McDonald Bernard F, Quinn Alison M, Devers Tomas, Cullen Alan, Coulter Ivan S, Marison Ian W, Loughran Sinéad T
Sigmoid Pharma Ltd., Dublin City University, Dublin, Ireland; Laboratory of Integrated Bioprocessing, Dublin City University, Dublin, Ireland.
J Pharm Pharmacol. 2015 May;67(5):685-95. doi: 10.1111/jphp.12372. Epub 2015 Feb 3.
Colorectal cancer (CRC) is a life-threatening disease that can develop as a consequence of a sustained chronic inflammatory pathology of the colon. Although not devoid of side effects, the anti-inflammatory drug celecoxib (CLX) has been shown to exert protective effects in CRC therapy. The purpose of this study was to develop and characterise a novel CLX microbead formulation suitable for use in the treatment and prevention of CRC, which has the potential to minimise the side effects associated with CLX.
The study involved the assessment of the effectiveness of CLX formulations in an in-vitro cell model (HT29 cells) and a comparison of these effects to that of the marketed CLX product, Celebrex. Liquid CLX formulations were developed as precursors to microbead formulations. The effect of liquid CLX formulations on HT29 cell viability (MTT and flow cytometry apoptotic assays) and motility (scratch wound assay) were assessed and compared with the effect of Celebrex. A correlation between the in-vitro dissolution performance of the formulations and the effect in the cell model was also explored. Liquid CLX formulations were translated into an optimised CLX microbead formulation, and a colonic targeted sustained release coat (Surelease) was applied to the beads with the aim of producing a formulation for a future in-vivo study to compare the effect of the coated CLX microbeads versus Celebrex in the attenuation of CRC tumours and inflammation in a CRC murine model. The production of CLX microbeads was scaled-up using vibrating-jet encapsulation technology to allow for the development of an optimised dissolution profile to enable colonic release.
In-vitro cell viability and motility were shown to be significantly reduced after treatment with CLX liquid formulations relative to the control, whereas the results for treatment with Celebrex were comparable with the control. Dissolution experiments and correlation analysis demonstrated that the formulations that showed a greater extent of drug release had reduced cell viability and motility. The CLX liquid formulations were translated into colon-targeted CLX microbeads suitable for use in a future in-vivo mouse study.
These results represent a significant step forward in the chemopreventative treatment of CRC using CLX, as the microbead formulation developed suggests the possibility of presenting CLX in a format that has the potential to minimise gastrointestinal and cardiovascular side effects.
结直肠癌（CRC）是一种危及生命的疾病，可因结肠持续的慢性炎症病变而发展。尽管抗炎药物塞来昔布（CLX）并非没有副作用，但已显示其在CRC治疗中具有保护作用。本研究的目的是开发并表征一种适用于CRC治疗和预防的新型CLX微珠制剂，该制剂有可能将与CLX相关的副作用降至最低。
该研究涉及在体外细胞模型（HT29细胞）中评估CLX制剂的有效性，并将这些效果与市售CLX产品西乐葆进行比较。液体CLX制剂被开发为微珠制剂的前体。评估液体CLX制剂对HT29细胞活力（MTT和流式细胞术凋亡检测）和运动性（划痕试验）的影响，并与西乐葆的效果进行比较。还探讨了制剂的体外溶出性能与细胞模型中效果之间的相关性。将液体CLX制剂转化为优化的CLX微珠制剂，并在微珠上应用结肠靶向缓释包衣（Surelease），目的是制备一种用于未来体内研究的制剂，以比较包衣CLX微珠与西乐葆在CRC小鼠模型中减轻CRC肿瘤和炎症方面的效果。使用振动喷射包封技术扩大CLX微珠的生产规模，以开发优化的溶出曲线，实现结肠释放。
相对于对照组，用CLX液体制剂处理后，体外细胞活力和运动性显著降低，而用西乐葆处理的结果与对照组相当。溶出实验和相关性分析表明，药物释放程度较大的制剂细胞活力和运动性降低。CLX液体制剂被转化为适合未来体内小鼠研究的结肠靶向CLX微珠。
这些结果代表了使用CLX进行CRC化学预防治疗的重要进展，因为所开发的微珠制剂表明有可能以一种有可能将胃肠道和心血管副作用降至最低的形式呈现CLX。
