Design, Development, and Optimisation of Smart Linker Chemistry for Targeted Colonic Delivery—In Vitro Evaluation

Abstract

Drug targeting is necessary to deliver drugs to a specific site of action at a rate dictated by therapeutic requirements. The pharmacological action of a drug can thereby be optimised while minimising adverse effects. Numerous colonic drug delivery systems have been developed to avoid such undesirable side effects; however, these systems lack site specificity, leaving room for further improvement. The objective of the present study was to explore the potential of amino-alkoxycarbonyloxymethyl (amino-AOCOM) ether prodrugs as a general approach for future colonic delivery. To circumvent inter- and intra-subject variabilities in enzyme activities, these prodrugs do not rely on enzymes but rather are activated via a pH-triggered intramolecular cyclisation–elimination reaction. As proof of concept, model compounds were synthesised and evaluated under various pH conditions, simulating various regions of the gastrointestinal tract (GIT). Probe 15 demonstrated excellent stability under simulated stomach- and duodenum-like conditions and protected 60% of the payload in a small intestine-like environment. Moreover, 15 displayed sustained release at colonic pH, delivering >90% of the payload over 38 h. Mesalamine (Msl) prodrugs 21 and 22 were also synthesised and showed better stability than probe 15 in the simulated upper GIT but relatively slower release at colonic pH (61–68% of Msl over 48 h). For both prodrugs, the extent of release was comparable to that of the commercial product Asacol. This study provides initial proof of concept regarding the use of a cyclisation-activated prodrug for colon delivery and suggests that release characteristics still vary on a case-by-case basis.

Novel Perspectives on the Design and Development of a Long-Acting Subcutaneous Raltegravir Injection for Treatment of HIV—In Vitro and In Vivo Evaluation

“…In contrast, prodrug 2 cyclises more slowly to form a sixmembered ring, releasing > 55% of the payload over 5 h at the same pH [24]. Increasing the methylene spacer length to four carbons-such as in prodrug 4, which we reported recently [25]-hinders the cyclisation further and slows down drug release accordingly (in this case, achieving 92% release of mesalamine over 6 d at pH 6.5). Therefore, in the case of RAL (where long-acting prodrugs are required), we tried extending the methylene spacer to five or six carbons (corresponding to eight-and ninemembered ring cyclisations) in our initial model probes, to obtain the very slow-release Therefore, in the case of RAL (where long-acting prodrugs are required), we tried extending the methylene spacer to five or six carbons (corresponding to eight-and ninemembered ring cyclisations) in our initial model probes, to obtain the very slow-release kinetics suitable for development of a long-acting SC injection.…”

“…In contrast, prodrug 2 cyclises more slowly to form a six-membered ring, releasing >55% of the payload over 5 h at the same pH [ 24 ]. Increasing the methylene spacer length to four carbons—such as in prodrug 4 , which we reported recently [ 25 ]—hinders the cyclisation further and slows down drug release accordingly (in this case, achieving 92% release of mesalamine over 6 d at pH 6.5).…”

“…Both prodrugs exhibited enhanced aqueous solubility and oral bioavailability compared with the parent compound [ 24 ]. Recently, we applied the same strategy to develop mesalamine prodrugs 3 and 4 —with three- and four-methylene spacers, respectively ( Figure 1 )—for colonic delivery [ 25 ]. In that study, a key finding was that increasing the methylene spacer length to five or six carbons led to pH-sensitive linkers with very slow-release profiles.…”

pH‐responsive polymers for drug delivery: Trends and opportunities

“…To evaluate the pH‐responsive behavior of this system, mesalamine was loaded in the polymeric nanocarriers. It was reported that this novel polymeric system released more than 90% of the drug at colonic pH, thus protecting a significant amount of the drug from the acidic environment of the stomach 167 …”

“…It was reported that this novel polymeric system released more than 90% of the drug at colonic pH, thus protecting a significant amount of the drug from the acidic environment of the stomach. 167…”