(M1030-03-19) A Complex Bitter Tale of In Vitro vs. In Vivo Findings

Purpose: Bitterness of medicines has long posed extra challenges to patient adherence, especially in children. Cyclodextrins (CD, commercially available for several decades) are widely used in taste masking strategies by forming complexes with bitter drugs, thereby preventing their interactions with taste buds [1]. However, this taste masking effect is not always sufficient. Cucurbit[n]urils (CB[n]) are another macrocyclic family that exhibit drug binding properties. Emerging literature suggests drug-CB complexes have relatively strong binding/affinity compared with drug-CD complexes, owing to an additional ion-dipole interaction [2]. This project explored the potential of stronger binding to enhance taste masking effects. Our systematic assessment compared in vitro and in vivo bitterness/aversiveness data. CB7 and HP-β-CD were chosen based on their safety profile, exceptional solubility, and comparable cavity sizes with Ranitidine HCl (RA) as bitter drug model.

Methods: Binding of RA with CB7 and HP-β-CD were evaluated using UV/Vis titration. A concentrated solution of CB7 or CD was added to RA diH2O solution. Binding constants were derived from absorbance changes triggered by the addition of CB7 or CD (up to 1:10) [3]. Binding was also measured in 10 mM KCl (INSENT electronic tongue media) and simulated salivary fluid [4]. To compare in vitro and in vivo taste masking efficiency of bindings, an electronic taste sensing system and the Rat Brief-Access Taste Aversion (BATA) model [5] were used. All the procedures were carried out in accordance with the Animals (Scientific Procedures) Act 1986. Electronic tongue TS-5000Z, mounted with 5 bitter/astringent sensors (BT0, AC0, AN0, C00 and AE1) measured RA samples at 5 mM (rat IC50) ± CB7/CD, and signals were analysed using Principal Component Analysis (PCA). The BATA data lick counts were analyzed using ChiPlot [6].

Results: Stronger binding of RA-CB7 relative to RA-CD was observed in vitro [Table 1], whereas the in vivo environment showed an opposite trend. Fig. 1 shows that RA-CB7 significantly changed the bitter taste of RA compared with RA-CD in the in vitro model, suggesting the stronger binding of RA-CB might contribute to taste masking. In the in vivo model, RA-CD taste masking appeared more effective (Figure 2) compared with RA-CB7[TC1] ; although there was no significant difference, it did not fully align with the binding hypothesis. It is possible that the rat saliva (salts/concentration/pH) might competitively intercat with CB7, thereby attenuating drug binding as described in [7]. In fact, Table 1 also denotes that RA-CB7 complexes were more sensitive to the saliva cationic environment shown by a decrease in K.

Conclusion: To ensure clinically relevant taste masking, binding effects in drug-macrocyclic host complexes needs to be assessed under buccal biorelevant conditions, leveraging extrapolated data for accurate clinical reflection. Further investigations with other drugs are ongoing.

References: [1]. DOI: 10.1517/17425247.4.4.417 [2]. DOI: 10.1021/ja052912c [3]. DOI: 10.37358/RC.08.3.1751 [4]. DOI: 10.1021/acs.molpharmaceut.9b00060 [5]. DOI: 10.1016/j.ejpb.2018.09.027 [6] https://www.chiplot.online [7]. DOI: 10.1021/ja908795y

Acknowledgements: All the procedures were carried out in accordance with the Animals (Scientific Procedures) Act 1986.