Development of a parenteral formulation for the anti-tumour agent acronycine

Acronycine is an anti-tumour alkaloid isolated from the bark of Acronychia baueri. It is active in a number of murine tumours and in multiple myeloma in humans. A serious limitation to broad clinical testing of acronycine is the lack of aqueous solubility due, in part, to its lipophilicity (log P value of 2.6). Acronycine powder was dissolved in the same co-solvent system used for etoposide (VP-16). This VP-16 diluent (VPD) consists of PEG 300, ethanol and polysorbate 80. Resulting acronycine solutions could then be further diluted with 5% dextrose, 0.9% sodium chloride or RPMI 1640 culture medium for 4-72 hours at temperatures from 0°C to 37°C. Acronycine in VPD retarded calf thymus DNA thermal denaturation in a pattern consistent with intercalation or some other non-covalent interaction. When dissolved in 5% DMSO, no such effect on DNA was produced. The aqueous formulation of acronycine in VPD was active against L-1210 leukaemia in vitro and was tolerated in mice at doses up to 30 mg/kg/day i.p. or 1.4 mg/kg/day i.v. for five consecutive days. Furthermore, an i.p. regimen of 25 mg/kg was active in mice bearing the MOPC-315 plasmacytoma tumour i.p. Since acronycine has shown anti-tumour activity in multi-drug-resistant CHO cells in vitro, and in human multiple myeloma (using a poorly-absorbed capsule formulation), the new availability of a tolerable parenteral solution could support further clinical testing of acronycine at increased dose levels.