Pharmacological Effects of Formulation Vehicles

Abstract

The non-ionic surfactants Cremophor EL (CrEL; polyoxyethyleneglycerol triricinoleate 35) and polysorbate 80 (Tween) 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound alteration of drug accumulation in erythrocytes, thereby reducing the free drug fraction available for cellular partitioning and influencing drug distribution as well as elimination routes. The existence of CrEL and Tween 80 in blood as large polar micelles has also raised additional complexities in the case of combination chemotherapy regimens with taxanes, such that the disposition of several coadministered drugs, including anthracyclines and epipodophyllotoxins, is significantly altered. In contrast to the enhancing effects of Tween 80, addition of CrEL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations. The drawbacks presented by the presence of CrEL or Tween 80 in drug formulations have instigated extensive research to develop alternative delivery forms. Currently, several strategies are in progress to develop Tween 80- and CrEL-free formulations of docetaxel and paclitaxel, which are based on pharmaceutical (e.g. albumin nanoparticles, emulsions and liposomes), chemical (e.g. polyglutamates, analogues and prodrugs), or biological (e.g. oral drug administration) strategies. These continued investigations should eventually lead to more rational and selective chemotherapeutic treatment.

Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment

“…Paclitaxel has traditionally been administered as Taxol® (Bristol-Myers Squibb), a formulation containing 50% Cremophor EL (polyethoxylated castor oil) and 50% ethanol, at a dose of 175 mg/m 2 as a three-hour infusion. Though necessary for paclitaxel solubility, Cremophor EL has been shown to not only alter the pharmacokinetics of paclitaxel, but also result in adverse clinical effects such as severe hypersensitivity reactions [3].…”

Feasibility of tailored, selective and effective anticancer chemotherapy by direct injection of docetaxel-loaded immunoliposomes into Her2/neu positive gastric tumor xenografts

“…Free docetaxel is solubilized in a polyoxyethylated surfactant prior to injection. A number of biological effects related to the use of this vehicle for the formulation of drugs for clinical use have been described, including acute hypersensitivity reactions and peripheral neuropathy (24). Furthermore, severe skin ulceration may occur during extravasation of docetaxel.…”

Conventional Chemotherapeutic Drug Nanoparticles for Cancer Treatment

“…In contrast to the enhancing effects of Tween 80, addition of Cremophor EL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations [105]. Nanoparticles of biodegradable polymers can provide an ideal solution to such an adjuvant problem and realize a controlled and targeted delivery of paclitaxel with better efficacy and less side-effects.…”