The characterisation of a fenoprofen prodrug

Abstract

The term "prodrug" refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. A nonenzymatic process, such as hydrolysis, can activate a prodrug via several routes. Prodrugs are mostly used to improve a drug's physical and chemical properties in order to optimise drug delivery. Not only can prodrugs prolong therapeutic effect, but sideeffects can also be minimised. Macromolecular prodrugs are one type of prodrug that have drawn a considerable amount of attention the last few years. Macromolecular prodrugs differ from ordinary carrier-linked prodrugs in the sense that the drug carrier is a macromolecule. Of all the macromolecular drug carriers, poly[a,p-(N-2-hydroxyethylDL- aspartamide)] (PHEA) is the most promising drug carrier because it is hydrophilic, non-toxic, non-antigenic, biodegradable in the presence of several enzymes, and produced easily and at low cost. These types of carriers can be used as possible drug carriers as well as plasma expanders, in order to decrease the required dose, dosage intervals and drug toxicity. Long term usage (with frequent high dosages) of the NSAIDs can lead to severe blooddisorders and the formation of peptic ulcers. These two problems encountered with NSAID therapy cause patients to quit NSAID treatment, and rather live with the illness than living with the side-effects. Macromolecular PHEA prodrugs is one attempt that can be made to improve major disadvantages of NSAID treatment, and because the advantages of the macromolecular prodrugs speak for themselves, it is worth trying to formulate some of the NSAIDs most commonly used over long-term into macromolecular prodrugs. If these drug carriers can be used to prolong pharmacological action and lower drug toxicity, some of the older NSAIDs (with limited usage at present) can again be used. Before any new synthesised prodrug can be used, it is necessary to develop new methods of analysis. These methods must be fully validated in order to quantitate the prodrug in different matrixes, depending on the purpose of the analysis. It is therefor essential to utilise methods that can selectively, accurately and precisely quantitate the prodrug in various matrixes with an acceptable limit of detection and limit of quantitation.

The aim of this study was therefore to develop an HPLC and a spectrophotometric method for the analysis of a PHEA-fenoprofen conjugate and to compare these two methods with each other. To fully validate the developed HPLC method, to determine fenoprofen drug loading in the conjugate by means of hydrolysis, to determine the release of fenoprofen from the conjugate under certain simulated biological conditions. To determine and describe the kinetics of fenoprofen release from the conjugate, and to determine the relevant physical properties influencing the analysis of the conjugate. This study has shown that PHEA-fenoprofen conjugate has different physical properties than fenoprofen calcium, and proves that fenoprofen is really chemically bound to PHEA and not merely dispersed or incorporated in PHEA. Analytical methods used for fenoprofen can be adapted for PHEA-fenoprofen conjugate analysis. Poor solubility of the conjugate in popular solvents used in analytical chemistry makes it difficult to analyse PHEA-fenoprofen conjugate. Fenoprofen release from PHEA follows pseudo first-order kinetics. Calculated reactions constants (k) are indicative of delayed release of fenoprofen from PHEA, which will most likely prolong fenoprofen's pharmacological action in vivo, and can be investigated further in future.