GenexolPM

Genexol-PM, developed by Samyang Co. (Korea), is a paclitaxel formulation based on PEG-b-PDLLA micelles. In 2004, results from a phase II clinical trial that evaluated Genexol-PM and cisplatin as treatment for patients with advanced gastric cancer was reported.96 In the first clinical trial, the AUC and Cmax of Genexol-PM was found to be lower than that of Taxol®; however, the maximum tolerated dose (MTD) was increased from 135 to 390 mg/m2.90 Preclinical studies also revealed similar pharmacokinetic profiles for Genexol-PM and Taxol® in the B16 melanoma murine model. There are two explanations for the above observations. First, the liquid-like core of PDLLA acts as a solubilization site for paclitaxel as opposed to an actual drug carrier,35 and second, the decrease in AUC and Cmax occurs as a result of the shift in the drug accumulation to the tumor tissues that was evidenced in preclinical biodistribution studies.97 Formulation development

35,37,91

of paclitaxel-loaded PEG-b-PDLLA micelles was mostly reported by Burt and co-workers. , 9

Genexol-PM is prepared by the evaporation method that involves co-dissolving paclitaxel and PEG-b-PDLLA in acetonitrile with subsequent evaporation of the solvent to form a copolymer-drug matrix. The matrix is then heated to 60°C with the addition of water or buffer for self-assembly of paclitaxel-loaded micelles.97 The evaporation method is much more suitable than the direct dissolution method because paclitaxel and PEG-b-PDLLA are relatively insoluble in aqueous media. Indeed, the method employed for preparation of the paclitaxel-loaded PEG-b-PDLLA micelles can influence the extent of drug loading and physical stability of the formulation. The choice of solvent strongly influences the extent to which paclitaxel can be solubilized in PEG-b-PDLLA micelles as reported by Zhang et al.37 Among many of the solvents tested, only acetonitrile resulted in a clear micelle solution with no evidence of drug precipitation. It was suggested that acetonitrile enhances the miscibility between paclitaxel and the PDLLA block that, in turn, reduces the possibility of phase separation during the solvent evaporation process.37

Burt and co-workers also studied the use of PEG-b-poly(D,L-lactide-co-caprolactone) and PEG-b-poly(glycolide-co-caprolactone) copolymers for encapsulation of paclitaxel. The addition of hydrophobic caprolactone to PDLLA could potentially increase paclitaxel loading through the increased hydrophobicity of the core-forming block. However, these micelles were found to have poor physical stability and resulted in the precipitation of paclitaxel.35 The PEG-b-PDLLA micelles can solubilize as much as 5% (w/v) paclitaxel and remain stable for up to 24 h. This is mainly attributed to the absence of crystalline paclitaxel in the paclitaxel/PEG-b-PDLLA matrix as revealed by x-ray diffraction studies. In fact, paclitaxel is molecularly dissolved in the PDLLA core that prevents drug precipitation and results in excellent solubilization of the drug.37,91

The amorphous state of the paclitaxel-PDLLA core can be problematic for in vivo applications. Studies have indicated that the presence of crystalline drug in the core can retard drug release.69,98 Therefore, the amorphous core of the paclitaxel-loaded PEG-b-PDLLA micelles can lead to a much faster drug release profile. As demonstrated by Burt et al. following intravenous administration paclitaxel rapidly dissociates from the micellar components in the circulation.35 Therefore, it is likely that Genexol-PM acts as a solubilizer for paclitaxel rather than as a true drug carrier.

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