title: A high-throughput combinatorial approach for the discovery of a cremophor EL-free paclitaxel formulation.
abstract: OBJECTIVE
  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.affiliation: TransForm Pharmaceuticals, Inc. 29 Hartwell Avenue, Lexington, Massachusetts 02421, USA. chen@transformpharma.com
authors.forename: Hongming
authors.initials: H
authors.lastname: Chen
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chris
authors.initials: C
authors.lastname: McNulty
authors.forename: Cameron
authors.initials: C
authors.lastname: Olbert
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Jang Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Kim
authors.forename: Min Hyo
authors.initials: MH
authors.lastname: Seo
authors.forename: Hun Seung
authors.initials: HS
authors.lastname: Oh
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Lemmo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ellis
authors.forename: Ken
authors.initials: K
authors.lastname: Heimlich
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D005079:Excipients / Q000737:chemistry*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D005079:Excipients; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol