A molecular imaging application was developed to characterize the drug distribution on CYPHER® and NEVO™ Drug-eluting Stents using MALDI Qq-ToF analytical methodology. The coating matrix, laser energy, laser frequency, spatial resolution (related to rastering speed) and mass spectrometer parameters were optimized to analyze drug distribution in both durable and biodegradable polymer matrices. The developed method was extended to generate data from stents explanted from porcine coronary arteries. Due to the method's intrinsic specificity, it offers a significant advantage over other techniques in that it allows low-level detection of the target molecule without biological interferences from the blood or tissue. The method is also capable of detecting drug-related degradation products both from the finished stent product and from explanted stents.
A sensitive and robust method for the determination of the elution of an active drug substance, sirolimus, from drug-eluting coronary stents was developed using a USP Apparatus 4 elution system. The closed-loop configuration of the elution apparatus and the small volume of eluent allow the low drug levels that elute from a single stent to be reproducibly monitored.The in vitro elution profile obtained from USP Apparatus 4 over 24 h mirrors the 30-day in vivo porcine profile, providing an in vitro release method that captures the entire in vivo release profile of the stent in a shorter time. This method discriminates between common manufacturing and formulation product defects that were intentionally made. The method employs a novel elution medium containing an organic solvent, which allowed the in vitro elution curve to be fit to the in vivo porcine profile.The method has been accepted by the FDA as a release method for the elution of sirolimus or rapamycin in cardiovascular stents.
Rapamycin is a natural macrolide immunosuppressant with a distinct mechanism of action. Quantitative analysis of rapamycin poses many challenges associated with facile degradation and the multitude of isomeric forms. The primary goal of this study was to compare degradation of rapamycin and its ring-opened isomer, secorapamycin, in aqueous solution under identical conditions. Reaction kinetics and mechanisms were studied in 30/70 vol/vol acetonitrile-water mixtures containing either MeCOONH 4 (apparent pH 7.3) or NaOH (apparent pH 12.2). Degradation kinetics was well described by the first-order rate law. For rapamycin in 237 and 23.7 mM solutions of MeCOONH 4 , apparent half-lives of 200 h and 890 h were obtained. When compared to the latter value, the rapamycin half-life was reduced by 3 orders of magnitude in the pH 12.2 solution. Under all conditions studied, secorapamycin degradation was significantly slower than that of the parent compound. Both specific and general base catalysis was observed for reactions of rapamycin and secorapamycin. Two primary products of rapamycin degradation were identified as individual isomers of secorapamycin and a hydroxy acid formed via lactone hydrolysis. No evidence for the interconversion between the products was obtained. In highly basic solutions, both products undergo fragmentation and water addition reactions.
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