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 oldest drug for the treatment of inflammatory bowel disease . Development of 5-ASA preparations began with salazosulfapyridine. Salazosulfapyridine is an azo compound composed of mesalazine and sulfapyridine and has a unique drug delivery system (DDS), which selectively releases mesalazine into the colon via azo bond cleavage by azoreductase, a bacterial enzyme present in the colon. . Due to its high efficiency, it is still used in the treatment of UC. However, the side effects of salazosulfapyridine, such as pigmentation of sweat, tears, urine, and rashes, are considered problematic, and sulfapyridine has been suggested to contribute to these effects. Medications containing only mesalazine have been developed to avoid the various side effects of salazosulfapyridine. They include TDPs coated with a porous film of mesalazine and ethyl cellulose and PDPs coated with a film of methacrylic acid copolymer [11, 12]. PDTs have the disadvantage that mesalazine begins to be released from the upper jejunum and rarely reaches the distal colon, even when given at a dose of 4.0 g/day, the maximum dose approved by the insurance system. Japanese national disease. PDPs, on the other hand, have a DDS in which the lining dissolves near the end of the ileum at pH ≥ 6.8 to 7.0, and therefore more mesalazine is delivered to the distal colon. [11, 12]. 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 concentration of mesalazine in the sigmoid colon is significantly higher than that obtained by PDT at a dose of 3 g/day. daytime . In addition, pH- and time-dependent formulations of MMX consist of a tablet containing mesalazine dispersed in a matrix consisting of a hydrophilic and lipophilic base, coated with a pH-sensitive polymer film. . When the drug is transported into the large intestine, the polymer film dissolves, the tablet is exposed to intestinal fluid, and the hydrophilic and lipophilic base inhibits the penetration of intestinal fluid into the tablet, resulting in the gradual release of mesalazine in 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 concentrations of mesalazine in the distal mucosa of the large intestine, although the concentrations achieved are not significantly different from those achieved by TDPs and PDPs. . In addition, MMX is administered once daily from the active period to the remission period, and therefore its use should improve treatment compliance. [2, 16].
In this way, various measures have been taken to improve the deliverability of mesalazine to the large intestine. In fact, the intramucosal concentration of mesalazine in the distal colon has been reported to increase in the following order: TDP, PDP, and MMX . Although PDPs and MMX have been developed to effectively release mesalazine in the colon, we often encounter cases of unwanted elimination of these tablets in patients with worsening UC and increased frequency of defecation. Due to the release mechanism of MMX tablets, if the coating of these tablets is intact when the tablets are excreted (insoluble excretion), the mesalazine contained in the tablets will not have been released, which may increase the risk of relapse or exacerbation. Indeed, in this study, a high defecation frequency at the start of treatment was found to be a risk factor for insoluble MMX excretion, regardless of the type of colitis present.
In a previous study, we looked at unwanted shedding in 95 patients who had just started PDPs in our hospital between 2014 and 2018, and the insoluble shedding rate was 12.6% (12/95 cases) ( data not shown). There was no significant difference in the rate of insoluble excretion between the different disease types: 2% (3/18 cases) for proctitis, 4% (6/15 cases) for proctosigmoiditis, 0% ( 0/11 cases) for the left side. 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 patients with a BSFS score ≥ 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 ≤ 4 experienced insoluble excretion, as did 9% (3/33 cases) of patients with unknown defecation frequency. However, there was no significant difference in the frequency of insoluble excretion between groups, suggesting that insoluble excretion of PDPs is less predictable than that of MMX.
In an in vitro study, Abinusawa A et al. compared the release rate of mesalazine from various 5-ASA formulations in acidic environments that changed over time from pH 1 to pH 6.0 and pH 6.8 . As a result, TDPs were found to 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, which which indicates that the release rate differs significantly 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 about 6-7 hours for 100 % of the mesalazine is released because the encapsulated tablet is protected by the film coating and the mesalazine is only released after the coating has dissolved.
The stagnation time of colonic contents is strongly influenced by the frequency of defecation. In other words, except in special cases, such as patients with tenesmus, more frequent defecation shortens the stagnation time in the large intestine, which is believed to be the reason why the insoluble excretion rate of MMX increases with the number of defecations. Defecation frequency and fecal characteristics during the active phase of the disease are strongly influenced by the extent of the disease, suggesting that the type of disease is a risk factor for insoluble MMX excretion.
In the photographs shown in Figure 2, a clear difference in the dissolution process of the pH-sensitive film coating can be observed between PDPs and MMX. In the case of MMX, the surface of the coating dissolves first, while in the case of PDPs, the edges dissolve first. It is considered that the edges of the PDPs dissolve faster than the surface, and the undissolved surface peels off easily (Fig. 2c), with the mesalazine inside being released in a short time. In fact, during lower endoscopy, we often encounter PDPs as so-called ghost pills; that is, pills from which mesalazine was released into the colon, leaving only the outer shell. Therefore, PDPs are considered to be less affected by defecation frequency than MMX.
One consequence of insoluble excretion is that the ability of the drug in question to induce or maintain remission cannot be fully elucidated. However, insoluble excretion of part 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. We considered that it would not be possible to determine whether insoluble shedding itself increased disease activity in this study, and therefore this question was not investigated.
Physicians and patients are generally unaware of the insoluble excretion that occurs; 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, for example by replacing it. In fact, switching to mesalazine has been reported to be effective in 33-59% of cases. . Adding the aforementioned treatments to such cases would represent a form of medical malpractice and would also have a significant impact on medical costs. Therefore, when PDPs or MMXs are selected, it is necessary to explain the possibility of insoluble excretion to patients in advance and have them monitor their stool.
This study had several limitations. First, it was a retrospective, single-center study with a small number of cases. Additionally, tablets can be easily buried in solid stools making them difficult to see, while they may be easier to see in muddy stools and diarrhea. Additionally, patients are considered to be more interested in their bowel movements during the active phase of UC and therefore they may notice insoluble excretion more often during this period. Conversely, patients in remission, who are less interested in their excrement, may be unaware of intractable excretion. Another important limitation of this study was the visual method used to detect insoluble excretion, the effectiveness of which may have been affected by the amount of fecal matter produced and/or the absolute amount of insoluble excretion. Therefore, there may have been instances where insoluble excretion was overlooked.
In this study, insoluble excretion was defined as when the pH-sensitive coating of the 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” (Figs. 2c,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” (Figs. 2a,b). Thus, we have started measuring urinary salicylic acid levels to detect whether the internal drug has been taken up, and a prospective study including such measurements should be performed. [19, 20].
In order to clarify the criteria for drug selection for UC, the definition of insoluble excretion needs to be re-examined and a prospective study is needed to avoid cases of insoluble excretion being overlooked. It is also necessary to assess whether insoluble excretion exacerbates UC or if insoluble excretion occurs due to an increased frequency of defecation associated with exacerbation of UC. It is hoped that further research will establish more precise drug use standards for UC.
In conclusion, the probability of excretion of insoluble MMX is influenced by the frequency of defecation and the extent of inflammation. However, clinicians should not avoid prescribing MMX based on the patient’s defecation frequency or disease activity. Rather, it is important that physicians and patients be aware that insoluble MMX excretion may occur, as it may delay healing.