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

• Published in: Drug delivery Vol. 24; no. 1; pp. 622 - 631
• Main Authors: Lu, Mengmeng, Xiong, Dan, Sun, Weiwei, Yu, Tong, Hu, Zixia, Ding, Jiafeng, Cai, Yunpeng, Yang, Shizhuang, Pan, Baoliang
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.11.2017; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Animals; Antiparasitic Agents - administration & dosage; Antiparasitic Agents - chemistry; Antiparasitic Agents - pharmacokinetics; Antiparasitic Agents - toxicity; bioavailability; Biological Availability; Castor Oil - analogs & derivatives; Castor Oil - chemistry; Castor Oil - toxicity; Cell Survival - drug effects; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Delayed-Action Preparations; Dogs; Drug Carriers; Drug Compounding; Fourier transforms; Hydrogenation; Injections, Subcutaneous; Ivermectin; Ivermectin - administration & dosage; Ivermectin - chemistry; Ivermectin - pharmacokinetics; Ivermectin - toxicity; Lipids; Madin Darby Canine Kidney Cells; Male; Microscopy, Electron, Scanning; Mite Infestations - drug therapy; Mite Infestations - parasitology; Mite Infestations - veterinary; physicochemical properties; Powder Diffraction; Psoroptidae - drug effects; Rabbits; solid lipid dispersion; Solubility; Spectroscopy, Fourier Transform Infrared; subcutaneous delivery; sustained release; Technology, Pharmaceutical - methods; physicochemical properties; solid lipid dispersion; bioavailability; sustained release; subcutaneous delivery; Ivermectin
• ISSN: 1071-7544; 1521-0464
• DOI: 10.1080/10717544.2017.1284945

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 T max 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.