PURPOSE: The purpose of this work was to replace Cremophor-EL in the commercial paclitaxel intravenous formulation, Taxol, using a novel high-throughput combinatorial formulation approach. METHODS: Full factorial combinations of 12 generally regarded as safe excipients at three different concentrations were screened using an automated liquid dispenser. The hit formulations were further optimized to give the final optimized formulation TPI-1. TPI-1 was then tested in rats to compare its pharmacokinetic profile to Taxol. RESULTS: Of the 9,880 combinations tested in the initial screen, 19 were identified as hit combinations. These were further optimized to give the final formulation TPI-1. When tested in rats, TPI-1 was well tolerated at both the low and high doses of 5 mg/kg and 10 mg/kg, whereas Taxol killed all the rats at the high dose. TPI-1 experienced slower elimination compared to Taxol. Similar to Taxol, TPI-1 also exhibited nonlinear pharmacokinetics. CONCLUSIONS: This study demonstrated the power of a high-throughput combinatorial approach for alternative paclitaxel formulations. We believe that this approach can be applied to drug formulation in general and it can improve the speed and efficiency of drug formulation design.
PURPOSE: The purpose of this work was to replace Cremophor-EL in the commercial paclitaxel intravenous formulation, Taxol, using a novel high-throughput combinatorial formulation approach. METHODS: Full factorial combinations of 12 generally regarded as safe excipients at three different concentrations were screened using an automated liquid dispenser. The hit formulations were further optimized to give the final optimized formulation TPI-1. TPI-1 was then tested in rats to compare its pharmacokinetic profile to Taxol. RESULTS: Of the 9,880 combinations tested in the initial screen, 19 were identified as hit combinations. These were further optimized to give the final formulation TPI-1. When tested in rats, TPI-1 was well tolerated at both the low and high doses of 5 mg/kg and 10 mg/kg, whereas Taxol killed all the rats at the high dose. TPI-1 experienced slower elimination compared to Taxol. Similar to Taxol, TPI-1 also exhibited nonlinear pharmacokinetics. CONCLUSIONS: This study demonstrated the power of a high-throughput combinatorial approach for alternative paclitaxel formulations. We believe that this approach can be applied to drug formulation in general and it can improve the speed and efficiency of drug formulation design.
Authors: O van Tellingen; J H Beijnen; J Verweij; E J Scherrenburg; W J Nooijen; A Sparreboom Journal: Clin Cancer Res Date: 1999-10 Impact factor: 12.531
Authors: P P Constantinides; K J Lambert; A K Tustian; B Schneider; S Lalji; W Ma; B Wentzel; D Kessler; D Worah; S C Quay Journal: Pharm Res Date: 2000-02 Impact factor: 4.200
Authors: L van Zuylen; M O Karlsson; J Verweij; E Brouwer; P de Bruijn; K Nooter; G Stoter; A Sparreboom Journal: Cancer Chemother Pharmacol Date: 2001-04 Impact factor: 3.333
Authors: J H Beijnen; M T Huizing; W W ten Bokkel Huinink; C H Veenhof; J B Vermorken; G Giaccone; H M Pinedo Journal: Semin Oncol Date: 1994-10 Impact factor: 4.929
Authors: Bernard Van Eerdenbrugh; Bernard Stuyven; Ludo Froyen; Jan Van Humbeeck; Johan A Martens; Patrick Augustijns; Guy Van den Mooter Journal: AAPS PharmSciTech Date: 2009-01-16 Impact factor: 3.246
Authors: Jacob M Berlin; Tam T Pham; Daisuke Sano; Khalid A Mohamedali; Daniela C Marcano; Jeffrey N Myers; James M Tour Journal: ACS Nano Date: 2011-07-15 Impact factor: 15.881
Authors: Jacob M Berlin; Ashley D Leonard; Tam T Pham; Daisuke Sano; Daniela C Marcano; Shayou Yan; Stefania Fiorentino; Zvonimir L Milas; Dmitry V Kosynkin; B Katherine Price; Rebecca M Lucente-Schultz; Xiaoxia Wen; M Gabriela Raso; Suzanne L Craig; Hai T Tran; Jeffrey N Myers; James M Tour Journal: ACS Nano Date: 2010-08-24 Impact factor: 15.881