Self-micellizing solid dispersion of thymoquinone with enhanced biopharmaceutical and nephroprotective effects

Abstract

The present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5–15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

Keywords:

• Biopharmaceutical
• nephroprotective
• oral absorption
• self-micellizing solid dispersion
• thymoquinone

Acknowledgements

The authors wish to thank the authority of the Semiconductor Research Center, the University of Dhaka, for their kindness in permitting the particle size analysis of the samples. The authors would also like to thank the University of Dhaka for supporting the Open Access Publication fees.

Author’s contributions

Shimul Halder: Conceptualization, Methodology, in vivo experiments, Validation, Formal analysis, Writing - Original Draft, Review & Editing, Visualization; Sanjida Afrose: Methodology, Investigation, in vivo experiments; Manik Chandra Shill:Validation, Investigation, in vivo experiments; Nahid Sharmin: Conceptualization, Project administration; Patricia Prova Mollick: Methodology, Investigation, in vivo experiments; Madhabi Lata Shuma^: Methodology, Formal analysis, Data Curation, Writing - Review & Editing; Md. Abdul Muhit: Methodology, Data Curation, Writing - Review & Editing; S. M. Abdur Rahman: resources, Project administration, Writing - Review & Editing. Manik Chandra Shill and Patricia Prova Mollick did euthanasia on the rats.

Ethical approval statement

Rats were chosen as an animal models to investigate the pharmacokinetics of TQM samples following oral administration and the potential for improved nephroprotective behavior. Male Wister rats weighing 220 ± 24 g (8–9 weeks old) were chosen in all animal experiments, were housed in three per cage in the laboratory with free access to food and water, and maintained on a 12 h dark/light cycle in a room with controlled temperature (24 ± 1 °C) and humidity (55 ± 5% RH). They were kept in a laboratory with free food and water access. The Institutional Animal Care and Ethical Committee of the University of Dhaka’s Faculty of Biological Sciences sanctioned the protocol number ‘Ref. No. 97/Biol. Scs./23.08.2020’ for carrying out animal experiments. The ARRIVE criteria were followed in all animal experiments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Upon a reasonable request, the corresponding author will provide access to the data supporting this study.

Additional information

Funding

This work was partly supported by a research grant from the University of Dhaka (Centennial Research Grant/Reg./Admin-3/47868, 2020-2021).