Development and Physicochemical Optimization of Octadecylamine–Triphenylphosphonium Cationic Liposomes for Coenzyme Q10 Delivery: A 2³ Factorial Design

Abstract

Background: Coenzyme Q10 (Q10) is a lipophilic mitochondrial cofactor and antioxidant. However, its poor aqueous solubility and low bioavailability limit its delivery, motivating the development of lipid-based carriers. Objectives: To synthesise a lipid-anchored octadecylamine–triphenylphosphonium (ODA–TPP) conjugate and to develop, physicochemically optimise, and evaluate ODA–TPP cationic liposomes for coenzyme Q10 using a 23 full factorial design. Methods: The ODA–TPP conjugate was prepared via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS)-mediated amidation and characterised by Fourier-transform infrared (FTIR) spectroscopy and 1H nuclear magnetic resonance (NMR). Liposomes were prepared using the thin-film hydration method, and a 23 factorial design was applied to assess the effects of the cholesterol-to-phosphatidylcholine (Chol:PC) ratio, phosphatidylcholine (PC) amount, and drug amount on particle size and entrapment efficiency (EE). Q10 was quantified using a validated high-performance liquid chromatography (HPLC) method. The optimised formulation was evaluated for particle size, polydispersity index (PDI), zeta potential, in vitro release, three-month ambient stability, and morphology using transmission electron microscopy (TEM). Results: The conjugate was obtained with an 84.6% yield and 96.8% HPLC purity, and the FTIR and 1H NMR spectra were consistent with amide-bond formation. The optimised formulation (Chol:PC 0.2; PC 25 mg; drug 2.5 mg) had a particle size of 129.3 nm, an EE of 95.0%, a PDI of 0.187, and a moderately positive zeta potential (+11.7 mV). In vitro release was sustained and diffusion-controlled (Higuchi R2 = 0.987; Korsmeyer–Peppas n = 0.458), in contrast to the first-order release of the free drug. TEM showed predominantly spherical, non-aggregated vesicles, and the particle size, zeta potential, and EE remained unchanged for three months at room temperature. Conclusions: A reproducible ODA–TPP cationic liposomal carrier for coenzyme Q10 with favorable physicochemical characteristics was developed. The moderately positive surface charge provides a physicochemical rationale for prospective studies of cellular uptake and mitochondrial targeting; cellular and in vivo evaluation is deferred to a subsequent phase of the project.