Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.694083
Title: Delivery of tyrosine kinase inhibitor to colorectal cancer cells using particulate systems
Author: Mustafa, Wesam Waleed
ISNI:       0000 0004 5989 9372
Awarding Body: Kingston University
Current Institution: Kingston University
Date of Award: 2016
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Abstract:
Solid dispersions have been employed as a method for improving the dissolution, and hence the bioavailability, and targeting the colon by Class II poorly-water soluble drugs. This project aims to enhance the solubility of the poorly water-soluble drug gefitinib (ZD), which is the first selective epidermal growth factor (EGFR) tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. Furthermore, to target the colon to improve the efficacy and to reduce the adverse effects of ZD by formulation as solid dispersions using spray drying. Methylmethacrylate polymers such as Eudragit S 100 was used for colon targeting, and Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC) were used to enhance the solubility of the drug. A rapid, cost-effective and precise reverse phase HPLC method has been developed to quantify ZD in the formulated solid dispersions. This method was validated using the recommended procedure, and it met the pharmaceutical industry guidelines that are recommended by the ICH and FDA. The developed method of analysis was reproducible, specific, and has demonstrated a isocratic separation mode of ZD. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD_, scanning electron microscope (SEM), and attenuated total reflectance (ATR) were used to investigate the crystalline structure changes of ZD in the dispersion as well as the molecular interaction between the drug and polymer, Dissolution studies (DS) were performed across a range of pH values. Formulations were evaluated by cytotoxicity studies (MTT & Neural red tests) using Caco-2 cell line. A rotating modified cylinder method was used to evaluate the duration of adhesion of HPMC and PVP formulated solid dispersions to excised goat intestine. DSC and XRPD studies confirmed that the spray dried dispersions were amorphous. Infrared spectroscopic experiments revealed the formation of hydrogen bonds between the drug and the two polymers used in the study. Dissolution studies showed a carrier controlled drug release that was achieved with solid dispersion containing a 10% drug loading with 80:20 PVP- Eudragit S 100, and HPMC- Eudragit S 100. The morphological differences between the pure drug, physical mixtures and solid dispersions were evident from the SEM images. The images revealed that the pure drug particles were needle shaped; the particle size was reduced in the solid dispersions that subsequently enhanced the drug dissolution profile. The formulated solid dispersions were subjected to accelerated storage conditions (40 [degrees]C [plus or minus] 2 [degrees] C/75%RH [plus or minus] 5%RH) over the period of 6 months. The presence of strong molecular interactions between drug and polymers and the high glass transition temperature of the resultant solid dispersions ensured they remained amorphous for at least six months under accelerated storage conditions. The mucoadhesion study showed that the HPMC solid dispersion formulations had a higher duration of adhesion than PVP solid dispersion formulation. The placebo formulation containing only the polymers showed no toxic effect on Caco-2 cell line in the cell viability assay. Therefore, it can be safely concluded that the formulated solid dispersions have no initial inhibitory effect compared to the pure drug.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.694083  DOI: Not available
Keywords: Cancer studies ; Pharmacy
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