Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850).
OBJECTIVE
To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.


METHODS
A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.


RESULTS
The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).


CONCLUSIONS
The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.
Straub
Julie A
JA
TAcusphere, Inc., Watertown, Massachusetts 02472, USA. julie.straub@acusphere.com
Chickering
Donald E
DE
Lovely
Jonathan C
JC
Zhang
Huimin
H
Shah
Bhavdeep
B
Waud
William R
WR
Bernstein
Howard
H
D000818:Animals; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism; D010316:Particle Size; D016062:Porosity; D051381:Rats; D017207:Rats, Sprague-Dawley
D017239:Paclitaxel