(W0930-07-44) Spray-Dried Solid Dispersions of Edaravone for Enhanced Oral Delivery

Purpose: Edaravone (EDA) (3-methyl-1-phenyl-2-pyrazolin-5-one) is a neuroprotective drug with free radical scavenging properties. EDA was first approved in Japan (2001) for Acute Ischemic Stroke and was subsequently approved by the FDA for Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. It is currently marketed as both an intravenous infusion (RADICAVA®) and an oral suspension (RADICAVA ORS®). While oral suspension offers greater convenience over the IV formulation, it comes with its own set of challenges including poor aqueous and chemical stability, taste masking issues, and excipient compatibility concerns resulting in short shelf-life. Despite its limitations, oral route remains the most patient compliant, flexible, and cost-effective method of drug administration. However, limited research has been conducted to explore the oral delivery of EDA in depth. The primary objective of our research is to enhance solubility and stability; and improve the oral bioavailability of EDA by formulating amorphous solid dispersions using spray drying technique. 

Methods: EDA solid dispersions were prepared using the spray drying technique. Lactose monohydrate was selected as the primary carrier. To enhance the particulate properties, L-leucine was incorporated at varying ratios. The solutions were prepared by incorporating 5% Ethanol as a co-solvent with 15% drug loading and a final solid content of 2%. EDA was weighed and dissolved in 5% ethanol, the excipients were weighed accordingly and added to the previous solution. Finally, the water was added just before the spray drying process. Spray drying was carried out using one nozzle Yamato ADL 311S spray dryer with the operating parameters under following conditions: inlet temperature: 100° C, pump   setting of 1.5, (~3ml/min) and blower (flow rate of drying air) was set at dial position 10  (0.78m3/min). The resulting spray-dried powders were collected, and their respective % yield and drug content were evaluated. Further, solid-state characterization was done using DSC and PXRD techniques. Based on the drug content data, formulation F-2 was selected for further studies, including in vitro dissolution testing. The study was conducted using a USP type-II Paddle apparatus at 37 °C, 50 RPM by loading the spray dried powder in a size “0” capsule. 

Results: The final spray-dried powders appeared white in color. Incorporation of L-leucine with lactose monohydrate resulted in improved % yield, from 39.9±1.3% to 56.1±2.7 %. However, no significant differences were observed with increasing concentrations of L-leucine. Although concerning drug content (F-2), 10% L-leucine incorporation showed higher drug content (115.1±39.5ug/mg) than F-3 20% L-leucine (71.6±0.6ug/mg) and F-4 30% L-leucine (76±30.3ug/mg). The DSC and XRPD studies were performed on all the formulations, which confirmed the semi-crystalline nature of the spray-dried powders. The in vitro dissolution demonstrated that more than 85% of the drug was released within an hour, indicating an efficient immediate release pattern. Further morphological characterization is underway to understand the amorphous powders' structure, size, and shape, which will be crucial for understanding the release behavior and solubility. 

Conclusion: Edaravone (EDA) solid dispersions were successfully prepared with lactose monohydrate and L-leucine using spray drying. The addition of L-leucine improved the final powder yield. Solid-state characterization revealed a semi-crystalline nature, and dissolution studies confirmed rapid drug release ( >85% within one hour). These findings suggest that spray-dried solid dispersions are a promising approach for improving the oral delivery of Edaravone (EDA). Further morphological studies will help us understand the impact of particle structure on dissolution and oral bioavailability. 

Acknowledgements: The present work was supported by research funds provided to VG by College of Pharmacy and Health Sciences (CPHS), St. John’s University. SD was supported by teaching assistantship from CPHS, Dept. of Pharmaceutical Sciences, St. John’s University. All authors declare no conflict of interest in this work.


Figure 1 Different compositions of Spray dried formulations


Figure 2 Solid state characterization of all spray dried formulations A) XRD spectra B) DSC thermograms


Figure 3 In-vitro dissolution profile for selected spray dried formulation (F2)