Review Article: Delivery and Efficacy of Topical 5-aminosalicylic Acid (Mesalazine) Therapy in the Treatment of Ulcerative Colitis

M. S. Harris; G. R. Lichtenstein


Aliment Pharmacol Ther. 2011;33(9):996-1009. 

In This Article

Abstract and Introduction


Background The use of topical therapy in the treatment of ulcerative colitis has declined in recent years despite evidence of good efficacy.
Aims To review US prescription trends for 5-aminosalicylic acid (5-ASA) since the US approval of Asacol extended-release oral mesalazine (mesalamine) in 1992; to estimate the optimal level of 5-ASA exposure in the distal colon; to determine factors influencing distal colonic exposures; and to compare the effectiveness of different 5-ASA formulations (oral, topical suspension, foam, suppositories) in clinical trials.
Methods Review of clinical trials, physiologic studies and prescription trends of various mesalazine formulations for treatment of distal ulcerative colitis.
Results Between 1992 and 2009, prescriptions for oral mesalazine increased sixfold, whereas topical suspensions declined by 10%. In clinical trials, topical therapy resulted in higher remission and clinical response rates than oral therapy, with trends to earlier improvement. The mucosal concentrations of 5-ASA achieved by topical agents in the distal colon were up to 200-fold higher than those achieved by oral administration alone. Despite active colitis, over 40% of a topically administered 4 g 5-ASA suspension (equal to 1.6 g) reached the sigmoid colon. This likely represents a therapeutic exposure of 5-ASA. Although topical therapies are less convenient than oral medications, treatment algorithms have failed to take into account quality of life improvements resulting from more rapid and complete treatment response.
Conclusions Topical mesalazine therapy is superior to oral therapy in distal ulcerative colitis for both therapeutic response and drug delivery. Practice patterns should be re-evaluated in light of this information.


Ulcerative colitis (UC) is a chronic inflammatory disease limited to the colonic mucosa, characterised by relapses and periods of remission. 5-Aminosalicylic acid [5-ASA, mesalazine (mesalamine)] has become the preferred treatment for mild-to-moderate UC. 5-ASA acts topically on the colonic mucosa but is rapidly absorbed if ingested. Sulfasalazine was the first 5-ASA derivative to be used for the treatment of UC. The azo-bonded sulfapyridine, an inactive moiety, protects the drug from absorption until the 5-ASA is released by azoreductases present in high concentration in the bacteria-rich colon.[1]

Use of sulfasalazine has been associated with allergic reactions and a significant number of side effects.[2,3] The prevalence of sulfasalazine intolerance has limited its use in clinical practice. To reduce the incidence of side effects and allergic reactions, manufacturers have developed preparations that protect 5-ASA from proximal small intestinal absorption. Two formulation strategies have been employed. The first is the incorporation of 5-ASA into a prodrug, in which 5-ASA is covalently bound to an inactive carrier molecule. This diazo bond makes the molecule resistant to small bowel absorption and metabolism. The covalent bond is cleaved by bacterial diazoreductases, releasing the 5-ASA, the active moiety, into the colon. Prodrugs include sulfasalazine itself, balsalazide (in which the 5-ASA molecule is coupled to a benzoic acid derivative) and olsalazine (in which the 5-ASA molecule is coupled to another 5-ASA molecule). The second strategy is to incorporate unmodified 5-ASA (mesalazine) into a pH-sensitive acrylic coating that delays 5-ASA release until luminal conditions approach pH 7, the pH of the distal bowel. This allows a bolus of 5-ASA to be released in the terminal ileum and proximal colon. Formulations employing this second strategy include Asacol (Warner Chilcott, Dublin, Ireland), Salofalk tablets (Axcan Pharma, Mont St Hilaire, QC, Canada) and Salofalk Granustix (Axcan Pharma). Newer formulations, such as Apriso (Salix Pharmaceuticals, Morrisville, NC, USA) and Lialda (Shire Corporation, Wayne, PA, USA), utilise both a pH-sensitive acrylic layer to delay 5-ASA release and a coating of lipophilic and hydrophilic excipients to extend release throughout the colon. These formulations commence releasing 5-ASA at or above pH 6 and 7 respectively. Pentasa (Shire Pharmaceuticals, Inc.; trademark licensed from Ferring A/S, Copenhagen, Denmark) encloses 5-ASA microspheres within a moisture-sensitive, ethylcellulose membrane that commences releasing 5-ASA in the duodenum and continues releasing drug throughout the entire GI tract.

Concerns that have been raised associated with use of these delayed and extended-release oral formulations include delivery of sufficient 5-ASA to the left colon[1,4,5] and release processes that may be variable or unreliable.[6,7] This could represent the effects of proximal absorption,[8] proximal inactivation,[8–10] rapid emptying of the distal colon,[11,12] and differences amongst individual patients in rates of 5-ASA mucosal transport, transit and luminal pH.[7]

Rectally administered 5-ASA formulations, which include suspensions, suppositories, gels and foams, offer the advantage of delivering a known amount of 5-ASA topically to the left colon. Published studies suggest that topical preparations result in better responses and earlier improvement in mild-to-moderate distal UC when compared with oral therapy.[13–18] The current practice guidelines of the American College of Gastroenterology emphasize the superiority of topical therapy, either alone or in combination with oral 5-ASA agents, for the treatment of distal UC.[19] A 2005 study by Marteau et al.[20] further demonstrated that topical 5-ASA suspensions, when used as an adjunct to oral therapy in extensive disease beyond the splenic flexure, result in higher clinical remission and response rates and more rapid improvement than oral therapy alone.

Despite the fact that most UC patients have mild-to-moderate attacks limited to the left or distal colon,[21,22] topical therapies in 2009 represented only a small fraction of the total 5-ASA market in the US.[23] In fact, the market presence of topical therapies, especially suspensions, expressed as the percentage of overall 5-ASA use, experienced a decline over the past two decades (Figure 1a,b). Between the 1992 and 2009 (an 18-year period, which witnessed the approvals of Asacol in 1992, Pentasa in 1993, Colazal (balsalazide, Salix Pharmaceuticals, Morrisville, NC, USA) in 2000, Asacol HD in 2007, and Lialda and Apriso in 2008), total 5-ASA prescriptions increased by 72%, a trend entirely accounted for by a sixfold increase in oral mesalazine prescriptions (Figure 1a). Prescriptions for topical 5-ASA as a class (suppositories and suspension) increased slightly in absolute numbers over this time period, but relative to total 5-ASA use, market share declined (from 11% to 9%) (Figure 1b). In contrast to suppositories, which enjoyed some sales growth during this time period, suspension prescriptions declined by 10% and its market share was cut in half (from 6% to 3%) (Figure 1b, insert). Topical 5-ASA lost market share in 1999 after withdrawal of Rowasa suppositories, but this trend reversed with introduction of Canasa suppositories (Axcan Pharma, Mont St Hilaire, QC, Canada) in 2001.

Figure 1.

Mesalazine (5-ASA) prescription trends between the years 1992 and 2009: (a) number of prescriptions; (b) % of total by 5-ASA class. Inserts: Topical 5-ASA use as rectal suspension vs. suppository. Between 1992 and 2009, total 5-ASA prescriptions increased by 72%, but this trend was entirely accounted for by the nearly sixfold increase in oral mesalazine prescriptions (Figure 1a). Use of topical therapy increased 30%, reflecting a nearly twofold increase in suppository use (Figure 1a). Despite the absolute increase in the absolute number of prescriptions for topical therapy, market share actually dropped from 11% to 9% as a percentage of total prescriptions. Absolute numbers of suspension prescriptions fell 10%, and the suspension market share was cut in half (6% to 3%) (Figure 1b). Note the transient decrease in topical 5-ASA prescriptions and market share between 1999 and 2001 secondary to discontinuation of 5-ASA suppositories during this time period. This 18-year span corresponded to approval of Asacol in 1992, Pentasa in 1993, Colazal (balsalazide) in 2000, Asacol HD in 2007, and Lialda and Apriso in 2008. Canasa suppositories were approved in 2001 approximately 2 years postdiscontinuation of Rowasa suppositories. Adapted with permission from IMS Research, Wellingborough, England, UK.23

Several explanations account for the decreasing utilisation of suspensions over this time period. First, prescription trends were likely impacted by active promotion of new oral 5-ASA preparations and suppositories. Much of the marketing surrounding the newer oral medications embodied novel, patented release mechanisms purporting to enhance distal colon 5-ASA release. Rowasa (Solvay Pharmaceuticals, Marietta, GA, USA), the sole proprietary 5-ASA rectal suspension in the US, lost patent protection in 2004. The product was not actively promoted following this event until the middle of 2008, after its purchase by Alaven Pharmaceutical LLC (Marietta, GA, USA). During this time period, suppositories continued to be actively marketed. Second, the viewpoint held by many practitioners (and potentially magnified by marketing) was that patients with active colitis have difficulty retaining rectal suspensions, a problem not attributable to oral medications and suppositories. This has been translated to signify reduced treatment effect, an assumption that remains unproven. Unfortunately, as time for patient encounters diminishes, less time is allotted for the instruction necessary to assure the proper use of topical therapies and make them acceptable to the patient. Third, topical therapies have been perceived to disrupt life style compared to oral formulations and suppositories. However, quality of life is more assuredly enhanced by faster and more complete control of symptoms, allowing more rapid return to prior lifestyles and productivity. There has been little written about quality of life outcomes with different formulations of 5-ASA therapy, and little to show differences in convenience and comfort after rapidity and completeness of response are considered.

The natural history of UC is not entirely understood, but there is mounting emphasis that focuses on the impact of achieving clinical and endoscopic remission and complete mucosal healing as related to disease outcome.[24–27] Earlier and more intense therapy of distal colitis with topical therapies could potentially result in more durable healing, with fewer relapses, reduced probability of proximal disease extension and improved long-term outcome.[27] This should be the subject of comparative clinical trials. The efficacy of therapies should be revisited, and the paradigms of acceptability and lifestyle should be re-evaluated against these trial outcomes.


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