(M1130-09-59) Investigating the Release Profiles of Mesalamine Matrix Granules: EUDRAGIT® NM 40 D vs. EUDRAGIT® NE 40 D

Purpose: EUDRAGIT^® NE 40 D contains nonoxynol which has raised environmental and health concerns due to its persistence in the environment, toxicity to aquatic organisms, and potential estrogenic activity. Consequently, regulatory authorities have placed restrictions on its application in cosmetic and personal care products, while it remains permitted in the pharmaceutical industry¹. In response to this issue, EUDRAGIT^® NM 40 D polymer has been developed by replacing the nonoxynol with an environment safe emulsifier i.e. Macrogol Stearyl Ether (20). This study aims to compare the processing, sustained release and stability performance of EUDRAGIT^® NE 40 D and EUDRAGIT^® NM 40 D in enteric coated extended release matrix granules of mesalamine.

Methods: Enteric-coated matrix granules of mesalamine were formulated through a systematic process involving wet granulation, extrusion, spheronization, and coating. Initially, granulation was achieved by combining mesalamine with either EUDRAGIT® NM 40 D or EUDRAGIT® NE 40 D, utilizing an aqueous dispersion of hydroxypropyl methylcellulose 3cps (HPMC) at a 1:0.36 ratio. The polymer content was maintained at 20% w/w of the total granule composition. The mesalamine powder blend was granulated until a homogeneous wet mass was obtained. Subsequently, the wet granules underwent extrusion using a single-screw apparatus equipped with a 1 mm sieve, operating at 40-60 RPM with a feed rate of 100 g/min. This was followed by spheronization on a round notched plate at 1700 RPM to achieve uniform granule size. The granules were then dried in a Fluidized Bed Dryer at 60°C until a loss on drying (LOD) of less than 2.5% was attained. For the coating process, 400 g of granules sized 14/25# were enteric coated with 20% EUDRAGIT® L 100 polymer using a hydroalcoholic system (ethanol-to-water ratio of 80:20) in a Fluidized Bed Processor (GPCG 1.1). The product temperature was maintained between 30-34°C, with a spray rate of 4-10 g/min. To evaluate the impact of curing on drug release, a curing study was conducted at 50°C for 24 hours for both formulations. Dissolution studies were performed using the USP Type 1 apparatus, where the coated granules were initially immersed in 0.1N hydrochloric acid for 120 minutes to simulate gastric conditions, followed by transfer to a 0.20M sodium phosphate buffer at pH 6.8 for drug release assessment at intervals of 150, 240, and 480 minutes. Stability studies for the EUDRAGIT® NM 40 D-based formulation were conducted under accelerated conditions (40°C, 75% RH) over a six-month period.

Results: The formulation of mesalamine matrix granules utilizing EUDRAGIT® NM 40 D demonstrated comparable processability to those made with EUDRAGIT® NE 40 D, requiring similar processing parameters. The dissolution profiles for both formulations were found to be analogous, exhibiting less than 10% drug release during the initial 120 minutes in the acidic environment, followed by a sustained release phase in the pH 6.8 buffer. Notably, curing studies indicated that there was no significant impact on the release profile for either polymer (Figure 1). Stability assessments of the EUDRAGIT® NM 40 D-based Mesalamine matrix granules confirmed consistent performance over a six-month period under accelerated conditions (40°C, 75% RH), with dissolution profiles remaining comparable to initial findings for both cured and uncured formulations. These results affirm the viability of EUDRAGIT® NM 40 D as a suitable replacement for EUDRAGIT® NE 40 D in modified release matrix formulations, maintaining similar processing efficiency, drug release characteristics, and stability (Figure 2 and 3).

Conclusion: The findings of this study support the successful substitution of EUDRAGIT® NE 40 D with EUDRAGIT® NM 40 D in the formulation of modified release matrix granules for mesalamine. Both polymers demonstrated similar processing characteristics and maintained comparable drug release profiles and stability under accelerated conditions. The performance of the EUDRAGIT® NM 40 D-based formulations proved to be consistent and reproducible, affirming its potential as a viable alternative in pharmaceutical applications while addressing environmental and health concerns associated with nonoxynol.

References: 1. https://www.echa.europa.eu/documents/10162/e5842a1e-e9f9-6096-2829-72f71c00eaab

Comparative dissolution profile of EUDRAGIT® NE 40 D and EUDRAGIT® NM 40 D: Effect of curing and reproducibility of EUDRAGIT® NM 40 D based mesalamine matrix granules

Image 2: Results of accelerated stability studies of EUDRAGIT® NM 40 D based mesalamine matrix granules (uncured) at 40°C/75%RH condition

Image 3: Results of accelerated stability studies of EUDRAGIT® NM 40 D based mesalamine matrix granules (Cured) at 40°C/75%RH condition