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      Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

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          Abstract

          Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy.

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          Most cited references 32

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          Hapten-induced model of chronic inflammation and ulceration in the rat colon.

          We have developed a simple and reproducible rat model of chronic colonic inflammation by the intraluminal instillation of a solution containing a "barrier breaker" and a hapten. Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (5-30 mg) in 0.25 ml of 50% ethanol as the "barrier breaker" produced dose-dependent colonic ulceration and inflammation. At a dose of 30 mg, trinitrobenzenesulfonic acid/ethanol-induced ulceration and marked thickening of the bowel wall persisted for at least 8 wk. Histologically, the inflammatory response included mucosal and submucosal infiltration by polymorphonuclear leukocytes, macrophages, lymphocytes, connective tissue mast cells, and fibroblasts. Granulomas were observed in 57% of the rats killed 3 wk after induction of inflammation. Langhan's-type giant cells were also observed. Segmental ulceration and inflammation were common. The characteristics and relatively long duration of inflammation and ulceration induced in this model afford an opportunity to study the pathophysiology of colonic inflammatory disease in a specifically controlled fashion, and to evaluate new treatments potentially applicable to inflammatory bowel disease in humans.
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            Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa.

            The size-dependent deposition of microparticles and nanoparticles after oral administration to rats using an experimental model colitis was examined. Local delivery of an entrapped drug could reduce side effects and would be a distinct improvement compared with existing colon delivery devices. Ulcerative colitis was induced in Lewis rats with trinitrobenzenesulfonic acid. Fluorescent polystyrene particles with a size of 0.1, 1, or 10 microm were administered for 3 days. The animals then were sacrificed and their guts resected. Particle distribution in the colon was imaged by confocal laser scanning microscopy and quantified by fluorescence spectrophotometry. In the inflamed tissue, an increased adherence of particles was observed at the thicker mucus layer and in the ulcerated regions. A size dependency of the deposition was found, and an increased number of attached particles to the colon was determined compared with the control group. For 10-micorm particles, only fair deposition was observed (control group: 1.4 +/- 0.6%; colitis: 5.2 +/- 3.8% of administered particle mass). One-micrometer particles showed higher binding (control group: 2.0 +/- 0.8%; colitis: 9.1 +/- 4.2%). Highest binding was found for 0.1-microm particles (control group: 2.2 +/- 1.6%; colitis: 14.5 +/- 6.3%). The ratio of colitis/control deposition increased with smaller particle sizes. The use of submicron-sized carriers holds promise for the targeted delivery of drugs to the inflamed colonic mucosal areas in inflammatory bowel disease.
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              Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study

              Objective Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). Design Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. Results 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. Conclusion Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                International Journal of Nanomedicine
                International Journal of Nanomedicine
                Dove Medical Press
                1176-9114
                1178-2013
                2015
                16 July 2015
                : 10
                : 4565-4580
                Affiliations
                College of Pharmacy, Pusan National University, Busan, South Korea
                Author notes
                Correspondence: Jin-Wook Yoo, College of Pharmacy, Pusan National University, 2 Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan 609-735, South Korea, Tel +82 51 510 2807, Fax +82 51 513 6754, Email jinwook@ 123456pusan.ac.kr
                Article
                ijn-10-4565
                10.2147/IJN.S87816
                4509535
                © 2015 Naeem et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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