Reduction of aversive taste of oral pediatric formulations using the rat Brief Access Taste Aversion (BATA) assay
Creators: name: Ives, Robert
name: Wassell, Emma
name: Ignatious, Francis
name: Bachmanov, Alexander
Publisher: name: F1000 Research Limited
Year: 2018

description: Purpose<br><br>Compound X is intended for use in adults and children in oral formulations to treat infections. Compound X has aversive taste, which poses a challenge for developing oral pediatric formulations acceptable to young children. The objectives of our studies were to find out whether Compound X at concentrations used in oral pediatric formulations has aversive taste, and whether this aversion can be attenuated by adding sweeteners and flavors.<br> <br>Methods<br><br>To minimize need in conducting taste tests with human panellists, we have conducted these studies in rats, using the brief access taste aversion (BATA) assay. Our previous studies have shown that rat taste responses in the BATA tests correlate well with human taste perception. Rats were trained to perform in the Davis Rig MS160 gustometer (DiLog Instruments), which automatically presents bottles filled with test solutions and records rats' licking rates to these solutions. Up to sixteen different solutions can be presented multiple times to each rat in a single test session. This allows us to generate concentration-response curves or evaluate responses to multiple compounds and mixtures in a single experiment. To motivate rats to perform in the gustometers, they were water deprived for 21 hours during 3-4 day periods, with fluid available to drink during BATA tests and during 2.5 hours after completion of each BATA. Test solutions were presented during 8-s trials in a pseudo-random order, with adjacent trials separated by a short (2-s) water rinse presentation (maximum 60 presentations per day). Water-deprived rats presented with water complete approximately 40-50 licks during the 8-s trial. When test solutions have an aversive (e.g., bitter) taste, licking rates decrease proportionally to the strength of aversion. The studies were conducted with 12 male Crl:CD (SD) rats (200-225 g and 6 to 7 weeks old at arrival, supplied by Charles River UK) housed in groups of 4. All animal studies were ethically reviewed and carried out in accordance with the Animals (Scientific Procedures) Act 1986 and GSK Policy on the Care, Welfare and Treatment of Animals.<br> <br>Results<br><br>Tests of multiple Compound X concentrations generated a concentration-response curve, which was fitted to a four parameter logistic curve to calculate IC<sub>50</sub> values (a concentration at which licking rate was equal to 50% of the licking rate to water). Based on relationships between rat and human taste responses established in our previous studies, we calculated a predicted adult human IC<sub>50</sub>. This predicted human IC<sub>50</sub> is lower than the likely concentration of Compound X in pediatric formulations, suggesting that humans will perceive aversive taste of these formulations. To prevent problems with compliance in pediatric populations, taste masking would likely be required. We therefore conducted several additional studies, in which we presented Compound X (at a concentration approximate to the IC<sub>50</sub>) alone or mixed with sweeteners (sweetener A and/or sweetener B) and flavors (flavor X or flavor Y) at different concentrations and in different combinations. These studies have identified several combinations of sweeteners and flavors that completely eliminated aversion to Compound X in rats. We predict that these sweetener and flavor combinations will be efficient in masking aversive taste of Compound X in humans.<br> <br>Conclusion<br><br>Based on this rat BATA study, a mixture of sweetener B with a flavor was recommended for an oral pediatric formulation to be used in an upcoming clinical study. Our study illustrates usefulness of the rat BATA assay in assessing palatability of drugs, which is important for optimizing oral and inhaled formulations.