Antioxidant micelles as optimal tools for delivery of unstable pharmacetical entities

INTRODUCTION Several compounds that are employed for pharmaceutical purposes suffer from instability in aqueous environment, mainly connected to hydrolysis, oxidation and photodegradation. Moreover, the discovery of many chemical entities that are found to be pharmaceutical active is usually abandoned at the early stages because of their solubility and stability limitations. A typical example are 3-hydroxy-quinolinone derivatives, poorly soluble compounds with promising properties in terms of cytotoxicity and cytostatic activity under in vitro conditions [1]. Preliminary studies performed with their DMSO solutions have confirmed a very high cytotoxic activity for some of these derivatives. Unfortunately, these compounds suffer from fast oxidative degradation in aqueous environment and they are also poorly soluble (1.5 µg/mL). Previously, liposomes have been found to be suitable vehicles, both solubilizing and stabilizing these types of derivatives [2]. In this work the solubilization and stabilization efficiency of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelles have been investigated for four of these quinolinone derivatives. RESULTS & DISCUSSION TPGS micelles were found to be suitable vehicles able to increase apparent solubility and stability of the investigated compounds. Using TPGS as a solubilizer, generally, higher apparent solubilities compared to the liposome formulations were gained, without observed degradation (24 hours). The trend of incorporation seen for the micelles was similar to the one previously observed for liposomal formulations and reflected the lipophilicity of the compounds. Average micellar sizes were found to be from 10 to 15 nm with a very narrow distribution (P.I. 0.05). Freeze drying of micelles was shown to be a suitable and easy technique to obtain solids for long-term storage without affecting size of micelles and drug loading after their reconstitution. TPGS micelles were proven to be a preferable carrier for poorly soluble lipophilic compounds.