Development of Solid Self-Nanoemulsifying Drug Delivery System of Rhein to Improve Biopharmaceutical Performance: Physiochemical Characterization, and Pharmacokinetic Evaluation

Sachin Madhusudan More1 *, Md Abdur Rashid,2 Rohini S Kharwade3 *, Murtada Taha,4 Yahya Alhamhoom,2 Gamal Osman Elhassan,5 Purushottam Gangane,3 Turky Omar Asar,6 Ajay Pise,7 Mohammed Kaleem,1 Md Ali Mujtaba8,9 1Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MH, 440037, India; 2Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia; 3Department of Pharmaceutics, Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MH, 440037, India; 4Department of Clinical Laboratory Science, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia; 5Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia; 6Department of Biology, College of Science and Arts at Alkamil, University of Jeddah, Jeddah, Saudi Arabia; 7Department of Regulatory Affairs Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MH, 440037, India; 8Department of Pharmaceutics, Faculty of Pharmacy, Northern Border University, Arar, Saudi Arabia; 9Center for Health Research, Northern Border University, Arar, Saudi Arabia* These authors contributed equally to this workCorrespondence: Md Ali Mujtaba; Mohammed Kaleem, Email [email protected]; [email protected]: Rhein, a natural bioactive lipophilic compound with numerous pharmacological activities, faces limitations in clinical application due to poor aqueous solubility and low bioavailability. Thus, this study aimed to develop a rhein-loaded self-nano emulsifying drug delivery system (RL-SNEDDS) to improve solubility and bioavailability.Methods: The RL-SNEDDS was prepared by aqueous titration method with eucalyptus oil (oil phase), tween 80 (surfactant), and PEG 400 (co-surfactant) and optimization was performed by 32 factorial design. The optimized formulation was characterized for Fourier transform infrared spectroscopy, differential scanning calorimetry, powdered X-ray diffraction, and Field emission scanning electron microscopy. Further, the oral bioavailability study and brain tissue pharmacokinetics study were performed on Sprague-Dawley rats.Results: The optimized RL-SNEDDS had an average droplet size of 129.3 ± 1.57 nm, zeta potential of − 24.6 mV ± 0.34, % transmittance of 94.82 ± 0.61, and encapsulation efficiency of 98.86 ± 0.23. Furthermore, RL-SNEDDS was transformed into solid RL-SNEDDS (RS-SNEDDS) to increase stability. In vitro release of rhein from RS-SNEDDS showed prolonged release up to 24h with 99.03± 1.04% drug release. Differential scanning calorimetry and powdered X-ray diffraction analysis confirmed the reduction in drug crystallinity and supported the results of the dissolution study. Field emission scanning electron microscopy analysis revealed the smooth and spherical nanosized globule of SNEDDS. Moreover, the in vivo pharmacokinetic study showed a significantly higher (p ≤ 0.05) value of Cmax and AUC0-t of RS-SNEDDS (8 ± 0.930 μg/mL and 37.79 ± 2.01 μg/mL*hr) compared to free rhein suspension (1.96 ± 0.712 μg/mL and 7.32 ± 0.946 μg/mL*hr) which indicated the enhancement of bioavailability of RS-SNEDDS. We also examined the Cmax and AUC0-t of RS-SNEDDS in the brain and it was found to be 2.90 ± 0.171 μg/mL and 18.18 ± 1.68 μg/mL*hr respectively.Conclusion: This study concludes that the RS-SNEDDS improves brain tissue concentration and oral bioavailability, both of which increase therapeutic potential. Keywords: rhein, bioavailability, solubility, nanoemulsion, drug release, pharmacokinetic