(T1330-03-20) Orally Disintegrating Tablet Formulation of Vardenafil Taste-Masked Pellets

Purpose: Masking the bitter taste of drugs is essential to improve patient convenience and compliance. An innovative approach for solid and liquid formulations is using reverse-enteric polymeric films to recover drug particles, avoiding the contact of the API with the taste buds. These polymers are suitable for taste-masking due to their insolubility in saliva pH (6.2 – 7.6) and high solubility in the stomach acid media. This study aims to develop a taste-masked vardenafil formulation, using this drug as a model due to its bitter taste. The API was layered on the surface of inert microcrystalline cellulose (MCC) pellets and then coated with Kollicoat^® Smartseal 30 D (Smartseal), a reverse-enteric polymer, to provide the taste-masking functionality. Further, final coated pellets were blended with selected excipients to produce orally disintegrating tablets (ODT).

Methods: Vardenafil HCl▪3H2O (ChemShuttle) was coated onto the substrate MCC spheres of 200-355 µm (Cellets^® -Glatt) using bottom spray coating in a lab fluid bed (SolidLab -Syntegon). The coating solution was produced by solubilizing the drug in water combined with the film-former Kollicoat^® IR (polyvinyl alcohol-polyethylene glycol copolymer – BASF) in the proportion of 70:30 drug: polymer, at 15% w/w solid contents. Drug-loaded pellets were coated with the aqueous polymer dispersion, Kollicoat^® Smartseal 30 D (methyl methacrylate and diethyl aminoethyl methacrylate copolymer - BASF). The taste-masking coatings were formulated with talc (Spectrum) as an anti-tacking agent, acetyl tributyl citrate (ATBC) (Tokyo Chemical Industry) as the plasticizer, and the antioxidant, butylated hydroxytoluene (BHT) (MP-Biomedicals). Tablets containing the coated pellets, or multiple unit pellets system (MUPS), were produced with different cushioning agents. Ludiflash^® (BASF), Ludipress^® (BASF), and MCC PH 102 (Roquette) were selected as major components of the cushioning system. Fumed silica (Aerosil^® 200 - Evonik), crospovidone super-fine (Kollidon^® CL-SF - BASF), and sodium stearyl fumarate (Pruv^® - JRS) were selected as the formulation adjuvants of MUPS. All formulation details are summarized in Figure 1. Since a reverse-enteric polymer does not dissolve in the saliva pH (pH 6.2 - 7.6), a taste-masked drug is expected to have a low or no release in the dissolution test at this pH range. Phosphate Buffer Solution (PBS) pH 6.8 was chosen to evaluate the taste-masking formulation effectiveness, and 0.1N HCl (pH 1.2) media was used to test the drug release, mimicking the stomach environment. Dissolution analyses were performed on cured Kollicoat^® Smartseal coated pellets and ODTs, using a dissolution tester (Erweka DT 126) with apparatus I (basket) at 100 rpm with 900 ml of the media pH 6.8 PBS and 0.1 N HCl (pH 1.2) at 37 °C ± 0.5 °C. MUPS and coated pellets were analyzed under scanning electronic microscopy (SEM) to evaluate their morphologic characteristics. They were also exposed to extreme-stress conditions (50°C/90% RH) for two weeks to evaluate the taste-masking functionality of Kollicoat^® Smartseal in the film-coating, with and without the antioxidant in the coating formulation, as well as its film robustness after crushing and under the stressed conditions.

Results: Low drug release values in PBS pH 6.8 (Figure 2) for initial and stressed stability samples in MUPS and pellets indicate the coating layer's effectiveness in masking the bitter taste of vardenafil. These formulations also show immediate drug release (within 5 min) in 0.1N HCl acid media, as typically intended for ODTs products. A negligible difference in drug release in buffer media for pellets and MUPS tablets represents the Smartseal film's strength and flexibility to withstand the compression pressure. All three cushioning agents studied (Ludiflash^®, Ludipress^®, and MCC PH 102) produced tablets of desired characteristics for ODTs with a 1:1 proportion of Smartseal-coated vardenafil pellets and diluents. Ludipress^® was the only cushioning agent impacted by the absence of BHT in the Kollicoat^® Smartseal coat, presenting differences to its initial and after stress stability study in 0.1N HCl (pH 1.2) dissolution study. The SEM pictures (Figure 3) highlight the coating uniformity of the Kollicoat^® Smartseal layer on the drug-loaded pellets' surface. Uniform distribution of coated pellets with film ruggedness is also observed in ODT MUPS formulation (Figure 3).

Conclusion: Drug-layered vardenafil pellets coated with Kollicoat^® Smartseal presented the taste-masking functionality. Pellets and MUPS exhibited immediate drug release in acidic pH with almost no release at pH 6.8. Orally disintegrating MUPS tablets of desired properties could be manufactured in a highly coated pellet load of 1:1 of Kollicoat^® Smartseal and the different cushioning agents studied. Taste-masked pellets and MUPS tablets exposure study at 50 °C and 90% RH depicted the Kollicoat^® Smartseal coating formulation's robustness in retaining taste masking behavior and reverse enteric properties even in these stressed storage conditions. BHT is recommended for Kollicoat^® Smartseal films and mandatory for lactose-based diluents (Ludipress^®) since its absence critically impacts the maintenance of the drug release profile in acidic media.

Formulation Composition of Vardenafil drug loading, Kollicoat® Smartseal Coating and MUPS tablets

Dissolution profile of Vardenafil taste masked pellets and MUPS tablets

Dissolution profile of pellets vs MUPS, Microscopic images of vardenafil taste masked pellets and MUPS tablets