Pharmacological Effects of Formulation Vehicles
Abstract
The non-ionic surfactants Cremophor? EL (CrEL; polyoxyethyleneglyceroltriricinoleate 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 ofrecent experimental data has indicated that both solubilisers are biologically andpharmacologically active compounds, and their use as drug formulation vehicleshas been implicated in clinically important adverse effects, including acutehypersensitivity reactions and peripheral neuropathy.
CrEL and Tween 80 have also been demonstrated to influence the dispositionof solubilised drugs that are administered intravenously. The overall resultingeffect is a highly increased systemic drug exposure and a simultaneouslydecreased clearance, leading to alteration in the pharmacodynamic characteristicsof the solubilised drug. Kinetic experiments revealed that this effect is primarilycaused by reduced cellular uptake of the drug from large spherical micellar-likestructures with a highly hydrophobic interior, which act as the principal carrier ofcirculating drug. Within the central blood compartment, this results in a profoundalteration of drug accumulation in erythrocytes, thereby reducing the free drugfraction available for cellular partitioning and influencing drug distribution aswell as elimination routes. The existence of CrEL and Tween? 80 in blood aslarge polar micelles has also raised additional complexities in the case of combinationchemotherapy regimens with taxanes, such that the disposition of severalcoadministered drugs, including anthracyclines and epipodophyllotoxins, is significantlyaltered. In contrast to the enhancing effects of Tween? 80, addition ofCrEL to the formulation of oral drug preparations seems to result in significantlydiminished drug uptake and reduced circulating concentrations.
The drawbacks presented by the presence of CrEL or Tween? 80 in drugformulations have instigated extensive research to develop alternative deliveryforms. Currently, several strategies are in progress to develop Tween? 80- andCrEL-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 morerational and selective chemotherapeutic treatment.
Fulltext Pharmacological effects of formulation vehicles.pdf
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