title: Overcoming instability and low solubility of new cytostatic compounds: a comparison of two approaches.
abstract: The pharmaceutical use of some 3-hydroxyquinolinone derivatives with high cytotoxic and cytostatic activities (under in vitro conditions) as well as potential immunosuppressive properties is seriously limited by their low solubility in water accompanied by instability in oxidative environment, like physiological fluids. In an attempt to improve the bioavailability and the stability of four of these derivatives, we propose here two different approaches: complexation with β-cyclodextrin derivatives and incorporation of these substances inside antioxidant micelles. The comparison of the two different methods is the focus of this work, as well as the investigation of some physicochemical properties of the micellar aqueous dispersions. Antioxidant micellar dispersions appear to be suitable for increasing the apparent solubility and stability for all the compounds studied, most probably because of the antioxidant activity of the specific surfactant used, combined with the low amount of water present in the center of the micelles. On this regard, (1)H NMR and UV-vis spectroscopy result as efficient tools to verify that the drug molecules are indeed placed in the core of the micelles. Moreover, freeze-drying provides a very easy and powerful technique to obtain solid formulations starting from micellar dispersions. On the contrary, cyclodextrins could potentially be used as solubilizing agents, but the drawback connected to degradation in aqueous media could not be overcome with this type of solubilizer.
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: di Cagno
authors.forename: Paul C
authors.initials: PC
authors.lastname: Stein
authors.forename: Jakub
authors.initials: J
authors.lastname: Styskala
authors.forename: Jan
authors.initials: J
authors.lastname: Hlaváč
authors.forename: Natasa
authors.initials: N
authors.lastname: Skalko-Basnet
authors.forename: Annette
authors.initials: A
authors.lastname: Bauer-Brandl
mesh_terms: D000975:Antioxidants / Q000737:chemistry; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D054697:Cytostatic Agents / Q000737:chemistry*; D004355:Drug Stability; D005612:Freeze Drying / Q000379:methods; D006912:Hydroxyquinolines / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008823:Micelles; D010316:Particle Size; D056951:Photoelectron Spectroscopy / Q000379:methods; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry; D014867:Water / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000975:Antioxidants; D054697:Cytostatic Agents; D006912:Hydroxyquinolines; D008823:Micelles; D013501:Surface-Active Agents; D047392:beta-Cyclodextrins; D014867:Water; D014810:Vitamin E; D011092:Polyethylene Glycols; C014225:tocophersolan