(M1030-12-81) Development of a Platform Coating Approach to Taste Masking Bitter Drugs in Micro-tablets for Pediatric Patients

Purpose: Palatability of oral dosage forms is important for their acceptability in the pediatric population. This study proposes a coating platform approach to effectively masking the aversive taste of drugs in micro-tablets, a preferred pediatric solid dosage form.¹ The strategy was to prevent the drug release from the coated micro-tablets in the mouth cavity while ensuring complete release in the stomach. An In-vitro dissolution method, mimicking the salivary and gastric pH conditions, was used as a screening tool to select the taste masking coating systems and their levels. The taste masking effectiveness of the selected coating systems was confirmed by a human sensory panel study.

Methods: Micro-tablets (1.2 mm diameter, 0.17 mg strength) of Quinine Sulphate (a model highly bitter drug) were manufactured by high-shear wet granulation using a Ganson granulator followed by compression using 12-tip tooling on a GEA Performa P compression machine. The micro-tablets were subsequently coated using a fluid bed bottom spray coater with a 6-inch Wurster column. Finally, the micro-tablets were coated to different weight gain levels of two reverse enteric coating systems (Eudragit^® EPO ready mix and Kollicoat Smartseal^® 30D), a barrier coating system (Surelease^® with HPMC E5 as a pore former), and a traditional aesthetic coating system (PVA-based Opadry II). Composite samples of coated micro-tablets were subjected to two-stage in-vitro dissolution testing using USP Type-I (Basket) at 100 RPM in 900 mL phosphate buffer pH 6.8 for 15 minute for stage-1 and USP Type-II (Paddle) at 75 RPM in 900 mL 0.01N HCl for 60 minutes at 37 ± 0.5 ℃. Based on the dissolution results, the coating systems and their weight gain levels were selected for the human sensory panel study (swirl and spit method). The participants self-administered coated and un-coated micro-tablets (dose strength of 68 mg) with 30ml of water, swirled in their mouth for 10 seconds, and then spat out. The taste of the samples was rated on an electronic Visual Analogue Scale (VAS) ranging from not aversive (0) to most aversive (100).

Results: High shear wet granulation process resulted in granules with acceptable particle size and flow for robust micro-tablet compression (Table 1). The micro-tablets had acceptable physical properties and dissolution performance (Table 1). Coated micro-tablets with 35% Surelease^®: HPMC E5 (80:20) system resulted in no drug release in pH 6.8 buffer and immediate release in 0.01 N HCl medium. The same system at a 25% level resulted in 22% drug release in pH 6.8, indicating >25% coating weight gains required for Surelease^®: HPMC E5 (80:20) to effectively mask quinine’s bitter taste. Coated micro-tablets with 20% Eudragit^® EPO resulted in ~66% drug release in pH 6.8, and the release was 0% at 30% or higher weight gains with immediate release in 0.01 N HCl. Kollicoat SmartSeal^>® 30 D coated micro-tablets at 15% and 25% weight gains resulted in 15% and 0% drug release, respectively, in phosphate buffer. Micro-tablets coated with 40% PVA-based Opadry II resulted in immediate release in pH 6.8, indicating a potential inability to taste mask quinine (Figure 1). Based on the in-vitro dissolution results, micro-tablets coated with 15% and 25% Kollicoat SmartSeal^® 30 D (a reverse enteric coating system) and 25% and 35% Surelease^®: HPMC E5 (80:20) (a pH-independent barrier coating system) were selected for human taste assessment. The human sensory panel study results suggested that all the coated micro-tablet samples, apart from the uncoated micro-tablets, were not aversive as indicated by the low median scores ( < 20) in contrast to the high median scores ( >80) for uncoated micro-tablets (Figure 2). The human sensory panel assessment results were in agreement with the in-vitro dissolution results with a trend of low to high taste masking effectiveness in the following order: uncoated tablets < 25% Surelease^®: HPMC E5 (80:20) < 35% Surelease^®: HPMC E5 (80:20) < 25% Kollicoat SmartSeal^® 30 D < 15% Kollicoat SmartSeal^® 30 D.

Conclusion: Ensuring palatability of micro-tablets of bitter drugs is essential to improve the acceptability in pediatric population. This study identified coating systems and their appropriate levels for effective taste-masking of quinine in micro-tablets using dissolution method mimicking the mouth cavity and stomach pH conditions. Taste masking effectiveness of the proposed coating systems were confirmed by the human sensory panel study. The study demonstrated that the two-stage dissolution test can be used as an effective in-vitro screening tool to identify the coating type and its level to mask the taste of bitter drugs while ensuring immediate release in the stomach. As a platform coating approach, 25% Kollicoat SmartSeal^® 30 D and 35% Surelease^®: HPMC (80:20) were proposed to taste mask bitter drugs in micro-tablets.

References: 1. Klingmann, V. Acceptability of Mini-Tablets in Young Children: Results from Three Prospective Cross-over Studies. AAPS PharmSciTech 18, 263–266 (2017).
2. Junshu Zhao, David Yin, Jasmine Rowe, Sherif Badawy, Faranak Nikfar, Preetanshu Pandey, Understanding the Factors That Control the Quality of Mini-Tablet Compression: Flow, Particle Size, and Tooling Dimension, Journal of Pharmaceutical Sciences, Volume 107, Issue 4, 2018.
3. Shashwat Gupta, Prajwal Thool, Saikishore Meruva, Jianmin Li, Jhalak Patel, Anjali Agrawal, Shyam Karki, William Bowen, Biplob Mitra, Development of low dose micro-tablets by high shear wet granulation process, International Journal of Pharmaceutics, Volume 587, 2020.

Acknowledgements: Ethical approval for the study was granted by the UCL Research Ethics Committee (project ID: 11675-007)

Figure 1. Two-Stage Dissolution of microtablets coated with different coating systems.

Figure 2. Taste scores from Human Sensory Panel Assessment of the uncoated micro-tablets and coated micro-tablets with Surelease®: HPMC E5 and Kollicoat Smartseal® 30D coating systems at different coating levels.

Table 1. Properties of the Final Blend and Micro-tablet