Skip to main content
SpringerLink
Log in

Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals—an In Vitro and In Vivo Evaluation

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication—anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. Harrison’s principles of internal medicine. 16th ed. New York: McGraw Hill; 2005.

    Google Scholar 

  2. Cugini P. The treatability of refractory or resistant hypertension by personalized antihypertensive chronotherapy based on ambulatory monitoring of the arterial pressure. Recent Prog Med. 1996;87:51–7.

    CAS  Google Scholar 

  3. Cugini P. Compliance and the chronotherapy of refractory arterial hypertension. Recent Prog Med. 1997;88:463–9.

    CAS  Google Scholar 

  4. Hermida RC, Calvo C, Ayala DE, Mojon A, Rodriguez M, Chayan L, et al. Administration time-dependent effects of valsartan on ambulatory blood pressure in elderly hypertensive subjects. Chronobiol Int. 2005;22:755–76.

    Article  CAS  PubMed  Google Scholar 

  5. Markham A, Goa KL, Valsartan. A review of its pharmacology and therapeutic use in essential hypertension. Drugs. 1997;54:299–311.

    Article  CAS  PubMed  Google Scholar 

  6. Nayak UY, Shavi GV, Nayak Y, Averinen RK, Mutalik S, Reddy SM, et al. Chronotherapeutic drug delivery for early morning surge in blood pressure: a programmable delivery system. J Control Rel. 2009;136(2):125–31.

    Article  CAS  Google Scholar 

  7. Sokar MS, Hanafy AS, El-Kamel AH, El-Gamal SS. Pulsatile core-in-cup valsartan tablet formulations: in vitro evaluation. Asian J Pharm Sci. 2013;8:234–43.

    Article  Google Scholar 

  8. Shah S, Patel R, Soniwala M, Chavda J. Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery. Drug Dev Ind Pharm. 2015;41:1835–46.

    Article  CAS  PubMed  Google Scholar 

  9. Brunella C, Cleelia DM, Maria I, Agnese M. Improvement of solubility and stability of valsartan by hydroxypropyl-β-cyclodextrin. J Incl Phenom Macro. 2006;54:289–94.

    Article  Google Scholar 

  10. Dressman JB, Reppas C. In vitro in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci. 2000;S2:S73–80.

    Article  Google Scholar 

  11. Crisp MT, Tucker CJ, Rogers TL, William RO, Johnston KP. Turbidimetric measurement and prediction of dissolution rate of poor soluble drug nanocrystals. J Control Release. 2007;117:351–9.

    Article  CAS  PubMed  Google Scholar 

  12. Jinno J, Kamada N, Miyaki M, Yamada K, Mukari T, Odomi M, et al. Effect of particle size reduction on dissolution and oral absorption of poor soluble drugs. J Control Release. 2006;111:56–64.

    Article  CAS  PubMed  Google Scholar 

  13. Park YJ, Lee HK, Im YB, Lee W, Han HK. Improved pH-independent dissolution and oral absorption of valsartan via the preparation of solid dispersion. Arch Pharm Res. 2010;33(8):1235–40.

    Article  CAS  PubMed  Google Scholar 

  14. Yan YD, Sung JH, Kim KK, Kim DW, Kim JO, Lee BJ, et al. Novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes. Int J Pharm. 2012;422:202–10.

    Article  CAS  PubMed  Google Scholar 

  15. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125:91–7.

    Article  CAS  Google Scholar 

  16. Guo Z, Zhang M, Li H, Wang J, Kougoulos E. Effect of ultrasound on antisolvent crystallization process. J Cryst Growth. 2005;273:555–63.

    Article  CAS  Google Scholar 

  17. Kaerger JS, Price R. Processing of spherical crystalline particles via a novel solution atomization and crystallization by sonication (SAXS) technique. Pharm Res. 2004;21:372–81.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang H, Hollis CP, Zhang Q, Li T. Preparation and antitumor study of camptothecin nanocrystals. Int J Pharm. 2011;415:293–300.

    Article  CAS  PubMed  Google Scholar 

  19. US Department of Health and Human Services, Food and Drug Administration. Guidance for industry: bioanalytical method validation. Rockville: Centre for Drugevaluation and Research; 2001.

    Google Scholar 

  20. Gao L, Zhang D, Chen M, Zheng T, Wang S. Preparation and characterization of an oridonin nanosuspension for solubility and dissolution velocity enhancement. Drug Dev Ind Pharm. 2007;33:1332–9.

    Article  CAS  PubMed  Google Scholar 

  21. Deng J, Huang L, Liu F. Understanding the structure and stability of paclitaxel nanocrystals. Int J Pharm. 2010;390:242–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Deng Z, Xu S, Li S. Understanding a relaxation behavior in a nanoparticle suspension for drug delivery applications. Int J Pharm. 2008;351:236–43.

    Article  CAS  PubMed  Google Scholar 

  23. Müller RH. Zetapotential und Partikeladung in der Laborpraxis. Suttgart: Wissenschaftliche Verlagsgeselschaft mbH; 1996.

    Google Scholar 

  24. Riddick TM. Zeta-meter manual. New York: Zeta-Meter Inc.; 1968.

    Google Scholar 

  25. Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov. 2004;3:785–96.

    Article  CAS  PubMed  Google Scholar 

  26. Xia DN, Quan P, Piao HZ. Preparation of stable nitrendipine nanosuspensions using the precipitation ultrasonication method for enhancement of dissolution and oral bioavailability. Eur J Pharm Sci. 2010;40:325–34.

    Article  CAS  PubMed  Google Scholar 

  27. Xu Y, Liu XY, Lian RY. Enhanced dissolution and oral bioavailability of aripiprazole nanosuspensions prepared by nano-precipitation/homogenization based on acid-base neutralization. Int J Pharm. 2012;438:287–95.

    Article  CAS  PubMed  Google Scholar 

  28. Joe JH, Lee WM, Park YJ, Joe KH, Oh DH, Seo YG, et al. Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus. Int J Pharm. 2010;395:161–6.

    Article  CAS  PubMed  Google Scholar 

  29. Oh DH, Park YJ, Kang JH, Yong CS, Choi HG. Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change. Drug Deliv. 2011;18:46–53.

    Article  CAS  PubMed  Google Scholar 

  30. Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.

    Article  Google Scholar 

  31. Gonnissen Y, Remon JP, Vervaet C. Effect of maltodextrin and superdisintegrant in directly compressible powder mixtures prepared via co-spray drying. Eur J Pharm Biopharm. 2008;68:277–82.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Wang J, Bai X, Jiang T, Zhang Q, Wang S. Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs. Mol Pharm. 2012;9:505–13.

    Article  CAS  PubMed  Google Scholar 

  33. Clark M, Jepson MA, Hirst BH. Exploiting M cells for drug and vaccine delivery. Adv Drug Deliv Rev. 2001;50:81–106.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We greatly acknowledge the Department of Science & Technology, Delhi (SR/FT/LS-21/2011) for funding this research. We would also like to thank BASF, USA and Ranbaxy Laboratories Ltd., India, for their free gift samples.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, 700032

    Nikhil Biswas & Ketousetuo Kuotsu

Authors
  1. Nikhil Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ketousetuo Kuotsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ketousetuo Kuotsu.

Ethics declarations

The study protocol was reviewed and approved by the Institutional Ethics Committee, Jadavpur University, Kolkata.

Conflict of Interest

The authors report no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Biswas, N., Kuotsu, K. Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals—an In Vitro and In Vivo Evaluation. AAPS PharmSciTech 18, 349–357 (2017). https://doi.org/10.1208/s12249-016-0511-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0511-5

KEY WORDS

Search

Navigation