Pro-Drugs of Beta-Blocking Agents

Abstract

To study the design of liquid controlled-release dosage forms based upon ion-exchange resins a series of ester prodrugs of propranolol were synthesised. Compounds ranging from acetyl to decanoyl were prepared and structural assignments were confirmed by 1H n.m.r. spectroscopy and mass-spectrometry. The physico-chemical properties including solubility, pKa and partition coefficient were studied and chemical and enzymatic stability kinetics of these esters were also investigated using high-performance liquid chromatography (HPLC) as the analytical technique. HPLC methods were developed for the quantitative analysis of the pro-drugs and their degradation products during kinetic assessments of stability and release profiles. The degradation of O-n-acyl propranolols under alkaline conditions was found to proceed via competing hydrolysis, to give the required propranolol and rearrangement to yield the corresponding N-acyl derivatives. The N-acyl derivatives were stable under these conditions and reaction did not proceed further. The formation of N-acyl derivatives is pH dependent with reaction being largely inhibited under acidic conditions. The hydrolysis rate is also dependent upon pH with a maximum stability demonstrated at pH 3 - 3.5. The rearrangement reaction was much suppressed with ester chain lengths higher than the O-hexanoyl] derivative. In enzymatic systems using isolated esterases and 90% rabbit serum, the reactivity profiles were somewhat different. The specifity of the enzyme was such that the competing rearrangement reaction was much reduced and with ester homologues larger than O-propionyl, no rearrangement was detected at all. The generation of propranolol under these conditions was found to occur at a maximal rate with the O-hexanoyl derivative but all compounds showed acceptable release rates for propranolol. These pro-drugs have been incorporated into controlled-release delivery systems suitable for formulation as liquid dosage forms using cationic ion-exchange resin. The effect of drug structure and the properties of the resin on the release profiles were studied to expose the factors controlling drug availability from these complexes. Better control of release rates was achievable when the drug-resin complex was coated with gelatin-acacia co-acervate and the liberation of the drug was further reduced when beads were double coated. The biovailability of the sustained-release formulation was studied following administration of an oral single-dose using aqueous propranolol as the standard reference.