Towards the Oral Treatment of Ileo-Colonic Inflammatory Bowel Disease with Infliximab Tablets: Development and Validation of the Production Process.

Bahez Gareb,Pauline Koopmans,Gerard Dijkstra,Silke Posthumus,Daan J Touw,Henderik W Frijlink,Max Beugeling,Jos G.W Kosterink

doi:10.3390/pharmaceutics11090428

Bahez Gareb, Pauline Koopmans + Show 6 more

Open Access

https://doi.org/10.3390/pharmaceutics11090428

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Abstract

Infliximab (IFX) is an intravenously administered monoclonal antibody antagonizing the effects of tumor necrosis factor-alpha (TNF) systemically and is efficacious in the treatment of inflammatory bowel disease (IBD). However, studies suggest that the anti-inflammatory effects result from local immunomodulation in the inflamed regions. Furthermore, topical inhibition of TNF in IBD ameliorates inflammation. We therefore hypothesized that orally administered IFX targeted to the ileo-colonic region in IBD may be an efficacious new treatment option. This study describes the development and validation of the production process of ileo-colonic-targeted 5 mg IFX tablets (ColoPulse-IFX) intended for the oral treatment of IBD by means of producing three consecutive validation batches (VAL1, VAL2, and VAL3, respectively). UV-VIS spectroscopy, HPLC-SEC analysis (content, fragments, aggregates), fluorescence spectroscopy (tertiary protein structure), and ELISA (potency) showed no noticeable deviations of IFX compounded to ColoPulse-IFX compared to fresh IFX stock. The average ± SD (n = 10) IFX content of VAL1, VAL2, and VAL3 was 96 ± 2%, 97 ± 3%, and 96 ± 2%, respectively, and complied with the European Pharmacopeia (Ph. Eur.) requirements for Content Uniformity. The average ± SD (n = 3) ColoPulse-IFX potency was 105 ± 4%, 96 ± 4%, and 97 ± 5%, respectively, compared to fresh IFX stock. The IFX release profile from the tablet core was complete (≥85%) after 10 min in simulated ileum medium. The in vitro coating performance of ColoPulse-IFX showed that the formulation was targeted to the simulated ileo-colonic region. Stability data showed that ColoPulse-IFX was stable for up to 6 months stored at 25 °C/60% RH. Based on these results, the production process can be considered validated and its application is discussed in light of the rationale and available evidence for the topical treatment of IBD with IFX.

Highlights

Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBD) affecting the gastrointestinal tract (GIT)
We have shown in five clinical trials that oral dosage forms coated with the ColoPulse coating can be targeted to the ileo-colonic region in healthy subjects as well as CD patients [38,40,41,42,43]
IFX-I was chosen as the optimal IFX-sugar glass powder for further compounding and the production of three consecutive validation batches of tablets (VAL1, VAL2, and VAL3, respectively)

Summary

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBD) affecting the gastrointestinal tract (GIT) Both diseases are characterized by their relapsing behavior, chronic mucosal inflammation, and frequent hospitalization, resulting in a marked decrease in quality of life. As a consequence, increased exposure of the intestinal wall to luminal antigens, such as microbiota and xenobiotics, induce an acute immune response driven by the innate immune cells. This immune response leads to tissue injury due to the secreted reactive oxygen species and pro-inflammatory mediators such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF). The activation of the adaptive immune cells by the pro-inflammatory cytokines perpetuate the inflammatory state, resulting in chronic inflammation [6,7,8,9]

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