Subcutaneously injected ivermectin-loaded mixed micelles: formulation, pharmacokinetics and local irritation study

Abstract

Clinical application of ivermectin (IVM) is limited by several unfavorable properties, induced by its insolubility in water. Slight differences in formulation may change the plasma pharmacokinetics and efficacy. In this study, an IVM-loaded Soy phosphatidylcholine-sodium deoxycholate mixed micelles (IVM-SPC-SDC-MMs) were developed to improve its aqueous solubility, aiming to make it more applicable for clinical use. First, IVM-SPC-SDC-MMs were prepared using the co-precipitation method. After formulation optimization, the particle size was 9.46 ± 0.16 nm according to dynamic light scattering. The water solubility of IVM in SPC-SDC-MMs (4.79 ± 0.02 mg/mL) was improved by 1200-fold, comparing with free IVM (0.004 mg/mL). After subcutaneous administration, the pharmacokinetic study showed that IVM-SPC-SDC-MMs and commercially available IVM injection were bioequivalent. Also, the local irritation study confirmed that IVM-SPC-SDC-MMs reduced side reactions of the commercially available IVM injection. These results indicated that IVM-SPC-SDC-MMs represented a promising new drug formulation suitable for subcutaneous delivery of IVM.

Current therapeutic applications and pharmacokinetic modulations of ivermectin

“…Hence, to overcome the problem of poor water solubility and obtain a stable injectable formulation of ivermectin, several commercial preparations have been developed which use organic solvents as vehicles. However, high concentrations of organic solvents have been reported to induce significant side effects in many species [26]. Frosch reported that pain and inflammation at the injection site were commonly observed side effects of commercial ivermectin preparations [27].…”

“…In this study, oleic acid was found to be an efficient vehicle for ivermectin due to its ability to enhance the solubility and transport by reducing the p-glycoprotein (P-gp)-mediated efflux of ivermectin. The composition of various formulations of ivermectin and their characteristic features is described in Table-1 [7,26,28,32-61]. Vehicles, such as oils, liposomes, and other microparticles, can reduce drug metabolism and can enhance the release of large quantities of the active form of the drug over a long period of time to the target site by altering its pharmacokinetics [62].…”

Nanomedicine Approaches Against Parasitic Worm Infections

“…For example, albendazole is essentially insoluble in water, thus poorly absorbed through gastrointestinal tract. Similarly, IVM has a solubility of only 4 ug mL −1 in water and must be solubilized by surfactants and administrated in the form of micelles. Second, these drugs are typically limited by short circulation time.…”

Preparation of ginsenoside compound-K mixed micelles with improved retention and antitumor efficacy

“…Phosphatidylcholine (PC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol 2000 (DSPE PEG 2000; DP) have been widely used as pharmaceutical excipients because of their proven safety. [27][28][29][30][31] High concentrations of DP can solubilize drugs to a large extent. PC can adjust the hydrophobic segment aggregates to form a stable inner core to promote drug accommodation via hydrophobic interactions.…”