Purpose: Ramipril (RMP)—an angiotensin-converting enzyme (ACE) inhibitor—and thymoquinone (THQ) suffer from poor oral bioavailability. Developing a combined liquid SNEDDS that comprises RMP and black seed oil (as a natural source of THQ) could lead to several formulations and therapeutic benefits. Methods: The present study involved comprehensive optimization of RMP/THQ liquid SNEDDS using self-emulsification assessment, equilibrium solubility studies, droplet size analysis, and experimentally designed phase diagrams. In addition, the optimized RMP/THQ SNEDDS was evaluated against pure RMP, pure THQ, and the combined pure RMP + RMP-free SNEDDS (capsule-in-capsule) dosage form via in vitro dissolution studies. Results: The phase diagram study revealed that black seed oil (BSO) showed enhanced self-emulsification efficiency with the cosolvent (Transcutol P) and hydrogenated castor oil. The phase diagram studies also revealed that the optimized formulation BSO/TCP/HCO-30 (32.25/27.75/40 % w/w) showed high apparent solubility of RMP (25.5 mg/g), good THQ content (2.7 mg/g), and nanometric (51 nm) droplet size. The in-vitro dissolution studies revealed that the optimized drug-loaded SNEDDS showed good release of RMP and THQ (up to 86% and 89%, respectively). Similarly, the isolation between RMP and SNEDDS (pure RMP + RMP-free SNEDDS) using capsule-in-capsule technology showed >84% RMP release and >82% THQ release. Conclusions: The combined pure RMP + RMP-free SNEDDS (containing black seed oil) could be a potential dosage form combining the solubilization benefits of SNEDDSs, enhancing the release of RMP/THQ along with enhancing RMP stability through its isolation from lipid-based excipients during storage.
Keywords: BIO-SNEDDS; black seed oil; combined delivery systems; hypertension; ramipril.