Enhanced oral bioavailability of ivermectin in pigs via a novel pH-sensitive enteric matrix granule formulation

Ivermectin (IVM) oral use is often limited by its instability in gastric acid and poor water solubility. Conventional oral formulations, such as premixes and tablets, are often associated with inaccurate dosing and variable bioavailability. This study aimed to develop a novel pH-sensitive enteric matrix formulation to protect IVM from gastric degradation and facilitate rapid release in the proximal small intestine. A novel pH-sensitive ivermectin enteric granule (IVM-EG) was prepared via a melt-dispersion technique using polyethylene glycol 6000 (PEG 6000) and hydroxypropyl methylcellulose phthalate (HPMCP-hp50) as matrix carriers. Following in vitro dissolution tests, a pharmacokinetic study was conducted in eighteen healthy pigs. The animals were randomly assigned to receive a single dose of ivermectin (0.3 mg/kg) through one of three treatments: intravenous injection (IVM-IV), oral gavage of the commercial premix (IVM-PMX), or oral gavage of the enteric granules (IVM-EG). Plasma concentrations were quantified using a validated HPLC-fluorescence detection method. The optimal formulation (IVM: PEG 6000: HPMCP-hp50 = 1:84:15) maintained macroscopic structural integrity in simulated gastric fluid for 2 h. Subsequently, cumulative release of ivermectin reached 94.43% within 2 h in simulated intestinal fluid (pH 5.1). In pigs, the absolute bioavailability (F) of IVM-EG (65.46%) was significantly higher than that of the commercial premix (36.48%, P < 0.01). The granules nearly doubled the C max (increasing from 15.90 ng/mL to 28.91 ng/mL, P < 0.01) and shortened the T max from 8.67 h to 6.33 h ( P < 0.05). The IVM-EG formulation effectively protects ivermectin from gastric degradation and significantly enhances its oral bioavailability in pigs. This enhanced absorption offers a potential strategy to optimize dosing regimens, combat drug resistance, and minimize environmental ecotoxicity by enabling potential dose reductions. Utilizing a carrier matrix for enteric delivery is a promising strategy for acid-labile antiparasitic drugs.