DEVELOPMENT OF OPTIMAL COMPOSITION FORMULATION OF RESVERATROL AND SOLUBILISERS

Introduction. Increasing of poorly soluble pharmaceutical substances bioavailability is one of important problems of pharmaceutical technology. Resveratrol is a plant origin polyphenol with a broad spectrum of biological effects. However, due to poor solubility and, as a result, low bioavailability, it is not promising for the development of oral drugs. Thus, today resveratrol is presented only as a biologically active substance that is component of biologically active food supplements.

The objective of the research is selection of the optimal solubilizer to increase the solubility of resveratrol by determining the solubilization parameters.

Materials and methods. The spectrophotometric characteristics of resveratrol were studied using three groups of solubilizers: poloxamers, polysorbates and cyclodextrins. Studies were carried out in 50 mM hydrochloric acid buffer(pH 1.2) and 50 mM phosphate buffer(pH 6.8). Spectrophotometric measurements were carried out on a spectrophotometer UV/VIS-3600 Shimadzu (Japan) in the wavelength range of 220–380 nm. The effect of solubilizers on the spectrophotometric characteristics of resveratrol was determined in buffer solutions containing the solubilizer and resveratrol in significantly less concentration of its own solubility in water. The used multiple excess of the solubilizer ensured the finding of all resveratrol in a solubilized form. During the determining parameters of solubilization, buffer solutions containing from 2 to 10 mM solubilizers were added to the obviously excess of resveratrol. The indicated amount of resveratrol ensured the presence of its precipitate in all experimentsto determine the completeness of solubilization of the studied polyphenol.

Results. Based on the obtained spectrophotometric characteristics of solubilizers solutions with resveratrol, the most effective for the further development of solid dosage forms for oral administration are poloxamer 407, polysorbate 80 and modified methyl-beta-cyclodextrin, which ensure complete dissolution of resveratrol when its content in the composition with a solubilizer is about 10 %.

Conclusion. Based on the data obtained on the spectrophotometric characteristics of resveratrol using solubilizers, it can be argued that it is possible to create drugs with improved solubility of the studied polyphenol. On the basis of its compositions with poloxamer 407, polysorbate 80 and modified methyl-beta-cyclodextrin, with the selection of appropriate excipients, solid dosage forms for oral intake can be developed. 

1. Park E.J., Pezzuto J.M. The pharmacology of resveratrol in animals and humans. Biochim Biophys Acta 2015;1852(6):1071–113. DOI: 10.1016/j.bbadis.2015.01.014.

2. Pangeni R., Sahni J.K., Ali J. et al. Resveratrol: review on therapeutic potential and recent advances in drug delivery. Expert Opin Drug Deliv 2014;11(8):1285–98. DOI: 10.1517/17425247.2014.919253.

3. Francioso A., Mastromarino P., Masci A. et al. Chemistry, Stability and Bioavailability of Resveratrol. Med Chem 2014;10(3):237–45. DOI: 10.2174/15734064113096660053.

4. van Hoogevest P., Liu X., Fahr A. Drug delivery strategies for poorly watersoluble drugs: the industrial perspective. Expert Opin Drug Deliv 2011;8(11):1481–500. DOI: 10.1517/17425247.2011.614228.

5. Hao J., Tong T., Jin K. et al. Folic acidfunctionalized drug delivery platform of resveratrol based on Pluronic 1 27/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles. Int J Nanomedicine 2017;12:2279–92. DOI: 10.2147/IJN.S130094.

6. Chang C.W., Wong C.Y., Wu Y.T. et al. Development of a Solid Dispersion System for Improving the Oral Bioavailability of Resveratrol in Rats. Eur J Drug Metab Pharmacokinet 2017;42(2):239–49. DOI: 10.1007/s13318-016-0339-0.

7. Calvo-Castro L.A., Schiborr C., David F. et al. The Oral Bioavailability of TransResveratrol from a Grapevine-Shoot Extract in Healthy Humans is Significantly Increased by Micellar Solubilization. Mol Nutr Food Res 2018;62(9):e1701057. DOI: 10.1002/mnfr.201701057.

8. Summerlin N., Qu Z., Pujara N. et al. Colloidal mesoporous silica nanoparticles enhance the biological activity of resveratrol. Colloids Surf B Biointerfaces 2016;144:1–7. DOI: 10.1016/j.colsurfb.2016.03.076.

9. Jadhav P., Bothiraja C., Pawar A. Resveratrol-piperine loaded mixed micelles: formulation, characterization, bioavailability, safety and in vitro anticancer activity. RSC Advances 2016;6(114):112795–805. DOI: 10.1039/C6RA24595A.

10. Berta G.N., Salamone P., Sprio A.E. et al. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)- induced oral carcinogenesis in hamster cheek pouch by topical application of resveratrol complexed with 2-hydroxypropyl-beta-cyclodextrin. Oral Oncol 2010;46(1):42–8. DOI: 10.1016/j.oraloncology.2009.10.007.

11. Moyano-Mendez J.R., Fabbrocini G., De Stefano D. et al. Enhanced antioxidant effect of trans-resveratrol: potential of binary systems with polyethylene glycol and cyclodextrin. Drug Dev Ind Pharm 2014;40(10):1300–7. DOI: 10.3109/03639045.2013.817416.

12. Yang G., Jain N., Yalkowsky S.H. Combined effect of SLS and (SBE)7M-β-CD on the solubilization of NSC-639829. Int J Pharm 2004;269(1):141–8. DOI: 10.1016/j.ijpharm.2003.09.001.

13. Zhao L., Li P., Yalkowsky S.H. Solubilization of fluasterone. J Pharm Sci 1999;88(10):967–9. DOI: 10.1021/js9901413.

14. Solubility enhancement with BASF pharma polymers: Solubilizer compendium. Ed by T. Reintjes. Lampertheim: BASF, 2011. 128 p.

15. Knoch H., Ulbrich M.H., Mittag Judith J. et al. Complex Micellization Behavior of the Polysorbates Tween 20 and Tween 80. Mol Pharm 2021;18(8):3147–57. DOI: 10.1021/acs.molpharmaceut.1c00406.

16. de Miranda J.C., Martins T.E.A., Veiga F., Ferras H.G. Cyclodextrins and ternary complexes: technology to improve solubility of poorly soluble drugs. Braz J Pharm Sci 2011;47(4):665–81. DOI: 10.1590/S1984-82502011000400003.

17. Crini G., Fourmentin S., Lichtfouse E. The History of Cyclodextrins. Ser.: Environmental Chemistry for a Sustainable World. Springer, Cham., 2020.