A budesonide prodrug accelerates treatment of colitis in rats.

Abstract

Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-p-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal ,B-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-P-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) A new group of corticosteroids has recently been developed. In comparison with conventional corticosteroids, these drugs display a high degree of topical anti-inflammatory activity but do not show appreciable systemic activity. This unique activity ratio is achieved because a very high potency is coupled with rapid metabolism of the drug to products that have minimal or no biological activity. This rapid metabolism, also referred to as high first-pass liver metabolism, allows for a high therapeutic efficacy and high systemic tolerability.Budesonide is a member of this group of steroids which display high first-pass liver metabolism. Budesonide is a non-halogenated glucocorticoid structurally related to 16-alpha-hydroxyprednisolone.4 Administration of this drug via inhalation has proved effective in the treatment of asthma and rhinitis. It also presented a low adverse drug event profile.4Budesonide, given as an enema, has also proved superior to other glucocorticoids in the treatment of distal ulcerative colitis.5Budesonide has now been formulated into an enterocapsule preparation which allows the drug to bypass the upper gastrointestinal tract, thus facilitating delivery of the active compound to the terminal ileum.6 Unfortunately, it was found that less than 5%/o of the compound was available beyond the ileum and caecum.6 Therefore, while this compound would be useful for the treatment of small intestinal Crohn's disease,7 it is not likely to have an appreciable effect on colonic inflammatory bowel disease. In addition, a recent dose ranging study showed that effective doses of budesonide (9 mg/d) cause significant adrenal suppression.8Because of these problems, we designed and synthesised an orally administered, colonspecific budesonide prodrug (budesonide-,-D-glucuronide) with a delivery mechanism that would increase budesonide concentrations along the colon relative to systemic drug concentrations, thereby increasing colonic drug efficacy and decreasing systemic side effects.9 The advantage of colon-specific delivery has been already documented in the case of the non-steroidal anti-inflammatory agent 5-aminosalicylic acid. In that instance, the prodrugs sulphasalazine and olsalazine, from which the active drug is released in the colon by the action of microbial azoreductases, were used.10-'2

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation, optimization andin vivoevaluation in rabbits

“…The change in absorbance at 460 nm was measured every minute for 4 min. One unit of MPO activity is defined as the amount which degrades 1 mmol of the peroxide per minute at 25 C (Cui et al, 1994;Kucharzik et al, 2001). The results were expressed as the mean ± standard deviation of the mean.…”

Modified Approaches for Colon Specific Drug Delivery System: A Review

“…The majority of bacteria are present in the distal gut although they are distributed throughout the GI tract Endogenous and exogenous substrates, such as carbohydrates and proteins, escape digestion in the upper GI tract but are metabolized by the enzymes secreted by colonic bacteria . Sulphasalazine, a prodrug consisting of the active ingredient mesalazine, was the first bacteria-sensitive delivery system designed to deliver the drug to the colon [26][27].…”

Budesonide for ulcerative colitis

“…Budesonide-beta-D-glucuronide is an oral prodrug targeted to deliver budesonide specifically to the colon, since this prodrug is not absorbed in the small intestine. Budesonide-beta-D-glucuronide is hydrolyzed by colonic bacterial and mucosal beta-glucuronidase in order to release free budesonide into the colon (19). Hydrolysis rates of budesonide-beta-D-glucuronide in human fecal samples from patients with UC and normal volunteers are similar (20), but it is not clear whether a pH reduction in the colon of IBD patients may inhibit the bacterial hydrolysis of this prodrug.…”