Analytical Studies Concerning the Stability of Betamethasone Valerate and Fusidic acid Hemihydrate in Topical Pharmaceutical Preparations

The research work presented in this thesis describes studies concerning the stability of the drug substances betamethasone 17-valerate and fusidic acid hemihydrate in topical pharmaceutical formulations. In particular, the work concentrates on formulation factors affecting the intra-molecular isomerisation of betamethasone 17-valerate to 21-valerate in a developmental topical cream for treatment of atopic dermatitis and psoriasis. Appropriate analytical tools for the simultaneous analysis of both drug substances have been developed and their suitability for use in the study demonstrated by validation experiments. The results of the isomerisation study indicate that the concentration of the emulsifier macrogolstearylether-21 significantly influences the isomerisation rate of the glucocorticoid. 5 % (w/w) of this substance in the formulation resulted in complete isomerisation within a number of months, whereas 1.5 % (w/w) gave rise to less than 3 % isomerisation after 3 years storage. The study data was used to develop a new topical drug formulation containing both betamethasone 17-valerate and fusidic acid which went to market in early 2017. Additionally, the influence of the polymorphic form of fusidic acid on its stability was investigated. Fusidic acid is known to exist in 4 polymorphic modifications and this study has shown that polymorphic forms I and III are currently available on the commercial market. Intrinsic dissolution – and in-vitro permeation studies demonstrate that both polymorphs have similar intrinsic dissolution rates, as well as comparable in-vitro release rates from the developmental cream. This indicates that both forms may be used interchangeably without affecting the safety and efficacy of concerned drug products. Finally, the plausibility of incorporating both drug substances into electrospun poly(caprolactone) (PCL) microfibers for potential use as an occlusive medicated dressing was examined. The effect of addition of the novel low molecular weight gelator, Fmoc-OH-C18, on the manufacture of the microfibers as well as on their in-vitro drug release rates was studied. The gelator was found to have a profound effect on the morphology of the resulting fibers but had little effect on the release rate of the active drug substances. The results suggest that the use of a medicated electrospun dressing containing betamethasone valerate and fusidic acid might be a viable treatment alternative to the current topical dosage forms. However, significant further work is needed in this regard

Analytical Studies Concerning the Stability of Betamethasone Valerate and Fusidic acid Hemihydrate in Topical Pharmaceutical Preparations

The research work presented in this thesis describes studies concerning the stability of the drug substances betamethasone 17-valerate and fusidic acid hemihydrate in topical pharmaceutical formulations. In particular, the work concentrates on formulation factors affecting the intra-molecular isomerisation of betamethasone 17-valerate to 21-valerate in a developmental topical cream for treatment of atopic dermatitis and psoriasis. Appropriate analytical tools for the simultaneous analysis of both drug substances have been developed and their suitability for use in the study demonstrated by validation experiments. The results of the isomerisation study indicate that the concentration of the emulsifier macrogolstearylether-21 significantly influences the isomerisation rate of the glucocorticoid. 5 % (w/w) of this substance in the formulation resulted in complete isomerisation within a number of months, whereas 1.5 % (w/w) gave rise to less than 3 % isomerisation after 3 years storage. The study data was used to develop a new topical drug formulation containing both betamethasone 17-valerate and fusidic acid which went to market in early 2017. Additionally, the influence of the polymorphic form of fusidic acid on its stability was investigated. Fusidic acid is known to exist in 4 polymorphic modifications and this study has shown that polymorphic forms I and III are currently available on the commercial market. Intrinsic dissolution – and in-vitro permeation studies demonstrate that both polymorphs have similar intrinsic dissolution rates, as well as comparable in-vitro release rates from the developmental cream. This indicates that both forms may be used interchangeably without affecting the safety and efficacy of concerned drug products. Finally, the plausibility of incorporating both drug substances into electrospun poly(caprolactone) (PCL) microfibers for potential use as an occlusive medicated dressing was examined. The effect of addition of the novel low molecular weight gelator, Fmoc-OH-C18, on the manufacture of the microfibers as well as on their in-vitro drug release rates was studied. The gelator was found to have a profound effect on the morphology of the resulting fibers but had little effect on the release rate of the active drug substances. The results suggest that the use of a medicated electrospun dressing containing betamethasone valerate and fusidic acid might be a viable treatment alternative to the current topical dosage forms. However, significant further work is needed in this regard

Performance of the Child Maintenance and Enforcement Commission: memorandum for the House of Commons Work and Pensions Committee

"This memorandum has been prepared for the House of Commons Work and Pensions Committee to provide an update on the performance of the current statutory child maintenance schemes, following completion of a three year improvement plan. This memorandum also sets out the progress made by the Child Maintenance and Enforcement Commission towards redesigning the child maintenance system in Great Britain, as set out in the Child Maintenance and Other Payments Act 2008" - clause 1.

Interaction Issues in Computer Aided Semantic\ud Annotation of Multimedia

The CASAM project aims to provide a tool for more efficient and effective annotation of multimedia documents through collaboration between a user and a system performing an automated analysis of the media content. A critical part of the project is to develop a user interface which best supports both the user and the system through optimal human-computer interaction. In this paper we discuss the work undertaken, the proposed user interface and underlying interaction issues which drove its development

DNA charge neutralisation by linear polymers I: irreversible binding

We develop a deterministic mathematical model to describe the way in which polymers bind to DNA by considering the dynamics of the gap distribution that forms when polymers bind to a DNA plasmid. In so doing, we generalise existing theory to account for overlaps and binding cooperativity whereby the polymer binding rate depends on the size of the overlap The proposed mean-field models are then solved using a combination of numerical and asymptotic methods. We find that overlaps lead to higher coverage and hence higher charge neutralisations, results which are more in line with recent experimental observations. Our work has applications to gene therapy where polymers are used to neutralise the negative charges of the DNA phosphate backbone, allowing condensation prior to delivery into the nucleus of an abnormal cell

DNA charge neutralisation by linear polymers II: reversible binding

We model the way in which polymers bind to DNA and neutralise its charged backbone by analysing the dynamics of the distribution of gaps along the DNA. We generalise existing theory for irreversible binding to construct new deterministic models which include polymer removal, movement along the DNA and allow for binding with overlaps. We show that reversible binding alters the capacity of the DNA for polymers by allowing the rearrangement of polymer positions over a longer timescale than when binding is irreversible. When the polymers do not overlap, allowing reversible binding increases the number of polymers adhered and hence the charge that the DNA can accommodate; in contrast, when overlaps occur, reversible binding reduces the amount of charge neutralised by the polymers

Guest inclusion by Borromean weave coordination networks

Reaction of N,Nʺ-ethylene-1,2-diylbis(3-pyridin-3-ylurea) (L) with AgNO3 in a variety of solvents gives a total of five 2-D Borromean weave coordination polymer networks that adopt three structural types depending on the interactions to the solvent pocket. The Borromean network is of formula [Ag2(L)3](NO3)2 ·solvent where the solvent is either a cluster of water molecules, mixtures of water and acetonitrile, water and methanol or chloroform and methanol. The Borromean structure is a thermodynamic sink and under fast crystallization conditions an alternative 2 + 2 metallomacrocycle forms that can result in metallogel formation. The metallogel structure transforms into the crystalline Borromean network over time