Development, Optimization, and Evaluation of Nano Self-Emulsifying Drug Delivery System Formulation Platform for Oral Bioavailability Enhancement of Sulfasalazine and Disulfiram in Lung Cancer Chemoprevention.

OBJECTIVE

Lung cancer chemoprevention modalities are gaining wide attention as it is the second most diagnosed cancer type and the leading cause of cancer-related deaths. Our previous studies reported unique lung cancer chemoprevention capability with a repurposed drug combination of sulfasalazine (SAS) and disulfiram (DSF). However, their efficacy is limited by poor bioavailability. To overcome this challenge, we developed bioenhanced oil-in-water (o/w) nano self-emulsifying drug delivery system (Nano-SEDDS) formulations of SAS and DSF.

METHODS

Unique isotropic Nano-SEDDS of SAS and DSF were developed and optimized using a single-step mix method followed by in vitro physicochemical characterization and stability studies. An in vivo pharmacokinetic and tissue-biodistribution study was undertaken to test the proposed hypothesis of bioavailability enhancement with Nano-SEDDS of SAS and DSF.

RESULTS

The optimal Nano-SEDDS formulation exhibited low nanodroplet sizes (< 200 nm), high drug content, and 4.5-fold (p < 0.01) and 3.75-fold (p < 0.01) enhancement in in vitro dissolution of SAS and DSF compared to the respective free drugs. The Nano-SEDDS formulations were also confirmed to be stable at room temperature in compliance with ICH guidelines. Further, SAS Nano-SEDDS showed a dose-dependent increment in oral bioavailability as shown by a significant 7.9-fold (p < 0.0001) enhancement in dose-normalized AUC at a dose of 10 mg/kg compared to free drug treatment at a control dose of 250 mg/kg.

CONCLUSION

Overall, the studies corroborated the successful formulation of bioavailability-enhanced SAS and DSF Nano-SEDDS with future co-delivery applications for lung cancer prevention.