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      Preparation of Colon-Targeted Acetylharpagide Tablets and its Release Properties in vivo and in vitro

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          Abstract

          Ethno Pharmacological Relevance: Acetylharpagide is a monomeric compound extracted from Ajuga decumbens, widely used for remedying infectious and inflammatory diseases in Southern China.

          Aim of the Study: The present study designed and investigated the formulation of colon-targeted acetylharpagide tablets according to the dual controlled release mechanisms of time-delay and pH-sensitivity.

          Materials and Methods: The core tablets of acetylharpagide were coated with the material used in time-delay systems such as ethyl cellulose and suitable channeling agent, followed by pH-dependent polymers, polyacrylic resin II and III in a combination of 1:4. Furthermore, the release and absorption performance of colon-targets tables were evaluated in vitro and in vivo. In the in vitro tests, the optimized formulation was not released in simulated gastric fluid in 2 h; the release was <5% at pH 6.8 simulated intestinal fluids for 4 h; the drug was completely released within 5 h at pH 7.6 simulated colon fluid. In the in vivo tests, pharmacokinetic characteristics of the colon-targeted tablets were investigated in dogs.

          Results: The results indicated that the acetylharpagide tablets with the technology of colon-targeting caused delayed T max, prolonged absorption time, lower C max, and AUCINF_obs. Meanwhile, the apparent volume of distribution (Vz_F_bs) of the colon-target tablets was higher than the reference.

          Conclusions: These results suggested that colon-targeted acetylharpagide tablets deliver the drug to the colon. The in vitro performance of colon-targeted acetylharpagide tablet was appropriately correlated with its performance in vivo.

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          Most cited references27

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          Colon-targeted oral drug delivery systems: design trends and approaches.

          Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.
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            Colon targeted drug delivery systems: a review on primary and novel approaches.

            The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process.
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              Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years.

              The colectomy rate in ulcerative colitis (UC) is related to morbidity and to treatment decisions made during disease course. The aims of this study were to determine the colectomy risk in UC in the first decade after diagnosis and to identify factors that may influence the choice of surgical treatment. In 1991-1993, 781 UC patients from 9 centers located in 7 countries in northern and southern Europe and in Israel were included in a prospective inception cohort study. After 10 years of follow-up, 617 patients had complete medical records, 73 had died, and 91 had been lost to follow-up. There were no significant differences in age, sex, or disease extent at diagnosis between patients followed for 10 years and those lost to follow-up. The 10-year cumulative risk of colectomy was 8.7%: 10.4% in the northern and 3.9% in the southern European centers (P < .001). Colectomy was more likely in extensive colitis than in proctitis, with an adjusted hazard ratio (HR) of 4.1 (95% CI: 2.0-8.4). Compared with the southern centers, the adjusted HR was 2.7 (95% CI: 1.3-5.6) for The Netherlands and Norway together and 8.2 (95% CI: 3.6-18.6) for Denmark. Age at diagnosis, sex, and smoking status at diagnosis had no statistically significant influence on colectomy rates. The colectomy rate was found to be lower than that in previous publications, but there was a difference between northern and southern Europe. Colectomy was associated with extensive colitis, but the geographic variations could not be explained.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                14 August 2018
                2018
                : 9
                : 832
                Affiliations
                Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing, China
                Author notes

                Edited by: Rosario Pignatello, Università degli Studi di Catania, Italy

                Reviewed by: Maria Cristina Bonferoni, University of Pavia, Italy; Paolo Giunchedi, University of Sassari, Italy

                *Correspondence: Jinyu Wang jinyu024@ 123456163.com

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2018.00832
                6103264
                30154716
                c666dcd7-0e92-4a0f-b9dd-33ffa59ff941
                Copyright © 2018 Liu, Yan, Kong, You, Li, Wang, Tong and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 May 2018
                : 10 July 2018
                Page count
                Figures: 6, Tables: 6, Equations: 2, References: 34, Pages: 9, Words: 7345
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                colon-targeted tablet,acetylharpagide,release property in vitro,pharmacokinetic characteristics in vivo,in vitro-in vivo correlation

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