Oral bioavailability of cinnarizine in dogs: relation to SNEDDS droplet size, drug solubility and in vitro precipitation

TY - JOUR

T1 - Oral bioavailability of cinnarizine in dogs

T2 - relation to SNEDDS droplet size, drug solubility and in vitro precipitation

AU - Larsen, Anne T

AU - Ohlsson, Anja G.

AU - Polentarutti, Britta

AU - Barker, Richard A

AU - Phillips, Andrew R

AU - Abu-Rmaileh, Ragheb

AU - Dickinson, Paul A

AU - Abrahamsson, Bertil

AU - Ostergaard, Jesper

AU - Müllertz, Anette

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2013/1/23

Y1 - 2013/1/23

N2 - The in vivo performance of self-nanoemulsifying drug delivery systems (SNEDDSs) with different in vitro physicochemical properties were determined with the purpose of elucidating the parameters determining the in vivo performance of SNEDDSs. The in vitro characterisation included the use of pulsed field gradient NMR and the dynamic lipolysis model. In vivo characterisation was carried out in dogs with elevated gastric pH. Four SNEDDSs containing cinnarizine were dosed orally, and the obtained PK profiles were related to in vitro characterisation data. The SNEDDSs with the lowest solubility of cinnarizine in the preconcentrates and the smallest droplet size had the highest AUC values after oral administration. No difference in C(max) and t(max) was observed between the SNEDDSs. Despite of precipitation occurring during in vitro lipolysis of one of the SNEDDS this SNEDDS performed as well in vivo as another SNEDDS that did not show any precipitation. The area under the colloidal dispersion curves as well as under the lipolysis curves could be used to rank order the in vivo performance of the SNEDDSs. Selection of in vitro optimisation parameters for SNEDDSs should be done carefully. It may not always be best to aim for the highest solubility in the preconcentrate and to avoid precipitation during in vitro lipolysis.

AB - The in vivo performance of self-nanoemulsifying drug delivery systems (SNEDDSs) with different in vitro physicochemical properties were determined with the purpose of elucidating the parameters determining the in vivo performance of SNEDDSs. The in vitro characterisation included the use of pulsed field gradient NMR and the dynamic lipolysis model. In vivo characterisation was carried out in dogs with elevated gastric pH. Four SNEDDSs containing cinnarizine were dosed orally, and the obtained PK profiles were related to in vitro characterisation data. The SNEDDSs with the lowest solubility of cinnarizine in the preconcentrates and the smallest droplet size had the highest AUC values after oral administration. No difference in C(max) and t(max) was observed between the SNEDDSs. Despite of precipitation occurring during in vitro lipolysis of one of the SNEDDS this SNEDDS performed as well in vivo as another SNEDDS that did not show any precipitation. The area under the colloidal dispersion curves as well as under the lipolysis curves could be used to rank order the in vivo performance of the SNEDDSs. Selection of in vitro optimisation parameters for SNEDDSs should be done carefully. It may not always be best to aim for the highest solubility in the preconcentrate and to avoid precipitation during in vitro lipolysis.

U2 - 10.1016/j.ejps.2012.11.004

DO - 10.1016/j.ejps.2012.11.004

M3 - Journal article

C2 - 23178440

SN - 0928-0987

VL - 48

SP - 339

EP - 350

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

IS - 1-2

ER -