Pharmacy - Masters by Research Theses

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    The evaluation of estradiol and indomethacin for incorporation into microneedle formulations
    (University College Cork, 2022) Lalchandani, Akash Parsram; Crean, Abina; Faisal, Waleed; Enterprise Ireland
    The objective of this thesis is the technical evaluation of the suitability of drug substances, estradiol and indomethacin, for incorporation into a patented dissolvable microneedle (DMN) platform technology for intradermal drug delivery. Estradiol and indomethacin were chosen based on their physicochemical properties (melting point, glass transition temperature, amorphous solid state after melt-cooling) which were favourable for manufacturing microneedles using the melt DMN technology. Oral dosage forms of both drugs, and transdermal patches of estradiol are available in the market. Currently no indomethacin transdermal patch formulation is available. This project aims to assess the feasibility of developing dosage forms of both drugs for microneedle-assisted, intradermal delivery. The research presented, initially provides a background to the drivers and challenges related to the development of microneedle (MN) drug combination products for inclusion in the mainstream pharmaceutical and medical device market. The thesis then focuses on the experimental studies evaluating the feasibility of developing DMN from the drug substances of interest, estradiol and indomethacin. Melt-cooled samples of both drugs were also prepared to simulate the processing stress of the DMN manufacturing process. Melt-cooled samples were evaluated for solid-state form by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and chemical composition by high performance liquid chromatography. Microneedle formulations of both drugs were produced using a previously developed manufacturing process and their mechanical strength and ability to penetrate pig skin analysed. A stability study was conducted to evaluate chemical and solid-state stability of the melt-cooled samples at 3 storage conditions: condition A (25°C/60% RH), condition B (40°C/ 75% RH), and condition C (2°C to 8°C in nitrogen filled vials) over a 3 month time period. The melt-cooled solid form of both drugs post melting was found to be chemically stable over the period of 3 months when stored at all 3 storage conditions studied. The amorphous melt-cooled samples of both drugs showed greatest stability at 2°C to 8°C in nitrogen. However, DSC and PXRD results identified crystallisation of the melt-cooled estradiol and indomethacin samples to when stored at 25°C/60% RH and 40°C/ 75% RH over 3 months. This loss in amorphous form was paramount for indomethacin when stored at 40°C/ 75% RH. These results indicated the need for storage and packaging precautions for MN of both drugs to prevent solid-state alterations upon storage which could impact on MN mechanical strength and dissolution in the skin. The MNs formed from both drugs, using the melt dissolvable microneedle technology, were found to be physically strong and capable of penetrating ex-vivo pig ear skin. The research presented illustrated that estradiol and indomethacin DMN can be manufactured using a melt DMN technology, but packaging and storage precautions are required to stabilise the drug solid-state form.
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    The impact of variation in freezing and thawing process parameters on the critical quality attributes of a monoclonal antibody
    (University College Cork, 2019-09-23) Day, Neil; Crean, Abina; Vucen, Sonja
    Therapeutic proteins or biopharmaceuticals have been playing an ever-increasing role in the treatment of human diseases over last 40 years. One of the main challenges with manufacture of these proteins is the stabilization of both the finished product and its processing intermediates during storage. Freezing and frozen storage is widely applied to improve stability of the bulk drug substance. The process of freezing a protein results in stresses that can cause protein degradation and subsequent aggregation. The aim of this project was to evaluate the effect of parameters involved with freezing and thawing of a formulated monoclonal antibody solution in polycarbonate bottles and to assess the scalability of these experiments to the respective full-scale commercial process. Initial experiments were performed to characterise the formulation and develop analytical methods that can detect change in unfolding and aggregation of a fully human IgG1 monoclonal antibody (‘Protein Y’). A designed set of experiments were then executed to understand the effect of parameters involved in freezing and thawing steps of a formulated therapeutic protein solution on protein aggregation and perturbations in tertiary structure. Results showed that the processing parameters studied caused significant variation in freeze and thaw process times, with the factors causing slower rates of freeze and thaw also shown to cause changes in the tertiary structure of Protein Y. Despite the observed changes in tertiary structure, the effect on aggregation was less pronounced, with only a significant change noted for the polydispersity index (PdI), as measured by dynamic light scattering (DLS).