Skip to main content

Advertisement

Log in

Chitosan nanoparticles laden contact lenses for enzyme-triggered controlled delivery of timolol maleate: A promising strategy for managing glaucoma

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

To improve drug bioavailability, eye drops can be replaced by drug-eluting contact lenses. However, issues of drug leaching from lenses during manufacture and storage, and sterilization, currently limit their commercial application. To address the issues, stimuli-(lysozyme)-sensitive chitosan nanoparticles were developed to provide controlled ocular drug delivery. Nanoparticles were prepared by ionic gelation and characterized by TEM, X-ray diffraction, DSC, and FTIR. In the flux study, conventional-soaked contact lenses (SM-TM-CL) showed high-burst release, while with direct drug-only laden contact lenses (DL-TM-CL) the drug was lost during extraction and sterilization, as well as having poor swelling and optical properties. The nanoparticle-laden contact lenses (TM-Cht-NPs) showed controlled release of timolol for 120 h in the presence of lysozyme, with acceptable opto-physical properties. In the shelf-life study, the TM-Cht-NPs contact lenses showed no leaching or alteration in the drug release pattern. In animal studies, the TM-NPs-CL lenses gave a high drug concentration in rabbit tear fluid (mean = 11.01 µg/mL for 56 h) and helped maintain a low intraocular pressure for 120 h. In conclusion, the chitosan nanoparticle-laden contact lenses demonstrated the potential application to treat glaucoma with acceptable opto-physical properties and addressed the issues of drug-leaching during sterilization and storage.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Data will be available on request to corresponding author.

References

  1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Agis Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429–40.

    Article  Google Scholar 

  3. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK, Wilson MR, Gordon MO, Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701–13.

    Article  PubMed  Google Scholar 

  4. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: Results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268–79.

    Article  PubMed  Google Scholar 

  5. Costagliola C, dell’Omo R, Romano MR, Rinaldi M, Zeppa L, Parmeggiani F. Pharmacotherapy of intraocular pressure–part II. Carbonic anhydrase inhibitors, prostaglandin analogues and prostamides. Expert Opin Pharmacother. 2009;10(17):2859–70.

    Article  CAS  PubMed  Google Scholar 

  6. Gupta B, Mishra V, Gharat S, Momin M, Omri A. Cellulosic polymers for enhancing drug bioavailability in ocular drug delivery systems. Pharmaceuticals. 2021;14(11):1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee DA, Higginbotham EJ. Glaucoma and its treatment: A review. Am J Health Syst Pharm. 2005;62(7):691–9.

    Article  PubMed  Google Scholar 

  8. Stamper RL. Primary drug treatment for glaucoma: Beta-blockers versus other medications. Surv Ophthalmol. 2002;47(1):63–7.

    Article  PubMed  Google Scholar 

  9. Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A comprehensive review on dry eye disease: Diagnosis, medical management, recent developments, and future challenges. Adv Pharm. 2015;2015.

  10. Manjappa A, Kumbhar P, John D, Pattekari S, Patravale VB. Formulation strategies for improved ophthalmic delivery of hydrophilic drugs. In: Micro-and nanotechnologies-based product development. CRC Press; 2021. p. 115–38.

    Chapter  Google Scholar 

  11. Kumari B. Ocular drug delivery system: Approaches to improve ocular bioavailability. GSC Biol Pharm Sci. 2019;6(3):01–010.

    Article  Google Scholar 

  12. Jones LW, Chauhan A, Di Girolamo N, Sheedy J, Smith E III. Expert views on innovative future uses for contact lenses. Optom Vis Sci. 2016;93(4):328–35.

    Article  PubMed  Google Scholar 

  13. Pereira-da-Mota AF, Phan CM, Concheiro A, Jones L, Alvarez-Lorenzo C. Testing drug release from medicated contact lenses: The missing link to predict in vivo performance. J Control Release. 2022;343:672–702.

    Article  CAS  PubMed  Google Scholar 

  14. Pereira-da-Mota AF, Vivero-Lopez M, Garg P, Phan CM, Concheiro A, Jones L, Alvarez-Lorenzo C. In vitro–in vivo correlation of drug release profiles from medicated contact lenses using an in vitro eye blink model. Drug Deliv Transl Res. 2022;13(4):1116–27.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lanier OL, Christopher KG, Macoon RM, Yu Y, Sekar P, Chauhan A. Commercialization challenges for drug eluting contact lenses. Expert Opin Drug Deliv. 2020;17(8):1133–49.

    Article  PubMed  Google Scholar 

  16. Maulvi FA, Desai DT, Shetty KH, Shah DO, Willcox MD. Advances and challenges in the nanoparticles-laden contact lenses for ocular drug delivery. Int J Pharm. 2021;608:121090.

    Article  CAS  PubMed  Google Scholar 

  17. Maulvi FA, Patil RJ, Desai AR, Shukla MR, Vaidya RJ, Ranch KM, Vyas BA, Shah SA, Shah DO. Effect of gold nanoparticles on timolol uptake and its release kinetics from contact lenses: In vitro and in vivo evaluation. Acta Biomater. 2019;86:350–62.

    Article  CAS  PubMed  Google Scholar 

  18. Xu J, Ge Y, Bu R, Zhang A, Feng S, Wang J, Gou J, Yin T, He H, Zhang Y. Co-delivery of latanoprost and timolol from micelles-laden contact lenses for the treatment of glaucoma. J Control Release. 2019;305:18–28.

    Article  CAS  PubMed  Google Scholar 

  19. Mehta P, Al-Kinani AA, Haj-Ahmad R, Arshad MS, Chang M-W, Alany RG, Ahmad Z. Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings. Eur J Pharm Biopharm. 2017;119:170–84.

    Article  CAS  PubMed  Google Scholar 

  20. Mehta P, Al-Kinani AA, Arshad MS, Chang M-W, Alany RG, Ahmad Z. Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers. Int J Pharm. 2017;532(1):408–20.

    Article  CAS  PubMed  Google Scholar 

  21. Maulvi FA, Kanani PA, Jadav HJ, Desai BV, Desai DT, Patel HP, Shetty KH, Shah DO, Willcox MD. Timolol-eluting graphene oxide laden silicone contact lens: Control release profile with improved critical lens properties. J Drug Deliv Sci Technol. 2022;69:103134.

    Article  CAS  Google Scholar 

  22. Mu C, Shi M, Liu P, Chen L, Marriott G. Daylight-mediated, passive, and sustained release of the glaucoma drug timolol from a contact lens. ACS Cent Sci. 2018;4(12):1677–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mohamdeen YMG, Tabriz AG, Tighsazzadeh M, Nandi U, Khalaj R, Andreadis I, Boateng JS, Douroumis D. Development of 3D printed drug-eluting contact lenses. J Pharm Pharmacol. 2022;74(10):1467–76.

    Article  PubMed  Google Scholar 

  24. Anirudhan T, Nair AS, Parvathy J. Extended wear therapeutic contact lens fabricated from timolol imprinted carboxymethyl chitosan-g-hydroxy ethyl methacrylate-g-poly acrylamide as a onetime medication for glaucoma. Eur J Pharm Biopharm. 2016;109:61–71.

    Article  CAS  PubMed  Google Scholar 

  25. Korogiannaki M, Guidi G, Jones L, Sheardown H. Timolol maleate release from hyaluronic acid-containing model silicone hydrogel contact lens materials. J Biomater Appl. 2015;30(3):361–76.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Behl G, Iqbal J, O’Reilly NJ, McLoughlin P, Fitzhenry L. Synthesis and characterization of poly (2-hydroxyethylmethacrylate) contact lenses containing chitosan nanoparticles as an ocular delivery system for dexamethasone sodium phosphate. Pharm Res. 2016;33:1638–48.

    Article  CAS  PubMed  Google Scholar 

  28. Mehta P, Al-Kinani AA, Arshad MS, Singh N, van der Merwe SM, Chang M-W, Alany RG, Ahmad Z. Engineering and development of chitosan-based Nanocoatings for Ocular Contact Lenses. J Pharm Sci. 2019;108(4):1540–51.

    Article  CAS  PubMed  Google Scholar 

  29. Craig JP, Willcox MD, Argüeso P, Maissa C, Stahl U, Tomlinson A, Wang J, Yokoi N, Stapleton F. The TFOS international workshop on contact lens discomfort: Report of the contact lens interactions with the tear film subcommittee. Invest Ophthalmol Vis Sci. 2013;54(11):TFOS123–56.

    Article  PubMed  Google Scholar 

  30. Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso M. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci. 1997;63(1):125–32.

    Article  CAS  Google Scholar 

  31. Jhaveri J, Raichura Z, Khan T, Momin M, Omri A. Chitosan nanoparticles-insight into properties, functionalization and applications in drug delivery and theranostics. Molecules. 2021;26(2):272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maulvi FA, Thakkar VT, Soni TG, Gandhi TR. Optimization of aceclofenac solid dispersion using Box-Behnken design: In-vitro and in-vivo evaluation. Curr Drug Deliv. 2014;11(3):380–91.

    Article  CAS  PubMed  Google Scholar 

  33. Koli AR, Ranch KM, Patel HP, Parikh RK, Shah DO, Maulvi FA. Oral bioavailability improvement of felodipine using tailored microemulsion: Surface science, ex vivo and in vivo studies. Int J Pharm. 2021;596:120202.

    Article  CAS  PubMed  Google Scholar 

  34. Patel HP, Gandhi PA, Chaudhari PS, Desai BV, Desai DT, Dedhiya PP, Maulvi FA, Vyas BA. Clozapine loaded nanostructured lipid carriers engineered for brain targeting via nose-to-brain delivery: Optimization and in vivo pharmacokinetic studies. J Drug Deliv Sci Technol. 2021;64:102533.

    Article  CAS  Google Scholar 

  35. Lux A, Maier S, Dinslage S, Süverkrüp R, Diestelhorst M. A comparative bioavailability study of three conventional eye drops versus a single lyophilisate. Br J Ophthalmol. 2003;87(4):436–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bengani LC, Hsu K-H, Gause S, Chauhan A. Contact lenses as a platform for ocular drug delivery. Expert Opin Drug Deliv. 2013;10(11):1483–96.

    Article  CAS  PubMed  Google Scholar 

  37. Erk N. Rapid and sensitive HPLC method for the simultaneous determination of dorzolamide hydrochloride and timolol maleate in eye drops with diode-array and UV detection. Pharmazie. 2003;58(7):491–3.

    CAS  PubMed  Google Scholar 

  38. Maulvi FA, Soni PD, Patel PJ, Desai AR, Desai DT, Shukla MR, Shah SA, Shah DO, Willcox MD. Controlled bimatoprost release from graphene oxide laden contact lenses: In vitro and in vivo studies. Colloids Surf B. 2021;208:112096.

    Article  CAS  Google Scholar 

  39. Saleh A, Ibrahimi I. Electrophoretic polymorphism in rabbit tear lysozyme. Comp Biochem Physiol B Biochem Mol Biol. 1995;112(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  40. Bonavida B, Sapse AT, Sercarz EE. Rabbit tear proteins. I. Detection and quantitation of lysozyme in nonstimulated tears. Invest Ophthalmol Vis Sci. 1968;7(4):435–40.

    CAS  Google Scholar 

  41. Du Sert NP, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P. Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020;18(7):e3000411.

    Article  Google Scholar 

  42. Jiménez-Gómez CP, Cecilia JA. Chitosan: A natural biopolymer with a wide and varied range of applications. Molecules. 2020;25(17):3981.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Pan C, Qian J, Zhao C, Yang H, Zhao X, Guo H. Study on the relationship between crosslinking degree and properties of TPP crosslinked chitosan nanoparticles. Carbohyd Polym. 2020;241:116349.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Gokce Y, Cengiz B, Yildiz N, Calimli A, Aktas Z. Ultrasonication of chitosan nanoparticle suspension: Influence on particle size. Colloids Surf A. 2014;462:75–81.

    Article  CAS  Google Scholar 

  46. Blackburn JR, Nordberg R, Stevie F, Albridge RG, Jones MM. Photoelectron spectroscopy of coordination compounds. Triphenylphosphine and its complexes. Inorg Chem. 1970;9(10):2374–6.

    Article  CAS  Google Scholar 

  47. Nunthanid J, Puttipipatkhachorn S, Yamamoto K, Peck GE. Physical properties and molecular behavior of chitosan films. Drug Dev Ind Pharm. 2001;27(2):143–57.

    Article  CAS  PubMed  Google Scholar 

  48. Abd El-halim SM, Amin MM, El Gazayerly ON, Abd El NA. Design and in-vitro evaluation of solid self nano-emulsifying drug delivery systems (S-SNEDDS) for BCS class II drug valsartan. Inventi Rapid: NDDS. 2015;2015(3):1–7.

  49. Jagdale S, Shewale N, Kuchekar BS. Optimization of thermoreversible in situ nasal gel of timolol maleate. Scientifica. 2016;2016:6401267

  50. Zhao R, Li J, Wang J, Yin Z, Zhu Y, Liu W. Development of timolol-loaded galactosylated chitosan nanoparticles and evaluation of their potential for ocular drug delivery. AAPS PharmSciTech. 2017;18(4):997–1008.

    Article  CAS  PubMed  Google Scholar 

  51. Varma R, Vasudevan S. Extraction, characterization, and antimicrobial activity of chitosan from horse mussel modiolus modiolus. ACS Omega. 2020;5(32):20224–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhao S-P, Xu W-L. Thermo-sensitive hydrogels formed from the photocrosslinkable polypseudorotaxanes consisting of β-cyclodextrin and Pluronic F68/PCL macromer. J Polym Res. 2010;17(4):503–10.

    Article  CAS  Google Scholar 

  53. Patil S, Ujalambkar V, Rathore A, Rojatkar S, Pokharkar V. Galangin loaded galactosylated pluronic F68 polymeric micelles for liver targeting. Biomed Pharmacother. 2019;112:108691.

    Article  CAS  PubMed  Google Scholar 

  54. Qi L, Xu Z, Jiang X, Hu C, Zou X. Preparation and antibacterial activity of chitosan nanoparticles. Carbohyd Res. 2004;339(16):2693–700.

    Article  CAS  Google Scholar 

  55. Islam N, Wang H, Maqbool F, Ferro V. In vitro enzymatic digestibility of glutaraldehyde-crosslinked chitosan nanoparticles in lysozyme solution and their applicability in pulmonary drug delivery. Molecules. 2019;24(7):1271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Velos P, Cherry PM, Miller D. An improved method for measuring human tear lysozyme concentration. Arch Ophthalmol. 1985;103(1):31–3.

    Article  CAS  PubMed  Google Scholar 

  57. Desai AR, Maulvi FA, Desai DM, Shukla MR, Ranch KM, Vyas BA, Shah SA, Sandeman S, Shah DO. Multiple drug delivery from the drug-implants-laden silicone contact lens: Addressing the issue of burst drug release. Mater Sci Eng, C. 2020;112: 110885.

    Article  CAS  Google Scholar 

Download references

Funding

The author gratefully acknowledges the funding of this work by Student Startup & Innovation Policy grant (SSIP/498/2021).

Author information

Authors and Affiliations

Authors

Contributions

Furqan A. Maulvi: Supervision, Methodology, Project administration, Writing - Review & Editing; Ashmi R. Patel: Writing - Original Draft, Formal analysis; Kiran H. Shetty: Data Curation, Software; Ditixa T. Desai: Resources, Conceptualization, Funding acquisition, Validation; Dinesh O. Shah: Supervision, Visualization; Mark D.P. Willcox: Supervision, Investigation.

Corresponding author

Correspondence to Ditixa T. Desai.

Ethics declarations

Ethics approval

The animal experiment was conducted in accordance with the ethical guidelines set forth by the animal ethical committee of Maliba Pharmacy College (Gujarat, India) and received prior approval under Protocol no: MPC/IAEC/01/2021.

Consent to participate

Not applicable.

Consent for publication

Authors agree and have given consent for publication.

Competing interests

The authors declare no known competing financial interests that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1580 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maulvi, F.A., Patel, A.R., Shetty, K.H. et al. Chitosan nanoparticles laden contact lenses for enzyme-triggered controlled delivery of timolol maleate: A promising strategy for managing glaucoma. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01543-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01543-8

Keywords

Navigation