Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles

Abstract

Harmonized methodologies are urgently required for the taste evaluation of novel pediatric medicines. This study utilized in vitro, in vivo and clinical data to evaluate the palatability of a novel midazolam chocolate tablet. In vitro dissolution experiments showed the crushed tablet to release within 5 min 1.68 mg of midazolam into simulated saliva. This translated to a drug level of 0.84 mg/ml in the oral cavity, which would be higher than the midazolam bitterness detection threshold concentration of 0.03 mg/ml determined in a rat 'brief access taste aversion' (BATA) model. The visual analogue scale scores of patients aged 4-16 years prescribed with midazolam pre-surgery showed a clear preference for the midazolam chocolate tablets (3.35 ± 1.04, n = 20) compared to the control midazolam solution (1.47 ± 0.62, n = 17). The clinical data was in agreement with the in vivo rodent data in showing the novel chocolate tablet matrix to be effective at taste-masking the bitter midazolam.

A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety

“…Consistent with in‐vitro and pre‐clinical data , we found a significant improvement in tolerability of midazolam when incorporated into the CDS tablet. Taste scores using a 5‐point facial hedonic scale were significantly better for the CDS tablet when scored by children, their parents and nursing staff caring for the child.…”

“…As an alternative solution to this problem, a novel chewable chocolate‐based tablet delivery system (CDS) was developed . Pre‐clinical data from both in‐vitro and animal studies have suggested an improved acceptability of the novel formulation.…”

Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms

“…The BATA model is showing great promise as a tool to assess the aversiveness of APIs and is gaining interest within the pharmaceutical industry [49]. It is possible that, in the future, its use could be expanded to assess the taste of formulations [50,51], in which case the BATA data obtained in this study would be extremely useful to facilitate the formulation development of these drugs.…”

“…Saturated Solubility of Drug × Saliva Saturability Index EC 50 or IC 50 (3) It can be seen that ethambutol dihydrochloride had the highest TI (calculated with both IC 50 and EC 50 ), even with a 40% saliva saturability index for this highly soluble hydrochloride salt; this high TI value reflects the concomitant low EC 50 /IC 50 . Of the four drugs, this will be the most problematic in terms of taste, as the concentration of a saturated solution will be approximately 72 times the EC 50 and 106 times the IC 50 .…”

In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates

“…Several attempts have, however, been made in the literature, but fail due to a lack of biorelevance and/or lack of correlation to real taste data. For example, in a study assessing the taste of a novel midazolam formulation for children, the authors utilised dissolution as one of their means to assess taste 35 . While simulated saliva was used in this study, release was assessed in a fixed 300 mL of media, which far exceeds the volume of saliva normally observed in the human oral cavity at any given time, and does not account for saliva production and swallowing.…”