Skip to main content

Advertisement

SpringerLink
Log in

Development of Timolol-Loaded Galactosylated Chitosan Nanoparticles and Evaluation of Their Potential for Ocular Drug Delivery

  • Research Article
  • Theme: Recent Trends in the Development of Chitosan-Based Drug Delivery Systems
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This study was conducted to develop timolol maleate (TM)-loaded galactosylated chitosan (GC) nanoparticles (NPs) (TM-GC-NPs) followed by optimization via a four-level and three-factor Box–Behnken statistical experimental design. The optimized nanoparticles showed a particle size of 213.3 ± 6.83 nm with entrapment efficiency of 38.58 ± 1.31% and drug loading of 17.72 ± 0.28%. The NPs were characterized with respect to zeta potential, pH, surface morphology, and differential scanning calorimetry (DSC). The determination of the oil–water partition coefficient demonstrated that the TM-GC-NPs had a high liposolubility at pH 6 as compared to timolol-loaded chitosan nanoparticles (TM-CS-NPs) and commercial TM eye drops. The in vitro release study indicated that TM-GC-NPs had a sustained release effect compared with the commercial TM eye drops. Ocular tolerance was studied by the hen’s egg chorioallantoic membrane (HET-CAM) assay and the formulation was non-irritant and could be used for ophthalmic drug delivery. The in vitro transcorneal permeation study and confocal microscopy showed enhanced penetration, and retention in the cornea was achieved with TM-GC-NPs compared with the TM-CS-NPs and TM eye drops. Preocular retention study indicated that the retention of TM-GC-NPs was significantly longer than that of TM eye drops. The in vivo pharmacodynamic study suggested TM-GC-NPs had a better intraocular pressure (IOP) lowering efficacy and a prolonged working time compared to commercial TM eye drops (P ≤ 0.05). The optimized TM-GC-NPs could be prepared successfully promising their use as an ocular delivery system.

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. Cheng YH, Hung KH, Tsai TH, Lee CJ, Ku RY, Chiu AW, et al. Sustained delivery of latanoprost by thermosensitive chitosan-gelatin-based hydrogel for controlling ocular hypertension. Acta Biomater. 2014;10:4360–6.

    Article  CAS  PubMed  Google Scholar 

  2. Leonardi A, Bucolo C, Drago F, Salomone S, Pignatello R. Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit. Int J Pharm. 2015;478:180–6.

    Article  CAS  PubMed  Google Scholar 

  3. Kim H-J, Zhang K, Moore L, Ho D. Diamond nanogel-embedded contact lenses mediate lysozyme-dependent therapeutic release. ACS Nano. 2014;8:2998–3005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Musumeci T, Bucolo C, Carbone C, Pignatello R, Drago F, Puglisi G. Polymeric nanoparticles augment the ocular hypotensive effect of melatonin in rabbits. Int J Pharm. 2013;440:135–40.

    Article  CAS  PubMed  Google Scholar 

  6. Jung HJ, Abou-Jaoude M, Carbia BE, Plummer C, Chauhan A. Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. J Control Release. 2013;165:82–9.

    Article  CAS  PubMed  Google Scholar 

  7. Yu S, Wang QM, Wang X, Liu D, Zhang W, Ye T, et al. Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate. Int J Pharm. 2015;480:128–36.

    Article  CAS  PubMed  Google Scholar 

  8. Kiland JA, Gabelt BT, Kaufman PL. Studies on the mechanism of action of timolol and on the effects of suppression and redirection of aqueous flow on outflow facility. Exp Eye Res. 2004;78:639–51.

    Article  CAS  PubMed  Google Scholar 

  9. Almeida H, Amaral MH, Lobao P, Lobo JM. In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations. Drug Discov Today. 2014;19:400–12.

    Article  CAS  PubMed  Google Scholar 

  10. Wu Y, Yao J, Zhou J, Dahmani FZ. Enhanced and sustained topical ocular delivery of cyclosporine A in thermosensitive hyaluronic acid-based in situ forming microgels. Int J Nanomed. 2013;8:3587–601.

    Google Scholar 

  11. Tran TH, Nguyen TD, Poudel BK, Nguyen HT, Kim JO, Yong CS, et al. Development and evaluation of artesunate-loaded chitosan-coated lipid nanocapsule as a potential drug delivery system against breast cancer. AAPS PharmSciTech. 2015;16:1307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gallarate M, Chirio D, Bussano R, Peira E, Battaglia L, Baratta F, et al. Development of O/W nanoemulsions for ophthalmic administration of timolol. Int J Pharm. 2013;440:126–34.

    Article  CAS  PubMed  Google Scholar 

  13. Ciolino JB, Stefanescu CF, Ross AE, Salvador-Culla B, Cortez P, Ford EM, et al. In vivo performance of a drug-eluting contact lens to treat glaucoma for a month. Biomaterials. 2014;35:432–9.

    Article  CAS  PubMed  Google Scholar 

  14. Rho S, Park I, Seong GJ, Lee N, Lee C-K, Hong S, et al. Chronic ocular hypertensive rat model using microbead injection: comparison of polyurethane, polymethylmethacrylate, silica and polystyene microbeads. Curr Eye Res. 2014;39:917–27.

    Article  CAS  PubMed  Google Scholar 

  15. Shukla SK, Mishra AK, Arotiba OA, Mamba BB. Chitosan-based nanomaterials: a state-of-the-art review. Int J Biol Macromol. 2013;59:46–58.

    Article  CAS  PubMed  Google Scholar 

  16. Cheng YH, Tsai TH, Jhan YY, Chiu AW, Tsai KL, Chien CS, et al. Thermosensitive chitosan-based hydrogel as a topical ocular drug delivery system of latanoprost for glaucoma treatment. Carbohydr Polym. 2016;144:390–9.

    Article  CAS  PubMed  Google Scholar 

  17. Li J, Liu H, Liu LL, Cai CN, Xin HX, Liu W. Design and evaluation of a brinzolamide drug-resin in situ thermosensitive gelling system for sustained ophthalmic drug delivery. Chem Pharm Bull. 2014;62:1000–8.

    Article  CAS  PubMed  Google Scholar 

  18. Tayel SA, El-Nabarawi MA, Tadros MI, Abd-Elsalam WH. Positively charged polymeric nanoparticle reservoirs of terbinafine hydrochloride: preclinical implications for controlled drug delivery in the aqueous humor of rabbits. AAPS PharmSciTech. 2013;14:782–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cho IS, Park CG, Huh BK, Cho MO, Khatun Z, Li Z, et al. Thermosensitive hexanoyl glycol chitosan-based ocular delivery system for glaucoma therapy. Acta Biomater. 2016;39:124–32.

    Article  CAS  PubMed  Google Scholar 

  20. Song B, Zhang W, Peng R, Huang J, Me T, Li Y, et al. Synthesis and cell activity of novel galactosylated chitosan as a gene carrier. Colloid Surf B. 2009;70:181–6.

    Article  CAS  Google Scholar 

  21. Elbialy NS, Abdol-Azim BM, Shafaa MW, El Shazly LH, El Shazly AH, Khalil WA. Enhancement of the ocular therapeutic effect of prednisolone acetate by liposomal entrapment. J Biomed Nanotechnol. 2013;9:2105–16.

    Article  CAS  PubMed  Google Scholar 

  22. Bucolo C, Drago F, Salomone S. Ocular drug delivery: a clue from nanotechnology. Front Pharmacol. 2012;3:1–3.

    Google Scholar 

  23. Suhonen P, Jarvinen T, Koivisto S, Urtti A. Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea. Eur J Pharm Sci. 1998;6:169–76.

    Article  CAS  PubMed  Google Scholar 

  24. Katiyar S, Pandit J, Mondal RS, Mishra AK, Chuttani K, Aqil M, et al. In situ gelling dorzolamide loaded chitosan nanoparticles for the treatment of glaucoma. Carbohydr Polym. 2014;102:117–24.

    Article  CAS  PubMed  Google Scholar 

  25. Lou J, Hu W, Tian R, Zhang H, Jia Y, Zhang J, et al. Optimization and evaluation of a thermoresponsive ophthalmic in situ gel containing curcumin-loaded albumin nanoparticles. Int J Nanomed. 2014;9:2517–25.

    Google Scholar 

  26. Hermans K, Van den Plas D, Everaert A, Weyenberg W, Ludwig A. Full factorial design, physicochemical characterisation and biological assessment of cyclosporine A loaded cationic nanoparticles. Eur J Pharm Biopharm. 2012;82:27–35.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang W, Li X, Ye T, Chen F, Yu S, Chen J, et al. Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions. Int J Nanomed. 2014;9:4305–15.

    Google Scholar 

  28. Katara R, Majumdar DK. Eudragit RL 100-based nanoparticulate system of aceclofenac for ocular delivery. Colloid Surf B. 2013;103:455–62.

    Article  CAS  Google Scholar 

  29. 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. Colloid Surf B. 2014;114:111–20.

    Article  CAS  Google Scholar 

  30. Shi S, Zhang Z, Luo Z, Yu J, Liang R, Li X, et al. Chitosan grafted methoxy poly(ethylene glycol)-poly(epsilon-caprolactone) nanosuspension for ocular delivery of hydrophobic diclofenac. Sci Rep. 2015;5:1–12.

    Google Scholar 

  31. Mishra V, Jain NK. Acetazolamide encapsulated dendritic nano-architectures for effective glaucoma management in rabbits. Int J Pharm. 2014;461:380–90.

    Article  CAS  PubMed  Google Scholar 

  32. Moya-Ortega MD, Alves TF, Alvarez-Lorenzo C, Concheiro A, Stefansson E, Thorsteinsdottir M, et al. Dexamethasone eye drops containing gamma-cyclodextrin-based nanogels. Int J Pharm. 2013;441:507–15.

    Article  CAS  PubMed  Google Scholar 

  33. Dai Y, Zhou R, Liu L, Lu Y, Qi J, Wu W. Liposomes containing bile salts as novel ocular delivery systems for tacrolimus (FK506): in vitro characterization and improved corneal permeation. Int J Nanomed. 2013;8:1921–33.

    Google Scholar 

  34. Liu R, Wang S, Fang S, Wang J, Chen J, Huang X, et al. Liquid crystalline nanoparticles as an ophthalmic delivery system for tetrandrine: development, characterization, and in vitro and in vivo evaluation. Nanoscale Res Lett. 2016;11:254.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kim H-G, Park J-W, Park S-W. Experimental chronic ocular hypertension by anterior chamber injection of 0.3% carbomer solution in the rat. Clin Exp Ophthalmol. 2013;41:404–12.

    Article  PubMed  Google Scholar 

  36. Singh KH, Shinde UA. Chitosan nanoparticles for controlled delivery of brimonidine tartrate to the ocular membrane. Pharmazie. 2011;66:594–9.

    CAS  PubMed  Google Scholar 

  37. Li XY, Li LL, Zhang ZL, Chen H. An overview on pharmacokinetics, disposition, and safety of nanoparticles in ocular applications. Curr Drug Metab. 2013;14:857–62.

    Article  CAS  PubMed  Google Scholar 

  38. Li J, Wu L, Wu W, Wang B, Wang Z, Xin H, et al. A potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate. Int J Pharm. 2013;455:75–84.

    Article  CAS  PubMed  Google Scholar 

  39. Abrego G, Alvarado HL, Egea MA, Gonzalez-Mira E, Calpena AC, Garcia ML. Design of nanosuspensions and freeze-dried PLGA nanoparticles as a novel approach for ophthalmic delivery of pranoprofen. J Pharm Sci. 2014;103:3153–64.

    Article  CAS  PubMed  Google Scholar 

  40. Loftsson T, Jansook P, Stefansson E. Topical drug delivery to the eye: dorzolamide. Acta Ophthalmol. 2012;90:603–8.

    Article  CAS  PubMed  Google Scholar 

  41. Vasi AM, Popa MI, Tanase EC, Butnaru M, Verestiuc L. Poly(acrylic acid)-poly(ethylene glycol) nanoparticles designed for ophthalmic drug delivery. J Pharm Sci. 2014;103:676–86.

    Article  CAS  PubMed  Google Scholar 

  42. Ibrahim MM, Abd-Elgawad AE, Soliman OA, Jablonski MM. Nanoparticle-based topical ophthalmic formulations for sustained celecoxib release. J Pharm Sci. 2013;102:1036–53.

    Article  CAS  PubMed  Google Scholar 

  43. Elkasabgy NA. Ocular supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) to enhance econazole nitrate bioavailability. Int J Pharm. 2014;460:33–44.

    Article  CAS  PubMed  Google Scholar 

  44. Abdullah TA, Ibrahim NJ, Warsi MH. Chondroitin sulfate-chitosan nanoparticles for ocular delivery of bromfenac sodium: improved permeation, retention, and penetration. Int J Pharm Investig. 2016;6:96–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Swaminathan S, Vavia PR, Trotta F, Cavalli R. Nanosponges encapsulating dexamethasone for ocular delivery: formulation design, physicochemical characterization, safety and corneal permeability assessment. J Biomed Nanotechnol. 2013;9:998–1007.

    Article  CAS  PubMed  Google Scholar 

  46. Ye T, Zhang W, Sun M, Yang R, Song S, Mao Y, et al. Study on intralymphatic-targeted hyaluronic acid-modified nanoliposome: influence of formulation factors on the lymphatic targeting. Int J Pharm. 2014;471:245–57.

    Article  CAS  Google Scholar 

  47. Rekha MR, Sharma CP. Simultaneous effect of thiolation and carboxylation of chitosan particles towards mucoadhesive oral insulin delivery applications: an in vitro and in vivo evaluation. J Biomed Nanotechnol. 2015;11:165–76.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the financial support from the Basic Research and Cutting-Edge Technology in Henan Province (122300410103). Moreover, we appreciate the Pharmaceutical College of Zhengzhou University for instrumental and technical support.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmaceutical Science, Zhengzhou University, 100 Kexue Dadao, Zhengzhou, 450001, Henan, People’s Republic of China

    Ruobing Zhao, Jingyi Wang, Zhenya Yin, Yongtao Zhu & Wei Liu

  2. Qilu Pharmaceutical Co., Ltd., Jinan, Shandong, People’s Republic of China

    Jing Li

Authors
  1. Ruobing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jingyi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenya Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yongtao Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Liu.

Ethics declarations

All studies were conducted in accordance with the Principles of Laboratory Animal Care (NIH Publication No. 92–93, revised in 1985) and were approved by the local ethics committees for animal experimentation.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Guest Editors: Claudio Salomon, Francisco Goycoolea, and Bruno Moerschbacher

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, R., Li, J., Wang, J. et al. Development of Timolol-Loaded Galactosylated Chitosan Nanoparticles and Evaluation of Their Potential for Ocular Drug Delivery. AAPS PharmSciTech 18, 997–1008 (2017). https://doi.org/10.1208/s12249-016-0669-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0669-x

KEY WORDS

Search

Navigation