Drug-eluting gastrointestinal (GI) stents are emerging as promising platforms for the treatment of GI cancers and provide the combined advantages of mechanical support to prevent lumen occlusion and as a reservoir for localized drug delivery to tumors. Therefore, in this work we present a detailed quality assurance study of 5-fluorouracil (5FU) drug-eluting stents (DESs) as potential candidates for the treatment of obstructive GI cancers.
The 5FU DESs were fabricated via a simple two-step sequential dip-coating process of commercial GI self-expanding nitinol stents with a 5FU-loaded polyurethane basecoat and a drug-free protective poly(ethylene-co-vinyl acetate) topcoat. The drug loading, content uniformity and drug stability were determined using a validated high-performance liquid chromatography (HPLC) method, which is also recommended in the United States Pharmacopeia. In vitro drug release studies were performed in phosphate buffered saline to determine the drug releasing properties of the two 5FU-loaded stents. Gas chromatography (GC) and HPLC were employed to determine total residual tetrahydrofuran and N,N-dimethylformamide in the stents remaining from the manufacturing process. Sterilization of the stents was performed using gamma radiation and stability testing was carried out for 3 months.
The drug loading analysis revealed excellent uniformity in the distribution of 5FU between and within individual stents. Determination of drug stability in the biorelevant release media confirmed that 5FU remains stable over 100 d. In vitro drug release studies from the stents revealed sustained release of 5FU across two different time scales (161 and 30 d), and mathematical modeling of drug release profiles revealed a diffusion-controlled mechanism for the sustained 5FU release. GC and HPLC analysis revealed that the daily residual solvent leached from the stents was below the United States (US) Food and Drug Administration (FDA) guidelines, and therefore, unlikely to cause localized/systemic toxicities. Sterilization of the stents with gamma radiation and accelerated stability tests over a period of 3 months revealed no significant effect on the stability or in vitro release of 5FU.