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Komissarova NG, Dubovitskii SN, Orlov AV, Shitikova OV. New Conjugates of Betulin with 2-Aminoethanesulfonic Acid. Chem Nat Compd 2019. [DOI: 10.1007/s10600-019-02672-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Shahdadi Sardo H, Saremnejad F, Bagheri S, Akhgari A, Afrasiabi Garekani H, Sadeghi F. A review on 5-aminosalicylic acid colon-targeted oral drug delivery systems. Int J Pharm 2019; 558:367-379. [PMID: 30664993 DOI: 10.1016/j.ijpharm.2019.01.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/08/2019] [Accepted: 01/08/2019] [Indexed: 02/08/2023]
Abstract
Site-specific colon drug delivery is a practical approach for the treatment of local diseases of the colon with several advantages such as rapid onset of action and reduction of the dosage of the drug as well as minimization of harmful side effects. 5-aminosalicylic acid (5-ASA) is a drug of choice in the treatment of inflammatory bowel disease and colitis. For the efficient delivery of this drug, it is vital to prevent 5-ASA release in the upper part of the gastrointestinal tract and to promote its release in the proximal colon. Different approaches including chemical manipulation of drug molecule for production of prodrugs or modification of drug delivery systems using pH-dependent, time-dependent and/or bacterially biodegradable materials have been tried to optimize 5-ASA delivery to the colon. In the current review, the different strategies utilized in the design and development of an oral colonic delivery dosage form of 5-ASA are presented and discussed.
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Affiliation(s)
- Hossein Shahdadi Sardo
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farinaz Saremnejad
- Department of Food Science and Technology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Sara Bagheri
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Akhgari
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Hadi Afrasiabi Garekani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Sadeghi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Chopade SS, Dhaneshwar SS. Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats. World J Gastroenterol 2018; 24:1093-1106. [PMID: 29563754 PMCID: PMC5850129 DOI: 10.3748/wjg.v24.i10.1093] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 12/31/2017] [Accepted: 01/23/2018] [Indexed: 02/07/2023] Open
Abstract
AIM To design colon-targeted codrugs of mycophenolic acid (MPA) and aminosugars as a safer option to mycophenolate mofetil (MMF) in the management of inflammatory bowel disease.
METHODS Codrugs were synthesized by coupling MPA with aminosugars (D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates (in vitro) and rat blood (in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control.
RESULTS The prodrugs resisted activation in HCl buffer (pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer (pH 7.4) and intestinal homogenates. Incubation with colon homogenates (in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine (MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA.
CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.
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Affiliation(s)
- Shakuntala Santosh Chopade
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune 411038, India
| | - Suneela Sunil Dhaneshwar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune 411038, India
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Sparks SM, Spearing PK, Diaz CJ, Cowan DJ, Jayawickreme C, Chen G, Rimele TJ, Generaux C, Harston LT, Roller SG. Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration. Bioorg Med Chem Lett 2017; 27:4673-4677. [PMID: 28916340 DOI: 10.1016/j.bmcl.2017.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 08/25/2017] [Accepted: 09/06/2017] [Indexed: 12/14/2022]
Abstract
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).
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Affiliation(s)
- Steven M Sparks
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
| | - Paul K Spearing
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Caroline J Diaz
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - David J Cowan
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Channa Jayawickreme
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Grace Chen
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Thomas J Rimele
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Claudia Generaux
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Lindsey T Harston
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
| | - Shane G Roller
- Enteroendocrine Discovery Performance Unit and Platform Technologies and Science, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, United States
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Bosquesi PL, Melo TRF, Vizioli EO, Santos JLD, Chung MC. Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach. Pharmaceuticals (Basel) 2011; 4:1450-1474. [PMID: 27721332 PMCID: PMC4060134 DOI: 10.3390/ph4111450] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 10/20/2011] [Accepted: 10/20/2011] [Indexed: 12/21/2022] Open
Abstract
The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer's disease, asthma, atherosclerosis, colitis, rheumatoid arthritis, depression, cancer; and disorders such as obesity and sexual dysfunction. Although inflammation is not the direct cause of these disorders, inflammatory processes often increase related pain and suffering. New anti-inflammatory drugs developed using molecular hybridization techniques to obtain multiple-ligand drugs can act at one or multiple targets, allowing for synergic action and minimizing toxicity. This work is a review of new anti-inflammatory drugs developed using the molecular modification approach.
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Affiliation(s)
- Priscila Longhin Bosquesi
- Lapdesf, Laboratory of Drug Design, Department of Drugs and Medicines, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Rodovia Araraquara-Jaú, km 1, Araraquara, SP, Cep. 14.802-901, Brazil.
| | - Thais Regina Ferreira Melo
- Lapdesf, Laboratory of Drug Design, Department of Drugs and Medicines, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Rodovia Araraquara-Jaú, km 1, Araraquara, SP, Cep. 14.802-901, Brazil
| | - Ednir Oliveira Vizioli
- Lapdesf, Laboratory of Drug Design, Department of Drugs and Medicines, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Rodovia Araraquara-Jaú, km 1, Araraquara, SP, Cep. 14.802-901, Brazil.
| | - Jean Leandro Dos Santos
- Lapdesf, Laboratory of Drug Design, Department of Drugs and Medicines, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Rodovia Araraquara-Jaú, km 1, Araraquara, SP, Cep. 14.802-901, Brazil.
| | - Man Chin Chung
- Lapdesf, Laboratory of Drug Design, Department of Drugs and Medicines, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Rodovia Araraquara-Jaú, km 1, Araraquara, SP, Cep. 14.802-901, Brazil.
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Kong H, Kim H, Do H, Lee Y, Hong S, Yoon JH, Jung Y, Kim YM. Structural effects of N-aromatic acyl-amino acid conjugates on their deconjugation in the cecal contents of rats: implication in design of a colon-specific prodrug with controlled conversion rate at the target site. Biopharm Drug Dispos 2011; 32:343-54. [PMID: 21800327 DOI: 10.1002/bdd.763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 05/31/2011] [Accepted: 06/16/2011] [Indexed: 11/06/2022]
Affiliation(s)
- Hyesik Kong
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Hyunjeong Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Heejeong Do
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Yonghyun Lee
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Sungchae Hong
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Jeong-Hyun Yoon
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Yunjin Jung
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
| | - Young Mi Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy; Pusan National University; Busan; Republic of Korea
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Jung Y, Kim YM. What should be considered on design of a colon-specific prodrug? Expert Opin Drug Deliv 2010; 7:245-58. [DOI: 10.1517/17425240903490401] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Joo K, Lee Y, Choi D, Han J, Hong S, Kim YM, Jung Y. An anti-inflammatory mechanism of taurine conjugated 5-aminosalicylic acid against experimental colitis: taurine chloramine potentiates inhibitory effect of 5-aminosalicylic acid on IL-1beta-mediated NFkappaB activation. Eur J Pharmacol 2009; 618:91-7. [PMID: 19616541 DOI: 10.1016/j.ejphar.2009.07.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Revised: 06/27/2009] [Accepted: 07/09/2009] [Indexed: 11/16/2022]
Abstract
Previously, we reported that oral administration of taurine conjugated 5-aminosalicylic acid, a colon-specific prodrug of 5-aminosalicylic acid (5-ASA), is effective in ameliorating experimental colitis and taurine elicits an additive anti-inflammatory effect upon cotreatment with 5-ASA. To explore a molecular mechanism for the anti-inflammatory property of the prodrug, we investigated the effect of the conjugate on IL-1beta-mediated NFkappaB activation. In human colon carcinoma Caco-2 and HCT116 cells, NFkappaB activity was accessed by a luciferase reporter assay and IL-6 secretion. Protein levels were determined by Western blotting. IL-6 levels were monitored by an Elisa kit. Treatment with either 5-ASA or taurine chloramine (TauCl) inhibited IL-1beta-mediated NFkappaB dependent luciferase expression and IL-6 secretion. In HCT116 cells, the inhibitory effect by TauCl or 5-ASA was through preventing IL-1beta-induced IkappaB kinase activation and subsequently interfering with IkappaBalpha degradation and p65 nuclear accumulation. Furthermore, combined TauCl/5-ASA treatment interfered additively with the activation process, leading to additive inhibitory effect on IL-1beta-mediated NFkappaB activation. Our results suggest that the anti-inflammatory effect of the prodrug on experimental colitis is attributed to the inhibition of the IL-1beta-mediated NFkappaB activation and the taurine effect is through TauCl potentiating the ability of 5-ASA to inhibit IL-1beta dependent NFkappaB activation.
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Affiliation(s)
- Kanghyun Joo
- Laboratory of Biomedicinal/Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea
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Vadnerkar G, Dhaneshwar S. Design and development of latentiated strategy for delivery of mesalazine to colon. J Drug Deliv Sci Technol 2009. [DOI: 10.1016/s1773-2247(09)50067-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Kim H, Kim D, Choi D, Jeon H, Han J, Jung Y, Kong H, Kim YM. Synthesis and Properties ofN,N′-Bis(5-Aminosalicyl)-L-Cystine as a Colon-Specific Deliverer of 5-Aminosalicylic Acid and Cystine. Drug Deliv 2008; 15:37-42. [DOI: 10.1080/10717540701828806] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Jung Y, Kim HH, Kim H, Kong H, Choi B, Yang Y, Kim Y. Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for treatment of experimental colitis. Eur J Pharm Sci 2006; 28:26-33. [PMID: 16455235 DOI: 10.1016/j.ejps.2005.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2005] [Revised: 10/06/2005] [Accepted: 12/12/2005] [Indexed: 01/16/2023]
Abstract
We previously reported that 5-aminosalicyltaurine (taurine-conjugated 5-ASA, 5-ASA-Tau) showed a potential as a colon-specific prodrug of 5-aminosalicylic acid (5-ASA) by in vitro evaluation. In this report, we in vivo-evaluated 5-ASA-Tau as a colon-specific prodrug for treatment of experimental colitis. Taurine conjugation of 5-ASA greatly reduced absorption of 5-ASA from the intestine. Oral administration of taurine-conjugated 5-ASA not only increased the colonic delivery efficiency of 5-ASA but also decreased the systemic absorption of free 5-ASA as compared with that of 5-ASA and, moreover, taurine is similarly effective to known colon-specific carriers for 5-ASA, glycine and aspartic acid, suggesting that taurine conjugation is an efficient way to increase the therapeutic effect and to reduce the adverse effects of 5-ASA. Intracolonic treatment with combined 5-ASA/taurine additively ameliorated TNBS-induced colitis rats indicating that taurine acted as not only a promoiety but also a therapeutically active agent. Furthermore, 5-ASA-Tau is slightly more effective than sulfasalazine in alleviating the colonic inflammation induced by TNBS. Taken together, our data suggest that 5-ASA-Tau is a potential colon-specific prodrug of 5-aminosalicylic acid with improved therapeutic activity against inflammatory bowel disease.
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Affiliation(s)
- Yunjin Jung
- Lab of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea
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Kim H, Jeon H, Kong H, Yang Y, Choi B, Kim YM, Neckers L, Jung Y. A molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-aminosalicylic acid in inflamed colon. Mol Pharmacol 2006; 69:1405-12. [PMID: 16407467 DOI: 10.1124/mol.105.020578] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In previous reports, a novel colon-specific prodrug, 5-aminosalicyltaurine (5-ASA-Tau) administered orally, is successfully delivered to and liberates 5-aminosalicylic acid (5-ASA) and taurine in the inflamed large intestine of rats. Furthermore, the prodrug ameliorates the 2,4,6-trinitrobenzene-sulfonic acid-induced colitis, and taurine acts not only as a carrier but also as an active therapeutic agent. In this study, we investigated the anti-inflammatory properties of the prodrug at a molecular level. After rectal administration of taurine, formation of taurine chloramine (TauCl) in the inflamed colonic tissue was examined using high-performance liquid chromatography. In human colon epithelial cell lines, nuclear factor-kappaB (NF-kappaB) activity was accessed using an NF-kappaB-dependent luciferase reporter gene. Protein levels were monitored by Western blotting. DNA binding activity of the NF-kappaB subunit p65 was determined using a DNA binding assay kit. A millimolar level of TauCl was formed in the inflamed tissue. TauCl inhibited tumor necrosis factor (TNF)-dependent NF-kappaB activation by modifying thiol(s) on p65 and blocking DNA binding. In addition, 5-ASA inhibited phosphorylation of p65 at serine 536, which is critical for transcriptional activity of NF-kappaB. Furthermore, combined TauCl/5-ASA treatment additively inhibited TNF-dependent NF-kappaB activation. Together, our data suggest that the colon-specific carrier taurine contributes to the clinical effect of the prodrug by potentiating the inhibitory effect of the active ingredient 5-ASA on a major proinflammatory signal, TNF-dependent NF-kappaB activation in the inflamed large intestine.
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Affiliation(s)
- Heejung Kim
- Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea 609-735
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Kesisoglou F, Zimmermann EM. Novel drug delivery strategies for the treatment of inflammatory bowel disease. Expert Opin Drug Deliv 2005; 2:451-63. [PMID: 16296767 DOI: 10.1517/17425247.2.3.451] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) encompasses two idiopathic inflammatory diseases of the intestinal tract: Crohn's disease and ulcerative colitis. Existing therapy for IBD consists mainly of orally or rectally administered small drug molecules, such as 5-aminosalicylates and corticosteroids, or potent systemic immune suppressants. IBD presents a challenging target for drug delivery, particularly by the oral route, as, contrary to most therapeutic regimens, minimal systemic absorption and maximal intestinal wall drug levels are desired. Several delivery strategies are employed to achieve this goal, including the chemical modification of the drug molecules, the use of controlled- and delayed-release formulations and the use of bioadhesive particles. The goal of this review is to summarise existing IBD therapy and examine novel approaches in intestinal drug delivery.
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Affiliation(s)
- Filippos Kesisoglou
- University of Michigan Department of Pharmaceutical Sciences, College of Pharmacy, Ann Arbor, MI 48109-1065, USA
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