(T1430-11-71) Development of Hydrogel Polymer-Based Bilayer Gastro-Retentive Modified-Release Tablets

Purpose: Gastro-retentive dosage forms (GRDFs) are characterized by prolonged retention of the formulation in the stomach and sustained release of the loaded drug for local action or slowly delivering the drug into the upper intestine for absorption. The latter is particularly useful for drugs with narrow absorption window. Several marketed GRDF drug products have used hydrogel polymers as swelling-based systems. However, one of the drawbacks of these systems is the limited flexibility to adjust the drug release. As such, a bilayer GR tablet is required, with a GR layer mainly containing the highly swellable hydrogel polymer polyethylene oxide (PEO) to enhance tablet swelling and a MR layer mainly containing hydroxypropyl methylcellulose (HPMC) to control the drug release. This study investigated the release of two drug substances, 5-Hydroxy-L-tryptophan (5-HTP) and Carbidopa from a bilayer GR tablet.

Methods: The composition of the GR layer was fixed with PEO Polyox Coagulant to Hypromellose K100M ratio at 1:1 and the weight was 500 mg, while the drug-loaded MR layer utilized different levels of Hypromellose K4M and K100M to achieve fast and slow drug release as a design space for flexible clinical assessment. Excipients for the GR and MR layers were weighed in separate containers and mixed in a T2 Turbula mixer before being compressed using a Natoli single-station tablet press with either GR-to-MR or MR-to-GR as the compression order. The final bilayer tablet was an oval convex-shaped with a total weight of 1000 mg. Tablets were characterized for hardness and drug content. The drug dissolution test was conducted using USP Apparatus III (6 x 250 mL of 0.1M HCl) at 30 dpm for up to 20 hours. Samples were taken at pre-determined time points and analyzed using a HPLC method. A USP disintegration test was also conducted for visual assessment of tablet swelling properties and robustness.

Results: Drug release from the bilayer tablet was affected by the type and level of HPMC in the MR layer as expected and it is also affected by the order of the GR and MR layer compression (Figure 1 and 2). When the bilayer tablet was pressed in the order of MR-to-GR, fast release of 5-HTP and Carbidopa (T80% at ~8.5 hours) was achieved from the MR layer containing 18% HPMC K4M and slow release (T80% at ~11hours) when 7% K4M and 25% K100M of HPMC were used. However, when the tablets with the same compositions were pressed in the order of GR-to-MR, the drug release from the formed fast and slow release bilayer tablets was accelerated with T80% at approximately 5 and 8 hours respectively for both drugs, with the gap between the fast and slow release at 90% release becoming wider. This indicated that when the bilayer tablets were pressed in the order of GR-to-MR, the drug release rate was faster and more sensitive to the polymers used in the MR layer.

The impact of the order of tablet compression on the drug release was further investigated, and it was hypothesized that the shift of the drug release could be due to the change of surface area of the MR layer. Figure 3 shows the cross-section illustration of the oval convex-shaped bilayer GR tablet and the visual appearance of each compression order. At the same 1:1 MR/GR ratio, when the MR layer was pressed first (MR-to-GR), there was less surface area available for drug release from the MR layer. The GR layer on top can also swell more than the MR layer, resulting in an additional decrease in surface area MR layer. However, when the GR layer was pressed first (GR-to-MR), the MR layer on top had more surface area and less chance to be covered by the swelled GR layer leading to faster drug release, which can be more effectively controlled by the polymer in the MR layer. This analysis was confirmed by the observation during the dissolution and disintegration tests showing more coverage over the MR layer by the Polyox-rich GR layer when the bilayer tablet was pressed in the order of MR-to-GR. However, there was no significant difference in the overall swelled tablet size between the two compression sequences.

Conclusion: Flexible drug release from hydrogel-based bilayer GR tablets can be adjusted by the grade and level of polymers used in the MR layer. The order of the two layers being compressed can also affect MR surface area and the drug release rate. This finding is useful for development of bilayer MR tablet to achieve optimal drug release profiles.

Figure 1: Fast and slow drug release from bilayer GR tablets with compression orders, MR-to-GR and GR-to-MR for 5-HTP

Figure 2: Fast and slow drug release from bilayer GR tablets with compression orders MR-to-GR and GR-to-MR for Carbidopa

Figure 3: Visual appearance and illustration of the bilayer oval convex-shaped GR tablet