Sulphasalazine (salicylazosulphapyridine) was one of the earliest prodrugs used in the treatment of inflammatory bowel disease. It contains 5-aminosalicyclic acid (mesalazine) linked covalently to sulphapyridine. 5-aminosalicyclic acid (5-ASA) is not effective orally because it is poorly absorbed, and is inactivated before reaching the lower intestine; therefore prior to its administration as a prodrug, its was only effective when given as a suppository or a rectal suspension enema. The prodrug sulphasalazine is similarly poorly absorbed after oral administration, but it is reduced to its active components by bacterial azoreductase in the colon. Additional prodrugs which rely on bacterial activation have also been introduced, including olsalazine (sodium azodisalicylate, a dimer of 5-aminosalicylate linked by an azo bond), ipsalazine (5-ASA:p-aminohippurate) and balsalazine (5-ASA:4-amino benzoylglycine) (Figure 7.9).
Bacterial metabolism includes enzymatic systems unique to a small region of the bowel, the most widely investigated being the bacterial azoreductase system, and several polymers have been devised which should be degraded by these enzymes. Hydrogels based on acrylic acid, N, N-dimethylacrylamide and N-terbutyl-acrylamide cross-linked with azoaromatic groups show pH-dependent swelling. At low pH the polymer does not swell. As it passes out of the stomach into the higher pH of the small intestine swelling occurs and, on reaching the colon, the hydrogel becomes sufficiently swollen to allow access to bacterial azoreductase. However, in vitro studies suggest that the polymer swelling is too slow to be successful in vivo. Alternative approaches have been described using azo-polymers containing different ratios of methylmethacrylate and hydroxyethyl methacrylate (HEMA)97 98. Hydrophilic polymers, those with a high HEMA content, showed the greatest susceptibility to colonic degradation. It was concluded that a balance needed to be achieved between hydrophilicity, to ensure effective reduction, and hydrophobicity, to provide adequate resistance to gastric and intestinal fluid. Early data suggested that oral delivery of
Figure 7.9 Azo prodrugs and enzyme activity in the gastrointestinal tract
Figure 7.9 Azo prodrugs and enzyme activity in the gastrointestinal tract peptides such as vasopressin and even insulin was possible using these polymers to protect the peptide99 although later investigations with these materials were less successful.
Concentrated senna extract contains anthracene derivatives in the form of glycosides which can be hydrolysed to anthraquinones, anthranols and oxanthrones. When sennosides are delivered directly to the colon no laxative activity occurs, but incubation of the compound with faeces or E. coli liberates free anthraquinones which promote peristalsis. More recently, drug glycosides have been synthesized and tested for their ability to deliver drugs, such as glucocorticosteroids and spasmolytic agents, to the large intestine. Glucuronide prodrugs of the budesonide and menthol have been tested in animal models with promising results100.
Complex carbohydrates are metabolized by caecal bacteria, hence matrices and coatings based on pectin, guar gum and starch have received extensive study for colon specific delivery systems101 102. Guar gum, locust bean gum, tragacanth, and xylan have been mixed with methacrylate copolymers (Eudragit O) and used to coat tablets. The beta-1,4-or alpha-1, 6-glycosidic links in locust bean galactomannan and dextran are biodegraded quickly in the human colon, but these carbohydrates are quite water-soluble and they must be transformed into insoluble derivatives103. Cyclodextrins are fermented to small saccharides by colonic microflora, whereas they are only slightly hydrolyzable and thus are not easily absorbed in the stomach and small intestine104.
Pectin and calcium pectate have been evaluated by several groups as colon-specific coatings and matrices105-107. Tablets prepared from calcium pectate mixed with indomethacin were compressed into tablets and the release of drug was evaluated in vitro108. Under controlled conditions, release of indomethacin into pH 7 buffer was minimal (<10% after 24 h). Adding caecal contents from rats that had been induced to produce pectinolytic enzymes to the dissolution medium resulted in a significant increase in indomethacin release (approximately 60% after 24 h). Similarly, a dissolution experiment in the presence of a
Table 7.4 Bacterial metabolism of some drugs
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