Evolutionary Advances in the Delivery of Aminosalicylates for the Treatment of Ulcerative Colitis

R. D. Cohen


Aliment Pharmacol Ther. 2006;24(3):465-474. 

In This Article

Summary and Introduction

Ulcerative colitis is a chronic and debilitating disease that involves inflammation of the colonic mucosa. Current therapies aim to reduce the symptom burden of ulcerative colitis and maintain disease quiescence. The standard first-line treatment for mild-to-moderate ulcerative colitis is 5-aminosalicylate therapy, which is available in oral and rectal (topical) formulations.
While current 5-aminosalicylate formulations are effective in the majority of patients, they are associated with a number of limitations including inconvenient dosing regimens and poor patient acceptability, which may lead to non-compliance with prescribed therapy. A variety of improved delivery mechanisms have been developed in an effort to overcome these limitations. Micropellet formulations and high-dose tablets appear to offer comparable efficacy and tolerability to conventional formulations, although any benefit in terms of long-term patient compliance remains to be proven. Novel methods of delivery, such as those using a combination of hydrophilic and lipophilic matrices, designed to provide once-daily dosing in a high-strength tablet, may offer a significant improvement in the therapy of active and quiescent ulcerative colitis.
This review examines the limitations of current 5-aminosalicylate formulations and reports on the evolution of novel oral formulations designed to overcome these limitations, maximize patient compliance during both induction and maintenance of quiescence, and optimize overall clinical outcomes.

Ulcerative colitis (UC) is a chronic and debilitating disease that involves inflammation of the colonic mucosa. The disease can affect individuals of any age but is most commonly diagnosed in patients aged between 15 and 30 years. In the Western world, the number of new cases of UC diagnosed each year (incidence rate) has been estimated to be about seven per 100 000,[1,2] with over 200 people per 100 000 living with UC at any given time.[2] UC typically follows a relapsing-remitting course and is characterized by the symptoms of abdominal pain and bloody diarrhoea. Patients also often experience fatigue, weight loss, rectal bleeding and loss of appetite as well as extracolonic symptoms including arthritis, inflammation of the eye, liver and biliary disease, osteoporosis, skin rashes and anaemia, all of which considerably diminish quality of life (QoL), particularly during the active phase of the disease.

The pathological cause of UC remains unclear. An inappropriate and excessive response to dietary triggers, unidentified infectious agents or the normal colonic bacterial population[3,4] by an inadequately regulated mucosal immune system are thought to play a major pathophysiological role in the chronic inflammation and manifestation of symptoms of UC.[5] In addition, there is some indication of a possible genetic predisposition to the development of UC.

Any part of the colon can be affected by UC, although left-sided disease is most common. Patients with UC almost always have rectal involvement. In as many as 55% of patients the disease is limited to this region at presentation, defined diagnostically as proctitis.[1] Approximately 30% of patients present with UC extending proximally to the splenic flexure or 60 cm from the anal verge, defined as left-sided or distal colitis. Only about 15% of patients present with disease extending beyond the splenic flexure, which is defined as extensive colitis.[1] However, subsequent proximal extension occurs in approximately 35% of patients with initial proctitis or left-sided colitis.[6]

Current treatments are aimed at reducing the symptom burden of UC and maintaining disease quiescence. The aminosalicylates are, at present, the treatment of choice for first-line therapy of mild-to-moderate disease, with demonstrated efficacy and safety in patients with UC.[7,8] Their action is thought to be predominantly topical at the site of inflammation within the colon. The clinical aim, therefore, is to maximize delivery of the active drug, 5-aminosalicylate [5-ASA; mesalazine (mesalamine)], to the affected regions of the colonic mucosa while minimizing systemic absorption.

The importance of long-term patient compliance with 5-ASA therapy in maintaining symptom quiescence has gained increasing recognition in recent years. A further benefit of long-term compliance is suggested by a number of observational studies that have suggested that regular use of 5-ASA is associated with an approximate twofold reduction in the risk of colorectal cancer development in patients with UC.[9,10] This is of particular relevance in this disease, as a meta-analysis of published studies showed that the 30-year risk of developing colorectal cancer is 18% in patients with UC.[11]

5-Aminosalicylate is available in a number of oral and rectal (topical) formulations including tablets, micropellets (granules), suppositories and enemas. Several oral formulations have been developed. Sulphasalazine, consisting of a sulphapyridine molecule bonded to a 5-ASA molecule, was the first formulation of 5-ASA shown to be therapeutically effective for the treatment of UC. This formulation largely resists gastric breakdown and systemic absorption until it reaches the colon, where bacterial azoreductase enzymes cleave the bond between the sulphapyridine and 5-ASA molecules. While sulphasalazine has been widely prescribed for the last four decades, due to its effectiveness and low cost, it is associated with a number of dose-dependent adverse events (including headache, nausea, dyspepsia and allergy) related to the sulphur in the sulphapyridine moiety.[12,13]

A number of new oral 5-ASA formulations also utilize colonic bacteria to release the active drug, but do not contain sulphapyridine. Olsalazine (Dipentum; Celltech Pharmaceuticals, Inc., Rochester, NY, USA) consists of two 5-ASA molecules linked together via an azo-bond, while balsalazide (Colazal; Salix Pharmaceuticals, Inc., Morrisville, NC, USA) comprises a 5-ASA molecule azo-bonded to a benzoic acid derivative. Other formulations, such as Asacol (Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA), do not bond 5-ASA to a carrier molecule, but instead utilize a gastro-resistant resin film (e.g. Eudragrit S) that dissolves at pH values exceeding 7 (equivalent to the pH found in the terminal ileum in some individuals) and thus are not broken down in the stomach or absorbed in the proximal small intestine. Pentasa (Shire US, Inc., Wayne, PA, USA) comprises microspheres that contain 5-ASA enclosed within an ethylcellulose semipermeable membrane, which allows pH-independent release of the active drug. In contrast to the formulations described above, Pentasa releases 5-ASA from the duodenum to the rectum, and is often used 'off label' to treat Crohn's disease in addition to its indicated use in UC. Indeed, both the American and British Gastroenterology Associations recommend the use of high-dose 5-ASA for the first-line treatment of mild ileal, ileocolonic or colonic Crohn's disease.[14,15]

All the sulphur-free 5-ASA formulations have excellent and comparable safety profiles. Moreover, a recent meta-analysis found no significant difference between the current oral formulations in terms of systemic exposure.[16] However, an almost 1000-fold variation in mucosal 5-ASA concentration between formulations was observed in a study assessing multiple biopsies taken at the same locations throughout patients' lower GI tracts, following cessation of 1-week therapy with different oral 5-ASA formulations.[17] In a well-designed study, with standardized time since last dose and standardized biopsy location, mucosal 5-ASA concentration was shown to be inversely correlated with endoscopic and histological scores.[18] The reported large variation in mucosal 5-ASA concentration[17] may, therefore, be a factor in the different efficacies reported for the various oral formulations.

The current delivery mechanisms for 5-ASA have a number of limitations. These have been found to impact considerably on patient compliance with therapy, particularly in the long-term periods of disease quiescence, and thus overall treatment success. This review examines these limitations and reports on the evolution of novel formulations designed to overcome these problems, maximize patient compliance with acute and maintenance therapy and optimize overall clinical outcomes.


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