Development of a SMEDDS for oral delivery of hydrophilic peptide difelikefalin acetate: Preparation, characterization, and PK/PD evaluation.

Difelikefalin acetate (DF) is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients undergoing hemodialysis. The marketed formulation is an injectable, while this study aims to develop an oral formulation to improve patient compliance. DF is designed to incorporated into lipid nanoparticles with 1,2-dipalmitoyl-rac-glycerol-3-phosphocholine (DPPC), 1,2-distearoyl-sn‑glycero-3-phospho-rac-(1-glycerol) sodium salt (DSPG), and cholesterol (CHOL) (at a ratio of 8:2:6), which are mixed with 20% oleic acid, 20% medium-chain triglycerides (MCT), 24% PEG-40 hydrogenated castor oil (RH40), and 36% transcutol to prepare a self-microemulsifying concentrate. The concentrate can achieve self-emulsification in purified water, pH 1.2(HCl solution), pH 4.5(acetate buffer), and pH 6.8(phosphate buffer) media, with a droplet size of 53-59 nm, polydispersity index (PDI) of 0.09-0.27, zeta potential of -36.39 to -6.1 mV, and drug loading of 90.3%. In vitro release results showed that the DF solution was almost completely released at 8 h in pH 6.8 medium, while the DF self-microemulsion only achieved approximately 20% release at 24 h. Enzymatic degradation experiments demonstrated that trypsin, elastase, and α-chymotrypsin could not effectively degrade DF. The rat pharmacokinetic study showed that, relative to intravenous administration, the oral bioavailability of the DF solution was 0.656%, whereas that of DF self-microemulsifying drug delivery systems (SMEDDS) was 2.04%, representing a 3-fold increase. In the mouse pharmacodynamic test, the scratching episodes inhibition of orally administered DF SMEDDS at a dose of 5 mg/kg was comparable to that of DF injection at 0.3 mg/kg.