Engineering solid dispersions of anticancer preclinical lead, IIIM-985: Physicochemical characterization and in vivo pharmacokinetics

Abstract IIIM-985, a synthetic analog of natural product fascaplysin, is a Cdk inhibitor, efficacious in the xenograft models of colon cancer. Its low aqueous solubility (∼0.35 μg/mL) has been considered as the primary reason for requirement of high dose to achieve the optimum in vivo efficacy. Thus, herein we aimed to explore binary and ternary solid dispersions of this lipophilic molecule to enhance its solubility and dissolution profile. A solubility-guided miniaturized multiwell screening protocol was developed to find out the suitable hydrophilic carrier/s for solid dispersions of IIIM-985. A combination of PVP-K30 and Kolliphor HS15 was identified as the most favourable carrier yielding a solid dispersion VKB-SD142 which displayed 90-fold improvement in aqueous solubility of IIIM-985. This ternary solid dispersion VKB-SD142 was prepared in gram-scale and was evaluated using DSC, p-XRD, FTIR, SEM, in vitro dissolution and oral pharmacokinetic studies. The oral administration of VKB-SD142 in BALB/c mice resulted in >5-fold improvement in AUC. These findings underline the rationale for further investigation of biopharmaceutically improved solid dispersion of IIIM-985 in preclinical studies.