Evaluation of carvedilol compatibility with lipid excipients for the development of lipid-based drug delivery systems

摘要

Carvedilol (CARV) is a widely used non-selective beta-blocker, which has shown low bioavailability after oral administration (20 %) due to its low water solubility and intense first-pass metabolism. Lipid-based drug delivery systems have been proposed to improve CARV oral bioavailability. An evaluation of drug-excipient compatibility is needed to clarify potential physical and chemical interactions between them and therefore guarantee a correct selection of excipients. However, to date there are no reports on the systematic evaluation of CARV-lipid excipient compatibility. Thus, the aim of this study was to evaluate the compatibility of CARV with the lipid excipients commonly used for the development of lipid-based formulations. Thermal analysis techniques (DTA and TG/DTG), Fourier transform infrared spectroscopy and isothermal stress testing (IST) were used for this purpose. The results of this study showed that 4 of the 10 lipid excipients studied were incompatible with CARV. The strongest thermal and spectroscopic modifications were observed in CARV mixtures with oleic acid, lauric acid, lauroyl polyoxylglycerides (Gelucire(A (R)) 44/14) and glyceryl caprylate/caprate (Capmul(A (R)) MCM). In addition, these mixtures resulted in significant decreases in drug content after aging. On the other hand, palmitic acid, stearic acid, glyceryl behenate (Compritol ATO(A (R)) 188), tribeheninPEG (Emulium(A (R)) 22), polyglyceryl-6-isostearate (Plurol Isostearique(A (R))) and diethylene glycol monoethyl ether (Transcutol HPA (R)) were considered good candidates for developing self-emulsifying drug delivery systems and for preparing lipid microparticle or nanoparticle containing CARV. These findings denote the relevance of combining thermal and spectroscopic techniques with thermal stress testing for the accurate determination of drug-lipid excipient compatibility.