Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation

• Main Authors: Mengmeng Lu, Dan Xiong, Weiwei Sun, Tong Yu, Zixia Hu, Jiafeng Ding, Yunpeng Cai, Shizhuang Yang, Baoliang Pan
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2017-01-01
• Series: Drug Delivery
• Subjects: ivermectin; sustained release; solid lipid dispersion; subcutaneous delivery; physicochemical properties; bioavailability
• Online Access: http://dx.doi.org/10.1080/10717544.2017.1284945
• ISSN: 1071-7544; 1521-0464

This work aimed to develop a sustained release solid dispersion of ivermectin (IVM-SD) in a lipid matrix (hydrogenated castor oil, HCO) for subcutaneous delivery. Solvent-melting technology was employed to prepare IVM-SDs using HCO. The physicochemical properties of the IVM-SDs were evaluated by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). The release of IVM from IVM-SDs was evaluated with HPLC in vitro. Pharmacokinetics of IVM was studied in rabbits following a single subcutaneous administration of IVM-SD formulations. The efficacy of IVM-SD against the ear mange mite was evaluated in rabbits. IVM was completely dispersed in HCO in an amorphous state at a drug:carrier ratio lower than 1:3. No chemical interactions between drug and carrier were found besides hydrogen bonding for the amorphous IVM-SDs. The amorphous IVM-SDs formulations exhibited a sustained release of IVM versus physical mixtures (PMs) of IVM and HCO. The drug release decreased as the drug:carrier ratios decreased, and the release kinetics of IVM were controlled via diffusion. Cytotoxicity of IVM-SD to MDCK cells was lower than native IVM. The IVM plasma concentration of SD1:3 remained above 1 ng/mL for 49 d. Higher AUC, MRT, and Tmax values were obtained at a SD1:3 relative to the IVM group. The IVM-SD improved almost 1.1-fold bioavailability of drug compared with IVM in rabbits. IVM-SD could provide longer persistence against rabbit’s ear mites than a commercial IVM injection. This study shows that these solid lipid dispersions are a promising approach for the development of subcutaneous IVM formulations.