Advertisement

AAPS PharmSciTech

, Volume 19, Issue 3, pp 1191–1204 | Cite as

Antioxidant-Based Eutectics of Irbesartan: Viable Multicomponent Forms for the Management of Hypertension

  • Jamshed Haneef
  • Renu Chadha
Research Article

Abstract

The present research work highlights the development of multicomponent solid form of the antihypertensive drug irbesartan (IRB) to improve its biopharmaceutical attributes. Mechanochemical synthesis of a new solid form of IRB with coformers having antioxidant properties (syringic acid, nicotinic acid, and ascorbic acid) resulted into three eutectic mixtures (EMs). Formation of eutectic was ascertained by differential scanning calorimetry whereas exact stoichiometry (50/50% w/w) was established by phase diagram and Tamman’s triangle. The strong homomeric interaction between individual components and steric hindrances is responsible for the eutectic formation. EMs exhibited superior apparent solubility (five- to nine fold) and significant enhancement in intrinsic dissolution rate (two- to three fold) as compared to the plain drug. In vivo pharmacokinetic and in vivo pharmacodynamic studies revealed a significant improvement in the biopharmaceutical performance of EMs. Marked protection against oxidative stress was observed in EMs over plain drug by controlling the level/activity of plasma H2O2 and antioxidant enzymes (superoxide dismutase and catalase) in the kidney matrix of dexamethasone (Dexa)-induced hypertensive rats. Thus, these solid forms of IRB can serve as viable multicomponent forms to be translated into product development for better therapeutic efficacy in the management of hypertension.

KEY WORDS

antihypertensive bioavailability eutectic mixtures mechanochemical synthesis oxidative stress 

Notes

Acknowledgements

The author Mr. Jamshed Haneef gratefully acknowledges the financial support from the Department of Science and Technology (DST), Ministry of Science & Technology, New Delhi, India, in the form of Inspire Fellowship (vide letter no. 2012/687) to carry out this research work. The authors highly acknowledge the services provided by the Sophisticated Analytical Instrumentation Facility (SAIF), Panjab University, India, to carry out the samples analysis. We are also thankful to Dr. B.N.Datta, Formerly Professor of Pathology at PGIMER, Chandigarh, India, for his expert guidance in the interpretation of histopathological results of kidney tissue.

Compliance with Ethical Standards

All the animal studies protocol was approved by Institutional Animal Ethics Committee, Panjab University, Chandigarh, India (PU/IAES/S/14/77).

Supplementary material

12249_2017_930_MOESM1_ESM.docx (1.4 mb)
ESM 1 (DOCX 1440 kb)

References

  1. 1.
    Almarsson O, Zaworotko MJ. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? ChemCommun. 2004;17:1889–96.Google Scholar
  2. 2.
    Desiraju GR. Crystal engineering: a holistic view. Angew Chem Int Ed Engl. 2007;46(44):8342–56.  https://doi.org/10.1002/anie.200700534.CrossRefPubMedGoogle Scholar
  3. 3.
    Cherukuvada S, Nangia A. Eutectics as improved pharmaceutical materials: design, properties and characterization. Chem Commun. 2014;50(8):906–23.  https://doi.org/10.1039/C3CC47521B.CrossRefGoogle Scholar
  4. 4.
    Chadha R, Sharma M, Haneef J. Multicomponent solid forms of felodipine: preparation, characterisation, physicochemical and in-vivo studies. J Pharm Pharmacol. 2017;69(3):254–64.  https://doi.org/10.1111/jphp.12685.CrossRefPubMedGoogle Scholar
  5. 5.
    Cherukuvada S, Guru Row TN. Comprehending the formation of eutectics and cocrystals in terms of design and their structural interrelationships. Cryst Growth Des. 2014;14(8):4187–98.  https://doi.org/10.1021/cg500790q.CrossRefGoogle Scholar
  6. 6.
    Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodriguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453(1):101–25.  https://doi.org/10.1016/j.ijpharm.2012.10.043.CrossRefPubMedGoogle Scholar
  7. 7.
    Duggirala NK, Perry ML, Almarsson O, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun. 2016;52(4):640–55.  https://doi.org/10.1039/C5CC08216A.CrossRefGoogle Scholar
  8. 8.
    Kuminek G, Cao F, Bahia de Oliveira da Rocha A, Goncalves Cardoso S, Rodriguez-Hornedo N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5. Adv Drug Deliv Rev. 2016;101:143–66.  https://doi.org/10.1016/j.addr.2016.04.022.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today. 2016;21(3):481–90.  https://doi.org/10.1016/j.drudis.2016.02.001.CrossRefPubMedGoogle Scholar
  10. 10.
    Thipparaboina R, Thumuri D, Chavan R, Naidu VGM, Shastri NR. Fast dissolving drug-drug eutectics with improved compressibility and synergistic effects. Eur J Pharm Sci. 2017;104:82–9.  https://doi.org/10.1016/j.ejps.2017.03.042.CrossRefPubMedGoogle Scholar
  11. 11.
    Goud NR, Suresh K, Sanphui P, Nangia A. Fast dissolving eutectic compositions of curcumin. Int J Pharm. 2012;439(1-2):63–72.  https://doi.org/10.1016/j.ijpharm.2012.09.045.CrossRefPubMedGoogle Scholar
  12. 12.
    Chadha K, Karan M, Chadha R, Bhalla Y, Vasisht K. Is Failure of cocrystallization actually a failure? Eutectic formation in cocrystal screening of hesperetin. J Pharm Sci. 2017;106(8):2026–36.  https://doi.org/10.1016/j.xphs.2017.04.038.CrossRefPubMedGoogle Scholar
  13. 13.
    Jain H, Khomane KS, Bansal AK. Implication of microstructure on the mechanical behaviour of an aspirin-paracetamol eutectic mixture. CrystEngComm. 2014;16(36):8471–8.  https://doi.org/10.1039/C4CE00878B.CrossRefGoogle Scholar
  14. 14.
    Sathisaran I, Dalvi SV. Crystal engineering of curcumin with salicylic acid and hydroxyquinol as coformers. Cryst Growth Des. 2017;17(7):3974–88.  https://doi.org/10.1021/acs.cgd.7b00599.CrossRefGoogle Scholar
  15. 15.
    Haneef J, Chadha R. Drug-drug multicomponent solid forms: cocrystal, coamorphous and eutectic of three poorly soluble antihypertensive drugs using mechanochemical approach. AAPS PharmSciTech. 2017;18(6):2279–90.  https://doi.org/10.1208/s12249-016-0701-1.CrossRefPubMedGoogle Scholar
  16. 16.
    Angell SY, De Cock KM, Frieden TR. A public health approach to global management of hypertension. Lancet. 2015;385(9970):825–7.  https://doi.org/10.1016/S0140-6736(14)62256-X.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    www.products.sanofi.ca. Product Monograph Avapro (irbesartan). Sanofi-aventis Canada Inc.; [cited accessed 01.08.16]; Available from: http://products.sanofi.ca/en/avapro.pdf.
  18. 18.
    Chawla G, Bansal AK. Improved dissolution of a poorly water soluble drug in solid dispersions with polymeric and non-polymeric hydrophilic additives. Acta Pharma. 2008;58:257–74.CrossRefGoogle Scholar
  19. 19.
    Chawla G, Bansal AK. A comparative assessment of solubility advantage from glassy and crystalline forms of a water-insoluble drug. Eur J Pharm Sci. 2007;32(1):45–57.  https://doi.org/10.1016/j.ejps.2007.05.111.CrossRefPubMedGoogle Scholar
  20. 20.
    Antoncic, Ljubljana, inventors; Polymorphic form of irbesartan patent A1 2006/050923. 2006 May 18.Google Scholar
  21. 21.
    Jacewicz V, inventor Mesylate salts of irbesartan and their preparation and pharmaceutical compositions patent A1 087399. 2008.Google Scholar
  22. 22.
    Jacewicz V, inventor Tosylate salts of irbesartan and their preparation and pharmaceutical compositions patent A1 087397. 2008.Google Scholar
  23. 23.
    Serajuddin ATM, Sheen P-C, Mufson D, Bernstein DF, Augustine MA. Preformulation study of a poorly water-soluble drug, alpha-Pentyl-3-(2-quinolinylmethoxy) benzenemethanol: selection of the base for dosage form design. J Pharm Sci. 1986;75(5):492–6.  https://doi.org/10.1002/jps.2600750514.CrossRefPubMedGoogle Scholar
  24. 24.
    Redon J, Oliva MR, Tormos C, Giner V, Chaves J, Iradi A, et al. Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension. 2003;41(5):1096–101.  https://doi.org/10.1161/01.HYP.0000068370.21009.38.CrossRefPubMedGoogle Scholar
  25. 25.
    Baradaran A, Nasri H, Rafieian-Kopaei M. Oxidative stress and hypertension: possibility of hypertension therapy with antioxidants. J Res Med Sci. 2014;19(4):358–67.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Houston M. Nutrition and nutraceutical supplements for the treatment of hypertension: part I. J Clin Hypertens. 2013;15:752–7.Google Scholar
  27. 27.
    Kizhakekuttu TJ, Widlansky ME. Natural antioxidants and hypertension: promise and challenges. Cardiovasc Ther. 2010;28(4):e20–32.  https://doi.org/10.1111/j.1755-5922.2010.00137.x.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Harrison DG, Gongora MC. Oxidative stress and hypertension. Med Clin North Am. 2009;93(3):621–35.  https://doi.org/10.1016/j.mcna.2009.02.015.CrossRefPubMedGoogle Scholar
  29. 29.
    Touyz RM, Briones AM. Reactive oxygen species and vascular biology: implications in human hypertension. Hypertens Res. 2011;34(1):5–14.  https://doi.org/10.1038/hr.2010.201.CrossRefPubMedGoogle Scholar
  30. 30.
    Varughese S, Sinha SB, Desiraju GR. Phenylboronic acids in crystal engineering: utility of the energetically unfavorable syn,syn-conformation in co-crystal design. Sci China Chem [journal article]. 2011;54(12):1909–19.  https://doi.org/10.1007/s11426-011-4412-x.CrossRefGoogle Scholar
  31. 31.
    Kumar S, Prahalathan P, Raja B. Syringic acid ameliorates (L)-NAME-induced hypertension by reducing oxidative stress. Naunyn Schmiedeberg's Arch Pharmacol. 2012;385(12):1175–84.  https://doi.org/10.1007/s00210-012-0802-7.CrossRefGoogle Scholar
  32. 32.
    Rodrigo R, Prat H, Passalacqua W, Araya J, Bachler JP. Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension. Clin Sci (Lond). 2008;114(10):625–34.  https://doi.org/10.1042/CS20070343.CrossRefGoogle Scholar
  33. 33.
    Ganji SH, Qin S, Zhang L, Kamanna VS, Kashyap ML. Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. Atherosclerosis. 2009;202(1):68–75.  https://doi.org/10.1016/j.atherosclerosis.2008.04.044.CrossRefPubMedGoogle Scholar
  34. 34.
    Ong SL, Zhang Y, Sutton M, Whitworth JA. Hemodynamics of dexamethasone-induced hypertension in the rat. Hypertens Res. 2009;32(10):889–94.  https://doi.org/10.1038/hr.2009.118.CrossRefPubMedGoogle Scholar
  35. 35.
    Gay C, Collins J, Gebicki JM. Hydroperoxide assay with the ferric-xylenol orange complex. Anal Biochem. 1999;273(2):149–55.  https://doi.org/10.1006/abio.1999.4208.CrossRefPubMedGoogle Scholar
  36. 36.
    Kono Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. 1978;186(1):189–95.  https://doi.org/10.1016/0003-9861(78)90479-4.CrossRefPubMedGoogle Scholar
  37. 37.
    Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47(2):389–94.  https://doi.org/10.1016/0003-2697(72)90132-7.CrossRefPubMedGoogle Scholar
  38. 38.
    Avula SGC, Alexander K, Riga A. Thermal analytical characterization of mixtures of antipsychotic drugs with various excipients for improved drug delivery. J Therm Anal Calorim. 2016;123(3):1981–92.  https://doi.org/10.1007/s10973-015-4763-1.CrossRefGoogle Scholar
  39. 39.
    Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.CrossRefPubMedGoogle Scholar
  40. 40.
    Lassegue B, Griendling KK. Reactive oxygen species in hypertension; An update. Am J Hypertens. 2004;17(9):852–60.  https://doi.org/10.1016/j.amjhyper.2004.02.004.CrossRefPubMedGoogle Scholar
  41. 41.
    Taguchi I, Toyoda S, Takano K, Arikawa T, Kikuchi M, Ogawa M, et al. Irbesartan, an angiotensin receptor blocker, exhibits metabolic, anti-inflammatory and antioxidative effects in patients with high-risk hypertension. Hypertens Res. 2013;36(7):608–13.  https://doi.org/10.1038/hr.2013.3.CrossRefPubMedGoogle Scholar
  42. 42.
    Araujo M, Wilcox CS. Oxidative stress in hypertension: role of the kidney. Antioxid Redox Signal. 2014;20(1):74–101.  https://doi.org/10.1089/ars.2013.5259.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    James SL, Adams CJ, Bolm C, Braga D, Collier P, Friscic T, et al. Mechanochemistry: opportunities for new and cleaner synthesis. Chem Soc Rev. 2012;41(1):413–47.  https://doi.org/10.1039/C1CS15171A.CrossRefPubMedGoogle Scholar
  44. 44.
    Friscic T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009;9(3):1621–37.  https://doi.org/10.1021/cg800764n.CrossRefGoogle Scholar
  45. 45.
    Das SS, Singh NP, Agrawal T, Gupta P, Tiwari SN, Singh NB. Studies of solidification behavior and molecular interaction in benzoic acid-o-chloro benzoic acid eutectic system. Mol Cryst Liq Cryst. 2009;501(1):107–24.  https://doi.org/10.1080/15421400802697350.CrossRefGoogle Scholar
  46. 46.
    Taulelle P, Astier JP, Hoff C, Pèpe G, Veesler S. Pharmaceutical compound crystallization: growth mechanism of needle-like crystals. Chem Eng Technol. 2006;29(2):239–46.  https://doi.org/10.1002/ceat.200500361.CrossRefGoogle Scholar
  47. 47.
    Maheshwari C, Andre V, Reddy S, Roy L, Duarte T, Rodriguez-Hornedo N. Tailoring aqueous solubility of a highly soluble compound via cocrystallization: effect of coformer ionization, pHmax and solute-solvent interactions. Cryst Eng Comm. 2012;14(14):4801–11.  https://doi.org/10.1039/c2ce06615g.CrossRefGoogle Scholar
  48. 48.
    Sanphui P, Rajput L. Tuning solubility and stability of hydrochlorothiazide co-crystals. Acta Cryst. 2014;B70:81–90.Google Scholar
  49. 49.
    Crawford DE, Casaban J. Recent developments in mechanochemical materials synthesis by extrusion. Adv Mater. 2016;28(27):5747–54.  https://doi.org/10.1002/adma.201505352.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced StudiesPanjab UniversityChandigarhIndia

Personalised recommendations