Analysis of Ge-132 and development of a simple oral anticancer formulation

Abstract

The anticancer activity of synthetic organogermanium, β- or bis-carboxyethylgermanium sesquioxide (Ge-132), has been demonstrated in several cancer cell models and human studies. Ge-132 increases pro-inflammatory responses by enhancing interferon-γ (IFN-γ), natural killer cell and T-cell activity, and is significantly less toxic than other widely used metal-based anticancer drugs such as cisplatin. In this small-scale laboratory study, we effectively assessed the physicochemical characteristics and purity of Ge-132, our main objective being to develop a novel oral anticancer formulation, using conventional tabletting excipients which do not alter the chemistry of Ge-132. We determined that solid Ge-132 decomposes at 330°C; is virtually insoluble in most common organic solvents; and readily dissolves in water (saturation solubility ≈1.28 g/100 ml) to form germane triol (pH 3.06–3.12). 1 H and 13 C nuclear magnetic resonance spectroscopy confirmed the structure of our compound showing two identical proton environments at 1.55 and 2.65 ppm (triplets) and three distinct carbon environments at 178.31, 27.37 and 12.93 ppm. The mass spectrum indicated the formation of numerous complex ion fragments with masses ranging from m/z 123.1 to m/z 478.3. FT-infrared and FT-Raman spectra showed characteristic sesquioxide peaks at 900.51, 900.26 and 800.04 cm −1 and, most importantly, confirmed the absence of toxic, inorganic GeO 2 , at 850 cm −1 . While parenteral formulations exist for many anticancer medicines, here we successfully developed uncoated tablets containing Ge-132 (5% w/w) by manual direct compression (powder particle size ≤180 µm). The tablets passed British Pharmacopoeia (BP) content uniformity testing (Ultraviolet–visible, 212 nm), and BP disintegration testing in both acidic and basic media, disintegrating between 2 min 55 s and 3 min 10 s, respectively. We prepared gastro-resistant formulations using Eudragit ® ; however, these failed content uniformity tests and had lower disintegration times (≤1 min 36 s), indicating that compatibility of polymers with Ge-132 requires further investigation. The results presented here support further larger-scale research on Ge-132 as a novel metal-based oral anticancer drug which can be conveniently administered alone or included within a chemotherapy regimen. Future formulation studies on Ge-132 could focus on compatibility assessments with nano-formulations in keeping with current advancements in metal-based anticancer therapies.