A high-throughput combinatorial approach for the discovery of a cremophor EL-free paclitaxel formulation.
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.
Chen
Hongming
H
TransForm Pharmaceuticals, Inc. 29 Hartwell Avenue, Lexington, Massachusetts 02421, USA. chen@transformpharma.com
Zhang
Zhong
Z
McNulty
Chris
C
Olbert
Cameron
C
Yoon
Hye Jeong
HJ
Lee
Jang Won
JW
Kim
Sung Chul
SC
Seo
Min Hyo
MH
Oh
Hun Seung
HS
Lemmo
Anthony V
AV
Ellis
Stephen J
SJ
Heimlich
Ken
K
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
D005079:Excipients; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol