Polymeric Micelles for parenteral delivery of Sagopilone: Physicochemical characterization, novel formulation approaches and their toxicity assessment in vitro as well as in vivo

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 75; no. 2; pp. 80 - 89
• Main Authors: Richter, Annett, Olbrich, Carsten, Krause, Michael, Hoffmann, Jens, Kissel, Thomas
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-06-2010; Elsevier
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Benzothiazoles - administration & dosage; Benzothiazoles - toxicity; Biological and medical sciences; Block copolymer micelles; Cytotoxicity; Drug Carriers - chemistry; Drug Stability; Drug Storage; Epothilone; Epothilones - administration & dosage; Epothilones - toxicity; Feasibility Studies; Female; General pharmacology; HeLa Cells; Humans; In vivo toxicity; Inhibitory Concentration 50; Lactones - chemistry; Lyophilization; Matus; Maximum Tolerated Dose; Medical sciences; Mice; Mice, Nude; Micelles; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyesters - chemistry; Polyethylene Glycols - chemistry; Polymeric films; Polymers - chemistry; Solubility; Solubilization; Temperature; Thermodynamics; Block copolymer micelles; In vivo toxicity; Epothilone; Cytotoxicity; Lyophilization; Solubilization; Polymeric films; Antineoplastic agent; Performance evaluation; Evaluation; Pharmaceutical technology; Control release polymer; Toxicity; Micelle; Sagopilone; Route of administration; In vitro; In vivo; Epothilone derivatives; Formulation; Block copolymer; Physicochemical properties
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2010.02.010

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.
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.
A drug–polymer ratio as low as 1:20 (w/w) was sufficient to solubilize Sagopilone effectively and to obtain stable dispersions (24
h: drug content ⩾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 (24
h at 37
°C: drug content ⩾90% compared to 30%, respectively). Lyophilization of PEG-
b-PCL micelles and storage stability of solid drug-loaded PEG
2000-
b-PLA
2200 films (3
m, 6
°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.
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.