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Advanced Drug Delivery Reviews (v.57, #2)
Regulation of intestinal epithelial function: a link between opportunities for macromolecular drug delivery and inflammatory bowel disease by Dario Siccardi; Jerrold R. Turner; Randall J. Mrsny (pp. 219-235).
The intestinal epithelium performs a multitude of tasks related to digestion and homeostasis. As a consequence of ingestion, this tissue must also participate in activities associated with protecting the body from potential pathogenic agents and toxic materials. To efficiently perform tasks associated with digestion and these protective functions, the intestinal epithelium has established several anatomical, biochemical and physiological barriers to impede unregulated uptake of materials. In order to perform functions of digestion and homeostasis, the intestinal epithelium uses mechanisms that allow dynamic modulation of regulated uptake pathways that can respond rapidly to changes in diet, health and challenges from pathogenic agents and macromolecules. This review focuses on specific, recent advances made in understanding cellular pathways and mechanisms that regulate dynamic processes of these barriers and examines the feasibility of drug delivery strategies focusing on macromolecular therapeutics potentially useful in the treatment of inflammatory bowel disease (IBD).
Keywords: Intestinal epithelium; Intestinal barrier; Crohn's disease; Ulcerative colitis; Inflammatory bowel disease; Antibody delivery; Peptide delivery
Are there predictors of Remicade treatment success or failure? by Chinyu Su; Gary R. Lichtenstein (pp. 237-245).
Infliximab (Remicade�) is an antitumor necrosis factor (TNF) therapy effective in both induction and maintenance of remission in Crohn's disease. Identifying predictors of response or relapse to infliximab is important given the potential toxicities and cost of this therapy. Currently available data suggest that concurrent immunosuppressant therapy, certain clinical characteristics, biological and immunological markers, and gene polymorphism may correlate with response to infliximab. However, no single variable has been consistently shown or definitely proven in studies to be a predictor of response to infliximab to be of practical value in current clinical practice. Data from the literature in these areas are reviewed in this article, pointing to the need for additional research in this topic.
Keywords: Crohn's disease; Tumor necrosis factor; Anti-TNF therapy; Therapy; Response; Smoking; Immunosuppressants; NOD2
New oral delivery systems for treatment of inflammatory bowel disease by David R. Friend (pp. 247-265).
Inflammatory bowel disease (IBD) is often localized to specific sites in the gastrointestinal tract (GIT). As a result, this disease can be treated with oral site-specific (targeted) drug delivery systems. Targeted delivery systems for treatment of IBD are designed to increase local tissue concentrations of antiinflammatory drugs from lower doses compared with systemic administration. This review addresses the impact disease has or may have on oral targeted delivery for treatment of IBD as well as a number of delivery approaches currently used in marketed products or under investigation. Delivery systems reviewed rely on temporal control, changes in pH along the GIT, the action of local enzymes to trigger drug release, and changes in intraluminal pressure. Dissolution of enteric polymer coatings due to a change in local pH and reduction of azo-bonds to release an active agent are both used in commercially marketed products. Newer approaches showing promise in treating IBD are based on polysaccharides. These materials are most effective when used as compression coatings around core tablets, which contain the active agent. More complex polymeric prodrugs systems are also under investigation. If the dose of the drug is sufficiently low, this approach may also prove useful in improving treatment of IBD.
Keywords: Oral targeted drug delivery; Large intestine; Colon; Inflammatory bowel disease; Anti-inflammatory
Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease by Ulrich Klotz; Matthias Schwab (pp. 267-279).
For targeting local and systemic inflammatory processes in inflammatory bowel disease (IBD) therapeutic agents of first choice (e.g. aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn's disease) and/or the colon (Crohn's disease and ulcerative colitis). However, it has to be realized that intestinal physiology (e.g. motility, intraluminal pH profiles), extent and pattern of IBD as well as drug disposition demonstrate large interindividual differences resulting in variable clinical response rates between about 35% and 75%. 5-Aminosalicylate (5-AS) can be delivered to the colon either by azo-prodrugs (e.g. sulfasalazine, olsalazine or balsalazide) or by direct rectal administration of 5-AS in form of enemas, foam or suppositories. Such formulations will be only effective in patients with ulcerative colitis (UC). Various slow/controlled release preparations of 5-AS have been developed for oral use. Some of them (e.g. Pentasa®, Salofalk®) release sufficient 5-AS already in the small bowel which could provide some additional benefit in Crohn's disease (CD). As urinary and faecal recoveries of total 5-AS are similar for all oral formulations, no major clinical differences can be expected. Extent of the disease, profile of adverse effects and patient's acceptance provide some guidance for selection of the particular agent.Rectal installation of several glucocorticosteroids has been employed for many years. More recently scientific and clinical interest has been focused on budesonide which is extensively presystemically metabolized in the intestinal wall and the liver. Therefore, its systemic availability is low (10–15%) independent whether budesonide is administered orally as controlled release formulation in patients with CD or rectally as enema in patients with UC. Numerous pharmacokinetic and clinical studies have documented the anticipated topical delivery and clinical efficacy of this corticosteroid without serious side effects such as cushingoid features. It can be assumed that for any novel therapeutic principle in IBD the approach of topical delivery will be also tried.
Keywords: Crohn's disease; Ulcerative colitis; Aminosalicylates; Budesonide; Drug disposition; Topical action
Mesalamine delivery systems: do they really make much difference? by Altamash I. Qureshi; Russell D. Cohen (pp. 281-302).
Sulfasalazine's role as the first-line of therapy in patients with inflammatory bowel disease has led to the development of other “designer�? aminosalicylates, which eliminate the sulfa-moiety, and attempt to target the topically active mesalamine to the inflamed bowel. Olsalazine sodium and balsalazide disodium utilize the same azo-bond structure as sulfasalazine, requiring release of active mesalamine by colonic bacteria, and thus targeting these agents to the colon. Other mesalamine delivery systems use pH-dependant- or moisture-release to liberate the active mesalamine in both the large and small bowel. Direct application of mesalamine via enema or suppository is also effective in patients with distal colitis.The pharmacology and thus the undesirable drug absorption rates differ between drugs, although the clinical importance of these characteristics is debatable. Differences in release-systems, the impact of the fed and fasting state, and unique patient intolerances to individual agents demand an understanding of each of these products, and their application to patient therapy.
Keywords: Aminosalicylates; Inflammatory bowel disease; Ulcerative colitis; Crohn's disease; Medical therapy; Sulfasalazine; Balsalazide disodium; Olsalazine sodium
Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide by Richard N. Fedorak; Lana Bistritz (pp. 303-316).
Budesonide is a potent corticosteroid with a high first-pass metabolism rate. Two commercially available enteric-coated pH-dependent release formulations (Entocort™ EC and Budenofalk®) deliver budesonide to the ileum and proximal colon, regions most commonly affected in Crohn's disease. The drug's effectiveness in this disease has been proven in multiple, placebo-controlled trials, where it has been shown to be superior to mesalamine and placebo, and equivalent to prednisolone for the control of mild to moderately active right-sided Crohn's disease. This beneficial therapeutic effect comes with less adrenal suppression and a small improvement in the clinical adverse effect profile, as compared to prednisolone. However, budesonide provides no benefit over conventional therapy for left-sided colonic disease, and it is less effective for treatment of more severe disease activity and more distal colonic disease. Continuous budesonide does not prolong remission and is, therefore, best used in an intermittent fashion to treat acute exacerbations.
Keywords: Budenofalk®; Collagenous colitis; Corticosteroid; Crohn's disease; Enteric-coated; Entocort™; Gastrointestinal; Glucocorticoid; inflammatory bowel disease; Ulcerative colitis