These include Asacol, Ipocol, Claversal, Salofalk, Apriso, and Lialda. In order to prevent proximal absorption, mesalamine is coated with pH-sensitive polymers. The two most common polymers used are Eudragit-S and Eudragit-L [8, 12].

Eudragit-S coating breaks down at pH > 7 and releases mesalamine in the terminal ileum and colon [12]. Asacol (Procter and Gamble Pharmaceuticals, Cincinnati, OH, USA) and Ipocol (Sandoz Pharmaceuticals, Bordon, Hampshire, UK) are examples of mesalamine preparations which are enteric coated with Eudragit-S [8, 12, 16]. Asacol is available as 400 and 800 mg tablets and administered 2–3 times per day [17]. Eudragit-L, a derivative of S-polymer, breaks down at a lower pH and releases mesalamine in the jejunum, terminal ileum, and colon [12]. Claversal (Merckle GMBH, Ulm, Germany) and Salofalk (Axcan Pharma, Mont St. Hilaire, Quebec, Canada, and Falk Pharma, Freiburg, Germany) are examples of mesalamine formulations coated with Eudragit-L [12]. Studies on healthy volunteers and ileostomy patients have demonstrated that Eudragit-L-coated mesalamine preparations are released more proximally than Eudragit-S-coated mesalamine preparations [12].

Apriso (Salix Pharmaceuticals Inc., Morrisville, NC, USA) has been approved by FDA only for the maintenance of remission in ulcerative colitis [8]. It consists of a gelatin capsule containing granules of mesalamine, which are coated with Eudragit-L polymer resin. The capsule dissolves in the stomach and releases the mesalamine granules which in turn break down at pH greater than 6. The granules also contain a polymer matrix, which swells and ensures gradual release of the mesalamine throughout the colon [8]. It is dosed once daily.

MMX mesalamine marketed as Lialda in the USA and Mezavant elsewhere is a novel pH-dependent once-daily mesalamine formulation [8, 12, 16]. FDA has approved it for both induction and maintenance of remission in ulcerative colitis patients. In this formulation, MMX technology is utilized. It contains both hydrophilic and lipophilic matrices, which are in turn coated by pH-sensitive Eudragit-S resin. The Eudragit-S coating delays release of mesalamine until the terminal ileum and colon where pH is greater than 7. The hydrophilic matrix then comes in contact with intestinal fluids and swells forming a viscous gel mass [12, 16]. The viscous gel mass ensures slow release of the mesalamine. The lipophilic core prevents the water from entering the core of the tablet and dissolving it. This helps to prolong the half-life of the drug [8, 12, 16]. MMX mesalamine is available as 1,200 mg tablets and administered once or twice daily [17].

This includes Pentasa (Shire Pharmaceuticals Inc., Wayne, PA, USA, licensed from Ferring A/S Copenhagen, Denmark), a controlled-release mesalamine formulation. It utilizes a semipermeable, moisture-sensitive ethyl cellulose coating [16]. This allows a slow and sustained release of mesalamine. It also differs from other mesalamine preparations by releasing mesalamine in the duodenum and jejunum, in addition to the terminal ileum. It is estimated that approximately about 20 % of mesalamine is released in the small intestine and the rest in the colon [12]. It is available as 250 and 500 mg tablets and 250 mg capsules. It is administered four times per day.

Both Pentasa and Salofalk are available as sachets (micropellet formulations). One of the advantages of micropellet formulations is that it facilitates prolonged release of the mesalamine, thereby allowing less frequent dosing. This has been demonstrated in two studies comparing tablets to micropellets [16].

These mesalamine formulations similar to sulfasalazine utilize a diazo bond (Fig. 7.2). The diazo bond is cleaved by colon bacteria’s azoreductase enzyme-releasing mesalamine. Balsalazide and olsalazine are examples of prodrugs. Balsalazide/Colazal (Salix Pharmaceutical Inc., Morrisville, NC) utilizes an inert molecule (4-aminobenzoyl-β-alanine) for binding with a single 5-ASA molecule. Balsalazide is available as 750 mg tablets and is administered three times per day [17]. Olsalazine (Alaven Pharmaceuticals, Marietta, GA/Dipentum (UCB Pharma, Brussels, Belgium)) contains two 5-ASA molecules linked by a diazo bond. Olsalazine is available as 250 mg capsules and is administered twice daily [17].

Topical mesalamine preparations deliver 5-ASA directly to the site of inflammation in the distal colon. They are available as suppositories, suspension enemas, gels, and foams. Currently in the USA, only mesalamine suppositories (Canasa) and suspension enemas (Rowasa) are available. Scintigraphy studies have demonstrated that suppositories deliver active drug to the rectum, while suspension enemas can reach as far as the splenic flexure [12].

Several randomized controlled studies and meta-analyses have demonstrated superiority of oral mesalamine preparations over placebo in the induction of remission. In one of the recent meta-analyses published by Ford et al. (included 11 RCTs and 2,086 patients), the relative risk of failure to induce remission with mesalamine compared to placebo was 0.79 (95 % CI 0.73–0.85, p = 0.009) [18]. This meta-analysis also found that the number needed to treat for mesalamine derivatives was 6 (95 % CI 5–8) [18]. Ford et al. did not find any significant differences between the type of oral mesalamine drug and their efficacy in inducing remission in active UC (Cochrane Q = 1.11, p = 0.77) [18].

The Cochrane meta-analysis published in 2006 also found that mesalamine preparations were superior to placebo for induction of remission as well as clinical and endoscopic improvement in patients with active UC. In terms of ability to induce clinical or global improvement or remission, the pooled Peto odds ratio between 5-ASA and placebo was 0.40 (95 % CI 0.30–0.53) [19].

Delayed-release mesalamine preparation like Asacol has been shown to be superior to placebo in two RCTs. Schroeder et al. compared 4.8 and 1.6 g/day of Asacol to placebo. Asacol 4.8 g/day produced statistically significant remission compared to placebo (p < 0.0001), while 1.6 g/day did not induce significant remission rates compared to placebo (p = 0.51) [20]. In another study comparing Asacol to placebo, Snisky found that Asacol 2.4 g/day induced remission in 32 % patients compared to only 9 % by placebo (p = 0.003) [21]

In a large multicenter double-blind RCT, Pentasa 2 g/day (57 %) and 4 g/day (59 %) produced significantly better clinical improvement compared to placebo, while Pentasa 1 g/day (36 %) could not induce statistically significant remission compared to placebo [22].

Lichtenstein et al. demonstrated that MMX mesalamine is superior to placebo in the induction of both clinical and endoscopic remission. In a large multicenter, double-blind RCT, 280 patients were randomized to either MMX mesalamine 4.8 g/day, MMX mesalamine 2.4 g/day, or placebo. MMX mesalamine 4.8 g/day induced remission in 29.2 % of patients, MMX mesalamine 2.4 g/day in 34.2 % patients, and placebo in 12.4 % patients [23].

In only RCT comparing clinical remission rates between olsalazine and placebo in patients with active UC, olsalazine was not superior to placebo [18, 24]. But if the results of three trials that compared clinical improvement rates (rather than clinical remission) between olsalazine and placebo were to be included in the analysis, then olsalazine would be superior to placebo (RR of no remission or improvement = 0.81, 95 % CI 0.68–0.96) [18, 25–27].

Scherl and colleagues demonstrated that balsalazide (3.3 g twice daily) was better than placebo in achieving remission in patients with mild to moderately active UC. The relative risk of failure to achieve remission between balsalazide and placebo was 0.82 (95 % CI 0.74–0.91) [28].

The Cochrane meta-analysis updated in 2006 suggested that the newer mesalamine drugs tended toward therapeutic benefit when compared to sulfasalazine in the induction of remission in patients with active UC [19]. The newer mesalamine preparations in comparison to sulfasalazine had a pooled Peto odds ratio of 0.83 (95 % CI 0.60–1.13) for failure to induce global/clinical improvement or remission and 0.66 (95 % CI 0.42–1.04) for failure to induce endoscopic improvement [19]. Also they noticed that newer mesalamine preparations had fewer side effects compared to sulfasalazine [19].

In another meta-analysis by Nikfar and his colleagues found that none of the new mesalamine formulations were superior to sulfasalazine in inducing overall improvement in patients with active UC (overall improvement defined as a positive change in at least two of the following criteria: sigmoidoscopic appearances, histologic appearances, clinical severity, and percentage of bloody stools) [29]. In four trials (three trials comparing delayed mesalamine and one trial comparing Pentasa to sulfasalazine), the relative risk of overall improvement between sulfasalazine and mesalamine was a nonsignificant value of 1.04 (95 % CI 0.89–1.21). In three trials comparing sulfasalazine and olsalazine, the relative risk for overall improvement was 1.14 (95 % CI 0.91–1.43, p = 0.16), again a nonsignificant value [29]. In two trials, comparing sulfasalazine and balsalazide, the relative risk of overall improvement was a nonsignificant value of 1.3 (95 % CI 0.93–1.81, p = 0.12) [29].

There have been few studies and meta-analyses comparing various oral mesalamine preparations in their ability to induce remission in patients with active UC. A meta-analysis by Rahimi et al. found that balsalazide was superior to mesalamine in the induction of both symptomatic and complete remission [30]. In the pooled analysis of three trials comparing balsalazide to mesalamine in their ability to induce symptomatic remission, the relative risk was 1.23 (95 % CI 1.03–1.47, p = 0.0204), while the relative risk for ability to induce complete remission was 1.3 (95 % CI 1.002–1.68, p = 0.0481) [30]. In a meta-analysis by Ford et al., there was no statistically significant difference between the type of mesalamine formulation and their ability to induce remission in patients with active UC (Cochrane Q = 1.11, p = 0.77) [18].