(T1130-01-03) Evaluating the Versatility of the New High Molecular Weight HPC in Dual Active Diabetic Controlled Release Dosages

Purpose: Dual-active controlled-release formulations for Type II diabetes provide several benefits, including reduced dosing frequency, improved glycemic control, and improved patient compliance. Common hydrophilic matrix-forming polymers such as Hydroxypropyl Methylcellulose (HPMC) usually comprise 20- 30% of the weight of a tablet to achieve an acceptable release profile and require intra-granulating binders to prevent the burst effect when dealing with highly water-soluble drugs such as Metformin. This can result in large, hard-to-swallow tablets with complex processing. This study evaluates the process versatility and the tablet size reduction capabilities of the new high molecular weight hydroxypropyl cellulose (HPC) to match the release profiles of a bi-layer dosage and a metformin HCl core tablet coated with an immediate-release drug substance for dual diabetic drug delivery.

Methods: The polymer gel strength of the new high molecular weight hydroxypropyl cellulose (HMW HPC) (klucel™ xtend) and hydroxypropyl methylcellulose (HPMC) K100M was determined using a Discovery Hybrid Rheometer (DHR-3) with a Peltier heating stage. Metformin was wet granulated with HPC at a w/w ratio of 85:15. Granules were dried in an oven at 65°C overnight, then milled with a 45-mesh Quadro Comil screen. Granules were then mixed with extra-granular materials and compressed as either a monolayer core or a bi-layer tablet with the drug dapagliflozin in the IR layer. The monolayer cores were later coated with a barrier layer, followed by a drug layer of empagliflozin using a Freund Vector LDCS® Tablet Coater. Both tablets were then cosmetically film-coated. All tablets, including the bi-layer Xigduo® XR and core/coated dual drug Synjardy® XR were characterized for dimensions, hardness, friability, and dissolution release profiles. Dissolution of each formulation was conducted in 900 mL of pH 6.8 0.050M phosphate buffer maintained at 37°C with USP Apparatus 1 (baskets) at 100 RPM. Samples were taken at intervals of up to 24 hours; quantitation was by HPLC with UV detection for all three drugs.

Results: Previous studies showed that the pure polymer gel strength of the new high molecular weight HPC was six times higher than HPMC, indicating better-hydrated tablet integrity (Fig. 1). This difference in gel strength is likely the key to the results found in the current study. The dapagliflozin/ metformin and empagliflozin/ metformin extended-release tablets formulated with the new HPC had comparable tablet hardness to Xigduo® XR and Synjardy® XR while simultaneously reducing total tablet volumes by 10% and 20%, respectively. The drug release on dissolution for both formulations showed F2 scores within the comparable range of the commercial products (Fig. 2). This was achieved without the need for polymers such as polyethylene oxide or sodium carboxymethylcellulose in the wet granulation of the Metformin which would have been necessary with the lower gel strength HPMC as the controlled release polymer to prevent the burst effect of such a highly water-soluble drug. The test tablets showed no burst effects, with tablets that were hard and had low friability.

Conclusion: Although HPMC is the most commonly used polymer for controlled release, it is not suitable by itself for very highly water-soluble drugs like Metformin. New high molecular weight hydroxypropyl cellulose (HPC) has high gel strength, which can limit any burst effect for the delivery of highly soluble drugs. In addition, the new HPC can not only enable smaller tablet sizes by using lower polymer level in the formulation, but also is excellent for bi-layer and coated formulations, where the release profile becomes more complex.


Figure 1: Gel Strength Comparison
Figure 2: (Left)Dissolution of Xigduo® XR compared to new HPC Bi-layer tablet (right) Dissolution of Synjardy® XR compared to New HPC metformin core.