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Recent Advances in Mesalamine Colonic Delivery Systems Mohammad F Bayan and Bayan Future Journal of Pharmaceutical Sciences (2020) 6:43 Future Journal of https://doi.org/10.1186/s43094-020-00057-7 Pharmaceutical Sciences REVIEW Open Access Recent advances in mesalamine colonic delivery systems Mohammad F. Bayan* and Rana F. Bayan Abstract Background: Increased attention has been focused on the continuous development and improvement of mesalamine colonic specific delivery systems, for the effective treatment of inflammatory bowel diseases; thus enhancing therapeutic efficacy and reducing potential side effects. Mesalamine is a class IV drug, according to the Biopharmaceutics Classification System, used usually to treat inflammation associated with colon related diseases such as Crohn’s disease and ulcerative colitis. Main text An ideal colon targeting system aims to deliver a therapeutic agent, selectively and effectively, to the colon. This system should ideally retain the drug release in the upper GI tract (stomach and small intestine); while trigger the drug release in the colon. Several approaches have been used to fabricate formulations to achieve a colon specific delivery of mesalamine such as; time dependent, pH responsive, enzymatic/microbial responsive and ultrasound mediated approaches. This overview outlines the recent advances in mesalamine-colon delivery approaches for the potential treatment of ulcerative colitis and Crohn’ disease. Conclusion: A combined pH-time dependent delivery system can improve mesalamine colonic drug delivery via employing carriers capable of retarding mesalamine release in the stomach and delivering it at predetermined time points after entering the intestine. The existence of specific enzymes, produced by various anaerobic bacteria present in the colon advocates the advantage of designing enzyme sensitive systems and combining it with pH- time dependent system to improve mesalamine colonic delivery. The use of ultrasound has shown promises to effectively treat inflammatory bowel diseases. Keywords: Mesalamine, 5-amino salicylic acid, Mesalazine, Crohn’s disease, Ulcerative colitis Background need to stick to a lifelong drug treatment [2]. The rec- Inflammatory bowel diseases represent inflammatory ommended treatment depends on the disease location conditions that affect the gastrointestinal tract and cause and its severity. Topical mesalamine, hydrocortisone or over 50,000 deaths per year [1]. The most common in- budesonide is recommended for patients with inflamma- flammatory bowel diseases are ulcerative colitis and tion limited to the left colon. Oral mesalamine or sulfa- Crohn's diseases. The main difference between these two salazine is recommended to be used in addition to the diseases is that Crohn's disease can affect any part of the topical treatment with cases extended beyond the left gastrointestinal tract, while ulcerative colitis is specific to colon. Oral prednisone or infliximab induction therapy the colon. The currently available curing choices are not is recommended for resistant patients. Intravenous always effective and can cause serious side effects. Add- steroids, infliximab or cyclosporine is recommended in itionally, there is no permanent treatment available for severe cases. Topical mesalamine is suggested as a re- inflammatory bowel diseases up to date, and patients mission maintenance therapy for patients with ulcerative proctitis, while oral mesalamine is suggested for more * Correspondence: [email protected] extensive cases. Azathioprine, 6-mercaptopurine or Faculty of Pharmacy, Philadelphia University, Amman, Jordan © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Bayan and Bayan Future Journal of Pharmaceutical Sciences (2020) 6:43 Page 2 of 7 infliximab agents are recommended in cases fail to also use additional polymeric matrices (such as in Lialda® maintain remission using mesalamine [3]. and Apriso®) designed to further control the drug release Mesalamine is a derivative of salicylic acid (5-amino rate and deliver mesalamine at predetermined time salicylic acid [5-ASA]) and also known as mesalazine. It points after entering the intestines. Pentasa® is an ex- is usually used as a first line anti-inflammatory agent to ample of pH independent oral marketed mesalamine, act locally on colonic mucosa and reduce inflammation which is usually taken up to 4 grams/day and mesala- for the treatment colon related diseases, such as Crohn’s mine is released slowly from the ethylcellulose coated disease and ulcerative colitis [4, 5]. Mesalamine was dis- tablets [13–18]. This review summarizes the recent ad- covered as the active moiety of sulfasalazine, where it is vances in mesalamine-colon drug delivery based on time bound to sulfapyridine (inactive moiety), via an azo bond dependent, pH responsive, enzyme sensitive and ultra- (cleaved by azoreductase enzyme present in the GIT). sound approaches. Sulfapyridine is believed to be responsible for the ad- verse and unwanted effects associated with sulfasalazine Main Text [6, 7]. The mechanism of action of mesalazine is not Time Dependent and pH Responsive Approaches fully clear in inflammatory bowel diseases, but it is be- The large variation of gastric retention time is the main lieved to be a topical effect at the inflammation site via obstacle of sustained or delayed oral delivery as it is dif- the direct interaction with the damaged epithelial cells. ficult to accurately predict the drug delivery time to the It is then metabolized to the inactive form (N-acetyl-5- colon. The pH approach usually employs polymers that ASA) by N-acetyltransferase 1 and excreted in the urine retard drug release in the stomach and permit its release [8]. This justify the failure of oral administration of pure at the higher intestinal pH, where the polymer can dis- 5-ASA in inflammatory bowel diseases and necessitates solve or swell. A pH-responsive carrier can enhance the the development of an efficient delivery system capable oral controlled delivery of mesalamine in two ways; 1) of retarding its release in the upper GI tract (stomach the pH-triggered swelling of a carrier may result in fast and small intestine); while triggering its release at the in- drug release and high drug concentration gradient. 2) flammation site [9]. Mesalamine is categorized as a BCS The pH-responsive swelling may enhance the carrier’s class IV drug (low solubility, low permeability) according mucoadhesion ability; thus improving the drug absorp- to the Biopharmaceutics Classification System. It is tion [19]. However, a colon specific delivery is difficult slightly soluble in water and poorly absorbed following to be achieved using the pH strategy alone due to inter/ its oral administration (approximately 25%) [10]. This intra pH variations and pH similarity between small in- fact necessitates the enhancement of its dissolution and testine and colon [20]. The small variability of the small absorption rates in order to increase its bioavailability. intestine transit time (3 ± 1 hours) advocates the advan- The development of colon specific drug delivery systems tage of developing a combined pH-time dependent deliv- of mesalamine has gained increased attention for the ery system to improve the site specificity. This system effective treatment of inflammatory bowel diseases employs carriers capable of preventing the drug release whereby high local concentration can be achieved; thus in the stomach and delivering it at predetermined time reducing side effects and enhancing therapeutic efficacy points after entering the intestines [21]. Mirabbasi et al. [11]. An ideal delivery system should protect the drug [22] synthesized mesalamine loaded nanoparticles, based and retard its release in the upper GI tract (stomach and on polyurethane-chitosan graft copolymer, as a time- small intestine); while permitting its release in the colon delayed colon drug delivery system. The in vitro release [12]. Various approaches have been used to develop co- studies had proven that the nanocarrier based formula- lonic delivery systems of mesalamine such as; time tion was able to control mesalamine release over 72 dependent, pH responsive, prodrug and enzymatic/mi- hours with 92.19% cumulative release is being achieved. crobial responsive approaches. Most of the oral mar- However, around 55% of the loaded drug were released keted mesalamine products utilizes a pH dependent within 8 hours. The release kinetics studies had shown coat, which is capable to retard 5-ASA release in the that the release data were best fitted to first order kinet- stomach and permit its release at the higher intestinal ics. It was concluded that the prepared carrier was suc- pH. Examples of such systems include; the employment cessful to sustain the drug release
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