Pharmaceutical development of selected novel anticancer agents : from drugs substance to dosage form

Abstract

Despite the substantial progress made over the last decades in the treatment of cancer, there still is a great need for novel therapies. Especially for patients with advanced disease, chemotherapy is the best option. Nature is the primary source of anticancer drugs with compounds isolated from plants or micro-organisms. Moreover, the marine ecosystem provides for a growing number of promising agents in clinical trials. Besides natural resources, the increasing knowledge of tumour pathology and drug resistance mechanisms boosts the development of rationally designed anticancer agents, i.e. chemically synthesised derivatives of known anticancer agents exhibiting more favourable characteristics or development of novel biomolecularly engineered agents. It is rarely the case that a drug can be administered to humans as the pure chemical compound itself. Therefore, to enable evaluation of the novel anticancer drug in humans, a pharmaceutical formulation has to be developed. Anticancer agents at the early stage of development are generally administered as an intravenous bolus injection or infusion in order to obtain absolute bioavailibility, circumvent possible disturbance of or degradation in the gastrointestinal tract, and to be able to adjust or stop administration of the drug instantaneously in case of acute toxicity. Consequently, the development of a pharmaceutical formulation of a novel anticancer agent is focused on issues associated with the design of sterile and stable injectable products.

This thesis describes the pharmaceutical development of three novel anticancer drugs, namely Imexon (chapter 1), C1311 (chapter 2), and ES-285.HCl (chapter 3). Imexon is a member of the class of 2-cyanoaziridine derivatives and recent in vitro research demonstrated high cytotoxic activity for lymphoid malignancies, such as malignant lymphomas and multiple myeloma. C1311 is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer drugs and exhibited significant cytotoxic activity in vitro towards several tumours and both in vitro and in vivo towards a range of colon tumours. ES-285.HCl was originally derived from the marine clam Spisula polynyma. It has shown in vitro and in vivo cytotoxic activity against various tumour cell lines with selectivity for certain solid tumours (i.e. hepatocellular, prostate and renal).

For each drug, the initial part of the chapter is dedicated to the development of a stability indicating assay for the novel anticancer drug. Moreover, the structural and analytical characterisation of the drug substance is described. Subsequently, the development of the pharmaceutical formulation and its stability upon storage is described. The chapters end with studies that were performed to evaluate the stability of the final formulated product in clinical practice, thus after reconstitution with an appropriate reconstitution solution and subsequent dilution in infusion solutions. Moreover, the (bio-)compatibility of the formulation solution with infusion systems and blood is described. The chapter dedicated to ES-285.HCl is concluded with a study on the compatibility of platinum catalysed silicone tubing with the complexing excipient 2-hydroxypropyl-Beta-cyclodextrin (HPbetaCD) used in the manufacture of ES-285.HCl.