European Journal of Pharmaceutical Sciences 16 (2002) 297–304 www.elsevier.nl / locate / ejps Isosorbide-based aspirin prodrugs II. Hydrolysis kinetics of isosorbide diaspirinate * John F. Gilmer , Louise M. Moriarty, Maeve N. Lally, John M. Clancy Department of Pharmaceutical Chemistry, School of Pharmacy, Trinity College, Dublin 2, Ireland Received 13 March 2002; received in revised form 13 June 2002; accepted 27 June 2002 Abstract Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 8C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 8C over the pH range 1.03–9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing a-chymotrypsin [EC 3.1.1.1] ( t 5200.9 min), carboxyl esterase [EC 3.1.1.1] (t 531.5 min), human serum albumin (t 5603 min), purified human serum 1/2 1/2 1/2 butyrylcholinesterase [EC 3.1.1.8] (80 mg/ml; t 59.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 mg/ml; 1/2 t 51.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 mM). The results indicate that a 1/2 specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.  2002 Elsevier Science B.V. All rights reserved. Keywords: Prodrug; Aspirin; Isosorbide; Hydrolysis; Butyrylcholinesterase 1. Introduction capable of acting as enzyme substrates, thus competing with the rapid O-acetyl hydrolysis. Examples of the former Aspirin prodrugs have been extensively investigated for approach include aspirin anhydrides (Levy and Gagliardi, many years as a means of depressing gastric toxicity 1963), benzodioxinone derivatives (Ankersen et al., 1989; (Jones, 1985) or increasing percutaneous absorption (e.g. Nielsen and Senning, 1990), acylal derivatives (Hussain et Lofttson et al., 1981). The major reason for the lack of al., 1974, 1979; Truelove et al., 1980), N-(hydroxyalkyl) progress in this area is that the aspirin O-acetyl ester, so amides (Bundgaard et al., 1988), and 2-formylphenyl essential to its unique pharmacological profile, is rendered derivatives (Abordo et al., 1998). One limitation of this highly susceptible to plasma-mediated hydrolysis relative approach is that increasing ester lability diminishes drug to aspirin itself by esterification of the aspirin carboxylic stability. The enzyme targeting approach has been more acid group (Nielsen and Bungaard, 1989). A successful intensively pursued, as successful candidates, although aspirin prodrug must undergo hydrolysis at the carrier ester highly susceptible to enzyme-mediated decomposition, at a greater rate than at the O-acetyl group, whose might also be chemically stable. Examples in this group hydrolysis the carrier group greatly accelerates. include alkyl and aryl esters (Rainsford and Whitehouse, Strategies to overcome this problem may be grouped 1976, 1980), triglycerides (Kumar and Billimoria, 1978; into those that exploit ester types that are intrinsically Paris et al., 1979, 1980), acyloxyalkyl esters (Los et al., chemically unstable, or those that use carrier groups 1982), sulfinyl or sulfonyl esters (Lofttson and Bodor, 1981a,b; Lofttson et al., 1981), phenylalanine derivatives (Banerjee and Amidon, 1981a,b,c; Muhi-Eldeen et al., *Corresponding author. Tel.: 1353-1-608-2795; fax: 1353-1-608- 1985), amino acid derivatives (Tsunematsu et al., 1991), 2793. E-mail address: gilmerjf@tcd.ie (J.F. Gilmer). glycolamide esters (Nielsen and Bungaard, 1989), and 0928-0987 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0928-0987(02)00124-0