(W0930-07-41) Evaluation of Plasticizer and Stabilizer Effect on Drug Release Profiles of Taste-Masked Vardenafil MUPS ODT

Purpose: The purpose of this study is to assess how plasticizers and stabilizers in the Kollicoat® Smartseal film affect the ability of coated pellets to mask taste after being compressed into MUPS (multi-unit pellet system) tablets using lactose- and MCC-based diluents and after exposing to accelerated stability study conditions. We compared drug dissolution in pH 6.8 phosphate buffer (resembling saliva pH) to evaluate taste masking and dissolution in an acidic pH environment, to assess the immediate drug release in the stomach region.

Methods: Vardenafil HCl▪3H₂O (ChemShuttle) and Kollicoat^® IR (polyvinyl alcohol-polyethylene glycol copolymer – BASF) in a 70:30 proportion were dissolved in water to obtain 15% w/w aqueous solution. The final drug film-coating solution was sprayed onto inert micro cellulose (MCC) spheres (Cellets^® 200-Glatt) using a fluid bed coater (SolidLab -Syntegon). Drug-layered pellets were then coated with the reverse-enteric polymer, Kollicoat^® Smartseal 30 D (Smartseal) (methyl methacrylate and diethyl aminoethyl methacrylate copolymer in an aqueous dispersion - BASF). Smartseal films are insoluble in neutral and basic media, including at saliva pH 6, but dissolves quickly under protonation at a pH below 5.5. It is a lipophilic polymer and requires around 13% of a hydrophobic plasticizer to avoid film cracking and loss of functionality. The lipophilic plasticizers, TPGS (tocopherol polyethylene glycol succinate) (Antares Health Products, Inc) and acetyl tributyl citrate (ATBC) (Tokyo Chemical Industry) were tested. To evaluate the need of stabilizer to protect the polymer amino-ester moiety, especially with sugar-based diluents, the antioxidant butylated hydroxytoluene (BHT) (MP-Biomedicals) was evaluated. Additionality TPGS also was assessed as a Smartseal stabilizer based on its antioxidant characteristics. The anti-tacking agent talc (Spectrum) was also included in the formulations. After the coating, pellets were submitted to the curing step for 2 hours at 60 ^°C. Later, the taste-masked pellets were blended with different diluents and compressed into ODT orally disintegrating tablets (ODTs) MUPS tablets using different cushioning agents. Lactose-based co-processed material, Ludipress^® (BASF), containing lactose, povidone and crospovidone, and MCC PH 102 (Roquette) were selected as major components of these 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. All formulation details are summarized in Figure 1. Phosphate buffer (pH 6.8) was chosen to evaluate the taste-masking effectiveness, and 0.1N HCl (pH 1.2) was used to test the immediate release profile. Dissolution tester (Erweka DT 126) with apparatus I (basket) at 100 rpm with 900 ml of the media at 37 °C ± 0.5 °C was selected for the dissolution analysis of ODTs containing the taste masked pellets. An accelerated stability study was conducted on MUPS ODTs to evaluate the effect of temperature and humidity on taste masking properties and immediate release characteristics in acidic pH conditions for both diluents, using different plasticizers and stabilizers.

Results: Low drug release values in pH 6.8 phosphate buffer (Figure 2) for initial and accelerated stability samples for ODT formulations indicate Kollicoat^® Smartseal coating layer's effectiveness in masking the vardenafil bitter taste in presence of plasticizers and stabilizers studied. Initial samples of MUPS containing TPGS demonstrated a faster drug release in acid, justified by its more hydrophilicity compared to the ATBC. MUPS tablets prepared with cushioning agents Ludipress^® and MCC PH 102 showed desired tableting properties of ODTs even with a 1:1 proportion of Smartseal-coated vardenafil pellets and tableting diluents. Furthermore, the amount and type of plasticizer added in the formulations provided sufficient film flexibility to avoid coating film breakage during the tableting process. No difference in acid media dissolution were observed (Figure 3) for accelerated stability sample of Ludipress^® formulations containing TPGS and ATBC with BHT. On the other hand, differences in acid media drug release were observed for Ludipress^®formulations containing ATBC without stabilizer. This emphasizes the stabilizing effect of BHT in Kollicoat^® Smartseal film when combined with lactose-based diluents. Instead, TPGS seems to protect the polymer amino moiety in the lactose-based formulation, exhibiting a dual role as plasticizer and stabilizer in Kollicoat^® Smartseal film. Comparative acid media dissolution analysis of initial and accelerated stability samples revealed no change in drug release for all ODT formulations made with MCC PH 102.

Conclusion: TPGS and ATBC are suitable as plasticizers for Kollicoat^® Smartseal taste mask film. The combination of Ludipress^® or MCC PH 102 with taste masked pellets of Kollicoat^® Smartseal at 1:1 ratio were suitable for manufacturing vardenafil MUPS ODT with desired tableting properties. For MUPS made with Ludipress^®, six months accelerated study indicated the stabilizing effect of TPGS and BHT in maintaining the drug release profile in acid. This underscores the plasticizer and stabilizing properties of TPGS on Smartseal’s film. Acid media dissolution profiles of MUPS made with MCC PH 102 were found to be stable, regardless of the presence or absence of an antioxidant.

Figure 1: Formulation details of Taste masked Orally disintegrating tablets of Vardenafil

Figure 2: Dissolution profiles of Taste masked Vardenafil ODTs in pH 6.8 phosphate buffer

Figure 3: Dissolution profiles of Taste masked Vardenafil ODTs in 0.1N HCl