Design of eudragit RL nanoparticles by nanoemulsion method as carriers for ophthalmic drug delivery of ketotifen fumarate

Document Type: Original Article


1 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

3 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): Ketotifen fumarate (KF) is a selective and noncompetitive histamine antagonist (H1-receptor) that is used topically in the treatment of allergic conditions of rhinitis and conjunctivitis. The aim of this study was to formulate and improve an ophthalmic delivery system of KF.Ocular nanoparticles were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery.
Materials and Methods:In the present study, ocular KF loaded Eudragit RL 100 nanoparticles were prepared using O/W solvent diffusion method. The nanoparticles were evaluated for particle size, entrapment efficiency, surface morphology, X-ray diffraction (XRD), Fourier transform spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro release and permeation studies were also carried out on nanoparticles.
Results: An average size range of 182 to 314.30 nm in diameter was obtained and encapsulation efficiency up to 95.0% was observed for all the formulations. Drug release for all formulations after 24 hr was between 65.51% and 88.82% indicating effective controlled release property of KF. The mechanism of drug release for best formulation was found to be fickian diffusion mechanism. KF nanoparticles containing high polymer concentration (1:15) presented a faster drug release and a higher drug penetration; on the contrary, nanoparticles containing low polymer concentration (1:7.5) were able to give a more sustained release of the drug and thus a slower KF permeation through the cornea.
Conclusion: The study revealed that KF NPs were capable of releasing the drug for a prolonged period of time and increasing the ocular bioavailability.


1. Patravale V, Kulkarni R. Nanosuspensions: a promising drug delivery strategy. J Pharm Pharmacol 2004; 56:827-840.

2. Modh N, Mehta D, Parejiya P, Popat A, Barot B. An overview of recent patents on nanosuspension. Recent Pat Drug Deliv Formul 2014; 8:144-154.

3. Pignatello R, Bucolo C, Ferrara P, Maltese A, Puleo A, Puglisi G. Eudragit RS100® nanosuspensions for the ophthalmic controlled delivery of ibuprofen. Eur J Pharm Sci 2002; 16:53-61.

4. Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm 2010; 399:129-139.

5. Leung D, Nelson TD, Rhodes TA, Kwong E. Nano-suspension process. Google Patents; 2012.US 20140256818 A1.

6. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Euro J Pharm Biopharm 2006; 62:3-16.

7. Tadros T, Izquierdo P, Esquena J, Solans C. Formation and stability of nano-emulsions. Adv Colloid Interface Sci 2004; 108:303-318.

8. Pignatello R, Ricupero N, Bucolo C, Maugeri F, Maltese A, Puglisi G. Preparation and characterization of eudragit retard nanosuspensions for the ocular delivery of cloricromene. AAPS PharmSciTech 2006; 7:E192-E198.

9. Nagarwal RC, Kant S, Singh P, Maiti P, Pandit JK. Polymeric nanoparticulate system: a potential approach for ocular drug delivery. J Control Release 2009; 136:2-13.

10. Pignatello R, Bucolo C, Spedalieri G, Maltese A, Puglisi G. Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials 2002; 23:3247-3255.

11. Cholkar K, Patel SP, Vadlapudi AD, Mitra AK. Novel strategies for anterior segment ocular drug delivery. J Ocul Pharmacol Ther 2013; 29:106-123.

12. Bielory L, Friedlaender MH. Allergic conjunctivitis. Immunol Allergy Clin North Am 2008; 28:43-58.

13. Tauber J, Raizman MB, Ostrov CS, Laibovitz RA, Abelson MB, Betts JG, et al. A multicenter comparison of the ocular efficacy and safety of diclofenac 0.1% solution with that of ketorolac 0.5% solution in patients with acute seasonal allergic conjunctivitis. J Ocul Pharmacol Ther 1998; 14:137-145.

14. Rathore K, Nema R, Sisodia S. An overview and advancement in ocular drug delivery systems. Int J Pharm Sci Res 2010; 1:11-23.

15. Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995; 35:209-219.

16. Gou M, Wu L, Yin Q, Guo Q, Guo G, Liu J, et al. Transdermal anaesthesia with lidocaine nano-formulation pretreated with low-frequency ultrasound in rats model. J Nanosci Nanotechnol 2009; 9:6360-6365.

17. Vega E, Egea M, Valls O, Espina M, Garcia M. Flurbiprofen loaded biodegradable nanoparticles for ophtalmic administration. J Pharm Sci 2006; 95:2393-2405.

18. Gilhotra RM, Gilhotra N, Mishra D. Piroxicam bioadhesive ocular inserts: physicochemical characterization and evaluation in prostaglandin-induced inflammation. Curr Eye Res 2009; 34:1065-1073.

19. Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol 2006; 168:1861-1868.

20. Sinha V, Bansal K, Kaushik R, Kumria R, Trehan A. Poly-ϵ-caprolactone microspheres and nanospheres: an overview. Int J Pharm 2004; 278:1-23.

21. Bala I, Hariharan S, Kumar MR. PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carrier Syst 2004; 21:387-422.

22. Abdelwahed W, Degobert G, Fessi H. Investigation of nanocapsules stabilization by amorphous excipients during freeze-drying and storage. Euro J Pharm Biopharm 2006; 63:87-94.

23. Mainardes RM, Urban MC, Cinto PO, Khalil NM, Chaud MV, Evangelista RC, et al. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets 2005; 6:363-371.

24. Das S, Suresh PK, Desmukh R. Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery. Nanomedicine 2010; 6:318-323.

25. Cegnar M, Premzl A, Zavašnik-Bergant V, Kristl J, Kos J. Poly (lactide-co-glycolide) nanoparticles as a carrier system for delivering cysteine protease inhibitor cystatin into tumor cells. Exp Cell Res 2004; 301:223-231.

26. Verwey EJW, Overbeek JTG, Overbeek JTG. Theory of the stability of lyophobic colloids: Courier Corporation; 1999;205 sidor.

27. Pignatello R, Bucolo C, Spedalieri G, Maltese A, Puglisi G. Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials 2002; 23:3247-3255.

28. Mandal B. Preparation and physicochemical characterization of Eudragit® RL100 Nanosus-pension with potential for Ocular Delivery of Sulfacetamide.  University of Toledo May, 2012.                                  

 29. Pignatello R, Ricupero N, Bucolo C, Maugeri F. Preparation and characterization of eudragit retard nanosuspensions for the ocular delivery of cloricromene. AAPS PharmSciTech 2006; 7:E192-E198.                 

30. Malhotra M, Majumdar D. Permeation through cornea. Indian J Exp biol 2001; 39:11-24.

31. Pahuja P, Arora S, Pawar P. Ocular drug delivery system: a reference to natural polymers. Exp Opin  Drug Deliv 2012; 9:837-861.

32. Basu S, Adhiyaman R. Preparation and characterization of nitrendipine-loaded Eudragit RL 100 microspheres prepared by an emulsion-solvent evaporation method. Trop J Pharm Res 2008; 7:1033-1041.

33. Ignatious F, Sun L. Electrospun amorphous pharmaceutical compositions. Google Patents 2003.US 20060013869 A1.

34. Swarnakar NK, Jain AK, Singh RP, Godugu C, Das M, Jain S. Oral bioavailability, therapeutic efficacy and reactive oxygen species scavenging properties of coenzyme Q10-loaded polymeric nanoparticles. Biomaterials 2011; 32:6860-6874.

35. Zakeri-Milani P, Loveymi BD, Jelvehgari M, Valizadeh H. The characteristics and improved intestinal permeability of vancomycin PLGA-nanoparticles as colloidal drug delivery system. Colloids Surf B Biointerfaces 2013; 103:174-181.

36. Graeser KA, Strachan CJ, Patterson JE, Gordon KC, Rades T. Physicochemical properties and stability of two differently prepared amorphous forms of simvastatin. Crys Growth Design 2008; 8:128-135.

37. Yadav SK, Mishra S, Mishra B. Eudragit-based nanosuspension of poorly water-soluble drug: formulation and in vitroin vivo evaluation. AAPS PharmSciTech 2012; 13:1031-1044.

38. Costa P, Lobo JS. Influence of dissolution medium agitation on release profiles of sustained-release tablets. Drug Dev Ind Pharm 2001;27:811-817.

39. Aksungur P, Demirbilek M, Denkbaş EB, Vandervoort J, Ludwig A, Ünlü N. Development             and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. J Control Release 2011; 151:286-294.