Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process
- Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process
- 용철순; 박재현[박재현]; 엄의동[엄의동]; 지상철[지상철]; 류원석; 우종수[우종수]; 최한곤[최한곤]; 황두형[황두형]; 스리니바산 샨무감[스리니바산 샨무감]
- INCLUSION COMPLEXES; DELIVERY; NANOPARTICLES; TAXOL; MICROPARTICLES; EMULSION; SYSTEMS; FLUIDS
- Issue Date
- JOURNAL OF PHARMACY AND PHARMACOLOGY, v.63, no.4, pp.491 - 499
- Objectives To avoid the major adverse effects induced by Cremophor EL formulated in the commercial paclitaxel products of Taxol. Methods An injectable paclitaxel solid dispersion free of Cremophor was prepared by a supercritical antisolvent process and then was fully characterized and investigated with regard to its short-term and long-term stability. Pharmacokinetics in rats was also evaluated compared with the commercial product. Key findings The solid dispersion system at a 1/20/40 weight ratio of paclitaxel/HP-beta-CD/HCO-40 had a paclitaxel solubility of about 10 mg/ml, an almost 10 000-fold increase over its aqueous solubility. This system was physically stable for at least six months or four weeks in accelerated conditions (40 +/- 2 degrees C; RH: 75 +/- 5%) and stress conditions (60 degrees C), respectively. The precipitation time of paclitaxel solid dispersion in 0.9% sodium chloride injection at a concentration of 1000 mu g/ml was above 70 h at room temperature. Intravenous administration of paclitaxel solid dispersion at a dose of 6 mg/kg revealed no significant differences when compared with the commercial product. However, our results obtained at a dose of 12 mg/kg showed a striking non-linear increase in the plasma Cmax and AUCall with increased dose. In addition, the concentrations of paclitaxel in various organs in the solid dispersion group were found to be higher than those of Taxol at 6 mg/kg, and the paclitaxel levels in these organs increased proportionately with increasing dose. Conclusions Nano-scale paclitaxel solid dispersion without Cremophor EL provided advantageous results over Taxol with respect to the physicochemical properties, safety, clinic convenience and pharmacokinetic behaviour in rats.
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