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Innovative Problem Solving for the Chemical and Pharmaceutical Industries

Taxemul™ is a preparation of  paclitaxel, the active ingredient in TaxolŽ, prepared for HemaGen/PFC. The currently marketed formulation exhibits significant toxicity upon intravenous infusion. This commercial product employs a 50:50 mixture of Cremophor-EL surfactant and ethanol in order to solubilize the drug. The Cremophor surfactant is suspect in the acute hypersensitivity reactions (HSRs) observed upon intravenous administration of TaxolŽ. Chronic toxicities, associated with the drug itself, include myelosuppression, severe neutropenia, thrombocytopenia, mucositis, and peripheral neuropathy. There is a clear need for an easily prepared, biocompatible, efficacious formulation of taxol exhibiting minimal side effects.

TaxDose.gif (2960 bytes)To address these issues, we directed the development of a stable lipid emulsion containing 5 mg/ml taxol, Taxemul™, which can be admixed with diluents such as 5% dextrose or 0.9% saline prior to administration. The elimination of the Cremophor surfactant dramatically improves the safety of the formulation.

Taxemul™ has been tested for efficacy in vitro against two lines of cancer cells: rat mammary adenocarcinoma and rat lymphocytic leukemia. Taxemul™ and TaxolŽ efficacy were identical in these tests. However, Taxemul™ displayed a distinct toxicological advantage when tested in vivo using a mouse tumor regression model – animals survived much higher doses of infused paclitaxel. TaxTumSz.gif (4927 bytes)When screened at dosages not achievable by the commercial product, Taxemul™ significantly improved the efficacy of the drug in retarding tumor growth. Hematology and clinical chemistry were performed on blood removed from the surviving animals. At 21 mg/kg, the values were unremarkable for a random rodent population. As mentioned, the high dose regime (42 mg/kg) killed the entire TaxolŽ treatment group, but Taxemul™ treatment presented only mild anemia, and a slight depression in serum albumin and total protein. Surprisingly, the reported thrombocytopenia and neutropenia were not observed in the Taxemul™ groups.

Copyright ChemVantage Consultants, LLC
July, 2002