Research paperOvercoming instability and low solubility of new cytostatic compounds: A comparison of two approaches
Graphical abstract
Schematic representation of the respective CD-compound- and TPGS-micelles-compound formulations. The compounds are only partially incorporated in the CDs and they are not protected against fast chemical degradation. On the contrary, TPGS micelles incorporate the compounds completely in their core, protecting the quinolinone ring from oxidative hydroxylation.
Introduction
It has been well known for considerable time that solubility and permeability through biological membranes are two of the main factors that influence the pharmaceutical activity of substances [1]. Nevertheless, in the last decade, the majority of new chemical entities that has been found pharmaceutically relevant unfortunately suffered of poor solubility in water and physiological fluids. It has been estimated that nearly 40% of drugs present on the market are poorly water-soluble substances, and because of that, development of innovative strategies to solubilize these types of substances has become a necessity [2]. The technologies that are commonly employed to overcome poor drug solubility can be generally divided into physical modifications (e.g. changing in physical state of the drugs), chemical modifications (e.g. salt formation, co-crystallization), and use of agent that can increase the apparent solubility of the drug mostly by stoichiometric complexing of the drug molecules (e.g. cyclodextrins) or forming nanosystems or microsystems to carry the drug in homogeneous dispersions (e.g. micelles, liposomes, nanoparticles, nanoemulsion) [2], [3], [4]. One class of poorly soluble compounds with promising properties in terms of very high cytotoxicity and cytostatic activity in in vitro conditions are 3-hydroxyquinolinone derivatives (flavones analogue) [5]. Due to their low solubility in any aqueous media, all the activity studies have been carried out using DMSO as a solvent, hampering a proper assessment of their real intrinsic cytotoxic activity. In an attempt to prepare these compounds for better tests by avoiding the use of organic solvents, we have previously shown that liposomes can be good vehicles for increasing solubility in aqueous media for these substances by a factor from 100 to 500, depending on the compound structures [6]. Unfortunately, the liposome dispersions were not able to stabilize these compounds over a sufficiently long period of time. Furthermore, for cancer therapy, poor solubility of drugs is not the only problem that has to be overcome for induction of a relevant pharmaceutical effect: the majority of anticancer drugs suffer from a very high metabolic clearance by the liver. Cyclodextrins, since their introduction in the 1950s, have been considered good vehicles to enhance apparent solubility and stability of poorly soluble drugs [7], [8], especially for oral administration purposes. Unfortunately, in the majority of the cases, insufficient accumulation of the drug in the tumor tissues was observed, resulting in inefficiency of the therapy and in the development of collateral effects. In the last years, several nanotechnologies have been developed to improve targeting efficiency in anticancer therapy such as liposomes, solid nanoparticles, and micelles [3], [9]. A major breakthrough in this field has been reached when it was discovered that big hydrophilic polymers, like polyethylene glycol (PEG), bonded on the nanocarrier surfaces, could significantly increase carrier circulation time in the blood stream [10] (the so-called stealth effect). Most recently, it has been shown that some of these hydrophilic polymers are also able to inhibit some drug efflux pumps (e.g. P-glycoprotein), resulting in a better drug accumulation in tumor cells [11]. As a consequence of all these improvements in nanoparticle drug delivery technology, a number of auto assembling systems containing hydrophilic polymers have been successfully developed as possible carriers for pharmaceutical substances [12]. In this work, the suitability of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a solubilizing agent, as well as some cyclodextrin derivatives, has been investigated. Moreover, solid mixtures composed of solubilizer and compounds obtained by freeze-drying were studied and developed as potential final formulations for in vivo and in vitro studies.
Section snippets
Materials
The quinolinone derivatives (Fig. 1) have been synthesized in the Department of Organic Chemistry (Faculty of Science) of Palacky University (Czech Republic) as described in [5]. All compounds were of high degree of purity, between 98.5% and 99.5%. Methyl-β-cyclodextrin (M-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) with molar degrees of substitution of 0.57 and 0.62, respectively, (kind gifts from Roquette Freres, Lestrem, France) were used for the complexation experiments. D-α-tocopheryl
Complexation with cyclodextrins
Complexation with cyclodextrins is a well-known and easy-to-use technique to enhance apparent solubility and stability of poorly soluble drugs [8]. Fig. 2 shows the recorded UV spectra for the compound Q1 in ethanol, phosphate buffer and in the presence of HP-β-CD and M-β-CD. It is obvious that both types of CD have a positive effect on the apparent solubility of compound Q1, justified by the increased absorbance that is observed at 250 nm (transition π → π*, benzyl chromophore) compared to the
Conclusions
In this work, TPGS micelles have proven to be excellent vehicles to solubilize and stabilize new potential cytotoxic and cytostatic quinolinone drugs. For the chemical stabilization, the antioxidant effect of the α-tocopherol motif in the surfactant molecules plays an important role as well as the absence of water in the core of the micelles, where the compounds seem to be placed. Freeze-drying was found to be an efficient technique to obtain formulations in the solid state, obtaining a better
Acknowledgments
Our thanks go to Roquette Freres for the donation of the cyclodextrins, to BASF SE for the donation of the TPGS and to the Ministry of Education, Youth and Sport of the Czech Republic, for the grant MSM6198959216 and for the project CZ.1.07/2.3.00/20.0009 supported by the European Social Fund.
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