Validation of a rat behavioral avoidance model from a drug delivery perspective.
Conventional taste-masking strategies are used to overcome the bitter taste perception of pharmaceuticals by coating the drug particles and/or adding flavoring agents. However, for certain product categories such as rapid dissolve sublingual tablets, taste-masking is challenging. Programs exploring such formulation strategies in the LO-CS phase or post CS phase possess very little toxicological information available in order to conduct human taste panel studies. The potential of a bitter taste perception can present a significant business risk. The objective of the study was to validate a rat behavioral avoidance model that identifies bitter-tasting compounds. Most classic bitter substances elicit a response in the micromolar concentration range while most drugs elicit a response in the millimolar range, hence a validation exercise was conducted to examine if the existing biological model was sensitive enough to identify known bitter tasting drugs as such. Five compounds: ergotamine tartrate, fluoxetine, sucrose, sumatriptan and povidone were chosen to represent a spectrum of compounds. The bitter tasting compounds were identified as such in the model. Based on these results, the assay may serve as a useful surrogate test to identify compounds that may have bitter taste issues.
Bhat
Meenakshi G
MG
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. mbhat@lilly.com
Jordt
Raymond M
RM
Khan
M Amin
MA
Foley
Christine E
CE
Gilbertson
Timothy A
TA
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004878:Ergotamine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D023421:Models, Animal; D051381:Rats; D015203:Reproducibility of Results; D018170:Sumatriptan / Q000494:pharmacology*; D013652:Taste Threshold / Q000187:drug effects; D014868:Water Deprivation
D005473:Fluoxetine; D018170:Sumatriptan; D004878:Ergotamine