Skip to main content
SpringerLink
Log in

Development and Evaluation of Diclofenac Sodium Loaded-N-Trimethyl Chitosan Nanoparticles for Ophthalmic Use

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

Abstract

The ophthalmic preparation of diclofenac sodium (DC) for relieving ocular inflammation is presently available in the market only as an eye drop solution. Due to its low occular bioavailability, it requires frequent application leading to low patients’ compliance and quality of life. This study was conducted to develop formulations of DC loaded-N-trimethyl chitosan nanoparticles (DC-TMCNs) for ophthalmic use to improve ocular biavailabiltiy of DC. DC-TMCNs varied in formulation compositions were prepared using ionic gelation technique and evaluated for their physicochemical properties, drug release, eye irritation potential, and ophthalmic absorption of diclofenac sodium. N-Trimethyl chitosan (TMC) with a 49.8% degree of quaternization was synthesized and used for DC-TMCNs production. The obtained DC-TMCNs had particle size in a range of 130–190 nm with zeta potential values of +4 to +9 mV and drug entrapment efficiencies of more than 70% depending on the content of TMC and sodium tripolyphosphate (TPP). The optimized DC-TMCNs formulation contained TMC, DC, and TPP at a weight ratio of TMC/DC/TPP = 3:1:1. Their lyophilized product reconstituted with phosphate buffer solution pH 5.5 possessed a drug release pattern that fitted within the zero-order model. The eye irritation tests showed that DC-TMCNs were safe for ophthalmic use. The in vivo ophthalmic drug absorption study performed on rabbits indicated that DC-TMCNs could improve ophthalmic bioavailability of DC. Results of this study suggested that DC-TMCNs had potential for use as an alternative to conventional DC eye drops for ophthalmic inflammation treatment.

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

Abbreviations

ANOVA:

analysis of variance

AUC:

area under curve

C max :

maximum concentration

cP:

centipoise

CV:

cell viability

DC:

diclofenac sodium

DC-TMCNs:

diclofenac sodium loaded-N-trimethyl chitosan nanoparticles

DQ:

degree of quaternization

EE:

drug entrapment efficiency

h:

hour

i.e.:

id est

K a :

absorption rate constant

K e :

elimination rate constant

min:

minute

LSD:

least significant difference

MTT:

methylthiazolydiphenyl-tetrazolium bromide

M w :

molecular weight

N :

normality

n.d.:

not determined

PI:

polydispersity index

rpm:

round per minute

STE:

short time exposure

t 1/2 :

half life

T max :

time to reach C max

TMC:

N-trimethyl chitosan

TMCNs:

N-trimethyl chitosan nanoparticles

TPP:

sodium ripolyphosphate

REFERENCES

  1. Hao J, Wang X, Bi Y, Teng Y, Wang J, Li F, et al. Fabrication of a composite system combining solid lipid nanoparticles and thermosensitive hydrogel for challenging ophthalmic drug delivery. Colloids Surf B: Biointerf. 2014;114:111–20.

    Article  CAS  Google Scholar 

  2. Badawi AA, El-Laithy HM, El Qidra RK, El Mofty H, El Dally M. Arch Pharm Res. 2008;31:1040–9.

    Article  CAS  PubMed  Google Scholar 

  3. Qi H, Gao X, Zhang L, Wei S, Bi S, Yang Z, et al. In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Eur J Pharmacol. 2013;705:20–5.

    Article  CAS  PubMed  Google Scholar 

  4. Glisoni RJ, García-Fernández MJ, Pino M, Gutkind G, Moglioni AG, Alvarez-Lorenzo C, et al. β-Cyclodextrin hydrogels for the ocular release of antibacterial thiosemicarbazones. Carbohydr Polym. 2013;93:449–57.

    Article  CAS  PubMed  Google Scholar 

  5. Ameeduzzafar AJ, Bhatnagar A, Kumar N, Ali A. Chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits. Int J Biol Macromol. 2014;65:479–91.

    Article  CAS  PubMed  Google Scholar 

  6. Mealy JE, Fedorchak MV, Little SR. In vitro characterization of a controlled-release ocular insert for delivery of brimonidine tartrate. Acta Biomater. 2014;10:87–93.

    Article  CAS  PubMed  Google Scholar 

  7. Araújo J, Gonzalez E, Egea MA, Garcia ML, Souto EB. Nanomedicines for ocular NSAIDs: safety on drug delivery. Nanomedicine. 2009;5:394–401.

    Article  PubMed  Google Scholar 

  8. de la Fuente M, Raviña M, Paolicelli P, Sanchez A, Seijo B, Alonso MJ. Chitosan-based nanostructures: a delivery platform for ocular therapeutics. Adv Drug Del Rev. 2010;62:100–17.

    Article  Google Scholar 

  9. Gupta H, Aqil M, Khar RK, Ali A, Bhatnagar A, Mittal G. Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery. Nanomedicine. 2010;6:324–33.

    Article  CAS  PubMed  Google Scholar 

  10. Gan L, Wang J, Jiang M, Bartlett H, Ouyang D, Eperjesi F, et al. Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug Discov Today. 2013;18:290–7.

    Article  CAS  PubMed  Google Scholar 

  11. Li N, Zhuang C, Wang M, Sun X, Nie S, Pan W. Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery. Int J Pharm. 2009;379:131–8.

    Article  CAS  PubMed  Google Scholar 

  12. de Britto D, Frederico FR, Assis OBG. Optimization of N, N, N-trimethyl chitosan synthesis by factorial design. Polym Int. 2011;60:910–5.

    Article  Google Scholar 

  13. Wang S, Zhang J, Jiang T, Zheng L, Wang Z, Zhang J, et al. Protective effect of coenzyme Q10 against oxidative damage in human lens epithelial cells by novel ocular drug carriers. Int J Pharm. 2011;403:219–29.

    Article  CAS  PubMed  Google Scholar 

  14. Zambito Y, Zaino C, Colo GD. Effect of N-trimethylchitosan on transcellular and paracellular transcorneal drug transport. Eur J Pharm Biopharm. 2006;64:16–25.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang J, Wang S. Topical use of coenzyme Q10-loaded liposomes coated with trimethylchitosan: tolerance, precorneal retention and anti-cataract effect. Int J Pharm. 2009;372:66–75.

    Article  CAS  PubMed  Google Scholar 

  16. Ahuja M, Sharma SK, Majumdar DK. In vitro corneal permeation of diclofenac from oil drops. Yakugaku Zasshi. 2007;127:1739–45.

    Article  CAS  PubMed  Google Scholar 

  17. Attama AA, Reichl S, Müller-Goymann CC. Diclofenac sodium delivery to the eye: in vitro evaluation of novel solid lipid nanoparticle formulation using human cornea construct. Int J Pharm. 2008;355:307–13.

    Article  CAS  PubMed  Google Scholar 

  18. Agnihotri SM, Vavia PR. Diclofenac-loaded biopolymeric nanosuspensions for ophthalmic application. Nanomedicine. 2009;5:90–5.

    Article  CAS  PubMed  Google Scholar 

  19. Polnok A, Borchard G, Verhoef JC, Sarisuta N, Junginger HE. Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride. Eur J Pharm Biopharm. 2004;57:77–83.

    Article  CAS  PubMed  Google Scholar 

  20. Mourya VK, Inamdar NN. Trimethyl chitosan and its applications in drug delivery. J Mater Sci Mater Med. 2009;20:1057–79.

    Article  CAS  PubMed  Google Scholar 

  21. Chen F, Zhang Z, Huang Y. Evaluation and modification of N-trimethyl chitosan chloride nanoparticles as protein carriers. Int J Pharm. 2007;336:166–73.

    Article  CAS  PubMed  Google Scholar 

  22. Takahashi Y, Koike M, Honda H, Ito Y, Sakaguchi H, Suzuki H, et al. Development of the short time exposure (STE) test: an in vitro eye irritation test using SIRC cells. Toxicol in Vitro. 2008;22:760–70.

    Article  CAS  PubMed  Google Scholar 

  23. Bozdağ S, Gümüş K, Gümüş Ö, Ünlü N. Formulation and in vitro evaluation of cysteamine hydrochloride viscous solutions for the treatment of corneal cystinosis. Eur J Pharm Biopharm. 2008;70:260–9.

    Article  PubMed  Google Scholar 

  24. Wu C, Qi H, Chen W, Huang C, Su C, Li W, et al. Preparation and evaluation of a carbopol/HPMC-based in situ gelling ophthalmic system for puerarin. Yakgaku Zasshi. 2007;127183–91.

  25. Riegel M, Ellis PP. High-performance liquid chromatographic assay for antiinflammatory agents diclofenac and flurbiprofen in ocular fluids. J Chromatogr B Biomed Appl. 1994;654:140–5.

    Article  CAS  PubMed  Google Scholar 

  26. Martins AF, Pereira AGB, Fajardo AR, Rubira AF, Muniz EC. Characterization of polyelectrolytes complexes based on N, N, N-trimethyl chitosan/heparin prepared at different pH conditions. Carbohydr Polym. 2011;86:1266–72.

    Article  CAS  Google Scholar 

  27. de Britto D, Campana-Filho SP, Assis OBG. Mechanical properties of N, N, N- trimethylchitosan chloride films. Polímeros. 2005;15:142–5.

    Article  Google Scholar 

  28. Rodrigues S, Costa AMR, Grenha A. Chitosan/Carrageenan nanoparticles: effect of cross-linking with tripolyphosphate and charge ratios. Carbohydr Polym. 2012;89:282–9.

    Article  CAS  PubMed  Google Scholar 

  29. Jintapattanakit A, Junyaprasert VB, Mao S, Sitterberg J, Bakowsky U, Kissel T. Peroral delivery of insulin using chitosan derivatives: a comparative study of polyelectrolyte nanocomplexes and nanoparticles. Int J Pharm. 2007;342:240–9.

    Article  CAS  PubMed  Google Scholar 

  30. De Campos AM, Sánchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. Int J Pharm. 2001;224:159–68.

    Article  PubMed  Google Scholar 

  31. Fan W, Yan W, Xu Z, Ni H. Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloid Surf B Biointerf. 2012;90:21–7.

    Article  CAS  Google Scholar 

  32. Subbiah R, Ramalingam P, Ramasundaram S, Kim DY, Park K, Ramasamy MK, et al. N, N, N-Trimethyl chitosan nanoparticles for controlled intranasal delivery of HBV surface antigen. Carbohydr Polym. 2012;89:1289–97.

    Article  CAS  PubMed  Google Scholar 

  33. de Britto D, de Moura MR, Aouada FA, Mattoso LHC, Assis OBG. N, N, N-trimethyl chitosan nanoparticles as a vitamin carrier system. Food Hydrocolloid. 2012;27:487–93.

    Article  Google Scholar 

  34. Antoniou J, Liu F, Majeed H, Qi J, Yokoyama W, Zhong F. Physicochemical and morphological properties of size-controlled chitosan–tripolyphosphate nanoparticles. Colloids Surf A Physicochem Eng Asp. 2015;465:137–46.

    Article  CAS  Google Scholar 

  35. Llinàs A, Burley JC, Box KJ, Glen RC, Goodman JM. Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms. J Med Chem. 2007;50:979–83.

    Article  PubMed  Google Scholar 

  36. Kumar M, Pandey RS, Patra KC, Jain SK, Soni ML, Dangi JS, et al. Evaluation of neuropeptide loaded trimethyl chitosan nanoparticles for nose to brain delivery. Int J Biol Macromol. 2013;61:189–95.

    Article  CAS  PubMed  Google Scholar 

  37. Freitas C, Müller RH. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN™) dispersions. Int J Pharm. 1998;168:221–9.

    Article  CAS  Google Scholar 

  38. Hansson A, Di Francesco T, Falson F, Rousselle P, Jordan O, Borchard G. Preparation and evaluation of nanoparticles for directed tissue engineering. Int J Pharm. 2012;439:73–80.

    Article  CAS  PubMed  Google Scholar 

  39. Rampino A, Borgogna M, Blasi P, Bellich B, Cesàro A. Chitosan nanoparticles: preparation, size evolution and stability. Int J Pharm. 2013;455:219–28.

    Article  CAS  PubMed  Google Scholar 

  40. Bharathi A, Srinivas NK, Reddy GR, Veeranjaneyulu M, Sirisha A, Kamala P. Formulation and in vitro evaluation of diclofenac sodium sustained release matrix tablets using melt granulation technique. Int J Res Pharm Biomed Sci. 2011;2:788–808.

    Google Scholar 

  41. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67:217–23.

    CAS  PubMed  Google Scholar 

  42. Huang X, Brazel CS. On the importance and mechanisms of burst release in matrix- controlled drug delivery systems. J Control Release. 2001;73:121–36.

    Article  CAS  PubMed  Google Scholar 

  43. Nishihata T, Keigami M, Kamada A, Fujimoto T, Kamide S, Tatsumi N. Clinical investigation of sodium diclofenac sustained-release suppositories. Int J Pharm. 1988;42:251–6.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the Office of the Higher Education Commission, The Thailand Research Fund, and Thammasat University for the financial support under The Research Grant for New Scholar: grant no. MRG5580096.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Thammasat University, Pathumthani, 12120, Thailand

    Rathapon Asasutjarit

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Rangsit University, Pathumthani, 12000, Thailand

    Thitaree Theerachayanan

  3. Group of Research and Development, Thailand Institute of Nuclear Technology (Public Organization), Nakhonnayok, 26120, Thailand

    Prartana Kewsuwan

  4. National Center For Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathumthani, 12120, Thailand

    Sukitaya Veeranodha

  5. National Metal and Materials Technology Center, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathumthani, 12120, Thailand

    Asira Fuongfuchat

  6. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Garnpimol C. Ritthidej

Authors
  1. Rathapon Asasutjarit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thitaree Theerachayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prartana Kewsuwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sukitaya Veeranodha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asira Fuongfuchat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Garnpimol C. Ritthidej
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rathapon Asasutjarit.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Asasutjarit, R., Theerachayanan, T., Kewsuwan, P. et al. Development and Evaluation of Diclofenac Sodium Loaded-N-Trimethyl Chitosan Nanoparticles for Ophthalmic Use. AAPS PharmSciTech 16, 1013–1024 (2015). https://doi.org/10.1208/s12249-015-0290-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-015-0290-4

KEY WORDS

Search

Navigation