Development, assessment and optimisation of oral famciclovir formulations for paediatric use
- Authors: Magnus, Laura
- Date: 2012
- Subjects: Drugs -- Dosage forms , Drugs -- Analysis , Capsules (Pharmacy) , Antiviral agents , Pediatrics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3870 , http://hdl.handle.net/10962/d1018244
- Description: Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.
- Full Text:
- Authors: Magnus, Laura
- Date: 2012
- Subjects: Drugs -- Dosage forms , Drugs -- Analysis , Capsules (Pharmacy) , Antiviral agents , Pediatrics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3870 , http://hdl.handle.net/10962/d1018244
- Description: Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.
- Full Text:
Biology and systematics of some southern African myrmeleontoid insects (order Neuroptera)
- Authors: Mansell, Mervyn W
- Date: 1979
- Subjects: Ant lions -- Africa, Southern
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:5594 , http://hdl.handle.net/10962/d1002044
- Description: The biology of southern African Myrmeleontidae and Nemopteridae (Neuroptera, Myrmeleontoidea) was studied with special emphasis on the nemopterid subfamily Crocinae. The superfamily Myrmeleontoidea is considered to be a monophyletic group derived from ancestors similar to the family Nymphidae. The Myrmeleontidae and Nemopteridae are the most highly evolved families, and the Nemopteridae have a sistergroup relationship with the other four myrmeleontoid families. Within the Nemopteridae, the Crocinae are considered more advanced than the subfamily Nemopterinae. An account of previous work on the two families is presented: literature relating to the Myrmeleontidae is catalogued in appendix 2 and publications dealing with the Nemopteridae are surveyed in the text . Biological and morphological information derived from the immature stages as well as the adults was used in the systematic study of the two families. The geographical distribution and phylogeny of the Myrmeleontoidea is discussed with particular reference to the Myrmeleontidae and Nemopteridae. The Myrmeleontidae have a world wide distribution whilst the Nemopteridae are more restricted, being limited to the arid and semi-arid regions of the world. It is concluded that the two families originated on Gondwanaland, and their present distribution is explained on the basis of evidence provided by plate tectonics. In southern Africa, the Myrmeleontidae show two distributional trends: there is a distinct western fauna including many endemics and an eastern fauna which comprises taxa with a wide distribution in central and east Africa, extending their ranges into the eastern parts of the subregion. The Nemopteridae occur predominantly on the western side of the subcontinent and over 90% of the species are endemic to southern Africa. A systematic revision of the southern African Crocinae is presented and summarized in a set of illustrated keys to the adults and larvae. There are now ten known crocin species in four genera from the subregion, four species being described for the first time in this thesis. The larvae of all ten species and the eggs of seven, have been correlated with the adults and are described. Two crocin genera, Concroce and Thysanocroce, have larvae with short prothoraxes, whilst those in Laurhervasia and Tjederia are elongated. Larvae of the first two genera live in plant detritus under rocks and in crevices whereas larvae of the latter two genera inhabit small dusty caves. These findings on the Myrmeleontidae and Nemopteridae are discussed in the context of general systematic theory, phylogeny and zoogeography.
- Full Text:
- Authors: Mansell, Mervyn W
- Date: 1979
- Subjects: Ant lions -- Africa, Southern
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:5594 , http://hdl.handle.net/10962/d1002044
- Description: The biology of southern African Myrmeleontidae and Nemopteridae (Neuroptera, Myrmeleontoidea) was studied with special emphasis on the nemopterid subfamily Crocinae. The superfamily Myrmeleontoidea is considered to be a monophyletic group derived from ancestors similar to the family Nymphidae. The Myrmeleontidae and Nemopteridae are the most highly evolved families, and the Nemopteridae have a sistergroup relationship with the other four myrmeleontoid families. Within the Nemopteridae, the Crocinae are considered more advanced than the subfamily Nemopterinae. An account of previous work on the two families is presented: literature relating to the Myrmeleontidae is catalogued in appendix 2 and publications dealing with the Nemopteridae are surveyed in the text . Biological and morphological information derived from the immature stages as well as the adults was used in the systematic study of the two families. The geographical distribution and phylogeny of the Myrmeleontoidea is discussed with particular reference to the Myrmeleontidae and Nemopteridae. The Myrmeleontidae have a world wide distribution whilst the Nemopteridae are more restricted, being limited to the arid and semi-arid regions of the world. It is concluded that the two families originated on Gondwanaland, and their present distribution is explained on the basis of evidence provided by plate tectonics. In southern Africa, the Myrmeleontidae show two distributional trends: there is a distinct western fauna including many endemics and an eastern fauna which comprises taxa with a wide distribution in central and east Africa, extending their ranges into the eastern parts of the subregion. The Nemopteridae occur predominantly on the western side of the subcontinent and over 90% of the species are endemic to southern Africa. A systematic revision of the southern African Crocinae is presented and summarized in a set of illustrated keys to the adults and larvae. There are now ten known crocin species in four genera from the subregion, four species being described for the first time in this thesis. The larvae of all ten species and the eggs of seven, have been correlated with the adults and are described. Two crocin genera, Concroce and Thysanocroce, have larvae with short prothoraxes, whilst those in Laurhervasia and Tjederia are elongated. Larvae of the first two genera live in plant detritus under rocks and in crevices whereas larvae of the latter two genera inhabit small dusty caves. These findings on the Myrmeleontidae and Nemopteridae are discussed in the context of general systematic theory, phylogeny and zoogeography.
- Full Text:
The dramatic theory of William Hazlitt : "Imagination in criticism"
- De Villiers, André Rex Wepener
- Authors: De Villiers, André Rex Wepener
- Date: 1964
- Subjects: Hazlitt, William, 1778-1830 , Drama -- History and criticism -- 19th century , English drama -- History and criticism -- 19th century
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:2320 , http://hdl.handle.net/10962/d1013383
- Full Text:
- Authors: De Villiers, André Rex Wepener
- Date: 1964
- Subjects: Hazlitt, William, 1778-1830 , Drama -- History and criticism -- 19th century , English drama -- History and criticism -- 19th century
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:2320 , http://hdl.handle.net/10962/d1013383
- Full Text:
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