(M1530-06-34) A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines

Purpose: The aim of this study was to evaluate bitterness by using “CCDP; Change in concentration-dependent potential” considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index in compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019).

Methods: Solutions (0.01, 0.03, 0.1 mM) of forty-eight APIs were evaluated by an artificial taste sensor using five kinds of membranes sensitive to bitterness. The dose–response slope of the sensor outputs was defined as CCDP. Various physicochemical properties using Fisher’s exact tests. Moreover, physicochemical properties which have high attribution to CCDP were extracted using multiple regression analysis, in order to verify the usefulness of CCDP as a bitterness evaluation index. The principal component analysis of taste sensor measurements was also performed. The hTAS2R14 model was built by submission of the amino acid sequence of hTAS2R14 obtained from National Center for Biotechnology Information (NCBI) to the I-TASSER server in accordance with a previous report, and the predicted structure of hTAS2R14 was then refined and minimized in energy using the Prime module in the Schrödinger suite (ver. 10.3). The generated structure of hTAS2R14 and the chemical structures of the studied drugs were prepared appropriately and docking simulations performed in accordance with previous reports¹⁾. Finally, the positions of the docked ligands were scored via the Glide module, and the docking structures were illustrated with molecular visualizing software PyMOL (Schrödinger).

Results: Fisher’s exact tests were carried out to examine the correlations between the physicochemical properties participated in an electric charge and hydrophobicity and CCDPs. Log P values ≥2.82 and absolute values of physiological charge ≥|1| significantly correlated with the responses of AN0, AC0 and BT0, respectively (p < 0.01). Log S values < ˗3 significantly correlated with the responses of BT0 (p < 0.01) and AN0 (p < 0.05). PSA < 45.59 Ų significantly correlated with the responses of AN0 and BT0 (p < 0.01). There were no significant correlations between polarizability or hydrogen bond acceptor or aromatic rings and the responses of the taste sensor. Judging from the fact that high log P values (≥2.82) absolute values of physiological charge (≥|1|), low log S values (< ˗3) and small PSA ( < 45.59 Ų) significantly correlated with the responses of basic bitterness sensors, it can be concluded that high lipophilicity, high physiological charge, low solubility and small PSA are factors associated with CCDP of basic bitterness. In general, bitter compounds are absorbed on the hydrophobic part of the taste sensor membrane and cause a change in membrane potential by changing the charge density. The results suggested that a low PSA value ( < 45.59 Ų) may be linked with bitterness, although there have been no previous reports of a relationship between bitterness and PSA. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual.

Conclusion: Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride

References: 1) Amin F. et al., Drug Des Devel Ther, 12, 3855–3866 (2018)

Acknowledgements:This work as supported by a Grant-in-aid for Scientific Research (S) from the Japan Society for Promotion of Science 21H05006 (to Takahiro Uchida) .