d1003220 , Metoprolol -- Controlled release , Chlorothiazide -- Controlled release , Diuretics , Hypertension -- Treatment
- Description: The use of controlled release dosage forms has increased significantly in recent years as they result in increased patient compliance and higher therapeutic efficiency. This research focused on the development of a once daily dosage form that could be used for the treatment of hypertension. Both a separate sustained release dosage of metoprolol tartrate and a combination dosage form that included both an immediate release hydrochlorothiazide and a sustained release metoprolol component, were developed and evaluated. A matrix tablet, consisting of an ethylcellulose ranulation of metoprolol tartrate compressed into a hydrophilic hydroxypropyl methylcellulose polymer matrix, effectively sustained metoprolol release over a 22-hour experimental period. A multiparticulate combination dosage form that consisted of six coated mini matrix tablets of metoprolol and a powder blend of hydrochlorothiazide packed into a gelatin capsule, displayed zero order release kinetics for metoprolol release over 22 hours (r2=0.9946). The release of hydrochlorothiazide was found to be comparable to that of a commercially available product tested. Differential Scanning Calorimetry was used to identify possible incompatibilities between MPTA and excipients initially, and long term stability testing was used to assess to behaviour of the dosage form. Dissolution testing of the dosage forms was performed using USP Apparatus III, which was found to be more discriminating between the batches assessed. Dissolution curves were evaluated for similarity and difference using f1 and f2 fit factors. Samples were analyzed using a high performance liquid chromatographic method that was developed and validated for the simultaneous determination of the compounds of interest. Various factors influencing drug release from the developed dosage forms were assessed and recommendations for further optimization of the formulation are made. Factors evaluated included the quantity of granulating fluid, matrix polymer content, drug load and process variables, including drying time and compression force. The influence of various coating levels on drug release was assessed and none of the levels assessed were found to adequately retarded drug release over a 22-hour period. Combinations of tablets coated to different levels allowed for the successful development of a sustained release metoprolol component, which could be included into the combination dosage form.
- Full Text:
- Date Issued: 2001
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