Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis

Abstract

<b><i>Background/Aims:</i></b> Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn’s disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. <b><i>Materials and Methods:</i></b> We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. <b><i>Results:</i></b> The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1β (IL-1β), and IL-6, and minimized the histological and morphometric changes. <b><i>Conclusion:</i></b> The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

“…It is often used as an excipient because it enables a pH-sensitive dissolution at about pH 7.2, allowing a specific release of the drug into the colon [ 109 ]. ES100 and ERS100 (a time-dependent polymer) were extensively used in targeted oral drug delivery systems; they were used singularly or coupled together [ 110 , 111 ] and even in the form of microspheres [ 112 ] and showed an effective response to pH changes along the gastrointestinal tract. They were exploited for IBD [ 113 ], IBS [ 114 , 115 , 116 ], and colon cancer treatments [ 117 ].…”

3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease

“…The therapeutic activity of tacrolimus has been previously described in other animal studies, in which tacrolimus was administered orally in the form of microparticles [44] and microspheres [45] prepared with pH sensitive polymers to allow drug delivery to the colon and nanoparticles [17] with enhanced adhesion to the inflamed tissue. Thus, the present study was focused on the development of a rectal dosage form that delivers the incorporate drug content directly to the colon, avoiding the side effects derived from an undesired early drug release in upper parts of the GI tract.…”

Metformin as an Adjuvant Therapy Attenuates Dextran Sulphate Sodium-induced Acute Colitis in Rats

“…However, in several cases, patients with IBDs are refractory to standard drugs. A recent study showed the efficacy of the potent immunosuppressant tacrolimus (TAC; FK506 ) in the management of colitis [8]. Similarly, sirolimus (SIR), also known as rapamycin, is a macrocyclic antibiotic and potent immunosuppressant.…”