Cinnarizine food-effects in beagle dogs can be avoided by administration in a Self Nano Emulsifying Drug Delivery System (SNEDDS).
OBJECTIVE
To elucidate if a SNEDDS approach can eliminate the food-effect on cinnarizine absorption and to, investigate if a nutritional drink, Fresubin energy, could mimic food effect in dogs for the poorly soluble compound cinnarizine.


METHODS
A conventional tablet, a SNEDDS capsule or a SNEDDS tablet, containing cinnarizine, were dosed to beagles dogs in fed or fasted state (n=5), with a one week wash-out period between dosing. Dogs were pre-treated with pentagastrin. Fed state was induced by a nutritional drink (Fresubin Energy®). The food-effect was evaluated by comparing Tmax, Cmax and Bioavailability (F) for the different formulations.


RESULTS
Food effect was observed on all three parameters for the conventional tablet; Tmax was delayed 2.5times and bioavailability increased in fed state (from 20.9±5.7 to 53.8±30.1). Apart from an extended Tmax (2.5 and 3.3 times longer in fed state compared to fasted state for the SNEDDS tablets and SNEDDS capsules respectively), food effect on absorption for the SNEDDS capsules and SNEDDS tablets was not observed. The SNEDDS capsules had a higher bioavailability in both fed and fasted state compared to SNEDDS tablets (Ffasted=58.1±16.7, vs. 32.7±11.5), (Ffed=79.3±14.7 vs. 43.7±6.7) There were no significant differences in bioavailability between the conventional tablet in fed state and the SNEDDS capsules.


CONCLUSIONS
Food effect was observed when dosing cinnarizine with ingestion of the nutritional drink Fresubin Energy. Food effect on cinnarizine could be significantly reduced by dosing either as a SNEEDS capsule or a SNEDDS tablet, however, the SNEDDS tablet resulted in an overall lower absorption than the SNEDDS capsules in both fed and fasted state. The delay in fed state absorption could not be changed by dosing with SNEDDS formulations.
University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
Martin Lau
ML
Christiansen
University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark; Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Rene
R
Holm
Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300 Copenhagen S, Denmark.
Jakob
J
Kristensen
University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mads
M
Kreilgaard
University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
Jette
J
Jacobsen
AstraZeneca R&D, 431 83 Mölndal, Sweden.
Bertil
B
Abrahamsson
University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer:FARMA, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark. Electronic address: anette.mullertz@sund.ku.dk.
Anette
A
Müllertz
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D002936:Cinnarizine / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004044:Dietary Proteins / Q000008:administration & dosage; D004285:Dogs; D004337:Drug Carriers; D005215:Fasting / Q000097:blood; D018565:Food-Drug Interactions; D007408:Intestinal Absorption; D008297:Male; D036103:Nanotechnology; D019518:Postprandial Period; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods
D002214:Capsules; D004044:Dietary Proteins; D004337:Drug Carriers; C048418:Fresubin; D013607:Tablets; D002936:Cinnarizine
Dogs; Enabling formulations; Food interaction; Low soluble compounds; SNEDDS