Journal of Nanoparticle Research

, Volume 13, Issue 3, pp 1253–1264 | Cite as

Controlled release of ketorolac through nanocomposite films of hydrogel and LDH nanoparticles

  • Zhi Ping Xu
  • Zi Gu
  • Xiaoxi Cheng
  • Firas Rasoul
  • Andrew K. Whittaker
  • Gao Qing Max Lu
Research Paper


A novel nanocomposite film for sustained release of anionic ophthalmic drugs through a double-control process has been examined in this study. The film, made as a drug-loaded contact lens, consists principally of a polymer hydrogel of 2-hydroxyethyl methacrylate (HEMA), in whose matrix MgAl-layered double hydroxide (MgAl-LDH) nanoparticles intercalated with the anionic drug are well dispersed. Such nanocomposite films (hydrogel-LDH-drug) contained 0.6–0.8 mg of MgAl-LDH and 0.08–0.09 mg of the ophthalmic drug (ketorolac) in 1.0 g of hydrogel. MgAl-drug-LDH nanoparticles were prepared with the hydrodynamic particle size of 40–200 nm. TEM images show that these nanoparticles are evenly dispersed in the hydrogel matrix. In vitro release tests of hydrogel-LDH-drug in pH 7.4 PBS solution at 32 °C indicate a sustained release profile of the loaded drug for 1 week. The drug release undergoes a rapid initial burst and then a monotonically decreasing rate up to 168 h. The initial burst release is determined by the film thickness and the polymerization conditions, but the following release rate is very similar, with the effective diffusion coefficient being nearly constant (3.0 × 10−12 m2/s). The drug release from the films is mechanistically attributed to anionic exchange and the subsequent diffusion in the hydrogel matrix.


Layered double hydroxide nanoparticles Double-control release Nanocomposite contact lens Hydrogel Ketorolac Sustained release Drug delivery 



Funding from the Australian Research Council for the ARC Centre of Excellence for Functional Nanomaterials and ARC Discovery project (DP0879769) is gratefully acknowledged.

Supplementary material

11051_2010_118_MOESM1_ESM.doc (359 kb)
Supplementary material 1 (DOC 359 kb)


  1. Ali M, Byrne ME (2009) Controlled release of high molecular weight hyaluronic acid from molecularly imprinted hydrogel contact lenses. Pharm Res 26:714–726CrossRefGoogle Scholar
  2. Ambrogi V, Fardella G, Grandolini G, Perioli L (2001) Intercalation compounds of hydrotalcite-like anionic clays with antiinflammatory agents—I. Intercalation and in vitro release of ibuprofen. Int J Pharm 220:23–32CrossRefGoogle Scholar
  3. Anthony D, Jasinski DM (2002) Postoperative pain management: morphine versus ketorolac. J Pediatr Nurs 17:30–42Google Scholar
  4. Barbu E, Verestiuc L, Nevall TG, Tsibouklis J (2006) Polymeric materials for ophthalmic drug delivery: trends and perspectives. J Mater Chem 16:3439–3443CrossRefGoogle Scholar
  5. Braterman PS, Xu ZP, Yarberry F (2004) Layered double hydroxides. In: Auerbach SM, Carrado KA, Dutta PK (eds) Handbook of layered materials. Marcel Dekker, Inc, New York, pp 373–474Google Scholar
  6. Brazel CS, Peppas NA (1999) Mechanisms of solute and drug transport in relaxing, swellable, hydrophilic glassy polymers. Polymer 40:3383–3398CrossRefGoogle Scholar
  7. Chowdhury MA, Hill DJT, Whittaker A (2005a) Mass uptake study of the diffusion of water and SBF into poly(2-hydroxyethyl methacrylate-co-tetrahydrofurfuryl methacrylate) containing aspirin or vitamin B12. J Biomater Sci Polym Ed 16:1047–1061CrossRefGoogle Scholar
  8. Chowdhury MA, Hill DJT, Whittaker A (2005b) Vitamin B12 release from P(HEMA-co-THFMA) in water and SBF: a model drug release study. Aust J Chem 58:451–456CrossRefGoogle Scholar
  9. Choy JH, Jung JS, Oh JM, Park M, Jeong J, Kang YK, Han OJ (2004) Layered double hydroxide as an efficient drug reservoir for folate derivatives. Biomaterials 25:3059–3064CrossRefGoogle Scholar
  10. Ciolino JB, Hoare TR, Iwata NG, Behlau I, Dohlman CH, Langer R, Kohane DS (2009) A drug-eluting contact lens. Invest Ophthalmol Vis Sci 50:3346–3352CrossRefGoogle Scholar
  11. Crank J (1979) The mathematics of diffusion. Clarendon Press, OxfordGoogle Scholar
  12. Genta I, Conti B, Perugini P, Pavanetto F, Spadaro A, Puglisi G (1997) Bioadhesive microspheres for ophthalmic administration of acyclovir. J Pharm Pharmocol 49:737–742Google Scholar
  13. Gu Z, Thomas A, Xu ZP, Campbell J, Lu GQM (2008) In vitro sustained release of low Molecular weight heparin from MgAl-layered double hydroxide nanohybrids. Chem Mater 20:3715–3722CrossRefGoogle Scholar
  14. Gulsen D, Chauhan A (2004) Ophthalmic drug delivery through contact lenses. Invest Ophthalmol Vis Sci 45:2342–2347CrossRefGoogle Scholar
  15. Gulsen D, Li C, Chauhan A (2005a) Dispersion of DMPC liposomes in contact lenses for ophthalmic drug delivery. Curr Eye Res 30:1071–1080CrossRefGoogle Scholar
  16. Gulsen D, Li C, Chauhan A (2005b) Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle. Int J Pharm 292:95–117CrossRefGoogle Scholar
  17. Gupta AK, Madan S, Majumdar DK, Maitra A (2000) Ketorolac entrapped in polymeric micelles: preparation, characterization and ocular anti-inflammatory studies. Int J Pharm 209:1–14CrossRefGoogle Scholar
  18. Hernandez-Moreno MJ, Ulibarri MA, Rendon JL, Serna CJ (1985) IR characteristics of hydrotalcite-like compounds. Phys Chem Miner 12:34–38Google Scholar
  19. Hughes PM, Olejnik O, Chang-Lin JE, Wilson CG (2005) Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev 57:2010–2032CrossRefGoogle Scholar
  20. Kim J, Conway A, Chauhan A (2008) Extended delivery of ophthalmic drugs by silicone hydrogel contact lenses. Biomaterials 29:2259–2269CrossRefGoogle Scholar
  21. Kothuri MK, Pinnamaneni S, Das NG, Das SK (2003) Microparticles and nanoparticles in ocular drug delivery. In: Mitra AK (ed) Ophthalmic drug delivery systems. Marcel Dekker, New York, pp 437–466CrossRefGoogle Scholar
  22. Meyn M, Beneke K, Lagaly G (1990) Anion-exchange reactions of layered double hydroxides. Inorg Chem 29:5201–5207CrossRefGoogle Scholar
  23. Meyn M, Beneke K, Lagaly G (1993) Anion-exchange reactions of hydroxy double salts. Inorg Chem 32:1209–1215CrossRefGoogle Scholar
  24. Mitra AK (2003) Ophthalmic drug delivery systems. Marcel Dekker, New YorkCrossRefGoogle Scholar
  25. Nanjawade BK, Manvi FV, Manjappa AS (2007) In situ-forming hydrogels for sustained ophthalmic drug delivery. J Control Release 122:119–134CrossRefGoogle Scholar
  26. Puglia C, Filosa R, Peduto A, Caprariis P, Rizza L, Bonina F, Blasi P (2006) Evaluation of alternative strategies to optimize ketorolac transdermal delivery. AAPS PharmSciTech 7:64CrossRefGoogle Scholar
  27. Smith LA, Carroll D, Edwards JE, Moore RA, McQuay HJ (2000) Single-dose ketorolac and pethidine in acute postoperative pain: systematic review with meta-analysis. Br J Anaesth 84:48–58Google Scholar
  28. Tronto J, Reis MJ, Silverio F, Balbo VR, Marchetti JM, Valim JB (2004) In intro release of citrate anions intercalated in magnesium aluminum layered double hydroxides. J Phys Chem Solids 65:475–480CrossRefGoogle Scholar
  29. Tyner KM, Schiffman SR, Giannelis EP (2004) Nanobiohybrids as delivery vehicles for camptothecin. J Control Release 95:501–514CrossRefGoogle Scholar
  30. Verestiuc L, Nastasescu O, Barbu E, Sarvaiya I, Green KL, Tsibouklis J (2006) Functionalized chitosan/NIPAM (HEMA) hybrid polymer networks as inserts for ocular drug delivery: synthesis, in vitro assessment, and in vivo evaluation. J Biomed Mater Res A 77:726–735Google Scholar
  31. Wang Z, Wang E, Gao L, Xu L (2005) Synthesis and properties of Mg2Al layered double hydroxides containing 5-fluorouracil. J Solid State Chem 178:736–741CrossRefGoogle Scholar
  32. Wilson CG (2004) Topical drug delivery in the eye. Exp Eye Res 78:737–743CrossRefGoogle Scholar
  33. Xu ZP, Braterman PS (2003) High affinity of dodecylbenzene sulfonate for layered double hydroxides (LDH) and the resulting morphologies. J Mater Chem 13:268–273CrossRefGoogle Scholar
  34. Xu ZP, Lu GQM (2006) Layered double hydroxide nanomaterials as potential cellular drug delivery agents. Pure Appl Chem 78:1771–1779CrossRefGoogle Scholar
  35. Xu ZP, Zeng HC (2001) Abrupt structural transformation in hydrotalcite-like compounds Mg1-xAlx(OH)2(NO3)x nH2O as a continuous function of nitrate anions. J Phys Chem B 105:1743–1749CrossRefGoogle Scholar
  36. Xu ZP, Stevenson G, Lu C-Q, Lu GQM, Bartlett P, Gray P (2006a) Stable suspension of layered double hydroxide nanoparticles in aqueous solution. J Am Chem Soc 128:36–37CrossRefGoogle Scholar
  37. Xu ZP, Stevenson G, Lu CQ, Lu GQM (2006b) Dispersion and size control of layered double hydroxide nanoparticles in aqueous solutions. J Phys Chem B 110:16923–16929CrossRefGoogle Scholar
  38. Xu ZP, Kurniawan ND, Bartlett PF, Lu GQM (2007a) Enhancement of relaxivities of Gd-DTPA complex via intercalation into layered double hydroxide nanoparticles. Chem Eur J 13:2824–2830CrossRefGoogle Scholar
  39. Xu ZP, Walker TL, Liu K-L, Cooper HM, Lu GQM, Bartlett PF (2007b) Layered double hydroxide nanoparticles as cellular delivery vectors of supercoiled plasmid DNA. Int J Nanomed 2:163–174Google Scholar
  40. Xu ZP, Niebert M, Porazik K, Walker TL, Cooper HM, Middelberg APJ, Gray PP, Bartlett PF, Lu GQM (2008) Subcellular compartment targeting of layered double hydroxide nanoparticles. J Control Release 130:86–94CrossRefGoogle Scholar
  41. Yasukawa T, Ogura Y, Sakurai E, Tabata Y, Kimura H (2005) Intraocular sustained drug delivery using implantable polymeric devices. Adv Drug Deliv Rev 57:2033–2046CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence for Functional Nanomaterials, The University of QueenslandBrisbaneAustralia
  2. 2.Centre for Advanced Imaging and Australian Institute for Bioengineering and Nanotechnology, The University of QueenslandBrisbaneAustralia

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