Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel.
OBJECTIVE
Paclitaxel is currently administered i.v. as a slow infusion of a solution of the drug in an ethanol:surfactant:saline admixture. However, poor solubilization and toxicity are associated with this drug therapy. Alternative drug delivery systems, including parenteral emulsions, are under development in recent years to reduce drug toxicity, improve efficacy and eliminate premedication.


METHODS
Paclitaxel emulsions were prepared by high-shear homogenization. The particle size of the emulsions was measured by dynamic light scattering. Drug concentration was quantified by HPLC and in vitro drug release was monitored by membrane dialysis. The physical stability of emulsions was monitored by particle size changes in both the mean droplet diameter and 99% cumulative distribution. Paclitaxel potency and changes in the concentration of known degradants were used as chemical stability indicators. Single dose acute toxicity studies were conducted in healthy mice and efficacy studies in B 16 melanoma tumor-bearing mice.


RESULTS
QW8184, a physically and chemically stable sub-micron oil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drug loading (8-10 mg/mL) having a mean droplet diameter of <100 nm and 99% cumulative particle size distribution of <200 nm. In vitro release studies demonstrated low and sustained drug release both in the presence and absence of human serum albumin. Based on single dose acute toxicity studies, QW8184 is well tolerated both in mice and rats with about a 3-fold increase in the maximum-tolerated-dose (MTD) over the current marketed drug formulation. Using the B16 mouse melanoma model, a significant improvement in drug efficacy was observed with QW8184 over Taxol.


CONCLUSIONS
QW8184, a stable sub-micron o/w emulsion of paclitaxel has been developed that can be filter-sterilized and administered i.v. as a bolus dose. When compared to Taxol, this emulsion exhibited reduced toxicity and improved efficacy most likely due to the composition and dependent physicochemical characteristics of the emulsion.
Constantinides
P P
PP
SONUS Pharmaceuticals, Bothell, Washington 98021, USA. panosc@sonuspharma.com
Lambert
K J
KJ
Tustian
A K
AK
Schneider
B
B
Lalji
S
S
Ma
W
W
Wentzel
B
B
Kessler
D
D
Worah
D
D
Quay
S C
SC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D005260:Female; D005374:Filtration; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D008815:Mice, Inbred Strains; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D010316:Particle Size; D012709:Serum Albumin / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000401:mortality; D012995:Solubility; D013242:Sterilization; D016019:Survival Analysis; D014810:Vitamin E / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D012709:Serum Albumin; D014810:Vitamin E; D017239:Paclitaxel