In vitro study of sirolimus release from a drug-eluting stent: Comparison of the release profiles obtained using different test setups.
In this study drug release from the CYPHER™ stent, the gold standard in drug-eluting stent therapy until the end of its marketing in 2011/2012, was systematically evaluated using different in vitro release tests. The test systems included incubations setups, the reciprocating holder apparatus (USP7), the flow-through cell apparatus (USP4) and the vessel-simulating flow-through cell (vFTC) specifically designed for stent testing. The results obtained show a large variability regarding the fractions released into the media after 7d ranging from 38.6% ± 4.5% to 74.6% ± 1.2%. The lowest fraction released was observed in the vFTC and the highest in an incubation setup with frequently changed media of a volume of 2 mL. Differences were even observed when using fairly similar and simple incubations setups with mere changes of the media volume, under maintenance of sink conditions, and of the vessel geometry. From these data it can be concluded, that in vitro release even from a slow releasing drug-eluting stent is greatly influenced by the experimental conditions and care must be taken when choosing a suitable setup. Comparison of the obtained in vitro release profiles to published in vivo data did not result in a distinct superiority of any of the tested methods regarding the predictability for the situation in vivo due to large differences in the reported in vivo data. However, this comparison yielded that the release observed in vitro using the 2 mL incubation setup and the reciprocating holder apparatus may be faster than the reported in vivo release. The results of this study also emphasize the necessity to use highly standardized release tests when comparisons between results from different experiments or even different labs are to be performed. In this context, the compendial methods are most likely offering the highest degree of standardization.
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany. Electronic address: anne.seidlitz@uni-greifswald.de.
Anne
A
Seidlitz
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Wiebke
W
Schick
Institute for Biomedical Engineering, University of Rostock, 18119 Rostock, Germany.
Thomas
T
Reske
Institute for Biomedical Engineering, University of Rostock, 18119 Rostock, Germany.
Volkmar
V
Senz
Institute for Biomedical Engineering, University of Rostock, 18119 Rostock, Germany.
Niels
N
Grabow
Institute for Biomedical Engineering, University of Rostock, 18119 Rostock, Germany.
Svea
S
Petersen
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Stefan
S
Nagel
Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Werner
W
Weitschies
D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D054855:Drug-Eluting Stents; D007700:Kinetics; D011474:Prosthesis Design; D015203:Reproducibility of Results; D020123:Sirolimus / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000592:standards
D002317:Cardiovascular Agents; D020123:Sirolimus
CYPHER™ sirolimus-eluting stent; Flow-through cell; In vitro release testing; Reciprocating holder; Vessel-simulating flow-through cell