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Cyclodextrin-based Formulations for Pulmonary Delivery of Chemotherapeutic Molecules

Binti Mohtar, Noratiqah; (2018) Cyclodextrin-based Formulations for Pulmonary Delivery of Chemotherapeutic Molecules. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

This study investigated cyclodextrin-based formulations for the delivery of fisetin (a flavonoid) and erlotinib (a tyrosine kinase inhibitor) to the lung. In the first part of the study, complexation of fisetin with β-cyclodextrin (β-CD) and its derivatives, namely hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was conducted. Complexation efficiency between fisetin and the cyclodextrins was in the order: SBE-β-CD > HP-β-CD > β-CD. Utilisation of 20%v/v ethanol during complexation with SBE-β-CD improved the solubilisation of fisetin 5.9-fold compared to using water alone. Spray-drying of the fisetin-SBE-β-CD complex from 20%v/v ethanol feed solution, produced a powder with a 2-fold increase in the fine particle fraction (FPF) compared to the spray-dried powder produced from a feed solution containing water alone, when characterised using the Next Generation Impactor (NGI). Addition of 20%w/w leucine into the powder produced from the ethanolic feed solution further improved the FPF by 2.3-fold compared to the powder without leucine. The preparation showed an unchanged cytotoxic activity of fisetin against the human lung adenocarcinoma (A549) cell line, when compared to fisetin solution. In the second part of the study, combinations of fisetin with three tyrosine kinase inhibitors (i.e. erlotinib, gefitinib, crizotinib) were evaluated for their cytotoxic activity against the A549 cell line. Combination of erlotinib and fisetin at 1: 2 molar ratio, showed the highest synergism in cell killing, when analysed using the median effect principle method. This combination was then used to form a complex with SBE-β-CD. Further improvement in the solubility of erlotinib and fisetin, was achieved with the addition of 50%v/v ethanol during complexation, compared to using water alone. The complex solution was lyophilised and reconstituted into a 3-times more concentrated preparation, prior to nebulisation into the NGI. The preparation showed a suitable aerosol size for inhalation of both drugs. In conclusion, cyclodextrin-based formulations in the form of a dry powder inhalation and nebuliser solution, showed promise for pulmonary delivery of fisetin and its combination with erlotinib, respectively, in the treatment of non-small cell lung cancer (NSCLC).

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Cyclodextrin-based Formulations for Pulmonary Delivery of Chemotherapeutic Molecules
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10054726
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