(T1330-03-18) Taking Medicines the Milky Way: How Does Milk Affect Disintegration of Mini-Tablets with a Taste-Masking Coating?

Purpose: The aim of the present study was to investigate the in vitro dissolution behaviour of frequently used taste-masking coatings after exposure to milk types with different nutrient compositions.

Methods: Riboflavin was used as a model drug. The coating polymers were HPMC, HPC, EC, PVA and Eudragit E. Whole-milk, condensed milk, butter milk and goat milk were used for the in vitro experiments. Manufacturing of coated mini-tablets: The components of the tabletting mixture, i.e., riboflavin, SMCC, magnesium stearate and Aerosil were sieved (500 µm), dry-mixed in a Turbula blender and then compressed to 5 mm biconvex mini-tablets using a rotary-type tablet press. After testing the tablet cores for uniformity of mass, resistance to crushing of tablets and friability, a batch size of 150 g tablet cores was transferred into a drum coater equipped with a 0.8 mm spray nozzle. The coating process with aqueous polymer solutions or dispersions was run until a weight gain of 2.5%, 5.0% or 7.5% (based on the tablet mass) was reached. The drum coating parameters (spray rate, atomizing air, pattern air, air flow rate, inlet and outlet air temperature) were adapted for each of the polymers used. Disintegration testing of coated mini-tablets: Disintegration of the coated mini-tablets was assessed in a modified setup of the compendial reciprocating-cylinder dissolution apparatus. In contrast to the pharmacopeial disintegration test, this setup allowed to precisely evaluate disintegration of individual coated tablets with regard to the onset of drug release, which proofed to be a valuable indicator for the onset of tablet disintegration. Each vessel was filled with 125 mL medium, pre-warmed to 37 °C and the reciprocating cylinders containing the coated mini-tablets were dipped at 30 dpm. The total test duration was 15 min. Samples of 250 µL were taken every minute and replaced with fresh medium. Riboflavin was detected by analyzing the samples in black 96-well plates in a plate reader by fluorimetry (excitation: 370 nm, emission: 530 nm). In vitro assessment of taste-masking properties: To assess the taste-masking properties of the formulated products, the coated mini-tablets underwent an in vitro release test resembling conditions of the oral cavity. In this test, the mini-tablets were placed in 10 mL of Simulated Saliva Fluid (SSF) in a glass vial equipped with a magnetic stir bar. The system was agitated at 150 rpm and maintained at 37 °C. Samples were withdrawn every 15 s over a total test duration of 3 min and subsequently analyzed using fluorimetry, as detailed in the previous section. The onset of drug release, indicated by the presence of dissolved drug, served as an indicator of the first perception of flavour.

Results: The coated mini-tablet formulations were subjected to disintegration tests in different milk types. Exemplarily, the results of these studies in whole milk (fat content: 3.5%) and condensed milk (fat content: 10%) are displayed in Figure 1. Expectedly, the coating level had a siginificant impact on the disintegration time. For experiments in whole milk, this was particularly evident for the Eudragit E- and the EC-based formulations that exhibited increasing disintegration times with increasing coating levels. The different dissolution behaviour of the taste-masking polymers tested became even clearer in condensed milk, i.e., the milky drink with the highest fat content (10%). In this case, almost all formulations exceeded the permitted maximum disintegration time of 15 minutes at the highest applied coating level of 7.5 % weight gain. At this coating level, only formulations with an HPMC/PEG 400 or PVA coating disintegrated reliably within 12 and 4 minutes respectively. Interestingly, the disintegration time of the PVA-coated mini-tablet formulations in this milky drink was not affected by the amount of coating applied. Overall, the disintegration time of the coated mini-tablet formulations in condensed milk was significantly prolonged compared to whole milk for all taste-masking polymers and coating levels used. In vitro taste evaluation studies in the novel test setup indicated that all formulations with a coating level of 2.5 % weight gain are capable of preventing drug release for at least 15 seconds. Increasing the coating level to 7.5 % weight gain led to a longer delay in the onset of drug release than the maximum test duration of 180 s for almost all polymer coatings tested. As already observed in the disintegration studies, HPMC/PEG 400 and PVA coatings were the only candidates that allowed the onset of drug release within the first 3 min while maintaining adequate taste-masking properties, i.e., preventing drug release for 135 s and 150 s, respectively.

Conclusion: The results of the current study indicate that the dissolution of taste-masking coatings and, consequently, the onset of in vivo of drug release can be significantly impacted by the type of milk co-administered with the medication. These results underline the importance of considering not only drug properties but also formulation characteristics when providing dosing recommendations.

References: 1. 1. Dressman, J.B., Reppas, C. In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs, Eur. J. Pharm. Sci. 11(Suppl: 2), S73-S80 (2000).


Figure 1: Disintegration times of mini-tablets with different taste-masking polymer coatings at different coating levels in whole milk (3.5% fat) (A) and condensed milk (10% fat) (B), means of n=3 ± S.D., *indicates a disintegration time of > 15 min.


Figure 2: Onset of drug release from mini-tablet formulations with different taste-masking polymer coatings in SSF as indicator for taste-masking properties; means of n=3 ± S.D., *indicates an onset of drug release of > 180 s.