(T0930-01-05) Influence of Protective Coating on Extended-Release Pellets and Maintaining Desired Drug Release from MUPS Tablets

Purpose: Multi-unit particulate systems (MUPS) are filled into a capsule or compacted with excipients to form a tablet. Recently, MUPS tablets have gained more popularity due to several advantages. Compared to capsules, tablets are more preferred oral solid dosage form given the convenience of use by patients, lower manufacturing costs and higher production rate. Additionally, MUPS tablets offer divisible dosage form without compromising the drug release characteristics of the individual units. To date, only a few pharmaceutical MUPS tablets are commercially available, due to several challenges associated with formulation and manufacture of MUPS tablets. Ideally, MUPS tablets should disintegrate rapidly in the gastrointestinal tract after oral administration resulting in the same drug release pattern as uncompressed multiparticulate. The main challenge in MUPS tablet production is that compression can damage the functional coating, leading to subsequent loss of the intended modified-release functionality of the dosage form. This study's purpose was to evaluate the influence of a protective coating on drug release for extended-release pellets in MUPS tablets.

Methods: Sugar pellets, (Suglets® PF053, Colorcon) were used as starting substrate, seal-coated with formulated ethyl cellulose organic coating system (Corelease EC^TM, Colorcon) with the aim to circumvent osmotic effect of sugar and its potential impact on drug release. Metoprolol succinate (Zhejiang Haixiang) was then loaded onto the seal coated beads using Hypromellose based Opadry® (Colorcon) as a binder. Corelease EC was applied on the drug layered pellets to achieve extended release functionality. A protective coating layer, composed of a Hypromellose based Opadry® and polyethylene glycol (PEG 3350, Dow) were subsequently applied on half of the pellets All coating systems were applied using a bottom spray fluid bed coater (Strea-1, Aeromatic fielder, GEA). Pellets with and without protective coating were separately blended with a mix of microcrystalline cellulose (Avicel® PH101, IFF), directly compressible starch (StarTab®, Colorcon) and crospovidone (Kollidon® CL, BASF) for 5 minutes. Sodium stearyl fumarate (PRUV®, JRS) was then added into the mixture and blended for another minute. Then both mixtures were compressed into tablets individually using a rotary tablet press (Remik). Dissolution testing was conducted on both tablet formulations as well as on uncompressed pellets (with/without protective coating), in 750 mL phosphate buffer, pH6.8 at a paddle speed of 100 rpm. Drug release was determined via UV detection (Cary 50, Varian) at 274 nm. Tablets containing pellets with protective coating were finally coated with Opadry® QX (Colorcon) in a 12" fully perforated coating pan (Labcoat M, O’Hara Technologies), and subjected to drug release testing using same criteria as above. Additionally, scanning electron microscopy (SEM, TM4000, Hitachi) was used to capture images of the tablet's cross sections.

Results: Dissolution results showed that drug release profiles from pellets with/without protection coating were similar (f2=83.4). After compression, drug release from MUPS tablets containing protective coated pellets was similar with the pellets before tableting (f2=80.9), but significantly different from the tablets that contained pellets without protective coating (f2=24.1). SEM result showed use of a protective coating resulted in round pellets that kept their integrity throughout the process after compression into a MUPS tablet. Furthermore, drug release from MUPS tablets coated with Opadry® QX was similar to that of uncoated MUPS tablet.

Conclusion: After compression, tablets containing the extended-release pellets without protective coating showed faster drug release compared to uncompressed pellets. Protective coating with Opadry and PEG had no influence on drug release from the Corelease EC coated pellets but resulted in enhanced protection of the ER pellets upon compression into MUPS tablets with comparable drug release profiles to the uncompressed pellets. Application of a protective coating using Opadry and PEG is an easy way to overcome the challenge of formulation development of MUPS tablet and achieve desired tablet properties and drug release without compromising the characteristics of the individual units.

References: 1. Tongkai Chen, et al. Tablets of multi-unit pellet system for controlled drug delivery, Journal of Controlled Release, 2017;9:222-231.
2. Girish S. Sonar, Swati Rawat. Formulation and design of multiunit particulate system (MUPS) tablet of pantoprazole by QbD: Effect of compression variables on the finished product. J App Pharm Sci, 2015; 5(10): 091-100.
3. J. Li, et al. Characterization of the mechanical properties of high drug loading pellets for compressed controlled release tablets, Prinston Pharmaceutical, CRS 2012.


Figure 1. Drug release from metoprolol succinate ER pellets with and without protective coating


Figure 2. Drug release from metoprolol succinate ER pellets before and after compression


Figure 3. SEM images of cross sections of metoprolol succinate MUPS tablet