(M1330-12-71) Application of Avicel® as Cushioning Agent in MUPS Tablets

Purpose: Multiple Unit Pellet System (MUPS) is an attractive novel solid dosage form because of many advantages such as reduction in local drug concentration, risk of toxicity, and side-effects ^[1]. Typically, modified release pellets are contained in MUPS tablets and many of them are enteric-coated pellets. Because the acid resistance and drug release of MUPS tablets depends on the integrity of the coating for enteric-coated pellets, it is very important and quite challenging for these MUPS tablets to keep the integrity of the pellets’ coating after compression. Cushioning agents are the fillers that absorb the pressures of compaction by re-arranging themselves within the tablet structure or by preferentially getting deformed and/or fractured thereby providing protection to the coated pellets. Microcrystalline cellulose is the most widely used cushioning agent due to its superior plasticity and compactibility. In this study, enteric coated esomeprazole pellets were used as model drug. The cushioning effects of different grades of Avicel® on the tableting were fully studied, meanwhile acid resistant performance and dissolution of MUPS tablets were evaluated accordingly.

Methods: Esomeprazole pellets were prepared by coating sugar seeds with drug layer, then sub-coating layer and enteric layer. The enteric coated Esomeprazole pellets were later mixed with Avicel®, crospovidone and Alubra® PG-100 and compressed into MUPS tablets at different compression force with weight of 570mg (40 mg dose strength). MUPS formulation details are shown in Table 1. Hardness and friability of tablets were tested to evaluate the compactibility of different grades of Avicel®. The optimized MUPS tablets were then coated with METHOCEL™ E6 Premium LV coating suspension for SEM (scanning electron microscopy), acid-resistance, and dissolution tests. The pellet morphology in these MUPS tablets was investigated by SEM. Acid-resistance was conducted by exposing MUPS tablet to 500ml acidic solution for 2 hours. After 2 hours the enteric pellets were collected and analyzed for content of the retained Esomeprazole ^[2]. Dissolution was performed by exposing tablet to 0.1 N hydrochloric acid 300 ml for 2 hours, and then to 1000 mL of pH6.8 phosphate buffer solution ^[2]. After 30 minutes the content of the dissolved Esomeprazole was analyzed using HPLC.

Results: Combining the result of compactibility (Figure 1, left) and friability (Figure 1, right), MUPS-3 (Avicel® SMCC 90 as cushioning agent) and MUPS-4 (blend of Avicel® PH-200 and 105 as cushioning agent) were preferred. Both had hardness more than 200N and friability less than 0.1% when compression force was higher than 8kN. The subsequent coating process proved that they were hard and strong enough to resist the tumbling and mechanical stress during coating. SEM images (Figure 2) showed that all pellets remained intact, and no obvious cracks were observed in the view scope although the pellets were compacted out of shape. The acid-resistant analysis showed that the retained esomeprazole content of MUPS-3 and MUPS-4 tablets was 93% and 91% respectively, and that of pellets prior to compaction is 93%, which indicates good cushioning effects of Avicel® SMCC 90 and blend of Avicel® PH-200 and 105. The dissolution analysis showed that the drug release within 30 minutes was 92% and 91% for MUPS-3 and MUPS-4 tablets respectively and was 94% for pellets prior to compaction. The drug release was not affected by the compaction process due to good cushioning effects and disintegrating capability of Avicel® SMCC 90 and blend of Avicel® PH-200 and 105.

Conclusion: Both Avicel® SMCC 90 and blend of Avicel® PH-200 and 105 provided high compactibility, low tablets friability and good cushioning functionality to protect the enteric coating. MUPS tablets formulated with those cushioning agents were hard enough to resist the tumbling and mechanical stress during coating process. Due to the high performing cushioning effect of Avicel®, acidic resistance and dissolution performance of these MUPS tablets was almost the same as the pellets prior to compaction. Maintaining the integrity of functional coating is critical for the formulation design of MUPS tablets containing enteric coated pellets. Both Avicel® SMCC 90 and blend of Avicel® PH-200 and 105 are superior cushioning agents for MUPS tablets to maintain coating integrity.

References: [1] Clarke GM., Newton JM., Short MD. Comparative gastrointestinal transit of pellet system of varying density. Int. J. Pharm. 1995,114: 1-11.
[2] Ch.P(2020) VolⅡ[S].2020: 146-148.Esomeprazole Magnesium Delayed-Release tablets monograph.


Table 1 Composition of MUPS tablets with different grade of Avicel®


Figure 1 Effect of cushioning agent on compactibility (left) and friability (right)


figure2 SEM images of cross section of MUPS-3 (left) and MUPS-4(right) tablets