5-ASA is a positional isomer of para-aminosalicylic acid (4-ASA), an antibacterial drug used to treat rheumatoid arthritis. It has been used since the 1940s, making it the longest-established drug for the treatment of inflammatory bowel disease [6]. The development of 5-ASA preparations began with salazosulfapyridine. Salazosulfapyridine is an azo compound consisting of mesalazine and sulfapyridine and has a unique drug delivery system (DDS), which selectively releases mesalazine into the colon via the cleavage of the azo bond by azoreductase, which is a bacterial enzyme found in the colon [7]. Due to its high efficacy, it is still used in the treatment of UC. However, the side effects of salazosulfapyridine, such as the pigmentation of sweat, tears, and urine and skin rashes, are considered to be problematic, and sulfapyridine has been suggested to contribute to these effects. Mesalazine-only drugs have been developed to avoid the various side effects of salazosulfapyridine. They include TDPs coated with a porous film of mesalazine and ethylcellulose and PDPs coated with a film of methacrylic acid copolymer [8, 9]. TDPs have the disadvantage that the mesalazine begins to be released from the upper jejunum, and it rarely reaches the distal colon, even when it is administered at a dose of 4.0 g/day, the maximum dose approved by the Japanese national health insurance system. PDPs, on the other hand, have a DDS in which the coating dissolves near the end of the ileum at pH ≥6.8 to 7.0, and hence, more mesalazine is delivered to the distal colon [8, 9]. PDPs are approved for use in Japan at doses up to 3.6 g/day, but even at a dose of 2.4 g/day, the intramucosal mesalazine concentration in the sigmoid colon is significantly higher than that achieved by TDPs at a dose of 3 g/day [10]. Furthermore, pH- and time-dependent MMX formulations consist of a tablet, containing mesalazine dispersed in a matrix consisting of a hydrophilic and lipophilic base, coated with a pH-responsive polymer film [11]. When the drug is transported to the large intestine, the polymer film dissolves, the tablet is exposed to intestinal fluid, and the hydrophilic and lipophilic base inhibit the penetration of intestinal fluid into the tablet, resulting in the gradual release of mesalazine into the large intestine. MMX preparations have been approved for use at a maximum dose of 4.8 g/day under the Japanese national health insurance system. They are reported to produce high mesalazine concentrations in the distal large intestine mucosa, although the concentrations achieved are not significantly different from those achieved by TDPs and PDPs [12]. Furthermore, MMX is administered once a day from the active period to the remission period, and hence, its use is expected to improve medication adherence [2,13].
In this way, various measures have been taken to improve the deliverability of mesalazine to the large intestine. In fact, it has been reported that the intramucosal mesalazine concentration in the distal colon increases in the following order: TDPs, PDPs, and MMX [12]. Although PDPs and MMX were developed to efficiently release mesalazine into the colon, we often encounter cases of unwanted elimination of such tablets in patients with worsening UC and an increased frequency of defecation. Due to the release mechanism of MMX tablets, if the coating of such tablets is intact when the tablets are excreted (insoluble excretion) the mesalazine within the tablets will not have been released, which may increase the risk of relapse or exacerbation. In fact, in this study a high defecation frequency at the start of treatment was found to be a risk factor for the insoluble excretion of MMX, regardless of the type of colitis present.
In a previous study, we examined unwanted excretion in 95 patients who were newly started on PDPs at our hospital between 2014 and 2018, and the insoluble excretion rate was 12.6% (12/95 cases) (data not shown). There was no significant difference in the insoluble excretion rate between different types of disease: 2% (3/18 cases) for proctitis, 4% (6/15 cases) for proctosigmoiditis, 0% (0/11 cases) for left-sided colitis, and 6% (3/51 cases) for extensive colitis. As for the effects of stool consistency at the start of treatment, 33.3% (7/22 cases) of the patients with a BSFS score of ≥6, 16.7% (2/12 cases) of those with a BSFS score of 5, and 8.3% (2/28 cases) of those with a BSFS score of ≤4 experienced insoluble excretion, as did 9% (3/33 cases) of the patients whose defecation frequency was unknown. However, there was no significant difference in the frequency of insoluble excretion among the groups, suggesting that the insoluble excretion of PDPs is less predictable than that of MMX.
In an in vitro study, Abinusawa A et al. compared the rate of mesalazine release from various 5-ASA formulations in acidic environments that changed with time from pH 1 to pH 6.0 and pH 6.8 [14]. As a result, it was found that TDPs release mesalazine at a constant rate over time, completely independent of pH, while PDPs and MMX only begin to release mesalazine at pH 6.8, indicating that the rate of release differs greatly between PDPs and MMX. In other words, in the case of PDPs almost 100% of the mesalazine is released within 2 hours after the environmental pH reaches 6.8, whereas for MMX it takes approximately 6 to 7 hours for 100% of the mesalazine to be released because the encapsulated tablet is protected by the film coating, and the mesalazine is only released after the coating dissolves.
The stagnation time of colonic contents is strongly influenced by the frequency of defecation. In other words, except for special cases, such as patients with tenesmus, more frequent defecation shortens the stagnation time in the large intestine, which is considered to be the reason why the insoluble excretion rate of MMX increases with the number of defecations. The frequency of defecation and fecal characteristics during the active phase of the disease are strongly influenced by the extent of the disease, suggesting that the disease type is an independent risk factor for insoluble MMX excretion.
In the photographs shown in Figure 2, a definite difference can be seen in the dissolution process of the pH-responsive film coating between PDPs and MMX. In MMX, the surface of the coating dissolves first, whereas in PDPs the edges dissolve first. In PDPs, it is considered that the edges dissolve faster than the surface, and the undissolved surface peels away easily (Figure 2-c), and the mesalazine inside is released within a short period of time. In fact, during lower endoscopy, we often encounter PDPs as so-called ghost pills; i.e., pills from which the mesalazine has been released into the colon and only the outer shell remains. Therefore, PDPs are considered to be less affected by defecation frequency than MMX.
One of the consequences of insoluble excretion is that the remission-inducing or remission-maintaining ability of the drug in question cannot be fully elucidated. The insoluble excretion of a portion of a dose may have little effect on a patient’s clinical course, depending on the frequency of such excretion, the extent of their lesions, and the degree of inflammation. However, both physicians and patients are generally unaware of insoluble excretion occurring; therefore, there is a risk that additional treatments, such as steroids, immunomodulators, or biologics, may be added unnecessarily. In many of these cases, it may be possible to induce remission by optimizing the mesalazine preparation, e.g., by switching it. In fact, it has been reported that mesalazine switching is effective in 33-59% of cases [15]. Adding the abovementioned treatments to such cases would represent a form of medical malpractice and would also have a considerable impact on medical costs. Therefore, when PDPs or MMX are selected, it is necessary to explain the possibility of insoluble excretion to patients in advance and have them monitor their stools.
The present study was a single-center retrospective study with a small number of cases. In addition, tablets can be easily buried, making them difficult to see, in solid stools, while in muddy stools and diarrhea tablets may be easier to detect. Moreover, it is considered that patients are more interested in their feces during the active phase of UC, and as a result they may notice insoluble excretion more often during this period. Conversely, it is undeniable that patients in remission, who have less interest in their excrement, may not be aware of insoluble excretion. These are the limitations of this study.
In this study, insoluble excretion was defined as when the pH-responsive coating of tablets did not dissolve, and the tablets were excreted in their original form. Due to the characteristics of MMX formulations, it is difficult for so-called “ghost pills” (Figures 1S-c,d), in which the outer shell partially dissolves and the mesalazine inside is released, to form. On the other hand, there are many cases in which the outer shell dissolves, but the MMX inside is excreted as a “melted tablet” (Figures 2-a,b), and a prospective study including these cases should be performed.
In order to clarify the drug selection criteria for UC, the definition of insoluble excretion needs to be reexamined, and a prospective study is required to prevent cases of insoluble excretion from being overlooked. It is also necessary to assess whether insoluble excretion exacerbates UC or whether insoluble excretion occurs due to an increase in the defecation frequency associated with the exacerbation of UC. It is hoped that further research will make it possible to establish more accurate drug usage standards for UC.
In conclusion, the insoluble excretion of MMX is strongly influenced by the defecation frequency, the extent of the disease, and stool consistency. It is important to consider the potential for insoluble excretion when prescribing MMX or when examining a relapsed patient taking MMX.