title: Non-ionic dendritic glycerol-based amphiphiles: novel excipients for the solubilization of poorly water-soluble anticancer drug Sagopilone.
abstract: The purpose of this study was to investigate dendritic glycerol-based amphiphiles as novel solubilizers using poorly water-soluble anticancer drug Sagopilone. The effect of different core structures on the solubilization, formulation stability, and cytotoxicity using human umbilical vein endothelial cells (HUVECs) were investigated and compared to standard excipients. Structurally, all amphiphiles were composed of 2nd generation polyglycerol (PG[G2]) as the hydrophilic part and a single C(18)-chain (PG[G2]-C(18)), a C(18)-chain coupled by a diaromatic spacer (PG[G2]-DiAr-C(18)), a C(18)-chain with a naphthyl or bisphenyl end group (PG[G2]-C(18)-Naph/-BiP), or two C(18)-chains (PG[G2]-(C(18))(2)) as the hydrophobic part. They formed small (7-10 nm), monodisperse (PDI 0.04-0.20) micelles with the exception of PG[G2]-(C(18))(2). The amphiphiles revealed a 2-3-fold higher solubilization of Sagopilone than Cremophor ELP and polysorbate 80 independent of the core structure. PG[G2]-DiAr-C(18) exhibited the highest solubilization capacity (56.7+/-1.3 mg/g) compared to Cremophor ELP (18.5+/-0.1 mg/g). The micellar dispersions were stable in drug content over 3 days (> or = 97%). In contrast to polysorbate 80, dilutions did not show any precipitation after 3 days at 37 degrees C (remaining drug content: > 95%). They did not induce significant cytotoxicity at a concentration of 0.01 g/L after 24 h, and PG[G2]-C(18)-Naph was the least cytotoxic structure after 72 h with values comparable to Cremophor ELP and polysorbate 80. Overall, these amphiphiles possess superior solubilization properties compared to standard excipients used in parenteral formulations with an excellent formulation stability profile and comparable cytotoxicity.
authors.affiliation: Pharmaceutical Technology, Bayer Schering Pharma AG, Muellerstr. 178, 13353 Berlin, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Richter
authors.forename: Achim
authors.initials: A
authors.lastname: Wiedekind
authors.forename: Michael
authors.initials: M
authors.lastname: Krause
authors.forename: Thomas
authors.initials: T
authors.lastname: Kissel
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.forename: Carsten
authors.initials: C
authors.lastname: Olbrich
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000737:chemistry; D002021:Buffers; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D042783:Endothelial Cells; D034261:Epothilones / Q000008:administration & dosage* / Q000737:chemistry; D005079:Excipients / Q000737:chemistry* / Q000494:pharmacology; D005990:Glycerol / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D008823:Micelles; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010316:Particle Size; D044367:Phase Transition; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*; D013696:Temperature; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002021:Buffers; D050091:Dendrimers; D004337:Drug Carriers; D034261:Epothilones; D005079:Excipients; D007477:Ions; D008823:Micelles; D013501:Surface-Active Agents; C530494:sagopilone; D005990:Glycerol