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Title: Developing fixed dose combinations for the geriatric population
Author: Bukhary, Haitham Abdulrahim
ISNI:       0000 0004 8507 5473
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Background: Successful therapeutic outcomes demand a patient's adherence to their dosage regimen, yet this is challenging to achieve among elderly people on multidrug therapies (polypharmacy). Therefore, it is the task of formulators to prepare medicines to minimise the burden on patients and maximise the likelihood of a dosage regimen being accurately followed. One route to improve adherence rates is to prepare fixed-dose-combinations (FDCs), in which multiple active ingredients are loaded into a single formulation. This thesis aims to develop different FDCs of multiple drug-polymer composite systems targeting specific conditions for the geriatric population utilising advanced pharmaceutical manufacturing techniques. Methods: Different biocompatible polymers were selected for each formulation based on dissolution behaviour in aqueous media. The polymers were mixed with the selected combination of drugs and then formulated. Initially, fast-dissolving materials based on poly(vinylpyrrolidone) (PVP) were generated by either film casting (a conventional technique used to prepare orodispersible films), or single-needle electrospinning (to prepare FDCs in the form of nanoscale fibres). Further modification of the electrospinning setup was then undertaken to prepare oral FDCs containing ibuprofen, famotidine, and prednisone. Three polymers (PVP, Eudragit-L100, and Eudragit-RSPO) were used to generate fibres, and sequential and multi-jet electrospinning employed to fabricated FDCs. Finally, core/shell fibres made of Eudragit-RLPO/PVP, as a platform for levodopa and carbidopa both equally loaded in each layer of the core and shell, for biphasic release oral FDCs was performed using coaxial electrospinning. Results: FDC in the form of PVP-based fast-dissolving oral films loaded with amlodipine besylate and valsartan were prepared by film casting between 5-30% w/w and electrospinning between 5-55% w/w. A comparison between the two types of formulations showed that 90% drug release could be achieved from the electrospun fibres within 2 minutes, while the cast film ODFs took 6 minutes. Next oral FDCs prepared from ibuprofen, famotidine, and prednisone proved the ability to generate different FDCs through modification of electrospinning setup by sequential and multi-jet electrospinning. Results from the in vitro drug release studies showed that the desired multi-phasic drug release could be obtained. This began with the immediate release of drug-loaded in the PVP layer instantly within ~1hr of sampling, followed by release from the Eudragit-L100 fibres triggered by the change of pH >6, and finally extended-release from the Eudragit-RSPO fibres to reach >80% after ~16 hours. Last FDC, the core/shell fibres gave similar release profiles for levodopa and carbidopa, with 50% immediate release from the PVP compartment, followed by 50% extended-release from Eudragit-RLPO. Overall the formulation provided the desired biphasic release profile. Conclusions: The appropriate selection of polymer and manufacturing technique, can fabricate effective drug-polymer composite systems for multiple drug delivery via FDCs. Ultimately, it is believed these could be applied to enhance patient adherence.
Supervisor: Orlu, M. ; Williams, G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available