Τίτλος:
Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation. © 2020
Συγγραφείς:
Ilie, A.-R.
Griffin, B.T.
Vertzoni, M.
Kuentz, M.
Kolakovic, R.
Prudic-Paus, A.
Malash, A.
Bohets, H.
Herman, J.
Holm, R.
Περιοδικό:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Λέξεις-κλειδιά:
cinnarizine; eudragit; labrasol; lipid; monoacylglycerol; poloxamer; cinnarizine; excipient; lipid, area under the curve; Article; drug absorption; drug bioavailability; drug delivery system; drug exposure; high throughput screening; in vitro study; in vivo study; miscibility; pilot study; precipitation; priority journal; solubilization; time to maximum plasma concentration; bioavailability; drug delivery system; solubility, Biological Availability; Cinnarizine; Drug Delivery Systems; Excipients; Lipids; Solubility
DOI:
10.1016/j.ejps.2020.105691
