Development of Hydrophobized Alginate Hydrogels for the Vessel-Simulating Flow-Through Cell and Their Usage for Biorelevant Drug-Eluting Stent Testing
The vessel-simulating flow-through cell (vFTC) has been used to examine release and distribution from drug-eluting stents in an in vitro model adapted to the stent placement in vivo. The aim of this study was to examine the effect of the admixture of different hydrophobic additives to the vessel wall simulating hydrogel compartment on release and distribution from model substance-coated stents. Four alginate-based gel formulations containing reversed-phase column microparticles LiChroprep® RP-18 or medium-chain triglycerides in form of preprocessed oil-in-water emulsions Lipofundin® MCT in different concentrations were successfully developed. Alginate and modified gels were characterized regarding the distribution coefficient for the fluorescent model substances, fluorescein and triamterene, and release as well as distribution of model substances from coated stents were investigated in the vFTC. Distribution coefficients for the hydrophobic model substance triamterene and the hydrophobized gel formulations were up to four times higher than for the reference gel. However, comparison of the obtained release profiles yielded no major differences in dissolution and distribution behavior for both fluorescent model substances (fluorescein, triamterene). Comparison of the test results with mathematically modeled data acquired using finite element methods demonstrated a good agreement between modeled data and experimental results indicating that gel hydrophobicity will only influence release in cases of fast releasing stent coatings.
KEY WORDSbiorelevant dissolution testing drug-eluting stent hydrophobized hydrogel release vessel-simulating flow-through cell
The authors thank Biotronik SE & Co. KG (Berlin, Germany) for supplying bare metal stent platforms. We are also grateful for the supply of Eudragit® by Evonik Industries AG (Essen, Germany). Additionally, the authors would like to acknowledge the laboratory work of Katja Semper, Marcus Schewe, and Thomas Brand. Furthermore, thanks are given to Grzegorz Garbacz for proposals regarding this work. This research was funded by the Federal Ministry of Education and Research (BMBF) within REMEDIS “Höhere Lebensqualität durch neuartige Mikroimplantate”.
- 7.Westedt U, Wittmar M, Hellwig M, Hanefeld P, Greiner A, Schaper AK, et al. Paclitaxel releasing films consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) and their potential as biodegradable stent coatings. J Contr Release. 2006;111(1–2):235–46. doi: 10.1016/j.jconrel.2005.12.012.CrossRefGoogle Scholar
- 11.Merciadez M, Alquier L, Metha R, Patel A, Wang A. A novel method for the elution of sirolimus (rapamycin) in drug-elution stents. Dissolution Technol. 2011; November: 37–42.Google Scholar
- 15.Thakkar AS, Abhyankar AD, Dani SI, Banker DN, Singh PI, Parmar SA, et al. Systemic exposure of sirolimus after coronary stent implantation in patients with de novo coronary lesions: Supralimus-Core® pharmacokinetic study. Indian Heart J. 2012;64(3):273–9.Google Scholar
- 17.Neubert A, Sternberg K, Nagel S, Harder C, Schmitz K-P, Kroemer HK, et al. Development of a vessel-simulating flow-through cell method for the in vitro evaluation of release and distribution from drug-eluting stents. J Contr Release. 2008;130(1):2–8. doi: 10.1016/j.jconrel.2008.05.012.CrossRefGoogle Scholar
- 22.Draget KI, Smidsrød O, Skjåk-Bræk G. Alginates from algae. Biopolymers Online. 2005. DOI: 10.1002/3527600035.bpol6008Google Scholar
- 25.Kanakasabai P, Vijay P, Deshpande AP, Varughese S. Crosslinked poly(vinyl alcohol)/sulfonated poly(ether ether ketone) blend membranes for fuel cell applications—surface energy characteristics and proton conductivity. J Power Sourc. 2011;196(3):946–55. doi: 10.1016/j.jpowsour.2010.08.094.CrossRefGoogle Scholar
- 32.Terry CM, Li L, Li H, Zhuplatov I, Blumenthal DK, Kim S-E, et al. In vivo evaluation of the delivery and efficacy of a sirolimus-laden polymer gel for inhibition of hyperplasia in a porcine model of arteriovenous hemodialysis graft stenosis. J Contr Release. 2012;160(3):459–67. doi: 10.1016/j.jconrel.2012.03.011.CrossRefGoogle Scholar
- 39.Di Mario C, Meneveau N, Gil R, de Jaegere P, de Feyter PJ, Slager CJ, et al. Maximal blood flow velocity in severe coronary stenoses measured with a Doppler guidewire: limitations for the application of the continuity equation in the assessment of stenosis severity. Am J Cardiol. 1993;71(14):D54–61. doi: 10.1016/0002-9149(93)90134-X.CrossRefGoogle Scholar
- 42.European Directorate for the Quality of Medicines & Healthcare. European Pharmacopoeia and Supplements 7.8 ed. Strassbourg.Google Scholar
- 43.Guilherme MR, Silva R, Girotto EM, Rubira AF, Muniz EC. Hydrogels based on PAAm network with PNIPAAm included: hydrophilic–hydrophobic transition measured by the partition of Orange II and Methylene Blue in water. Polymer. 2003;44(15):4213–9. doi: 10.1016/S0032-3861(03)00370-7.CrossRefGoogle Scholar