Polymeric micelles for parenteral delivery of sagopilone: physicochemical characterization, novel formulation approaches and their toxicity assessment in vitro as well as in vivo.
OBJECTIVE
The block copolymers PEG(2000)-b-PLA(2200), PEG(2000)-b-PCL(2600) and PEG(5000)-b-PCL(5000) have been currently identified as optimal solubilizing agents for Sagopilone, a poorly water-soluble anticancer drug. In the present study, the stability, formulation feasibility and in vitro as well as in vivo toxicity were evaluated.


METHODS
Dispersion media, storage conditions, and dilutions were varied for stability assessment. The critical micelle concentration (CMC) was determined using a fluorescent probe technique. Lyophilizates and polymeric films were investigated as formulation options. Furthermore, the toxicity was studied in vitro and in vivo using HeLa/MaTu cells and a nude mouse model, respectively.


RESULTS
A drug-polymer ratio as low as 1:20 (w/w) was sufficient to solubilize Sagopilone effectively and to obtain stable dispersions (24h: drug content >or= 95%). Although the micelles exhibited a similar thermodynamic stability (CMC: 10(-7)-10(-6)M), PEG-b-PCL micelles were kinetically more stable than PEG(2000)-b-PLA(2200) (24h at 37 degrees C: drug content >or= 90% compared to 30%, respectively). Lyophilization of PEG-b-PCL micelles and storage stability of solid drug-loaded PEG(2000)-b-PLA(2200) films (3m, 6 degrees C: drug content of (95.6+/-1.4)%) were demonstrated for the first time. The high antiproliferative activity has been maintained in vitro (IC(50)<1 nM). Carrier-associated side effects have not been observed in vivo and the maximum tolerated dose of micellar Sagopilone was determined to be 6 mg/kg.


CONCLUSIONS
The results of this study indicate that polymeric micelles, especially PEG-b-PCL micelles, offer excellent potential for further preclinical and clinical cancer studies using Sagopilone.
Richter
Annett
A
Pharmaceutical Technology, Bayer Schering Pharma AG, Berlin, Germany.
Olbrich
Carsten
C
Krause
Michael
M
Hoffmann
Jens
J
Kissel
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D034261:Epothilones / Q000008:administration & dosage* / Q000633:toxicity; D005240:Feasibility Studies; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D013696:Temperature; D013816:Thermodynamics
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004337:Drug Carriers; D034261:Epothilones; D007783:Lactones; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C521904:poly(ethylene glycol)-block-poly(epsilon-caprolactone); D011092:Polyethylene Glycols; C033616:poly(lactide); C530494:sagopilone