Development of a Novel Oral Colon Delivery System for High-Dose Mesalamine

INTRODUCTION Mesalamine, also known as 5-aminosalicylic acid (5-ASA), is a first-line treatment for mild-to-moderate ulcerative colitis and is often administered in high daily doses for therapeutic efficacy [1]. Targeted delivery to the colon is needed, so that the entire dose reaches the site of inflammation thereby improving the treatment outcome and reducing systemic side effects. However, the development of high-strength mesalamine colon delivery systems for once-a-day administration regimens poses important challenges. These include attaining tablet cores with acceptable size and shape for swallowing, adequate mechanical resistance and rapid disintegration in the colonic environment, where water availability is limited. Restricted scope for adding excipients further hampers the formulation and manufacturing phases. Accordingly, the present study was first aimed at developing a high-dose mesalamine tablet core having adequate physico-technological characteristics. Subsequently, a double coating step, needed for reliable colon targeting based on a recently proposed delivery technology, was addressed [2]. EXPERIMENTAL METHODS Micronized mesalamine powder as such or in admixture with a superdisintegrant (Explotab®CLV) was granulated with an aqueous povidone solution, followed by coating of the obtained granules with polyethylene glycol (PEG) 1500 to increasing weight gains (2.5-10%) using a bottom-spray fluid bed (GPCG 1.1, Glatt, DE) [3]. The coated granules were compacted into tablets having ≥1200 mg drug dose. A low-viscosity hydroxypropyl methylcellulose (HPMC) inner and a Eudragit® S/guar gum outer layer were applied to the resulting tablets by rotating pan (GS, GS Coating, IT) [2]. Differential scanning calorimetry and powder X-ray diffraction analyses were performed to assess structural integrity of the drug molecule. In vitro release testing was carried out by means of a Eur. Ph. Dissolution apparatus (Dissolution System 2100B, Distek, IT, 900 mL HCl 0.1 N followed by phosphate buffer pH 7.4, 37±0.5°C, 100 rpm, 240 nm UV detection). RESULTS AND DISCUSSION Granules obtained by wet granulation of mesalamine were coated with PEG1500 to enhance their cohesion properties, which made tableting possible with no need for additional compression aids. However, higher PEG1500 levels were related to longer disintegration times. To address this issue, a superdisintegrant was added prior to granulation, thus helping reduce the disintegration time as desired. Tablet cores showing a proper balance of size, mechanical resistance and disintegration properties underwent physico-chemical characterization, which confirmed mesalamine stability, and two sequential coating steps that were both successfully accomplished. The resulting delivery system was proved to withstand exposure to the acidic medium and release mesalamine after a lag phase at intestinal pH. These findings support the potential of the investigated double-coated formulation for targeted colonic delivery of high doses of mesalamine, offering improved therapeutic efficacy, tolerability and patient compliance in the treatment of ulcerative colitis. REFERENCES 1. GR D'Haens et al, Alimentary Pharmacology & Therapeutics, 46, 292-302, 2017. 2. S Moutaharrik et al, International Journal of Pharmaceutics, 653, 123874, 2024. 3. S Moutaharrik et al, Drug Delivery and Translational Research, 14(3), 826-838, 2024.