Oral System for Effective Delivery of High-Dose Mesalamine to the Colon

INTRODUCTION Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory condition affecting the gastrointestinal tract, mainly in the form of ulcerative colitis and Crohn’s disease. The epidemiology of IBD has considerably changed since its emergence over a century ago [1]. Initially thought to primarily affect children and young adults, its incidence is now rising among the adult and elderly population. Moreover, there is a concerning increase of IBD rates in developing and newly developed countries [2]. In the Western world, it involves important healthcare costs and indirect costs [3]. The introduction of biologics, particularly TNF-α antagonists, has expanded the therapeutic options, reducing resort to surgery and improving patients' quality of life [4]. However, not all IBD sufferers respond to these new drugs. Furthermore, the annual cost of biologics per patient remains high compared to other medications [3]. In addition to developing new treatments, improving the colon targeting potential of existing ones could help address these issues. To mitigate the risks of both premature release in the proximal intestine and failed release in the large bowel, a novel delivery strategy has been proposed involving a dual coating [5-7]. An inner coating consists of low-viscosity hydroxypropyl methylcellulose (HPMC), while an outer one comprises an enteric polymer, Eudragit®S, having a dissolution pH threshold of 7, and guar gum, a natural polysaccharide that is selectively degraded by the colon bacteria. The outer coating protects the dosage form in the upper gastrointestinal tract when pH is <7, whereas guar gum acts as a pore former in the colon enabling drug release even if the enteric polymer is not dissolved due to insufficient exposure to pH above the dissolution threshold. Finally, the inner HPMC coating provides an additional lag phase before drug release through dissolution/erosion undergone in aqueous fluids, which would help rule out early release in the small intestine when the outer layer is dissolved prior to colon arrival. Using the described technology, the aim of the present work was to allow for improved site-selective delivery of mesalamine to the colon, thus increasing its concentration at the inflammation site and reducing the systemic side effects frequently observed with existing oral products of the drug. Given the established non-inferiority of once- vs. multiple-daily administration regimens [9], a high-strength mesalamine formulation was sought to promote patients’ adherence to the therapy and add related benefits in terms of clinical outcome. METHODS Mesalamine powder (Chemi S.p.A., d90=40 µm) was wet granulated using an aqueous 7.5% w/w povidone solution and forced through a 1250 µm mesh sieve. The wet granules were dried overnight at 40°C and subsequently mixed with selected excipients. Tablets were manufactured from an 86.96% mesalamine, 1.95% Vivapharm®PVP K30, 8.59% Avicel®PH200, 2.00% Explotab®CLV and 0.50% magnesium stearate powder mixture by a rotary press (AM-8S, Officine Ronchi, IT; 22x10 mm oblong punches, 35 kN compression force), characterized for mass uniformity, crushing strength, friability and disintegration time, coated in a tangential-spray fluid bed apparatus (GPCG1.1, Glatt, DE) first with an aqueous 8%w/w low-viscosity HPMC (Methocel™E50) solution to a 100 µm layer thickness and then with a hydro-alcoholic Eudragit®S/guar gum (7:3 solid weight ratio) coating dispersion to 7 mg/cm2 of polymethacrylate applied, and finally cured at 40 °C for 24 h. After each coating step, the coating thickness (digital micrometer, Absolute, Mitutoyo; n=20), weight gain and amount of Eudragit®S applied per unit area were assessed. Photomicrographs were acquired using a scanning electron microscope (SEM, LEO1430, Carl Zeiss, IT). The double-coated systems were tested in a paddle dissolution apparatus (Dissolution System 2100B, Distek, IT; UV/Vis detection at 240 nm) using 900 ml of 0.1 N HCl for 2 h followed by phosphate buffer (PB) pH 7.4, at 37±0.5 °C. Lag time was calculated as the time to 10% release after medium change. RESULTS AND DISCUSSION Formulation and manufacturing of immediate-release tablet cores containing 1200 mg of mesalamine posed several challenges. Tablets of acceptable size and shape were needed despite the high drug load, so that the final delivery systems could easily be swallowed. Thus, there was limited scope for addition of fillers or other auxiliary substances, making the desired physico-technological and release characteristics more difficult to achieve. Particularly, given the large amount of micronized active pharmaceutical ingredient (API) to be incorporated, poor flowability and high apparent volume were a major hindrance to smooth powder processing and mass uniformity of the dosage forms. Moreover, the API in use exhibited poor compaction properties that could have impaired mechanical resistance of the tableted cores. Disintegrating tablets were required so that timely release of mesalamine into the proximal colon would have helped reach effective concentrations of the drug at the disease site counteracting its relatively low and pH-dependent solubility. To address most of these issues, wet granulation of the API powder was preliminarily undertaken. Further formulation components, along with compression forces to be applied with the oblong punches in use, were selected through a trial-and-error approach based on the mechanical properties and disintegration time of the obtained tablets as the main criteria. Satisfactory physico-technological properties and disintegration within 1 min were finally attained. The two sequential coating processes were then set up, requiring adaption of previously tuned operating conditions to the substrate. The resulting double-coated systems exhibited reproducible weight gains and continuous overlapping layers of consistent thickness. The release study performed showed that gastroresistance was not impaired by the polysaccharide in the enteric coating. As desired, a lag phase was observed after the pH change, followed by quantitative drug release with no evidence of diffusional phenomena. CONCLUSION An oral high-strength mesalamine formulation for improved selective colon delivery was designed, manufactured and evaluated, showing proper physico-technological characteristics and the desired in vitro performance. This may lay the basis for more effective and tolerated IBD treatments without entailing the costs and risks of already available non-first-line drug therapies or the burden of developing new ones. REFERENCES 1. Agrawal, M. and Jess, T. Implications of the changing epidemiology of inflammatory bowel disease in a changing world. United Eur. Gastroenterol. J. 10, 1113–1120 (2022). 2. Ng, S.C.; Shi, H.Y.; Hamidi, N.; Underwood, F.E.; Tang, W. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2017). 3. Kaplan, G. G. The global burden of IBD: From 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015). 4. Ahluwalia, B., Moraes, L., Magnusson, M. K. and Öhman, L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand. J. Gastroenterol. 53, 379–389 (2018). 5. Moutaharrik, S.; Maroni, A.; Melocchi, A.; Zema, L.; Foppoli, A. et al. Oral colon delivery platform based on a novel combination approach: Design concept and preliminary evaluation. J. Drug Deliv. Sci. Technol. 66, 102919 (2021). 6. Moutaharrik, S.; Maroni, A.; Neut, C.; Dubuquoy, C.; Dubuquoy, L. et al. In vitro and in vivo evaluation of a pH-, microbiota- and time-based oral delivery platform for colonic release. Eur. J. Pharm. Biopharm. 183, 13–23 (2023). 7. Moutaharrik, S.; Meroni, G.; Soggiu, A.; Foppoli, A.; Cerea, M. et al. Guar gum as a microbially degradable component for an oral colon delivery system based on a combination strategy: Formulation and in vitro evaluation. Drug Deliv. Transl. Res. 14, 826–838 (2024). 8. Murray, A.; Nguyen, T.M.; Parker, C.E.; Feagan, B.G. and MacDonald, J.K. Oral 5‐aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst. Rev. 8, CD000544 (2020)