title: Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation.
abstract: 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 Tmaxvalues 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.
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Lu
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xiong
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Tong
authors.initials: T
authors.lastname: Yu
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Zixia
authors.initials: Z
authors.lastname: Hu
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Jiafeng
authors.initials: J
authors.lastname: Ding
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Cai
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Shizhuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: a The Department of Veterinary Parasitology, College of Veterinary Medicine, China Agriculture University , Hai Dian District , Beijing , China.
authors.forename: Baoliang
authors.initials: B
authors.lastname: Pan
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D001682:Biological Availability; D002368:Castor Oil / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003692:Delayed-Action Preparations; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding; D006865:Hydrogenation; D007279:Injections, Subcutaneous; D007559:Ivermectin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008855:Microscopy, Electron, Scanning; D008924:Mite Infestations / Q000188:drug therapy / Q000469:parasitology / Q000662:veterinary*; D033362:Powder Diffraction; D040042:Psoroptidae / Q000187:drug effects*; D011817:Rabbits; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000977:Antiparasitic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007559:Ivermectin; D002368:Castor Oil
keywords: Ivermectin; bioavailability; physicochemical properties; solid lipid dispersion; subcutaneous delivery; sustained release