Drug Delivery and Translational Research

, Volume 9, Issue 5, pp 867–878 | Cite as

Effect of formulation parameters on pharmacokinetics, pharmacodynamics, and safety of diclofenac nanomedicine

  • Dhanya Narayanan
  • Gopikrishna J. Pillai
  • Shantikumar V. NairEmail author
  • Deepthy MenonEmail author
Original Article


This study reports the development of a nanoformulation of diclofenac sodium, a potent non-steroidal anti-inflammatory drug, at its clinical dose, utilizing a FDA approved polymer, hydroxyethyl starch. The study specifically focused on the control of pharmacokinetics, pharmacodynamics, and biodistribution by particle surface functionalization and alteration of excipient levels in the final formulation. Stable diclofenac sodium–loaded hydroxyethyl starch nanoparticles (nanodiclo) of size 170 ± 5 nm and entrapment efficiency 72 ± 3% were prepared. Free diclofenac, nanodiclo, nanodiclo surface functionalized by PEGylation, nanodiclo with excipients removed, and finally PEGylated nanodiclo with excipients removed were all tested comparatively at two different doses. The results showed substantial impact of both excipients and PEGylation on the pharmacokinetics and pharmacodynamics in vivo. Further, the results proved that excipient removed PEGylated nanodiclo at lower dose achieved clinical therapeutic levels in blood for up to 120 h, with minimal accumulation in critical organs, and much better efficacy than other controls.


Diclofenac sodium Excipients Hydroxyethyl starch nanoparticles Pharmacokinetics Pharmacodynamics 



Authors gratefully acknowledge Centre for Nanosciences and Molecular Medicine, Amrita Viswavidyapeetham, for providing the infrastructure for the successful completion of this work. Thanks to Themis Medicare for providing the drug diclofenac sodium, to Mr. Sajin P Ravi for SEM analysis, and to Dr. AKK Unni, Dr. Reshmi P, Mr. Sunil, Mr. Sajith, and Mrs. Sunitha for their help with animal studies.

Compliance with ethical standards

All institutional and national guidelines for the care and use of laboratory animals were followed. The experiments comply with the current laws of the country in which they were performed. All animal experiments were carried out after obtaining ethical approval from the Institutional Animal Ethical Committee of Amrita Institute of Medical Sciences & Research Centre, Kochi, India.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13346_2018_614_MOESM1_ESM.docx (29 kb)
ESM 1 (DOCX 28 kb)


  1. 1.
    Kean WF, Buchanan WW. The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacology. 2005;13:343–70.CrossRefPubMedGoogle Scholar
  2. 2.
    Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18–24.PubMedGoogle Scholar
  3. 3.
    Carson J, Notis WM, Orris ES. Colonic ulceration and bleeding during diclofenac therapy. N Engl J Med. 1989;323:135–7.Google Scholar
  4. 4.
    Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96:7563–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Willis JV, Kendall MJ, Flinn RM, Thornhill DP, Welling PG. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol. 1979;16:405–10.CrossRefPubMedGoogle Scholar
  6. 6.
    McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8:e1001098.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kinn AC, Elbarouni J, Seideman P, Sollevi A. The effect of diclofenac sodium on renal function. Scand J Urol Nephrol. 1989;23:153–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Knights KM, Mangoni AA, Miners JO. Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity. Expert Rev Clin Pharmacol. 2010;3:769–76.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang L. Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther. 2008;83:761–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53:283–318.PubMedGoogle Scholar
  11. 11.
    Farokhzad OC, Langer R. Nanomedicine: developing smarter therapeutic and diagnostic modalities. Adv Drug Deliv Rev. 2006;58:1456–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Shaffer C. Nanomedicine transforms drug delivery. Drug Discov Today. 2005;10:1581–2.CrossRefPubMedGoogle Scholar
  13. 13.
    Alexis F. New frontiers in nanotechnology for cancer treatment. Urol Oncol Semin Orig Investig. 2008;26:74–85.CrossRefGoogle Scholar
  14. 14.
    Narayanan D, Nair SV, Menon D. A systematic evaluation of hydroxyethyl starch as a potential nanocarrier for parenteral drug delivery. Int J Biol Macromol. 2015;74:575–84.CrossRefPubMedGoogle Scholar
  15. 15.
    Duarte Junior AP, Tavares EJM, Alves TVG, de Moura MR, da Costa CEF, Silva Júnior JOC, et al. Chitosan nanoparticles as a modified diclofenac drug release system. J Nanopart Res. 2017;19:274. Scholar
  16. 16.
    El-Sousi S, Nacher A, Mura C, Catalan-Latorre A, Merino V. Hydroxypropylmethylcellulose films for the ophthalmic delivery of diclofenac sodium. J Pharm Pharmacol. 2013;65:193–200.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu D, Ge Y, Tang Y, Yuan Y, Zhang Q. Solid lipid nanoparticles for transdermal delivery of diclofenac sodium: preparation, characterization and in vitro studies. J Microencapsul. 2010;27:726–34.CrossRefPubMedGoogle Scholar
  18. 18.
    Seth BL. Comparative pharmacokinetics and bioavailability study of percutaneous absorption of diclofenac from two topical formulations containing drug as a solution gel or as an emulsion gel. Arzneimittelforschung. 1992;42:120–2.PubMedGoogle Scholar
  19. 19.
    Kandadi P, Syed MA, Goparaboina S, Veerabrahma K. Albumin coupled lipid nanoemulsions of diclofenac for targeted delivery to inflammation. Nanomedicine. 2012;8:1162–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Schipper ML, Iyer G, Koh AL, Cheng Z, Ebenstein Y, Aharoni A, et al. Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small. 2009;5:126–34.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, et al. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine. 2009;5:410–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Narayanan D, M.G. G, H. L, Koyakutty M, Nair S, Menon D. Poly-(ethylene glycol) modified gelatin nanoparticles for sustained delivery of the anti-inflammatory drug ibuprofen-sodium: an in vitro and in vivo analysis. Nanomedicine. 2013;9:818–28.CrossRefPubMedGoogle Scholar
  24. 24.
    Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5:505–15.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pillai GJ, Greeshma MM, Menon D. Impact of poly (lactic-co-glycolic acid) nanoparticle surface charge on protein, cellular and haematological interactions. Colloids Surf B: Biointerfaces. 2015;136:1058–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K. Long-circulating poly (ethylene glycol)-poly(D,L-lactide) block copolymer micelles with modulated surface charge. J Control Release. 2001;77:27–38.CrossRefPubMedGoogle Scholar
  27. 27.
    Singhvi G, Singh M. In vitro drug release characterization models. Int J Pharm Stud Res. 2011;2:77–84.Google Scholar
  28. 28.
    Chaovanalikit A, Dougherty MP, Camire ME, Briggs J. Ascorbic acid fortification reduces anthocyanins in extruded blueberry-corn cereals. J Food Sci. 2003;68:2136–40.CrossRefGoogle Scholar
  29. 29.
    Bort R, Ponsoda X, Jover R, Gómez-Lechón MJ, Castell JV. Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J Pharmacol Exp Ther. 1999;288:65–72.PubMedGoogle Scholar
  30. 30.
    Nel A. Toxic potential of materials at the nanolevel. Science. 2006;311:622–7.CrossRefPubMedGoogle Scholar
  31. 31.
    He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657–66.CrossRefPubMedGoogle Scholar
  32. 32.
    International Pharmaceutical Excipients Council. The IPEC excipient information package (EIP): template and user guide. Brussels: IPEC; 2009.Google Scholar
  33. 33.
    Aleeva GN, et al. The role of excipients in determining the pharmaceutical and therapeutic properties of medicinal agents. Pharm Chem J. 2009;43:51–6.CrossRefGoogle Scholar
  34. 34.
    Chaudhari SP, Patil PS. Pharmaceutical excipients: a review. Int J Adv Pharm Biol Chem. 2012;1:21–34.Google Scholar
  35. 35.
    Bertrand N, Leroux J. The journey of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release. 2012;161:152–63.CrossRefPubMedGoogle Scholar
  36. 36.
    Merkel TJ, Jones SW, Herlihy KP, Kersey FR, Shields AR, Napier M, et al. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc Natl Acad Sci. 2011;108:586–91.CrossRefPubMedGoogle Scholar
  37. 37.
    Kumar R, Chen MH, Parmar VS, Samuelson LA, Kumar J, Nicolosi R, et al. Supramolecular assemblies based on copolymers of PEG600 and functionalized aromatic diesters for drug delivery applications. J Am Chem Soc. 2004;126:10640–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Tang SY, Sivakumar M, Ng AM-H, Shridharan P. Anti-inflammatory and analgesic activity of novel oral aspirin-loaded nanoemulsion and nano multiple emulsion formulations generated using ultrasound cavitation. Int J Pharm. 2012;430:299–306.CrossRefPubMedGoogle Scholar
  39. 39.
    Hemmila MR, Mattar A, Taddonio MA, Arbabi S, Hamouda T, Ward PA, et al. Topical nanoemulsion therapy reduces bacterial wound infection and inflammation after burn injury. Surgery. 2010;148:499–509.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Garg V, Jain GK, Nirmal J, Kohli K. Topical tacrolimus nanoemulsion, a promising therapeutic approach for uveitis. Med Hypotheses. 2013;81:901–4.CrossRefPubMedGoogle Scholar
  41. 41.
    Food and Drug Administration. Single dose acute toxicity testing for pharmaceuticals. Fed Regist. 1996;61:43934.Google Scholar
  42. 42.
    Campbell WI, Watters CH. Venous sequelae following i.v. administration of diclofenac. Br J Anaesthol. 1989;62:545–7.CrossRefGoogle Scholar
  43. 43.
    Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med. 2015;105:13S–9S.CrossRefGoogle Scholar
  44. 44.
    Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol. 1996;25:9–21.CrossRefGoogle Scholar
  45. 45.
    Ponsoda X, et al. The use of cultured hepatocytes to investigate the mechanisms of drug hepatotoxicity. Cell Biol Toxicol. 1997;13:331–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Kretzrommel A, Boelsterli UA. Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol Appl Pharmacol. 1993;120:155–61.CrossRefGoogle Scholar
  47. 47.
    El-Ashmawy ZK, El-Ashmawy I. Hepato-renal and hematological effects of diclofenac sodium in rats. Glob J Pharmacol. 2013;7:123–32.Google Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.Centre for Nanosciences & Molecular MedicineAmrita Institute of Medical Sciences & Research CentreKochiIndia

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