Release profile of Salofalk 750 mg tablets

OVER THE PAST 10 YEARS, VARIOUS preparations of mesalamine (5aminosalicylic acid [5-ASA]) have become available to treat Crohn’s disease and ulcerative colitis. They have the advantage over sulfasalazine of having fewer side effects. In addition, some are formulated to release 5-ASA in the small bowel; hence, they may be effective in small bowel disease treatment (1). Recently a new mesalamine preparation, Salofalk 750 mg tablets (Axcan Pharma), was developed that has a water-based, pH sensitive Eudragit LD 30 coating, different from the solventbased, pH-sensitive coating on the 250 mg Salofalk preparations. These tablets offer two potential benefits over other mesalamine preparations. First, they contain a larger dose of medication so fewer tablets must be ingested, which may lead to increased patient compliance. Second, in vitro studies show that Salofalk 750 mg is released in the more proximal bowel (2). They may, therefore, be more effective in treating patients with Crohn’s disease involving the more proximal small bowel and patients who have had previous surgical resections. The objective of this study was to determine the in vivo release profile of Salofalk 750 mg tablets and to determine the urinary and fecal excretion of both 5-ASA and its metabolite, N-ac-5-ASA.

comprised 10 subjects who had had a proctocolectomy plus either a small bowel resection (seven subjects) or loop ileostomy, constructed at least 35 cm proximal to the ileocecal junction (three subjects).Group 2 comprised 11 subjects who had had a proctocolectomy without a small bowel resection or exclusion.All subjects had ulcerative colitis.Subjects were excluded if they had a history of renal disease, were known to be allergic to sulfasalazine or mesalamine, or were pregnant or nursing.Experimental design: Baseline samples of plasma, urine and ileostomy effluent were taken at 08:00, following an overnight fast.Subjects then ingested one tablet of Salofalk 750 mg and four plastic markers.The latter were used to determine the small bowel transit time.At 09:00, 12:00 and 18:00 subjects ate standardized meals.Throughout the 24 h period they were allowed water ad libitum.All medications, other than acetylsalicylic acid, sulfasalazine and mesalamine, were continued, including antidiarrheal medications.The subjects remained at the Clinical Investigation Unit at the Toronto Hospital, General Division, Toronto, Ontario from 08:00 to 20:00.The following morning at 08:00 subjects returned for the final collection of samples.Activity was unrestricted throughout the duration of the study.
Ethics approval was obtained from the Toronto Hospital Committee for Research on Human Subjects and each subject gave informed consent.Laboratory methods -Plasma samples: Five millilitre samples of blood were drawn into heparinized vacutainers at baseline and at hourly intervals for 6 h, then at 8, 12 and 24 h.Each sample was centrifuged at 10°C and the plasma was stored at -10°C until 5-ASA and N-ac-5-ASA (a metabolite of 5-ASA) were assayed.Additionally, serum creatinine was measured at baseline and at 24 h.Urine samples: A baseline urine sam-ple was collected at 08:00.Then urine was collected every 4 h for 12 h, and for 12 h until 08:00 the next morning.The volume of each sample was recorded and a 20 mL aliquot saved and stored at -10°C for 5-ASA and N-ac-5-ASA assays.The urine recovery of 5-ASA and N-ac-5-ASA was calculated by multiplying the respective urine concentration by the total volume of the urine excreted.Then, the total urine recovery of 5-ASA was calculated by adding the urine recovery of 5-ASA and N-ac-5-ASA, the latter expressed as equivalent milligrams of 5-ASA.Ileostomy effluent: A sample of ileostomy effluent was collected at 08:00 for the baseline sample.Subsequently, the effluent was collected every 2 h for 8 h, then at 12 and 24 h.Each sample was strained, and any undissolved tablet and intestinal transit markers were looked for.If present, they were removed and the time at which they passed was recorded.The small bowel transit time for each subject was determined by calculating the mean time of passage of the four markers.

Subjects:
The characteristics of the subjects are given in Table 1.The subjects were similar with the exception of age: subjects in group 1 were significantly older than those in group 2 (P<0.01).In group 1, the mean length of small bowel resected or out of circuit was 65±22 cm (range 35 to 110 cm).Two subjects (one from each group) did not pass all four small bowel transit markers and were not included in the small bowel transit time calculations.Although the mean small bowel transit time was shorter in group 1, the difference was not significant.
Four subjects complained of symptoms possibly related to the medication: gas (one subject), headache (one) and watery ileostomy effluent (two).Plasma: The mean plasma concentrations of N-ac-5-ASA and 5-ASA are shown in Figures 1 and 2, respectively.Both substances were first detected in the plasma at 1 h.Mean times of the peak concentration of N-ac-5-ASA and 5-ASA were similar in both groups (N-ac-5-ASA: 3.40±1.78h in group 1 and 3.45±2.16h in group 2; 5-ASA: 3.10±1.91h and 3.27±2.28h, respectively).Additionally, there were no significant differences in the mean peak concentrations of either N-ac-5--ASA (5.42± 3.71 mg/mL in group 1 versus 6.75±5.06mg/mL in group 2) or 5-ASA (6.12±5.16mg/mL versus 6.66±4.86mg/ mL, respectively).Ileostomy and urine excretion: Urine and ileostomy effluent recovery data are given in Table 2.There was no significant difference in the mean urine volume passed by the two groups whereas the mean total volume of ileostomy effluent was significantly greater in group 1 versus in group 2 (P<0.05).
The mean recovery of both 5-ASA and N-ac-5-ASA in urine was significantly less in group 1 compared with group 2 (40.9±12.8%versus 62.9±10.3%,P=0.001).Approximately one-quarter of the amount recovered in the urine in all subjects was excreted as 5-ASA.
Conversely, the mean recovery of both 5-ASA and N-ac-5-ASA in the ileostomy effluent of group 1 was greater than in group 2 although this difference did not reach statistical significance (33.1±16.9%versus 21.2± 9.8%, P=0.06).Of the mean total amount recovered in the ileostomy effluent, 69.6% was recovered as 5-ASA in group 1 subjects and 43.1% as 5-ASA in group 2 subjects.The mean total recovery of both substances in both ileostomy effluent and urine was 74.0±21.2% in group 1 compared with 84.0±14.2% in group 2 (P>0.20).

DISCUSSION
The effectiveness of mesalamine in the treatment of inflammatory bowel disease is attributed mainly to its topical action on the intestinal mucosa.Mesalamine is readily absorbed from the small intestine so various polymeric coatings allowing delayed release of the medication have been developed to prevent release of mesalamine until the drug reaches the target site in the small bowel or colon.Most of these coatings are pH-dependent.Thus, release characteristics of the different tablets vary depending on the coating and are important inpredicting the site of drug activity.The Salofalk 750 mg tablets   CAN J GASTROENTEROL VOL 9 NO 5 JULY/AUGUST 1995 have an enteric coating composed of a water-based, pH-sensitive polymer, Eudragit LD 30.In previous in vitro studies, maximal dissolution occurred between pH 6 and 7.5.In simulated intestinal pH 6.8, there was evidence of dissolution at 2 h and these tablets were completely dissolved by 3.5 h (2).
In the present study, ileostomates were chosen as models to study the release profile of Salofalk 750 mg tablets in the small bowel.Group 1 subjects were chosen to simulate patients who had a small resection and group 2 subjects to simulate those with normal intestinal anatomy.In both groups there was evidence that the tablets disintegrated (based on plasma levels and urine excretion) yet the medication was incompletely absorbed and present in the distal small bowel.Thus, these results suggest that the Salofalk 750 mg tablets should be effective in the treatment of small bowel disease.
As one would predict, because of the shorter intestinal surface area, group 1 subjects had a shorter mean small bowel transit time and an increased mean ileostomy effluent output, although only the latter was statistically significant compared with group 2 subjects.The mean plasma concentrations of 5-ASA and N-ac-5-ASA in group 1 was not significantly smaller than in group 2. However, urinary excretion of mesalamine was significantly decreased in group 1, suggesting that there was decreased total absorption of mesalamine in subjects in whom there was less small bowel surface area.On the other hand, a higher proportion of mesalamine was recovered in the ileostomy effluent of group 1 than in group 2. Again, these results are predictable in group 1 because of the previous small bowel resection in these subjects.
The abbreviated results from a similar study with Rowasa I tablets (a 250 mg preparation of mesalamine available only in the United States (Solvay Pharmaceuticals, Georgia) are given in Table 3 (3).The two groups of subjects in that study were similar to those in the present study: group 1 comprised ileostomates who had had a small bowel resection while group 2 comprised ileostomates with an intact small bowel.The mean peak plasma concentrations of N-ac-5-ASA (5-ASA was not detected in any subjects receiving Rowasa I tablets) were significantly higher in both groups ingesting Salofalk compared with those receiving Rowasa I.In addition, a greater proportion of the mesalamine was recovered in the urine and a smaller proportion in the ileostomy effluent of both groups of subjects taking Salofalk.These differences can be explained, only in part, by differences in the subject groups.In the present study, group 1 subjects had a shorter mean small bowel resection (65.0±22.4cm versus 95±25 cm), longer mean intestinal transit time (10.9±5.0 h versus 7.1±3.6h) and lower mean volume of ileostomy effluent (918±336 mL versus 1321±299 mL) than the group 1 subjects receiving Rowasa I.However, group 2 subjects in both studies had similar characteristics.Thus, the differences seem to be due, at least in part, to differences in the release characteristics of the medications.Salofalk 750 mg has a water-based, pH-sensitive, Eudragit enteric coating, whereas the Rowasa I coating is based on a matrix erosion system that is also pH-dependent.

CONCLUSIONS
These data suggest that Salofalk tablets disintegrate in the more proximal part of the small intestine compared with Rowasa I, resulting in greater absorption and less active 5-ASA available in the terminal ileum.Further investigation by gamma scintigraphy to confirm the exact release site of Salofalk 750 mg tablets in the small bowel would be useful.If it is indeed a more proximal release, Salofalk 750 mg may have greater efficacy in the treatment of Crohn's disease present in the proximal small bowel or in patients who have had a significant small bowel resection.

TABLE 1 Characteristics of the two study groups
Group 1 (n=10) comprised small bowel resection patients; Group 2 (n=11) comprised patients without small bowel resection.NA Not applicable.*P<0.01;†Mean of nine subjects; ‡ Mean of 10 subjects

TABLE 3 Abbreviated Rowasa I* recovery results Mean total dose in urine Mean total volume of ileostomy effluent Mean total dose of ileostomy effluent
*Available only in the United States(Solvay Pharmaceuticals, Georgia)