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Manufacturing issues of Mesalazine

Describe about The Metabolism of Mesalamine And Its Possible Use In Colonic Diverticulitis As An Anti-Inflammatory Agent?

Mesalazine (Synonyms: Mesalamine, 5-Aminosalicylic acid), being an anti inflammatory drug, is used for the treatment of Crohn’s disease, Ulcerative Colitis and other Inflammatory Bowel Disease. It is also known to possess anti oxidant activity. The formulation efficacy of Mesalazine has been found to be dependent on pH especially in case of Ulcerative Colitis. If the drug release happens in the colon at a pH greater than or equal to 7, it can be effective in cases of terminal ileum and caecum, extending to the colon. If the drug release happens in the colon at a pH greater than or equal to 6, cases involving ileum can be effectively treated. Therefore, the scope of the present report is to identify the manufacturing and regulatory issues of Mesalazine and a comparative study with Cyclosporin.

Inflammatory bowel disease is an inflamed condition of the small intestine including the colon. The existing therapies do not give satisfactory diminution to the patients with inflammatory bowel disease and other related diseases. The dosage form manufacturing needs a changeover to provide maximum therapeutic efficacy with the minimum effective concentration. Novel drug delivery system can be a novel approach to achieve this condition.

Mesalazine, being a drug of choice for inflammatory bowel disease, cannot be formulated in alternative release patterns. The conventional dosage forms have not been found to be satisfying in this regard. Anti adhesion molecules has the gut selectivity property. Therefore, it can be an interesting mode of treatment. Adaptive immune response in the gut happens because of the antigen presenting cells which are further professional or non-professional, regulatory T cells, effector cells and mucosal B cells. The most targeted site of the anti adhesion molecule therapies is the integrin family. Monoclonal antibodies are developed for targeting the integrins. Selective blockers may also be used as alternative therapy agents. Since Mesalazine is used as a conventional method of treatment and not presently manufactured as anti adhesion molecules, it cannot achieve the prolonged and desirable results as can be achieved by them (1).

The mechanism of action in the intestinal endothelium of the adhesion molecules and the anti adhesion drug blockage

The mechanism of action in the intestinal endothelium of the adhesion molecules and the anti adhesion drug blockage

Source: (1)

However, Since Mesalazine is the drug of choice in the first line of treatment in inflammatory bowel disease, it has been modified and manufactured accordingly to bring about the best possible therapeutic effects. The manufacturers also designed and rectified its formulation issues to achieve better results with Mesalazine.  One of the recent development in its manufacturing is the Mesalazine rectal suppository, which provides comfort to use to the patients of inflammatory bowel disease. The achievable drug load is upto 35% to 50%. The melting point can be set in the range 32 to 35.5ºC. Sufficiently larger surface area of the drug molecules provides better bioavailability for the granules. The weight can also be drastically reduced (2).

Regulatory issues of Mesalazine

Dissolution profile of Mesalazine with three different variables.

Graph 1: Dissolution profile of Mesalazine with three different variables.

Source: (2)

Another interesting approach to overcome the manufacturing limitations and its subsequent therapeutic effects is the formulation of Mezavant XL tablet. It has the ingredients as per the manufacturer’s formula, which has been listed below.

Carmellose Sodium

Carnauba Wax

Stearic Acid

Silicon Dioxide

Sodium Starch Glycollate

Purified Talc

Magnesium Stearate

Methacrylic Acid Copolymer

Triethyl Citrate

Titanium Dioxide (E171)

Red Oxide of Iron (C177491)

Macrogol 6000

The tablet core consists of the active pharmaceutical ingredient Mesalamine  mesalazine (5-aminosalicylic acid) along with the following ingredients Carmellose Sodium, Carnauba Wax, Stearic Acid, Silicon Dioxide, Sodium Starch Glycollate, Purified Talc and Magnesium Stearate. The film coating material consists of Purified Talc, Methacrylic Acid – Methyl Methacrylate Copolymers (1:1) and (1:2), Triethyl Citrate, Titanium Dioxide, Red Ferric Oxide and Macrogol 6000.

It is a novel drug delivery system with once a day drug regime. TNO gastrointestinal model can be used to study the release kinetics of the drug. It is a dynamic system that simulates in vitro adult human GIT conditions under fasted and fed conditions. The formulation effectively delays the release from the tablet until it reaches the colon. The release is prolonged in the colon (3).

 Recovery of Mesalazine in the colon dialysate during gut passage under simulated conditions of fasted and fed.

Graph 2: Recovery of Mesalazine in the colon dialysate during gut passage under simulated conditions of fasted and fed.

Source: (3)

According to WHO, newer formulations are being invented and studied which are found to be bioequivalent to Mesalazine. These are from herbal sources and are found to possess potent activity in inflammatory bowel disease, much similar to Mesalazine. By virtue of their herbal nature, they are reported to find minimum side effects with similar therapeutic efficacy (4). One of the natural alternatives is Slippery Elm. This contains mucilage, which forms a gel when mixed with water. It soothes and coats the intestine and stomach and its antioxidant property helps in relieving the IBD conditions. It also increases the production of mucus in the GI tract, which provides protection against acidity and ulcers. Even medicinal cannabis has been found to be significantly beneficial for the patients suffering from IBD.

The Mesalazine market in the UK is 56% for Asacol and 25% for Pentasa (5). The regulatory approval of Mesalazine involves the relevance of comparison of the clinical and pharmacokinetic end point studies. In vitro dissolution studies of the new and existing products should be compared to establish the fact that the new Mesalazine product is pharmaceutically equivalent. In vitro dissolution should be carried out on a wide range of pH under simulated GI conditions. Comparative pharmacokinetic studies give the exact differences in the drug release patterns of the new and existing Mesalazine products, which is essential for the regulatory filing of Mesalazine (6).

Conclusion

As per MHRA, British National Formulary and the National Prescribing Centre recommend that the prescriptions for all the formulations of Mesalazine should be made based on the severity of the patient (7). Mesalazine is a medication that can be obtained only with a prescription. Therefore, the physician, as per the severity of the patient, will decide the dosage. A dosage of upto 4g may be prescribed in divided doses in case of the treatment of a colitis attack. However, to prevent further attacks a single dose of 2g may be prescribed.

Systemic bioequivalence, as a standard regulatory assessment process, is not sufficient for evaluating oral, modified release and topical products. Therefore, the new trend for determining the bioequivalence of oral Mesalazine involves the combination of bioequivalence, adequate comparative trial and dissolution. Assessment of the new products having modified release should be rigorous enough to boost the confidence of the physicians and patients regarding their usage (8). Modified release products provide better bioavailability. More the release duration, more is the duration of action. Therefore, this will consequently reduce the dosing frequency and reduce the costs in the end. Finally, these modified release products will benefit both, the patient and physician, which will be effective in the treatment of intestinal disorders with lesser proportion of medications consumed by the patient.

Established preparation of Mesalazine (Oral, modified release) in UK market

Table 1: Established preparation of Mesalazine (Oral, modified release) in UK market

Source: (8)

Conclusion

The process of drug development involves provision of safe, affordable, timely and effective therapies to the patients with inflammatory bowel disease. The designs of clinical trials should be standardized and improved in case of inflammatory bowel disease for improved patient profile. Therefore, the manufacturing issues of Mesalazine should be well scrutinized for improved therapeutic products and better regulatory issues, providing enhanced market appeal, to survive the ever-growing challenge of novel drug delivery system and market competencies.

References

Cohen HD, Das KM. The Metabolism Of Mesalamine And Its Possible Use In Colonic Diverticulitis As An Anti-Inflammatory Agent. Journal of clinical gastroenterology. 2014 Aug 1;40:S150-4.

Dobis DR, Sawyer RT, Gillespie MM, Newman LS, Maier LA, Day BJ. Sulfasalazine and mesalamine modulate beryllium-specific lymphocyte proliferation and inflammatory cytokine production. American journal of respiratory cell and molecular biology. 2012 Oct;43(4):458-64.

Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. European Journal of Pharmaceutics and Biopharmaceutics. 2015 Jan 31;89:157-62.

Guada M, Sebastián V, Irusta S, Feijoó E, del Carmen Dios-Viéitez M, Blanco-Prieto MJ. Lipid nanoparticles for cyclosporine A administration: development, characterization, and in vitro evaluation of their immunosuppression activity. International journal of nanomedicine. 2015;10:6541.

Gupta SK. Regulatory filing strategy for generic mesalazine modified release formulations. Indian journal of pharmacology. 2015 Apr;43(2):221.

Ham M, Moss AC. Mesalamine in the treatment and maintenance of remission of ulcerative colitis. Expert review of clinical pharmacology. 2012 Mar 1;5(2):113-23.

Hanauer SB, Sandborn WJ. European evidence-based consensus on the diagnosis and management of Crohn’s disease. Gut. 2014 Feb 1;56(2):161-3.

Karn PR, Jin SE, Lee BJ, Sun BK, Kim MS, Sung JH, Hwang SJ. Preparation and evaluation of cyclosporin a-containing proliposomes: a comparison of the supercritical antisolvent process with the conventional film method. International journal of nanomedicine. 2014;9:5079.

Lobaton T, Vermeire S, Assche G, Rutgeerts P. Review article: antiâ€Âadhesion therapies for inflammatory bowel disease. Alimentary pharmacology & therapeutics. 2014 Mar 1;39(6):579-94.

Miroux C, Morales O, Ghazal K, Othman SB, De Launoit Y, Pancré V, Conti F, Delhem N. In vitro effects of cyclosporine A and tacrolimus on regulatory T-cell proliferation and function. Transplantation. 2012 Jul 27;94(2):123-31.

Singer BD, King LS, D’Alessio FR. Regulatory T cells as immunotherapy. Front Immunol. 2014 Feb 11;5(46.10):3389.

Tenjarla S, Romasanta V, Zeijdner E, Villa R, Moro L. Release of 5-aminosalicylate from an MMX mesalamine tablet during transit through a simulated gastrointestinal tract system. Advances in therapy. 2013 Jul 1;24(4):826-40.

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