Mesalazine is a 5-aminosalicylic acid compound (5-ASA) indicated for the treatment of mild to moderate inflammatory bowel disease as well as for the induction and maintenance of remission. The precise mechanism of action is still unknown, although it appears its local anti-inflammatory effect may, at least in part, be due to its inhibition of cyclooxygenase.

An array of oral and rectal preparations have been formulated with numerous drug delivery methods in order to decrease systemic absorption and increase drug availability at the diseased area of the intestinal mucosa.

The selection of the most appropriate formulation involves tailoring of the therapy to the individual in addition to factors such as:

  • Disease extent and severity;
  • Efficacy;
  • Adverse effects;
  • Pill burden;
  • Patient preference; and
  • Compliance and adherence.

The different brands of mesalazine are not interchangeable due to their varying formulation and release characteristics. There are a number of different mesalazine formulations that release mesalazine in specific areas of the intestine at a particular pH range and release rate.

The following tables list the different mesalazine formulations available on the Pharmaceutical Benefits Scheme (PBS). However, as per PBS regulations, authority streamline approval is required for all mesalazine formulations (except suppositories). To qualify for PBS subsidised oral agents, patients must be intolerant to sulfasalazine or have a documented allergy to a sulfonamide.

Table 1. Enteric coated mesalazine formulations.

Drug Formulation Site of drug release Optimal drug release pH
250mg (Mesasal®) Eudragit-L coating Mid ileum to colon ≥6
500mg (Salofalk®) Eudragit-L coating Mid ileum to colon ≥6
800mg (Asacol®) Eudragit-S coating Terminal ileum onwards, colon ≥7

Enteric coated tablets have a pH-dependent release:

The resin film forms the enteric coating designed to release mesalazine only at a particular pH. This prevents untargeted disintegration in an acidic environment of the intestine and proximal bowel. Hence, it is suggested that pH-dependent formulations should not be co-administered with lactulose or medications that lower colonic pH as this inhibits the release of 5-ASA from the pH-dependent Eudragit coating, reducing its efficacy.

Time-dependent release from modified release tablets and granules:

Table 2. Modified release mesalazine tablet and granule formulations.

Drug Formulation Site of drug release Optimal drug release pH
500mg and 1gm (Pentasa® tablets) Microgranules coated with an ethylcellulose semi-permeable membrane Throughout the GI tract Any enteral pH
1.2gm (Mezavant® tablets)

 

Multi-matrix system coated with methacrylic acid copolymers Terminal ileum and entire colon ≥7
500mg, 1gm, 1.5gm and 3gm (Salofalk® granules)

 

Eudragit-L functional coating with matrix system inside the particle core Terminal ileal region Dependent of pH
1gm, 2gm and 4gm (Pentasa® granules)

 

Ethylcellulose semi-permeable membrane coated microgranules Duodenum to colon Any enteral pH

Another method of delivery from the enteric coated tablets is the time-dependent release of 5-ASA from microspheres encapsulated in an ethyl cellulose semi-permeable membrane. This formulation allows the moisture and time-dependent release of mesalazine, independent of the luminal pH. Mezavant®, a multi-matrix system, is a once-daily formulation. The lipophilic matrix incorporates mesalazine which is then dispersed within a hydrophilic matrix. Exposure of the hydrophilic matrix to the intestinal fluid causes it to swell to form a viscous gel mass. Mesalazine is then released in a slow and controlled manner throughout the colon.

Non-adherence to medication has important clinical implications in inflammatory bowel disease patients, including increased risk of relapses, possible risk of developing colorectal cancer, and the increased health care costs associated with managing poorly controlled disease.

The modified release formulations:

  • Increase compliance;
  • Reduce pill burden;
  • Offer less frequent dosing;
  • Improve tolerability; and
  • May allow once-daily dosing.

These modified release tablet formulations allow higher doses to be administered in the form of fewer tablets. The modified release sachets increase patient adherence as it resolves the issue of swallowing relatively large tablets.

Mesalazine is also available on the PBS in the form of suppositories, enemas, and rectal foams which act on the rectum, descending colon, and sigmoid and rectum respectively.

Practise points:

  • If the patient is tolerating a particular brand and their disease is well-controlled, the brand should not be changed.
  • Bioequivalence of capsules and tablets has not been established; advise patient to monitor for symptoms if preparations are changed.
  • Tablets and granules are to be swallowed whole; they must not be chewed or crushed. Granules are presented in a sachet; the contents of which may be emptied onto the tongue and washed down with water or juice.

References:

  1. Alex G, Andrews JM, Bell S, Connor S, Moore G, Ward M, et al. Clinical Update for General Practitioners and Physicians – Inflammatory bowel disease updated 2018. Gastroenterological Society of Australia.
  2. Bei Y, van Langenberg DR. Mesalazine preparations for the treatment of ulcerative colitis: are all created equal? World J Gastrointest Pharmacol Ther. 2015; 6(4): 137–44.
  3. Department of Health. The Pharmaceutical Benefits Scheme. Canberra, Australia.
  4. eMims [internet]. New South Wales: UBM Medica Australia Pty Ltd; 2018.
  5. Gastrointestinal Expert Group. Inflammatory bowel disease [revised 2018 March]. In: eTG complete [Online]. Melbourne: Therapeutic Guidelines Limited; 2018.
  6. Iacucci, Marietta, Shanika de Silva, and Subrata Ghosh. Mesalazine in inflammatory bowel disease: a trendy topic once again? Can J Gastroenterol. 2010; 24(2): 127–33.
  7. Rossi S, editor. Drugs for inflammatory bowel disease. In: Australian Medicines Handbook 2018 [online]. Adelaide: Australian Medicines Handbook Pty Ltd; 2018.

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