Eplerenone Crystal Nanosuspension for Solubility Enhancement: Preparation and Evaluation

Authors

Hawraa k. Khafeef, Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, IraqFollow
Nawal A. Rajab, Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq

Abstract

Eplerenone is an aldosterone receptor inhibitor utilized for management of hypertension and chronic heart failure. However, it’s low solubility and dissolution-dependent absorption lead to reduced oral bioavailability (The absolute bioavailability of eplerenone is 69%). This study aimed to develop and optimize eplerenone nanosuspension (EPLNS) to enhance its solubility and improve dissolution rate. The nanosuspension (NS) was produced using the solvent anti-solvent precipitation method, and an investigation was conducted to assess the effect of variables such as stabilizer type, stabilizer concentration, and stirring rate on particle size (PS) and polydispersity index (PDI). The results showed that most of the prepared EPLNS formulations exhibited particle sizes in the nanoscale range. The optimized EPLNS formulation (F9), stabilized with tween 80 at an amount of 10 mg under a stirring rate of 1000 rpm, exhibited the minimum particle size (165.5 nm) and an appropriate PDI (0.2199). Moreover, this formulation displayed an enhanced dissolution velocity in phosphate buffer pH 6.8, with 92.5% drug release achieved within 15 minutes. The dissolution rate of the prepared EPLNS exhibited a significant enhancement when compared to that of the pure EPL powder.

Recommended Citation

Khafeef, Hawraa k. and Rajab, Nawal A. (2023) "Eplerenone Crystal Nanosuspension for Solubility Enhancement: Preparation and Evaluation," Maaen Journal for Medical Sciences: Vol. 2 : Iss. 2 , Article 6.
Available at: https://doi.org/10.55810/2789-9136.1024

References

1. Gao, L., et al., Application of drug nanocrystal technologies on oral drug delivery of poorly soluble drugs. Pharmaceutical research, 2013. 30: p. 307-324.

2. Chang, T.-L., et al., Nanocrystal technology for drug formulation and delivery. Frontiers of Chemical Science and Engineering, 2015. 9: p. 1-14.

3. Jamzad, S. and R. Fassihi, Role of surfactant and pH on dissolution properties of fenofibrate and glipizide—a technical note. Aaps Pharmscitech, 2006. 7: p. E17-E22.

4. KiMURA, K., et al., Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-β-cyclodextrin complex. Chemical and pharmaceutical bulletin, 2000. 48(5): p. 646-650.

5. Miao, X., et al., Investigation of nanosized crystalline form to improve the oral bioavailability of poorly water-soluble cilostazol. Journal of Pharmacy & Pharmaceutical Sciences, 2011. 14(2): p. 196-214.

6. Gigliobianco, M.R., et al., Nanocrystals of poorly soluble drugs: drug bioavailability and physicochemical stability. Pharmaceutics, 2018. 10(3): p. 134.

7. Mandal, B., K.S. Alexander, and A.T. Riga, Sulfacetamide loaded Eudragit RL100 nanosuspension with potential for ocular delivery. J Pharm Pharm Sci, 2010. 13(4): p. 510-523.

8. Gulsun, T., et al., Preparation and characterization of furosemide nanosuspensions. Journal of Drug Delivery Science and Technology, 2018. 45: p. 93-100.

9. Pınar, S.G., et al., Formulation Strategies of Nanosuspensions for Various Administration Routes. Pharmaceutics, 2023. 15(5): p. 1520.

10. Abdelhakeem, E., M. El-Nabarawi, and R. Shamma, Lipid-based nano-formulation platform for eplerenone oral delivery as a









potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment. Drug Delivery, 2021. 28(1): p. 642-654.

11. Weinberger, M.H., et al., Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. American journal of hypertension, 2002. 15(8): p. 709-716.

12. Chatziralli, I., et al., Eplerenone in the treatment of central serous chorioretinopathy: a review of the literature. International Journal of Retina and Vitreous, 2018. 4(1): p. 1-5.

13. .

14. Khames, A., Formulation and characterization of eplerenone nanoemulsion liquisolids, an oral delivery system with higher release rate and improved bioavailability. Pharmaceutics, 2019. 11(1): p. 40.

15. Lainscak, M., et al., Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone. International journal of cardiology, 2015. 200: p. 25-29.

16. Özdemir, S., et al., Eplerenone nanoemulsions for treatment of hypertension. Part I: experimental design for optimization of formulations and physical characterization. Journal of drug delivery science and technology, 2018. 45: p. 357-366.

17. Abdelhakeem, E., M. El-Nabarawi, and R. Shamma, Effective ocular delivery of eplerenone using nanoengineered lipid carriers in rabbit model. International Journal of Nanomedicine, 2021. 16: p. 4985.

18. Deniz, E., C. Toprak, and G. Gün, Investigation of Dry Granulation and Wet Granulation Effect on Dissolution Profile of the Developed Film Coated Tablets Containing Eplerenone. J Drug Res Dev, 2021. 7(2): p. 2470-1009.164.

19. Rashid, A.M. and S.N. Abd-Alhammid, Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi J Pharm Sci, 2019. 28(2): p. 124-133.

20. Sunil, R., et al., Effect of polymers on in-vitro performance of Eplerenone sustained release matrix tablets. Archives of Pharmacy Practice, 2012. 3(3): p. 223.

21. Dong, Y., et al., Preparation and characterization of spironolactone nanoparticles by antisolvent precipitation. International



journal of pharmaceutics, 2009. 375(1-2): p. 84-88.

22. Alwan, R.M. and N.A. Rajab, Nanosuspensions of Selexipag: Formulation, Characterization, and in vitro Evaluation. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512), 2021. 30(1): p. 144-153.

23. Gadad, A.P., et al., Rosuvastatin loaded nanostructured lipid carrier: For enhancement of oral bioavailability. Indian Journal of Pharmaceutical Education and Research, 2016. 50(4): p. 605-611.

24. Dabhi, M.R., et al., Formulation, optimization and characterization of candesartan cilexetil nanosuspension for in vitro dissolution enhancement. African Journal of Pharmacy and Pharmacology, 2015. 9(5): p. 102-113.

25. Sathukumati, A., N. Potnuri, and J. Sharma, Solubility and dissolution enhancement of eplerenone by using nanoprecipitation technique. Asian Journal of Science and Technology, 2020. 11(12): p. 11360-11367.

26. Patil, A.S., et al., Exploring the solvent-anti-solvent method of nanosuspension for enhanced oral bioavailability of lovastatin. Turkish Journal of Pharmaceutical Sciences, 2021. 18(5): p. 541.

27. Shariare, M.H., et al., The impact of process parameters on carrier free paracetamol nanosuspension prepared using different stabilizers by antisolvent precipitation method. Journal of Drug Delivery Science and Technology, 2018. 43: p. 122-128.

28. Hussein, A.A. and H.S. Mahmood, Preparation and evaluation of cefixime nanocrystals. Iraqi J Pharm Sci, 2014. 23(2): p. 1-12.

29. U.S. Food and Drug Administration. Eplerenone prescribing information [Internet]. Silver Spring, M.U.S.F.a.D.A.A.f.h.w.a.

30. Rajab, N.A., Z.E. Jassim, and A.M. Hameed, Preparation and characterization of lacidipine as an oral fast dissolving film. Journal of Pharmacy Research, 2018. 12(3): p. 321.

31. Kalvakuntla, S., et al., Preparation and characterization of nanosuspension of aprepitant by H96 process. Advanced Pharmaceutical Bulletin, 2016. 6(1): p. 83.

32. Sukmawati, A., et al. Effect of tween 80 on nanoparticle preparation of modified chitosan for targeted delivery of combination doxorubicin and curcumin analogue. in IOP Conference Series: Materials Science and Engineering. 2018. IOP Publishing.

33. Fan, W., et al., Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids and surfaces B: Biointerfaces, 2012. 90: p. 21-27.

34. Patil, O.A., et al., Formulation optimization and evaluation of Cefdinir nanosuspension using 23 Factorial design. Marmara Pharm J, 2018. 22(4): p. 587-598.

35. Mohamed, M.S., et al., Optimization, in-vitro release and in-vivo evaluation of gliquidone nanoparticles. AAPS PharmSciTech, 2020. 21: p. 1-12.

36. Bhargav, E., et al., A Design of Experiment (DoE) based approach for development and optimization of nanosuspensions of telmisartan, a BCS class II antihypertensive drug. Future Journal of Pharmaceutical Sciences, 2020. 6(1): p. 1-13.

37. Hashim, A.A.-J. and N.A. Rajab, Anastrozole Loaded Nanostructured Lipid Carriers: Preparation and Evaluation. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512), 2021. 30(2): p. 185-195.

38. Khan, M.A., et al., Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability. Drug Delivery, 2021. 28(1): p. 2510-2524.

39. Alhagiesa, A.W. and M.M. Ghareeb, The Formulation and Characterization of Nimodipine Nanoparticles for the Enhancement of solubility and dissolution rate. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512), 2021. 30(2): p. 143-152.