(T1030-01-03) Development and Characterization of Multi-layer Self-Nanoemulsifying Pellets Using Fluid Bed Coating Technique to Enhance the Dissolution and Stability of Ramipril

Purpose: Ramipril (RMP), an angiotensin-converting enzyme (ACE) inhibitor, suffers from two major problems: dissolution rate limited oral bioavailability and chemical instability. Self-nanoemulsifying drug delivery systems (SNEDDS) have the potential to enhance RMP oral bioavailability due to their ability to enhance gastrointestinal solubilization of such poorly water-soluble drug. However, the stability of liquid SNEDDS could be a major issue (e.g. leaching, incompatibility with capsule shell, rancidity and formulation discoloration). Furthermore, these liquid systems may not be suitable for drugs that experience solution state or pH-catalyzed degradation such as RMP. To overcome these limitations, the present research aims to investigate the solidification of RMP liquid SNEDDS into solid self-nanoemulsifying pellets (SNEP) via fluid bed coating.

Methods: The current study was involved comprehensive optimization of RMP liquid SNEDDS using equilibrium solubility studies, self-emulsification assessment and experimentally designed phase diagrams. The optimized liquid SNEDDS was then solidified using fluid bed coating. The solidification process was designed to produce single-layer and multi-layer self-nanoemulsifying pellets (SL-SNEP and ML-SNEP, respectively). In SL-SNEP, RMP was loaded within the SNEDDS excipients in a single layer. While in ML-SNEP, RMP layer was completely isolated from the SNEDDS layer via a protective layer. Subsequently, a moisture-sealing layer and an anti-adherent layer were applied to minimize RMP hydrolysis and pellet agglomeration upon storage, respectively. Process and formulation variables were optimized to ensure minimal agglomeration and minimal spray drying in each coating layer. The obtained SNEP was further characterized using scanning electron microscopy (SEM), pellet sizing, differential scanning calorimetry (DSC), x-ray diffraction (XRD), reconstitution study, and droplet size analysis. The optimized SNEP was evaluated against the liquid SNEDDS and marketed Sandoz® Ramipril tablet (2.5mg) using in-vitro dissolution studies. Finally, comprehensive stability studies were conducted to evaluate the formulations at accelerated and long-term storage conditions.

Results: The phase diagram study showed that black seed oil (BSO 35%) showed enhanced self-emulsification efficiency with cosolvent (Transcutol P- TCP) and Hydrogenated castor oil (HCO-30). The solubility study showed that TCP presents the highest RMP solubility (95mg/g). Accordingly, the BSO/TCP/HCO-30 system was selected as the optimum RMP-SNEDDS formulation, which exhibited excellent self-emulsification along with 49.6 nm droplet size and 55 mg/g RMP solubility. Regarding solidification process optimization, inlet air volume above 35 m3/h led to remarkable spray drying with minimal agglomeration. Regarding formulation variables, HPMC E3 reduced the pellet tackiness compared to PVP K30. In contrast to talc, plasacrylTMT20 didn`t hinder the complete dissolution of RMP. The optimum concentration of coating solution was 15% and the optimum SNEDDS proportion in the coating layer was 38%. The image from SEM analysis showed multiple well-defined coating layers of ML-SNEP. DSC and XRD confirmed the amorphous state of RMP within the drug layer. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. The in-vitro dissolution studies showed that ML-SNEP experienced significantly higher ( > 92.5%, p < 0.05) dissolution efficiency at pH 1.2 & 6.8, compared to pure RMP and the marketed tablet. Furthermore, ML-SNEP showed robust stability and maintained > 92% RMP at accelerated and long-term storage conditions.

Conclusion: ML-SNEP could be an excellent dosage form that offer the enhancement of RMP dissolution and stability upon storage.

Acknowledgements: This work was supported by National Plan for science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Saudi Arabia, Award Number (2-17-03-001-0048)