Tanya Tong-En Fong, Chee Chin Chu, Jia Woei Wong, Kar Lin Nyam, Puxvadee Chaiku
Terpenes and terpenoids, a structurally diverse class of isoprene-derived compounds have gained significant attention as chemical penetration enhancers in transepidermal drug delivery. However, their influence on drug encapsulation within vesicular systems remains poorly understood. In this study, a terpene/terpenoid-engineered proniosomal gel (PNG) was developed to investigate the effect of terpenoid structural diversity on bilayer organization and drug incorporation of palm tocotrienol-rich fraction (TRF). PNGs were prepared using Span® 60, soy lecithin, and cholesterol with terpenoids of varying polarity and lipophilicity (d-limonene, squalene, menthone, nerolidol, and 1,8-cineole). Entrapment efficiency (EE%) of terpenes/terpenoids and TRF was determined using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) respectively. The performance of the modified PNG was found to depend on the lipophilicity and polarity of the incorporated terpenes/terpenoid. An inverse relationship was observed between TRF and terpene/terpenoid entrapment efficiencies (Pearson correlation = -0.690, p = 0.197), suggesting competition for bilayer incorporation sites. Among the tested formulations, formulation with D-limonene at 2% w/w produced the highest TRF EE% (92.73 ± 0.84%). Zeta potential analysis revealed a stable negative surface charge ranging from −52.49 ± 9.16 to −60.33 ± 2.77 mV. Transmission Electron Microscopy (TEM) analysis of the optimized formulation (D2) revealed non-aggregated, spherical, and uniform niosomal vesicles with sizes ranging from approximately 146 to 364 nm. Fourier-transform infrared (FTIR) analysis confirmed intermolecular interactions among terpenes/terpenoids, TRF, and the vesicular matrix, while hydrogen peroxide scavenging assays hydrogen peroxide scavenging activity ranged from 12.72 ± 0.73% to 17.56 ± 0.36% confirmed preservation of TRF bioactivity.