International Journal of Drug Delivery Technology
Volume 14, Issue 2

Potential of Native Cyclodextrins and L-Lysine for Enhancing Ellagic Acid Aqueous Solubility

Isaïe Nyamba1,2,3*, Charles B Sombie2, Anna Lechanteur1, Rasmané Semde2, Brigitte Evrard1

1Laboratory of Pharmaceutical Technology and Biopharmacy, Center for Interdisciplinary Research on Medicines (CIRM), Université de Liège, Liège, Belgium.

2Laboratory of Drug Development, Center of training, research and expertise in pharmaceutical sciences (CFOREM), Doctoral School of Sciences and Health, Université Joseph KI-ZERBO, Ouagadougou, Burkina Faso.

3Institut Supérieur des Sciences de la Santé (INSSA), Université Nazi Boni, Dioulasso, Burkina Faso

Received: 30th March, 2024; Revised: 03rd May, 2024; Accepted: 20th May, 2024; Available Online: 25th June, 2024 

ABSTRACT

This study aimed to examine the influence of β cyclodextrin (βCD) and γ cyclodextrin (γCD) alone and in combination with L-lysine on ellagic acid (EA) solubility. Indeed, complexation with cyclodextrins can be used to improving the solubility of drugs poorly soluble in water such as EA. EA is a Biopharamceutical Classification System (BCS) IV bioactive polyphenol with numerous therapeutic activities, including antimalarial activities. However, its unfavorable physicochemical properties limit its therapeutic use. Therefore, after a phase solubility study, we successfully prepared EA-βCD and γ CD binary solid complexes using the freeze-drying technique. Methods including proton nuclear magnetic resonance (1H-NMR) analysis and fourier-transform infrared (FTIR) spectroscopy were used to characterize the inclusion behaviors of the complexes of EA with cyclodextrins both in solution and solid forms. The results of the phase solubility study indicated Ap-type diagrams of EA with the two cyclodextrins (CDs). The solubility of EA was multiplied by 9.92 and 2.98 in the presence of γCD and βCD respectively. Moreover, the complexes characterization by FTIR spectroscopy revealed the involvement of the C=O and EA OH groups in the interaction with the CDs. The results of NMR spectroscopic characterization revealed that the formation of EA inclusion complexes with βCD was partial. However, these results did not indicate the appearance of EA inclusion complexes with γCD. These relatively modest results in terms of increased EA solubility, obtained with cyclodextrins, prompted us to use a third compound, l-lysine, to enhance CDs complexation. Thus, the formation of ternary complexes led to a very significant increase EA solubility. Indeed, the incorporation of EA into EA-L-lysine-βCD and γ CD complexes increased its water solubility at pH 7.4 by a factor of 555 and 663, respectively.

Keywords: Antimalarial, L-lysine, Cyclodextrins, Ellagic acid, Solubility.

International Journal of Drug Delivery Technology (2024); DOI: 10.25258/ijddt.14.2.48

How to cite this article: Nyamba I, Sombie CB, Lechanteur A, Semde R, Evrard B. Potential of Native Cyclodextrins and L-Lysine for Enhancing Ellagic Acid Aqueous Solubility. International Journal of Drug Delivery Technology. 2024;14(2):925-931.

REFERENCES

  1. Word Malaria Report 2021. Word Malaria report Geneva: World Health Organization. (2021). Licence: CC. 2021. 2013–2015 p.
  2. Haidara M, Haddad M, Denou A, Marti G, Bourgeade-Delmas S, Sanogo R, et al. In-vivo validation of anti-malarial activity of crude extracts of Terminalia macroptera, a Malian medicinal Malar J [Internet]. 2018;17(1):1–10. Available from: https:// doi.org/10.1186/s12936-018-2223-7
  3. Kos J, Degotte G, Pindjakova D, Strharsky T, Jankech T, Gonec T, et Insights into Antimalarial Activity of N-Phenyl-Substituted Cinnamanilides. Molecules. 2022;27(22):7799.
  4. Aditya NP, Vathsala PG, Vieira V, Murthy RSR, Souto EB. Advances in nanomedicines for malaria treatment. Adv Colloid Interface Sci [Internet]. 2013;201–202:1–17.
  5. Uwimana A, Legrand E, Stokes BH, Ndikumana JLM, Warsame M, Umulisa N, et Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med. 2020;26(10):1602–8.
  6. Müller O, Lu GY, Von Seidlein L. Geographic expansion of artemisinin resistance. J Travel Med. 2019;26(4):1–6.
  7. Baudou E, Lespine A, Durrieu G, André F, Gandia P, Durand C, et c or r e sp ondence Deletion of. new engl J Med. 2020;February(Coorespondance):2008–9.
  8. Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, et al. In vitro and in-vivo properties of ellagic acid in malaria treatment. Antimicrob Agents Chemother. 2009;53(3):1100–6.
  9. Muganga R, Angenot L, Tits M, Frédérich In vitro and in-vivo antiplasmodial activity of three rwandan medicinal plants and identification of their active compounds. Planta Med. 2014;80(6):482–9.
  10. Seeram NP, Lee R, Heber Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta. 2004;348(1–2):63–8.
  11. Xiang Q, Li M, Wen J, Ren F, Yang Z, Jiang X, et al. The bioactivity and applications of pomegranate peel extract: A review. Vol. 46, Journal of Food Biochemistry. 2022.
  12. Li Y, Zhang Y, Dai W, Zhang Q. Enhanced oral absorption and anti-inflammatory activity of ellagic acid via a novel type of case in nanosheets constructed by simple coacervation. Int J Pharm [Internet]. 2021;594(November 2020):120131. Available from: https://doi.org/10.1016/j.ijpharm.2020.120131
  13. Zheng D, Lv C, Sun X, Wang J, Zhao Z. Preparation of a supersaturatable self-microemulsion as drug delivery system for ellagic acid and evaluation of its antioxidant activities. J Drug Deliv Sci Technol [Internet]. 2019;53(August):101209. Available from: https://doi.org/10.1016/j.jddst.2019.101209
  14. Nyamba I, Lechanteur A, Semdé R, Evrard B. Physical formulation approaches for improving aqueous solubility and bioavailability of ellagic acid: A Eur J Pharm Biopharm. 2021;159(November 2020):198–210.
  15. Nyamba I, Jennotte O, Sombié CB, Lechanteur A, Sacre PY, Djandé A, et al. Preformulation study for the selection of a suitable polymer for the development of ellagic acid-based solid dispersion using hot-melt Int J Pharm. 2023;641(May).
  16. Bijwar R, Tare H. Solubility and Taste Masked Behaviour of Cyclodextrin Molecular Inclusion Complex of Lumefantrin. 2023;3–7.
  17. Price DJ, Nair A, Kuentz M, Dressman J, Saal Calculation of drug- polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations. Eur J Pharm Sci [Internet]. 2019;132(February):142–56. Available from: https://doi.org/10.1016/j.ejps.2019.03.006
  18. Loftsson T, Brewster Pharmaceutical applications of cyclodextrins : 2010;1607–21.
  19. Bulani VD, Kothavade PS, Nagmoti DM, Kundaikar HS, Degani MS, Juvekar AR. Characterisation and anti-inflammatory evaluation of the inclusion complex of ellagic acid with hydroxypropyl-β-cyclodextrin. J Incl Phenom Macrocycl Chem [Internet]. 2015;82(3):361–72.
  20. Bulani VD, Kothavade PS, Kundaikar HS, Gawali NB, Chowdhury AA, Degani MS, et Inclusion complex of ellagic acid with β-cyclodextrin: Characterization and in vitro anti- inflammatory evaluation. J Mol Struct. 2016;1105:308–15.
  21. Xiao CF, Li K, Huang R, He GJ, Zhang JQ, Zhu L, et al. Investigation of inclusion complex of Epothilone A with cyclodextrins. Carbohydr Polym. 2014;102(1):297–305.
  22. Ribeiro A, Figueiras A, Santos D, Veiga Preparation and solid- state characterization of inclusion complexes formed between miconazole and methyl-β-cyclodextrin. AAPS PharmSciTech. 2008;9(4):1102–9.
  23. Koch N, Jennotte O, Gasparrini Y, Vandenbroucke F, Lechanteur A, Evrard B. Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers. Int J Pharm [Internet]. 2020;589(August):119812. Available from: https://doi. org/10.1016/j.ijpharm.2020.119812
  24. Zime-diawara H, Dive G, Moudachirou M, Frederich M, Evrard Understanding the interactions between artemisinin and cyclodextrins: spectroscopic studies and molecular modeling. 2012;305–15.
  25. Li H, Chang SL, Chang TR, You Y, Wang XD, Wang LW, et al. Inclusion complexes of cannabidiol with β-cyclodextrin and its derivative: Physicochemical properties, water solubility, and antioxidant J Mol Liq [Internet]. 2021;334:116070. Available from: https://doi.org/10.1016/j.molliq.2021.116070
  26. Muankaew C, Jansook P, Stefánsson E, Loftsson Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: Influence of pH and excipients. Int J Pharm [Internet]. 2014;474(1–2):80–90.
  27. Lv P, Zhang D, Guo M, Liu J, Chen X, Guo R, et al. Structural analysis and cytotoxicity of host-guest inclusion complexes of cannabidiol with three native cyclodextrins. J Drug Deliv Sci Technol [Internet]. 2019;51(February):337–44. Available from: https://doi.org/10.1016/j.jddst.2019.03.015
  28. Lu Y, Yang L, Zhang W, Xie S, Zhao F, Peng X, et al. Enhancement of the oral bioavailability of isopropoxy benzene guanidine though complexation with hydroxypropyl-β-cyclodextrin. Drug Deliv [Internet]. 2022;29(1):2824–30.
  29. Savic IM, Jocic E, Nikolic VD, Popsavin MM, Srdjan J, Savic- gajic IM, et The effect of complexation with cyclodextrins on the antioxidant and antimicrobial activity of ellagic acid. Pharm Dev Technol [Internet]. 2019;24(4):410–8. Available from: https:// doi.org/10.1080/10837450.2018.1502318
  30. Mura Analytical techniques for characterization of cyclodextrin complexes in aqueous solution: A review. J Pharm Biomed Anal [Internet]. 2014;101:238–50.
  31. Qiu N, Zhao X, Liu Q, Shen B, Liu J, Li X, et al. Inclusion complex of emodin with hydroxypropyl-β-cyclodextrin: Preparation, physicochemical and biological properties. J Mol Liq [Internet]. 2019;289:111151. Available from: https://doi. org/10.1016/j.molliq.2019.111151
  32. Li H, Zhao QS, Chang SL, Chang TR, Tan MH, Zhao B. Development of cannabidiol full-spectrum oil/2,6-di-O- methyl-β-cyclodextrin inclusion complex with enhanced water solubility, bioactivity, and thermal J Mol Liq [Internet]. 2022;347:118318. Available from: https://doi.org/10.1016/j. molliq.2021.118318
  33. Das S, Subuddhi U. Studies on the complexation of diclofenac sodium with β-cyclodextrin: Influence of method of J Mol Struct. 2015;1099:482–9.
  34. Elder DP, Holm R, De Diego HL. Use of pharmaceutical salts and cocrystals to address the issue of poor Int J Pharm [Internet]. 2013;453(1):88–100.
  35. STEPHENSON GA, ABURUB A, WOODS T. Physical Stability of Salts ofWeak Bases in the Solid-State. J Pharm Sci. 2012;101(7):2271–80.