Layer-by-Layer Engineering of Black Seed Oil Based SNEDDSs (BSO-SNEDDSs): Optimizing Chemical Stability and Bioavailability in Ramipril Formulations

Ahmad Abdul-Wahhab Shahba,1,2 Abdelrahman Y Sherif,1,2 Ehab M Elzayat,1 Shaukat Ali,3 Mohsin Kazi1,2 1Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia; 2Kayyali Chair for Pharmaceutical Industries, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia; 3Ascendia Pharma, Inc, North Brunswick, NJ, 08902, USACorrespondence: Mohsin Kazi, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box-2457, Riyadh, 11451, Kingdom of Saudi Arabia, Tel +966114677372, Email [email protected] Ahmad Abdul-Wahhab Shahba, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box-2457, Riyadh, 11451, Kingdom of Saudi Arabia, Tel +966114677372, Email [email protected]: The inherent chemical instability of ramipril (RMP) can lead to reduced therapeutic efficacy and safety, emphasizing the need for innovative formulation strategies for increased stability and bioavailability. This study aims to develop RMP-loaded liquid and solid self-nanoemulsifying formulations (SNEDDSs) that incorporate cardioprotective black seed oil (BSO) as a natural source of bioactive thymoquinone (THQ) for comprehensive chemical stability and pharmacokinetic evaluation.Methods: A systematic approach was employed to transform liquid SNEDDSs into both single-layer (Single-SNEPs) and multilayer (Multi-SNEPs) self-nanoemulsifying pellets through fluid bed coating technology. Extensive characterization encompassing morphological analysis, dissolution studies, chemical stability assessments, and pharmacokinetic profiling, was conducted.Results: In vitro dissolution studies demonstrated that the multilayered 5L-SNEPs formulation exhibited the highest dissolution efficiency compared with that of pure RMP (p > 0.05) and pure THQ (P < 0.05). Notably, the 5-layer pellets (5L-SNEPs) exhibited superior chemical stability of RMP (p < 0.05) compared with the liquid SNEDDS and other pellet variants. In-vivo pharmacokinetic analysis in rats revealed that liquid SNEDDS showed a numerically greater maximum plasma concentration (Cmax = 106 ± 34 ng/mL) and area under the curve (AUC = 454 ± 265 ng·h/mL) compared to pure RMP (Cmax = 90 ± 17 ng/mL; AUC = 308 ± 213 ng·h/mL), indicating a 1.5-fold higher AUC from the liquid SNEDDS. However, the difference was not statistically significant. Interestingly, 5L-SNEPs resulted in the lowest RMP exposure among the tested formulations, with a Cmax of 60 ± 18 ng/mL and an AUC of 155 ± 59 ng·h/mL, although the differences were not statistically significant compared to the other groups. The time to maximum concentration (Tmax) was 0.8 hours for liquid SNEDDS, 0.6 hours for the 5L-SNEPs, and 0.5 hours for pure RMP.Conclusion: While liquid SNEDDSs exhibit promisingly greater oral bioavailability than crystalline drugs do, the performance of multilayer solid SNEDDSs necessitates further refinement. Nonetheless, this comprehensive investigation establishes a robust foundation for continued research on multifunctional bioactive oil-based SNEDDSs to enhance the bioavailability of drugs with limited water solubility. Keywords: ramipril, solid self-nanoemulsifying formulations, SSNEDDSs, self-nanoemulsifying pellets, hypertension, oral bioavailability