(M1230-03-19) Preparation of Osmotic Tablets Using a Direct-to-Hopper Formulated Push Layer Based on Polyethylene Oxide

Purpose: The purpose of this study was to investigate the use of a direct-to-hopper push layer blend for use in the direct compression manufacture of bilayer push-pull osmotic pump (PPOP) tablets. These specialized dosage forms are designed to deliver zero-order drug release and valuable patient benefits in terms of safety, efficacy and convenience compared to other solid dosage forms (Figure 1). PPOPs often contain polyethylene oxide (PEO) and during manufacture require multiple processing and cleaning steps, which are time-consuming, complicated and can potentially introduce safety hazards. Use of a fully formulated PEO-based push layer blend will eliminate multiple processing steps (e.g., solvent-based wet granulation and drying) and reduce the cleaning burden associated with PEO. This push layer blend consists of a high viscosity PEO as the swelling agent, sodium chloride as the osmogen, an iron oxide pigment for identification of the layer, and magnesium stearate as an optional lubricant. The PPOP manufacturing process was further simplified by producing the drug layer formulation with an ordered mixing approach, where a uniform blend is created by adhering fine particles to the surface of coarse particles primarily by electrostatic forces. This simplified direct compression approach negates the need for a granulation step and provides a high level of blend uniformity.

Methods: The push layer blend was prepared using a high viscosity grade of polyethylene oxide (POLYOX Coagulant, IFF; 73.5-74.0% w/w), sodium chloride (25% w/w), iron oxide (1% w/w) and optionally magnesium stearate (0.5% w/w), using dry blending process in a twin shell blender. The drug layer blend was prepared using low viscosity grade polyethylene oxide (POLYOX N80, IFF; 94.4% w/w) and micronized glipizide (5.6% w/w; d90 ~4 µm) using an ordered mixture, dry blending process in a Turbula blender. The drug layer blend was evaluated for uniformity and then used to prepare glipizide (11.2 mg total;10.0 mg dose) bilayer PPOP tablets, which were coated with Opadry^® CA fully formulated osmotic coating system and then laser drilled.

Results: The drug layer blend was prepared by using the ordered mixture approach described earlier, which involved sieving of micronized glipizide API and PEO N80, then mixing these materials together in a Turbula blender. The three-dimensional blending action of the Turbula blender provided a thorough layering of the micronized glipizide particles on the surfaces of the coarser PEO particles (Figure 2), yielding favorable blend uniformity within a short blending time (n=6; 95.3% +/- 3.5% confirmed by HPLC analysis). Drug release was similar (f₂=65) for PPOP tablets manufactured with and without magnesium stearate in the push layer formulation, with equivalent lag times and showing zero-order release profiles (Figure 3).

Conclusion: A formulated direct compression push layer blend was prepared, along with the ordered mixture pull layer blend, to manufacture bilayer PPOP tablets which (after Opadry CA coating and laser-drilling) showed favorable zero-order dissolution results. The ready-to-use push layer can offer ease-of-use, requiring less processing steps when compared to a solvent-based wet granulation process. This results in safer operation and facilitates a direct-to-hopper approach in the manufacture of osmotic tablets.

Figure 1. PPOP Tablet Illustration and Example Drug Release Profiles.

Figure 2. Ordered Mixture Process and SEM Images of Drug Layer Blend.

Figure 3. Drug Release Profiles for Glipizide PPOP Tablets (11.2 mg total content to deliver 10.0 mg dose); Opadry CA Coating at 10 % weight gain.