Skip to main content
SpringerLink
Log in

Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and −23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model.

Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Muller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001;47:3–19.

    Article  CAS  PubMed  Google Scholar 

  3. Junghanns JU, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3:295–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Miyako Y, Khalef N, Matsuzaki K, Pinal R. Solubility enhancement of hydrophobic compounds by cosolvents: role of solute hydrophobicity on the solubilization effect. Int J Pharm. 2010;393:48–54.

    Article  CAS  PubMed  Google Scholar 

  5. Joshi HN, Tejwani RW, Davidovich M, Sahasrabudhe VP, Jemal M, Bathala MS, et al. Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture. Int J Pharm. 2004;269:251–8.

    Article  CAS  PubMed  Google Scholar 

  6. Ben Zirar S, Astier A, Muchow M, Gibaud S. Comparison of nanosuspensions and hydroxypropyl-beta-cyclodextrin complex of melarsoprol: pharmacokinetics and tissue distribution in mice. Eur J Pharm Biopharm. 2008;70:649–56.

    Article  CAS  PubMed  Google Scholar 

  7. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release. 2001;73:137–72.

    Article  CAS  PubMed  Google Scholar 

  8. Kawakami K, Oda N, Miyoshi K, Funaki T, Ida Y. Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents. Eur J Pharm Sci. 2006;28:7–14.

    Article  CAS  PubMed  Google Scholar 

  9. Chakraborty S, Shukla D, Mishra B, Singh S. Lipid—an emerging platform for oral delivery of drugs with poor bioavailability. Eur J Pharm Biopharm. 2009;73:1–15.

    Article  CAS  PubMed  Google Scholar 

  10. Ravichandran R. Nanotechnology-based drug delivery systems. NanoBiotechnology. 2009;5:17–33.

    Article  CAS  Google Scholar 

  11. Willems L, van der Geest R, de Beule K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther. 2001;26:159–69.

    Article  CAS  PubMed  Google Scholar 

  12. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590–8.

    Article  CAS  PubMed  Google Scholar 

  13. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol. 1993;20:1–15.

    CAS  PubMed  Google Scholar 

  14. Jain S, Sharma JM, Agrawal AK, Mahajan RR. Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement. J Biomed Nanotechnol. 2013;9:1862–74.

    Article  CAS  PubMed  Google Scholar 

  15. Jain S, Sharma JM, Jain AK, Mahajan RR. Surface-stabilized lopinavir nanoparticles enhance oral bioavailability without coadministration of ritonavir. Nanomedicine (Lond). 2013;8:1639–55.

    Article  CAS  Google Scholar 

  16. Abrahamsson B, Odman J. Candesartan or candesartan cilexetil; improved bioavailability. In.: Google Patents; 2007.

  17. Hoppe K, Sznitowska M. The effect of polysorbate 20 on solubility and stability of candesartan cilexetil in dissolution media. AAPS PharmSciTech. 2014;15:1116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Satturwar P, Eddine MN, Ravenelle F, Leroux JC. pH-responsive polymeric micelles of poly(ethylene glycol)-b-poly(alkyl(meth)acrylate-co-methacrylic acid): influence of the copolymer composition on self-assembling properties and release of candesartan cilexetil. Eur J Pharm Biopharm. 2007;65:379–87.

    Article  CAS  PubMed  Google Scholar 

  19. Nekkanti V, Karatgi P, Prabhu R, Pillai R. Solid self-microemulsifying formulation for candesartan cilexetil. AAPS PharmSciTech. 2010;11:9–17.

    Article  CAS  PubMed  Google Scholar 

  20. Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation. Drug Deliv. 2014;1–10.

  21. Zhang Z, Gao F, Bu H, Xiao J, Li Y. Solid lipid nanoparticles loading candesartan cilexetil enhance oral bioavailability: in vitro characteristics and absorption mechanism in rats. Nanomedicine. 2012;8:740–7.

    CAS  PubMed  Google Scholar 

  22. Shaikh SM, Avachat AM. Enhancement of solubility and permeability of candesartan cilexetil by using different pharmaceutical interventions. Curr Drug Deliv. 2011;8:346–53.

    Article  CAS  PubMed  Google Scholar 

  23. Gurunath S, Nanjwade BK, Patila PA. Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs. Saudi Pharm J. 2014;22:246–57.

    Article  CAS  PubMed  Google Scholar 

  24. Detroja C, Chavhan S, Sawant K. Enhanced antihypertensive activity of candesartan cilexetil nanosuspension: formulation, characterization and pharmacodynamic study. Sci Pharm. 2011;79:635–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nekkanti V, Pillai R, Venkateshwarlu V, Harisudhan T. Development and characterization of solid oral dosage form incorporating candesartan nanoparticles. Pharm Dev Technol. 2009;14:290–8.

    Article  CAS  PubMed  Google Scholar 

  26. Vaculikova E, Grunwaldova V, Kral V, Dohnal J, Jampilek J. Preparation of candesartan and atorvastatin nanoparticles by solvent evaporation. Molecules. 2012;17:13221–34.

    Article  CAS  PubMed  Google Scholar 

  27. Van Eerdenbrugh B, Vermant J, Martens JA, Froyen L, Van Humbeeck J, Augustijns P, et al. A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci. 2009;98:2091–103.

    Article  PubMed  Google Scholar 

  28. Jain S, Chauhan D, Jain A, Swarnakar N, Harde H, Mahajan R, Kumar D, Valvi P, Das M, Datir S. Stabilization of the nanodrug delivery systems by lyophilization using universal step-wise freeze drying cycle. Indian Patent Application No 2559/DEL. 2011 filed on September. 2011;6.

  29. Zhou L, Yang L, Tilton S, Wang J. Development of a high throughput equilibrium solubility assay using miniaturized shake-flask method in early drug discovery. J Pharm Sci. 2007;96:3052–71.

    Article  CAS  PubMed  Google Scholar 

  30. Yanni S, Thakker DR. Prodrugs: absorption, distribution, metabolism, excretion (ADME) issues. In. Prodrugs: Springer; 2007. p. 1043–81.

  31. Kakran M, Shegokar R, Sahoo NG, Gohla S, Li L, Müller RH. Long‐term stability of quercetin nanocrystals prepared by different methods. J Pharm Pharmacol. 2012;64:1394–402.

    Article  CAS  PubMed  Google Scholar 

  32. Dahan A, Miller JM, Hilfinger JM, Yamashita S, Yu LX, Lennernas H, et al. High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations. Mol Pharm. 2010;7:1827–34.

    Article  CAS  PubMed  Google Scholar 

  33. Jain AK, Thanki K, Jain S. Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity. Mol Pharm. 2013;10:3459–74.

    Article  CAS  PubMed  Google Scholar 

  34. Swarnakar NK, Thanki K, Jain S. Lyotropic liquid crystalline nanoparticles of CoQ10: implication of lipase digestibility on oral bioavailability, in vivo antioxidant activity, and in vitro-in vivo relationships. Mol Pharm. 2014;11:1435–49.

    Article  CAS  PubMed  Google Scholar 

  35. Oh D-M, Curl RL, Yong C-S, Amidon GL. Effect of micronization on the extent of drug absorption from suspensions in humans. Arch Pharm Res. 1995;18:427–33.

    Article  CAS  Google Scholar 

  36. Lobenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm. 2000;50:3–12.

    Article  CAS  PubMed  Google Scholar 

  37. Qian F, Tao J, Desikan S, Hussain M, Smith RL. Mechanistic investigation of Pluronic based nano-crystalline drug-polymer solid dispersions. Pharm Res. 2007;24:1551–60.

    Article  CAS  PubMed  Google Scholar 

  38. Mullin JW. Crystallization. Oxford, UK: Butterworth-Heinemann; 2001.

  39. Weinberg M. A few topics concerning nucleation and crystallization in glasses. J Non-Cryst Solids. 1999;255:1–14.

    Article  CAS  Google Scholar 

  40. Kamalakkannan V, Puratchikody A, Ramanathan L. Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion. Res Pharm Sci. 2013;8:125–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shchekin A, Rusanov A. Generalization of the Gibbs–Kelvin–Köhler and Ostwald–Freundlich equations for a liquid film on a soluble nanoparticle. J Chem Phys. 2008;129:154116.

    Article  CAS  PubMed  Google Scholar 

  42. Mller RH, Akkar A. Drug nanocrystals of poorly soluble drugs. In. Encyclopedia of nanoscience and nanotechnology. Steveson Ranch, USA: American Scientific Publishers; 2004. p. 627–38.

  43. Mosharraf M, Nyström C. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int J Pharm. 1995;122:35–47.

    Article  CAS  Google Scholar 

  44. Hasegawa Y, Higashi K, Yamamoto K, Moribe K. Direct evaluation of molecular states of piroxicam/poloxamer nanosuspension by suspended-state NMR and Raman spectroscopies. Mol Pharm. 2015;12:1564–72.

    Article  CAS  PubMed  Google Scholar 

  45. Wei CC, Ge ZQ. Influence of electrolyte and poloxamer 188 on the aggregation kinetics of solid lipid nanoparticles (SLNs). Drug Dev Ind Pharm. 2012;38:1084–9.

    Article  CAS  PubMed  Google Scholar 

  46. Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991;175:880–5.

    Article  CAS  PubMed  Google Scholar 

  47. Sun D, Yu LX, Hussain MA, Wall DA, Smith RL, Amidon GL. In vitro testing of drug absorption for drug ‘developability’ assessment: forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel. 2004;7:75–85.

    CAS  PubMed  Google Scholar 

  48. Hecq J, Nollevaux G, Deleers M, Fanara D, Vranckx H, Peulen O, et al. Nifedipine nanocrystals: pharmacokinetic evaluation in the rat and permeability studies in Caco-2/HT29-5M21 (co)-cultures. J Drug Delivery Sci Technol. 2006;16:437–42.

    Article  CAS  Google Scholar 

  49. Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci. 2015;10:13–23.

    Article  Google Scholar 

  50. Ahuja BK, Jena SK, Paidi SK, Bagri S, Suresh S. Formulation, optimization and in vitro-in vivo evaluation of febuxostat nanosuspension. Int J Pharm. 2015;478:540–52.

    Article  CAS  PubMed  Google Scholar 

  51. Cai Z, Wang Y, Zhu LJ, Liu ZQ. Nanocarriers: a general strategy for enhancement of oral bioavailability of poorly absorbed or pre-systemically metabolized drugs. Curr Drug Metab. 2010;11:197–207.

    Article  CAS  PubMed  Google Scholar 

  52. Thanki K, Gangwal RP, Sangamwar AT, Jain S. Oral delivery of anticancer drugs: challenges and opportunities. J Control Release. 2013;170:15–40.

    Article  CAS  PubMed  Google Scholar 

  53. Wei Z, Yuan S, Hao J, Fang X. Mechanism of inhibition of P-glycoprotein mediated efflux by Pluronic P123/F127 block copolymers: relationship between copolymer concentration and inhibitory activity. Eur J Pharm Biopharm. 2013;83:266–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to the Director, NIPER, for providing necessary infrastructure facilities. Authors also thank Rahul R Mahajan for providing technical assistance with scanning electron microscopy.

Author information

Author notes

    Authors and Affiliations

    1. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar (Mohali), Punjab, 160062, India

      Sanyog Jain, Venkata Appa Reddy, Sumit Arora & Kamlesh Patel

    Authors
    1. Sanyog Jain
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Venkata Appa Reddy
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Sumit Arora
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Kamlesh Patel
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Sanyog Jain.

    Ethics declarations

    Conflict of interest

    There is no conflict of interest during the execution of the research work undertaken as well as during the preparation of manuscript.

    Additional information

    Sanyog Jain and Venkata Appa Reddy contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jain, S., Reddy, V.A., Arora, S. et al. Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability. Drug Deliv. and Transl. Res. 6, 498–510 (2016). https://doi.org/10.1007/s13346-016-0297-8

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13346-016-0297-8

    Keywords

    Search

    Navigation