TY - JOUR
T1 - Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens
T2 - in vivo and in vitro evaluations
AU - Siqueira, Scheyla D V S
AU - Müllertz, Anette
AU - Gräeser, Kirsten
AU - Kasten, Georgia
AU - Mu, Huiling
AU - Rades, Thomas
PY - 2017/3/1
Y1 - 2017/3/1
N2 - The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq (super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq (CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension. The CIN dose was kept constant for all dosing regimens. Therefore, the super-SNEDDS solution and super-SNEDDS suspension contained 2.5-fold less SNEDDS pre-concentrate than SNEDDS 80% and the Chasing principle. In vivo, a higher AUC after dosing CIN in SNEDDS 80% and the Chasing principle was obtained when compared to the super-SNEDDS solution, super-SNEDDS suspension, and aqueous suspension. In vitro, a higher extent of CIN in the aqueous phase was observed for all SNEDDS-containing dosing regimens, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption and solubilization, whereas the drug load, or amount of co-dosed lipid, significantly influenced CIN bioavailability.
AB - The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq (super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq (CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension. The CIN dose was kept constant for all dosing regimens. Therefore, the super-SNEDDS solution and super-SNEDDS suspension contained 2.5-fold less SNEDDS pre-concentrate than SNEDDS 80% and the Chasing principle. In vivo, a higher AUC after dosing CIN in SNEDDS 80% and the Chasing principle was obtained when compared to the super-SNEDDS solution, super-SNEDDS suspension, and aqueous suspension. In vitro, a higher extent of CIN in the aqueous phase was observed for all SNEDDS-containing dosing regimens, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption and solubilization, whereas the drug load, or amount of co-dosed lipid, significantly influenced CIN bioavailability.
KW - Journal Article
U2 - 10.1208/s12248-016-0038-4
DO - 10.1208/s12248-016-0038-4
M3 - Journal article
C2 - 28070714
SN - 1550-7416
VL - 19
SP - 587
EP - 594
JO - A A P S Journal
JF - A A P S Journal
IS - 2
ER -