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      Conjugation of metronidazole with dextran: a potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes


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          Metronidazole (MTDZ), the drug of choice for the treatment of protozoal infections such as luminal amebiasis, is highly susceptible to colonic metabolism, which may hinder its conversion from a colon-specific prodrug to an effective anti-amebic agent targeting the entire large intestine. Thus, in an attempt to control the colonic distribution of the drug, a polymeric colon-specific prodrug, MTDZ conjugated to dextran via a succinate linker (Dex-SA-MTDZ), was designed. Upon treatment with dextranase for 8 h, the degree of Dex-SA-MTDZ depolymerization (%) with a degree of substitution (mg of MTDZ bound in 100 mg of Dex-SA-MTDZ) of 7, 17, and 30 was 72, 38, and 8, respectively, while that of dextran was 85. Depolymerization of Dex-SA-MTDZ was found to be necessary for the release of MTDZ, because dextranase pretreatment ensures that de-esterification occurs between MTDZ and the dextran backbone. In parallel, Dex-SA-MTDZ with a degree of substitution of 17 was found not to release MTDZ upon incubation with the contents of the small intestine and stomach of rats, but it released MTDZ when incubated with rat cecal contents (including microbial dextranases). Moreover, Dex-SA-MTDZ exhibited prolonged release of MTDZ, which contrasts with drug release by small molecular colon-specific prodrugs, MTDZ sulfate and N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}- d, l-glycine. These prodrugs were eliminated very rapidly, and no MTDZ was detected in the cecal contents. Consistent with these in vitro results, we found that oral gavage of Dex-SA-MTDZ delivered MTDZ (as MTDZ conjugated to [depolymerized] dextran) to the distal colon. However, upon oral gavage of the small molecular prodrugs, no prodrugs were detected in the distal colon. Collectively, these data suggest that dextran conjugation is a potential pharmaceutical strategy to control the colonic distribution of drugs susceptible to colonic microbial metabolism.

          Most cited references31

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          Polysaccharides in colon-specific drug delivery.

          Natural polysaccharides are now extensively used for the development of solid dosage forms for delivery of drug to the colon. The rationale for the development of a polysaccharide based delivery system for colon is the presence of large amounts of polysaccharidases in the human colon as the colon is inhabited by a large number and variety of bacteria which secrete many enzymes e.g. beta-D-glucosidase, beta-D-galactosidase, amylase, pectinase, xylanase, beta-D-xylosidase, dextranase, etc. Various major approaches utilizing polysaccharides for colon-specific delivery are fermentable coating of the drug core, embedding of the drug in biodegradable matrix, formulation of drug-saccharide conjugate (prodrugs). A large number of polysaccharides have already been studied for their potential as colon-specific drug carrier systems, such as chitosan, pectin, chondroitin sulphate, cyclodextrin, dextrans, guar gum, inulin, amylose and locust bean gum. Recent efforts and approaches exploiting these polysaccharides in colon-specific drug delivery are discussed.
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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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              Dextrans for targeted and sustained delivery of therapeutic and imaging agents.

              Dextrans are glucose polymers which have been used for more than 50 years as plasma volume expanders. Recently, however, dextrans have been investigated for delivery of drugs, proteins/enzymes, and imaging agents. These highly water soluble polymers are available commercially as different molecular weights (M(W)) with a relatively narrow M(W) distribution. Additionally, dextrans contain a large number of hydroxyl groups which can be easily conjugated to drugs and proteins by either direct attachment or through a linker. In terms of pharmacokinetics, the intact polymer is not absorbed to a significant degree after oral administration. Therefore, most of the applications of dextrans as macromolecular carriers are through injectable routes. However, a few studies have reported the potential of dextrans for site (colon)-specific delivery of drugs via the oral route. After the systemic administration, the pharmacokinetics of the conjugates of dextran with therapeutic/imaging agents are significantly affected by the kinetics of the dextran carrier. Animal and human studies have shown that both the distribution and elimination of dextrans are dependent on the M(W) and charge of these polymers. Pharmacodynamically, conjugation with dextrans has resulted in prolongation of the effect, alteration of toxicity profile, and a reduction in the immunogenicity of drugs and/or proteins. A substantial number of studies on dextran conjugates of therapeutic/imaging agents have reported favorable alteration of pharmacokinetics and pharmacodynamics of these agents. However, most of these studies have been carried out in animals, with only a few being extended to humans. Future studies should concentrate on barriers for the clinical use of dextrans as macromolecular carriers for delivery of drugs, proteins, and imaging agents.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                14 February 2017
                : 11
                : 419-429
                Laboratory of Biomedicinal Chemistry, Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
                Author notes
                Correspondence: Yunjin Jung, College of Pharmacy, Pusan National University, 2, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea, Tel +82 515102527, Fax +82 515136753, Email jungy@ 123456pusan.ac.kr
                © 2017 Kim et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                dextran–metronidazole conjugate,colon-specific prodrug,metronidazole,dextran,polymeric prodrug,controlled release


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