|Institution:||Dublin City University|
|Department:||School of Biotechnology|
|Keywords:||Biology; Pharmacology; Biochemistry; Colorectal cancer; Chemoprevention; Oral drug delivery; Targeted delivery|
|Full text PDF:||http://doras.dcu.ie/20409/|
The anti-inflammatory drug celecoxib (CLX) has been shown to exert protective effects in colorectal cancer (CRC) therapy. The primary objective of this study was to develop and characterize a novel CLX multiparticulate drug delivery technology suitable for use in the treatment and prevention of CRC which has the potential to minimize the side effects associated with CLX. Liquid CLX formulations were developed as precursors to CLX microbeads and the effect of formulated CLX samples on the viability and motility of a CRC cell line was examined. CLX liquid formulations were shown for the first time to have an enhanced effect in comparison to the marketed CLX product Celebrex®. Liquid CLX formulations were translated into an optimized CLX microbead formulation which met a number of pre-defined critical quality attributes. A sustained release coat was applied to the beads. An in-vivo study was performed to compare the effect of the coated CLX microbeads versus Celebrex® in the attenuation of CRC tumours and inflammation in a CRC mouse model. Whilst the level of CRC tumour attenuation and inflammation was comparable between both formulations, the CLX microbead statistically outperformed Celebrex®. Microbead production was scaled-up and subsequent coating optimisation studies were performed resulting in products that met pre-defined target product profiles for both murine and human colon delivery. Finally a screening study to assess the applicability of the platform formulation to a range of APIs other than CLX was performed with 50% of the actives screened being successfully incorporated into microbeads. In summary, the in-vitro and in-vivo results described in this thesis present a significant step forward in CRC therapy using CLX, as the microbead formulation developed poses the possibility of presenting CLX in a format that has the potential to minimize GI and CV side effects whilst enhancing the effectiveness of the treatment.