pH‑dependent vs. constant release of mesalazine in the treatment of ulcerative colitis: Do drug delivery concepts determine therapeutic efficacy? (Review)

Abstract

Inflammatory bowel diseases (IBD) have developed to become a major global health problem. Ulcerative colitis (UC) is one of two main types of IBD, and >90% of patients suffering from mild or moderate forms of UC are treated with mesalazine, a well-tolerated and cost-effective drug. To allow oral administration, the drug has to be protected from resorption before it can reach the affected sites in the colon. The drug is therefore released from most currently used medications either constantly slow (time-dependent) or triggered by an increased pH during gastrointestinal transition. Both variants are widely used in clinical practice and it is surprising that they have not yet been compared directly in a large clinical study. In this overview, the evidence that may suggest preferential use of one type of mesalazine formulation over the other in general or for defined subgroups of patients is summarized and evaluated. Data from in vitro modelling of drug release and measurements of drug concentrations in colonic mucosa suggest that in many cases, constant release and pH-dependent formulations are of similar therapeutic efficiency; however, pH-triggered release may be superior in patients with proctitis-type UC or sites of inflammation in the proximal colon. Additionally, patients with a long gastric residence time, slow small intestinal transition, disease-related diarrhea or sensitivity to systemic adverse effects may benefit more from pH-dependent release formulations. In general, medications based on both concepts show similar efficacies, but the pH-dependent release formulations seem to be more robust in the treatment of a not further classified group of patients with UC. Future comparative clinical studies are required to clearly define the subgroups of patients that should be treated preferably with constant or pH-dependent release formulations of mesalazine.

Oral Drug Delivery Systems Applied to Launched Products: Value for the Patients and Industrial Considerations

“…165 In another clinical study, significant efficacy was observed with Asacol, but not with Pentasa, in proctitis-type UC patients, albeit that overall assessment of the two types of formulation was similar. 8 These data indicated that the colon-targeted DDS could deliver a medical solution with a high efficacy to patients. Intestinal pH and transit have intrasubject variability, which is a disadvantage of this type mechanism.…”

“…Compared with Pentasa sustained release tablet, consisting of EC-coated microgranules of mesalamine, and Salazopyrin EN-tabs, a mesalamine prodrug, a clinical study also showed high drug concentrations in the sigmoid colon mucosa after dosing Asacol to patients . In another clinical study, significant efficacy was observed with Asacol, but not with Pentasa, in proctitis-type UC patients, albeit that overall assessment of the two types of formulation was similar . These data indicated that the colon-targeted DDS could deliver a medical solution with a high efficacy to patients.…”

“…Many clinical studies and several analyses of development and market status have shown the contribution of DDS to the value and benefit of patients. For example, new formulations have provided patients with increased new medical options, − greater efficacy, ,, faster onset, and reductions in adverse events and risk. ,− Moreover, DDS have also provided patients with fewer doses , and clinic visits, easier administration, less unpleasant sensation, higher quality of life, ,, and greater adherence and satisfaction. , We also review the patient value of each of these technologies to showcase their usefulness and provide hints for the appropriate technology selection.…”

Pharmacological Management of Inflammatory Bowel Disease: a Century of Expert Opinions in Cecil Textbook of Medicine

“…31 By contrast, mesalazine action is triggered by the higher pH of the colon and therefore protected from systemic absorption before it reaches the area affected by IBD. 31,37 Earlier studies have suggested that olsalazine may be safer than mesalazine preparation because it was associated with lower serum concentration of the potentially nephrotoxic molecule. 38 However, a recent Cochrane review found no clinically significant difference in efficacy or safety between the various 5-aminosalicylate drugs when used for induction of remission in UC.…”

Significance of 5-Aminosalicylic Acid Intolerance in the Clinical Management of Ulcerative Colitis

“…Therefore, this formulation is used for both UC and Crohn's disease. In contrast, the pH-dependent release formulation releases 5-ASA when the threshold pH value is exceeded during gastrointestinal transition from the small intestine to the large intestine [ 16 ]. In the terminal ileum, where the pH is > 7, the pH-dependent release formulation of 5-ASA starts to dissolve and exerts its effect mainly in the large intestine.…”