(M1330-12-78) A Novel Approach for Targeted Pulmonary Delivery of Thymoquinone as Dry Powder Inhaler (DPI)

Purpose: This study aimed to investigate the delivery of thymoquinone- nanoaggregate using poly(ester-amide) based on L-arginine. The present investigation aimed to synthesise a nanoparticulate delivery system for TQ targeted to the lungs to avoid first-pass metabolism and its distribution to a non-targeted site. This may lead to a decrease in peripheral side effects.

Methods: Thymoquinone loaded poly(ester- amide) based on L-arginine nanoparticles were prepared using interfacial polycondensation method and were characterized on the basis of nuclear magnetic resonance (NMR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), surface morphology, in vitro aerodynamic performance and release. FTIR and NMR studies confirmed the production of the poly(ester- amide)- L arginine polymer.

Results: Transmission electron microscopy and zeta sizer confirmed the particle diameter was around 52 nm. High dose formulation possessed entrapment efficiency and loading capacity of TQ to be 99.77% and 35.56% respectively. An XRD study proves that TQ dispersed in the nanoparticles did not change its crystallinity, and incorporation within the polymer was through physical attraction and hydrogen bond both within the polymer and onto the surface. That was further confirmed by the DSc study and the release study that showed an initial burst effect of around 50% of TQ within 2 hours followed by slow release of the remaining over 22 hours. Optimized nanoparticles were evaluated further for their in vitro aerodynamic performance which proved an effective delivery of 22.7-23.7% of the nominal dose into the lower parts of the lungs. The high drug-targeting potential and efficiency demonstrates the significant role of the TQ loaded poly(ester- amide) based on L-arginine nanoparticles for potential application in respiratory conditions.

Conclusion: TQ loaded poly (ester- amide) based on L-arginine nanoparticles were successfully prepared using interfacial polycondensation method. The morphological and molecular profiling of the nanoparticles supported the suitability for pulmonary drug delivery as the nanoparticles produce aggregates in favourable micron size of 1-5 µm. The in-vitro assessment of the aerodynamic particle size distribution releveled that almost 475 µg can be delivered to the lower parts of the respiratory system. The results suggest pulmonary delivery of TQ to be a promising approach for optimal targeting as well as in reducing the systemic exposure.

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Acknowledgements: The authors greatly acknowledged the National Center for Biotechnology, Life Science & Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. The authors would like to acknowledge the Promising Centre for Sensors and Electronic Devices (PCSED) at Najran University, Kingdom of Saudi Arabia.

FTIR spectra of (a) Thymoqunone (b) di-p-toluenesulfonic acid salt of O,O’-bis-( L-arginine)- diethylene glycol monomer, (B) poly (easter amide) based on L-arginine, (C) Thymoquinone poly(ester amide) formula .

: (a) 1H NMR of di-p-Toluenesulfonic acid salt of O,O’-bis-( L-arginine)- diethylene glycol monomer, (b) 1H NMR of poly-(easter amide) based on L-arginine, (c) 13C NMR of di-p-Toluenesulfonic acid salt of O,O’-bis-( L-arginine)- diethylene glycol monomer (d) 13C NMR poly (easter amide) based on L-arginine.

TEM images of (A-B) the poly (ester amide) based on L-arginine and (C-D) thymoquinone loaded nanoparticles.