Enhanced Solubility, Stability, and Safety through Busulfan/Sulfobutyl Ether β-Cyclodextrin Inclusion Complexes

Abstract

Busulfan (Bu) is a bifunctional alkylating agent of dimethylsulfonate, which is widely used for pretreatment before bone marrow transplantation. However, due to its poor solubility, the marketed injectable (Busulfex) employs a large amount of N,N-dimethylacetamide (DMA) to dissolve the drug, which results in significant hepatic toxicity and thus imposes high physical demands on patients. Moreover, the injectable solution is only stable at room temperature for 8 h after dilution, posing risks of drug degradation and precipitation, which limits its clinical application. To overcome these drawbacks, we intend to utilize cyclodextrin inclusion complex technology to embed Bu into the cavity structure of sulfobutylether-β-cyclodextrin, forming a cyclodextrin inclusion complex of Bu. Subsequently, this complex was lyophilized to produce injectable Bu (Bu-I). The physical properties and stability of Bu-I were investigated in vitro, and its pharmacokinetic and pharmacodynamic characteristics were evaluated in vivo. The safety of Bu-I was assessed in terms of hemolysis, intravenous irritation, and acute toxicity. After complexation, the solubility of Bu was increased by approximately 70-fold. Our stability studies demonstrated that Bu-I exhibited significantly enhanced dilution stability at room temperature compared with Busulfex, with the drug content remaining above 98% over 12 h. In rats, Bu-I showed bioequivalence to Busulfex following intravenous injection. Moreover, Bu-I exhibited markedly reduced vascular irritation compared with Busulfex. The LD50of Bu-I was 2.65 times that of Busulfex, and Bu-I had significantly decreased hepatic toxicity, thereby greatly improving clinical safety. Overall, the inclusion complex technology employed in this study is a simple and effective formulation strategy that enhances drug stability while preserving therapeutic efficacy, circumvents the irritation and hepatic toxicity associated with DMA, and holds great promise for clinical application.