(W1130-09-52) Insights in Designing Osmotic Modified Release Delivery Platform for Solid Dispersions: Challenges and Conception

Purpose: Over the past decades, significant advances have been made towards improving the solubility of drugs. Spray dried dispersion (SDD) is one of the widely used approaches to address the solubility related challenges of molecules. Designing modified release delivery platform for SDD offers several advantages such as constant and prolonged therapeutic effect which may improve patient compliance allowing for once daily dosing in addition to addressing the solubility related issue. . In this work, we have utilized swellable core technology (SCT) tablet to deliver SDD as modified release platform. SCT is a bilayer layer osmotic tablet comprising of an active layer and a sweller layer formulated with functional semi-permeable membrane coating and laser drilled hole acting as drug delivery port. The rate of drug delivery is controlled by factors such as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the degree of hydrophilicity of the hydrogel layer. We have evaluated the influence of SDD loading on hydration of active layer, viscosity entrainment and dissolution performance.

Methods: SDD utilized for this work comprised of API dispersed in HPMCAS polymer matrix spray dried at 50% drug loading. The impact on viscoelastic properties of the active layer blends of various SDD loading were evaluated using rheometer (TA instrument DHR2) utilizing flow sweep test mode to analyze the samples, yielding flow curves of viscosity versus shear rate. SCT bilayer tablets were compressed using 11 mm tooling on Styl’One compaction simulator. Compression profiles for all the blends were generated using parameters for Korsch XM12 at press speed of 20 rpm. Following compression, functional coating was performed using Freund Vector LDCS-5 Pan coater, 1.3 L pan and cellulose acetate: Polyethylene glycol 3350 (78.5:21.5) as coating solution. Tablets were coated to target coating weight for desired T₈₀ of 6 hours, 9 hours and 12 hours as predicted by in-silico model developed inhouse. Following coating, coating thickness of tablet face and bands were assessed, and a 1 mm delivery port was drilled on the active side of the bilayer tablets. Furthermore, sink dissolution was performed on all the coated tablets using USP 2 dissolution apparatus, method using 0.5% SLS in 50 mM sodium acetate pH 4.5 media with 50 rpm paddles followed by an infinity spin.

Results: Rheological evaluation of the various blends suggested that initial viscosities of the blends increased proportionally with the SDD loading as can be seen in Figure 1A. Increase in the SDD loading in the blend resulted in a decrease in rate index (power-law) suggesting most pseudoplastic flow for 40% drug loading blend. SCT bilayer tablets were made with 400 mg active layer weight and 600 mg total core tablet weight using blends of various SDD loading ranging from 10 % to 40%. Compression profiles of the bilayer tablets suggested that increase in the SDD loading in tablet blends resulted in increase in tensile strength and tablet core density as seen in Figure 1B. In-silico model predicted that the coating weight of the tablets for T₈₀ values of 6 hours, 9 hours, and 12 hours to be ~40 mg/tab, 60 mg/tab and 79 mg/tab. The tablets were successfully coated to the predicted coating weight as shown in Figure 1C. Results of dissolution studies (Figure 2) demonstrated that 10% SDD loaded tablets displayed complete release of drug with measured T₈₀ values of 7.5 hours, 9.25 hours and 11.25 hours which was in accordance with the model predicted values. However, with increase in SDD loading in tablets the release was incomplete as can be seen in figure 3, which can be attributed to viscoelastic changes of active layer, insufficient hydration of active layer, and membrane rupture as observed in 40% SDD load tablets.

Conclusion: SCT bilayer tablets can serve as a potential delivery strategy for modified release of SDDs for sustained release of drug. Increase in the SDD load in tablet blend influences the viscoelastic properties and therefore may hinder in the release of the SDD from the bilayer tablets. In-silico model accurately predicted the coating weight required for desired T₈₀ values as validated by the experimental results. Dissolution studies revealed incomplete release at high drug loading with membrane rupture suggesting the need for changes in the active layer rheological properties. These challenges may be addressed by designing the SCT tablet with high aspect ratio, thereby providing increased active layer for achieving higher dose and improved dissolution behavior (e.g. more complete release from higher SDD loaded osmotic SCT extended release drug product).

Figure 1: (A) Rheological flow curves of viscosity versus shear rate of various tablet blends (B) Tensile strength Vs. Tablet core density obtained from compression profile of various tablet blends (C) Plot representing coating thickness Vs. coating weight obtained from coating run for desired T80 values.

Figure 2: Representative dissolution profile of various tablets at different SDD loading coated at desired target T80 values. The dotted line represents infinity spin after dissolution.

Figure 3: Images of representative tablets after dissolution before infinity spin demonstrating the release of the active layer.