Optimization and Comprehensive Characterization of High-Stability Amygdalin Nanoliposomes Using Response Surface Methodology for Enhanced Oral Delivery

Amygdalin is a cyanogenic glycoside with clinically established antitussive, anti-inflammatory, and anticancer properties. Its translation into oral therapies is significantly hindered by its inherent oral bioavailability of less than 5% because of its high hydrophilicity, inadequate membrane permeability, and fast breakdown at gastric pH 1.2. In this study, we sought to develop an acid-resistant and intestine-targeted nanoliposome (AMY-NLs-1) to significantly improve the oral administration of amygdalin. The Box-Behnken response-surface optimization revealed the best formulation, with a lipid-to-cholesterol ratio of 3:1 (w/w), a lipid-to-amygdalin ratio of 20:1 (w/w), and an organic-to-aqueous phase volume ratio of 3:1 (v/v), yielding an encapsulation efficiency of 64.42 ± 0.15% and an amygdalin loading capacity of 3.75%. The AMY-NLs-1 demonstrated a mean particle size of 152 ± 1.23 nm, a PDI of 0.291, and a zeta potential of -53.1 ± 1.28 mV; the encapsulation efficiency was maintained at 61.97% after 15 days of storage at 4 °C in the dark. In vitro gastrointestinal release studies revealed less than 10% leakage in simulated gastric fluid within 2.5 h, followed by 65% cumulative release in simulated intestinal fluid over 8 h, indicating distinct pH-responsive behavior. For the first time, acid protection and intestine-targeted sustained release have been combined into a single nanocarrier created by a scalable one-step thin-film hydration technique, providing a versatile platform for the oral delivery of other highly water-soluble active compounds. A necessary oral dry weight of 15 g may be lowered by enhancing the drug-loading capacity or by concentrating the liposomal suspension.