Skip to main content

Advertisement

SpringerLink
Log in

Co-delivery of Brinzolamide and Timolol from Micelles-laden Contact Lenses: In vitro and In Vivo Evaluation

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Traditional eye drops exhibit a modest bioavailability ranging from 1 to 5%, necessitating recurrent application. Thus, a contact lens-based drug delivery system presents substantial benefits. Nonetheless, pharmaceutical agents exhibiting poor solubility may compromise the quintessential characteristics of contact lenses and are, consequently, deemed unsuitable for incorporation. To address this issue, the present study has engineered a novel composite drug delivery system that amalgamates micellar technology with contact lenses, designed specifically for the efficacious conveyance of timolol and brinzolamide.

Methods

Utilizing mPEG-PCL as the micellar material, this study crafted mPEG-PCL micelles loaded with brinzolamide and timolol through the film hydration technique. The micelle-loaded contact lens was fabricated employing the casting method; a uniform mixture of HEMA and EGDMA with the mPEG-PCL micelles enshrouding brinzolamide and timolol was synthesized. Following the addition of a photoinitiator, 50 μL of the concoction was deposited into a contact lens mold. Subsequently, the assembly was subjected to polymerization under 365 nm ultraviolet light for 35 min, resulting in the formation of the micelle-loaded contact lenses.

Results

In the present article, we delineate the construction of a micelle-loaded contact lens designed for the administration of brinzolamide and timolol in the treatment of glaucoma. The study characterizes crucial properties of the micelle-loaded contact lenses, such as transmittance and ionic permeability. It was observed that these vital attributes meet the standard requirements for contact lenses. In vitro release studies revealed that timolol and brinzolamide could be gradually liberated over periods of up to 72 and 84 h, respectively. In vivo pharmacodynamic evaluation showed a significant reduction in intraocular pressure and a relative bioavailability of 10.84 times that of commercially available eye drops. In vivo pharmacokinetic evaluation, MRT was significantly increased, and the bioavailability of timolol and brinzolamide was 2.71 and 1.41 times that of eye drops, respectively. Safety assessments, including in vivo irritation, histopathological sections, and protein adsorption studies, were conducted as per established protocols, confirming that the experiments were in compliance with safety standards.

In conclusion

The manuscript delineates the development of a safe and efficacious micelle-loaded contact lens drug delivery system, which presents a novel therapeutic alternative for the management of glaucoma.

Graphical Abstract

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

Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or its supplementary materials].

References

  1. Patel KD, Silva LB, Park Y. Recent advances in drug delivery systems for glaucoma treatment. Mater Today Nano. 2022;18:100178.

    Article  CAS  Google Scholar 

  2. Yanagisawa M, Namekata K, Aida T, Katou S, Tanaka K. EAAT1 variants associated with glaucoma. Biochem Biophys Res Commun. 2020;529(4):943–9.

    Article  CAS  PubMed  Google Scholar 

  3. Mhatre S, Opere CA, Singh S. Unmet needs in glaucoma therapy: the potential role of hydrogen sulfide and its delivery strategies. J Control Release. 2022;347:256–69.

    Article  CAS  PubMed  Google Scholar 

  4. Peral A, Martinez-Aguila A, Pastrana C, Huete-Toral F, Carpena-Torres C, Carracedo G. Contact lenses as drug delivery system for glaucoma: a review. Appl Sci. 2020;10(15):5151.

    Article  CAS  Google Scholar 

  5. Carvalho IM, Marques CS, Oliveira RS, Coelho PB, Costa PC, Ferreira DC. Sustained drug release by contact lenses for glaucoma treatment—a review. J Control Release. 2015;202:76–82.

    Article  CAS  PubMed  Google Scholar 

  6. Maulvi FA, Mangukiya MA, Patel PA, Vaidya RJ, Koli AR, Ranch KM, Shah DO. Extended release of ketotifen from silica shell nanoparticle-laden hydrogel contact lenses: in vitro and in vivo evaluation. J Mater Sci Mater Med. 2016;27(6):113.

    Article  PubMed  Google Scholar 

  7. Alvarez-Lorenzo C, Anguiano-Igea S, Varela-García A, Vivero-Lopez M, Concheiro A. Bioinspired hydrogels for drug-eluting contact lenses. Acta Biomater. 2019;84:49–62.

    Article  CAS  PubMed  Google Scholar 

  8. Xu J, Xue Y, Hu G, Lin T, Gou J, Yin T, He H, Zhang Y, Tang X. A comprehensive review on contact lens for ophthalmic drug delivery. J Control Release. 2018;281:97–118.

    Article  CAS  PubMed  Google Scholar 

  9. Chaudhari P, Ghate VM, Lewis SA. Next-generation contact lenses: towards bioresponsive drug delivery and smart technologies in ocular therapeutics. Eur J Pharm Biopharm. 2021;161:80–99.

    Article  CAS  PubMed  Google Scholar 

  10. Rykowska I, Nowak I, Nowak R. Soft contact lenses as drug delivery systems: a review. Molecules. 2021;26(18):5577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sartini F, Menchini M, Posarelli C, Casini G, Figus M. In vivo efficacy of contact lens drug-delivery systems in glaucoma management a systematic review. Appl Sci. 2021;11(2):724.

    Article  CAS  Google Scholar 

  12. Rodrigues FS, Campos A, Martins J, Ambrósio AF, Campos EJ. Emerging trends in nanomedicine for improving ocular drug delivery: light-responsive nanoparticles, mesoporous silica nanoparticles, and contact lenses. ACS Biomater Sci Eng. 2020;6(12):6587–97.

    Article  CAS  PubMed  Google Scholar 

  13. Sedlácek J. Possibility of the application of ophthalmic drugs with the use of gel contact lenses [Moznosti aplikace ocních lék gel-kontaktními cockami]. Ceskoslovenská Oftalmologie. 1965;21(6):509–12.

    PubMed  Google Scholar 

  14. Li CC, Chauhan A. Ocular transport model for ophthalmic delivery of timolol through p-HEMA contact lenses. J Drug Deliv Sci Technol. 2007;17(1):69–79.

    Article  Google Scholar 

  15. Kim J, Chauhan A. Dexamethasone transport and ocular delivery from poly(hydroxyethyl methacrylate) gels. Int J Pharm. 2008;353(1–2):205–22.

    CAS  PubMed  Google Scholar 

  16. Maulvi FA, Desai DT, Shetty KH, Shah DO, Willcox MDP. 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, Choksi HH, Desai AR, Patel AS, Ranch KM, Vyas BA, Shah DO. pH triggered controlled drug delivery from contact lenses: addressing the challenges of drug leaching during sterilization and storage. Colloids Surf B Biointerfaces. 2017;157:72–82.

    Article  CAS  PubMed  Google Scholar 

  18. Maulvi FA, Parmar RJ, Desai AR, Desai DM, Shah DO. Tailored gatifloxacin Pluronic F-68-loaded contact lens: addressing the issue of transmittance and swelling. Int J Pharm. 2020;581(1): 119279.

    Article  CAS  PubMed  Google Scholar 

  19. Maulvi FA, Lakdawala DH, Shaikh AA, Desai AR, Choksi HH, Vaidya RJ, Ranch KM, Koli AR, Vyas BA, Shah DO. In vitro and in vivo evaluation of novel implantation technology in hydrogel contact lenses for controlled drug delivery. J Control Release. 2016;226:47–56.

    Article  CAS  PubMed  Google Scholar 

  20. Kim HJ, 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 

  21. Maulvi FA, Mangukiya MA, Patel PA, Vaidya RJ, Koli AR, Ranch KM, Shah DO. Extended release of ketotifen from silica shell nanoparticle-laden hydrogel contact lenses: in vitro and in vivo evaluation. J Mater Sci Mater Med. 2016;27(6):1–13.

    Article  CAS  Google Scholar 

  22. Wang Z, Li X, Zhang X, Sheng R, Lin Q, Song W, Hao L. Novel contact lenses embedded with drug-loaded zwitterionic nanogels for extended ophthalmic drug delivery. Nanomaterials (Basel). 2021;11(9):2328.

    Article  CAS  PubMed  Google Scholar 

  23. Prisnyi A, Zhilyakova E, Naplekov D, Malyutina A, Bondarev A, Novikov O, Lebedeva O. New drug delivery system in ophthalmology: results studying the surface structure of soft contact lenses from various polymer. BIO Web of Conf. 2021;40:03002.

    Article  Google Scholar 

  24. He H, Lu Y, Qi J, Dong X, Zhao W. In vivo fate of polymeric micelles. In. [C] 0[2024-02-08].

  25. Li Z, Liu M, Ke L, Wang LJ, Wu C, Li C, Li Z, Wu YL. Flexible polymeric nanosized micelles for ophthalmic drug delivery: research progress in the last three years. Nanoscale Adv. 2021;3(18):5240–54.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Naageshwaran V, Bigonne H, Gum G, Malla S, Sol Cd, Bon C, Xu X, Vo A, Smith W, Beringhs AOR, Kozak D, Tan M-L, Babiskin A, Urtti A, Amo EMd, Ranta V-P. Topical pharmacokinetics of brinzolamide suspensions in rabbits and variability analysis for sample size and design considerations. Int J Pharm. 2023;642:123183.

    Article  CAS  PubMed  Google Scholar 

  27. Uner B, Ozdemir S, Pilevne SN, Celebi ARC. Timolol-loaded ethosomes for ophthalmic delivery: reduction of high intraocular pressure in vivo. Int J Pharm. 2023;640: 123021.

    Article  CAS  PubMed  Google Scholar 

  28. Sui Y, Li J, Qu J, Fang T, Zhang H, Zhang J, Wang Z, Xia M, Dai Y, Wang D. Dual-responsive nanovaccine for cytosolic delivery of antigens to boost cellular immune responses and cancer immunotherapy. Asian J Pharm Sci. 2022;17(4):583–95.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ba-Salem AO, Duhamel J. Determination of the aggregation number of pyrene-labeled gemini surfactant micelles by pyrene fluorescence quenching measurements. Langmuir. 2021;37(19):6069–79.

    Article  CAS  PubMed  Google Scholar 

  30. Jumelle C, Gholizadeh S, Annabi N, Dana R. Advances and limitations of drug delivery systems formulated as eye drops. J Control Release. 2020;321:1–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sun R, Ma S, Chen X, Deng Y, Gou J, Yin T, He H, Wang Y, Tang X, Zhang Y. Inflammation-responsive molecular-gated contact lens for the treatment of corneal neovascularization. J Control Release. 2023;360:818–30.

    Article  CAS  PubMed  Google Scholar 

  32. Peng CC, Kim J, Chauhan A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing Vitamin E diffusion barriers. Biomaterials. 2010;31(14):4032–47.

    Article  CAS  PubMed  Google Scholar 

  33. Nguyen DCT, Dowling J, Ryan R, McLoughlin P, Fitzhenry L. Pharmaceutical-loaded contact lenses as an ocular drug delivery system: a review of critical lens characterization methodologies with reference to ISO standards. Cont Lens Anterior Eye. 2021;44:101487.

    Article  PubMed  Google Scholar 

  34. Mehta P, Al-Kinani AA, Arshad MS, Singh N, Ahmad Z. Engineering and development of chitosan-based nanocoatings for ocular contact lenses. J Pharm Sci. 2018;108(4):1540–51.

    Article  PubMed  Google Scholar 

  35. Fernandes AC, Silva D, Nunes TG, Colaco R. The effect of albumin and cholesterol on the biotribological behavior of hydrogels for contact lenses. Acta Biomater. 2015;26:184–94.

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Maulvi FA, Soni TG, Shah DO. Extended release of timolol from ethyl cellulose microparticles laden hydrogel contact lenses. Open Pharm Sci J. 2015;2(1):1–12.

    Article  Google Scholar 

  38. Xu J, Ge Y, Bu R, Zhang A, Feng S, Wang J, Gou J, Yin T, He H, Zhang Y, Tang X. 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 

  39. Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther. 1944;82(3):105–7.

    Google Scholar 

  40. Li Z, Liu M, Ke L, Wang LJ, Wu C, Li C, Li Z, Wu YL. Flexible polymeric nanosized micelles for ophthalmic drug delivery: research progress in the last three years. Nanoscale Adv. 2021;3(18):5240–54.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fuentes R, Fernández E, Pascual I, et al. UV-visible transmittance of silicone-hydrogel contact lenses measured with a fiber optic spectrometer[C] Iberoamerican optics meeting & latin american meeting on optics. Int Soc Opt Photonics. 2013. https://doi.org/10.1117/12.2025710.

    Article  Google Scholar 

  42. Efron N. Development of contact lenses from a biomaterial point of view – materials, manufacture, and clinical application[J]. Compr Biomater. 2011:517–541. https://doi.org/10.1016/B978-0-08-055294-1.00270-1.

  43. Yang H, Zhao M, Xing D, Zhang J, Fang T, Zhang F, Nie Z, Liu Y, Yang L, Li J, Wang D. Contact lens as an emerging platform for ophthalmic drug delivery: a systematic review. Asian J Pharm Sci. 2023;18(5):100847.

  44. Insua Pereira E, Lira M. Comfort, ocular dryness, and equilibrium water content changes of daily disposable contact lenses. Eye Contact Lens. 2018;44 Suppl 2:S233–240. https://doi.org/10.1097/ICL.0000000000000441.

    Article  PubMed  Google Scholar 

  45. Tranoudis I, Efron N. Parameter stability of soft contact lenses made from different materials. Cont Lens Anterior Eye. 2004;27(3):115–31.

    Article  PubMed  Google Scholar 

  46. Nasr FH, Khoee S, Dehghan MM, Chaleshtori SS, Shafiee A. Preparation and evaluation of contact lenses embedded with polycaprolactone-based nanoparticles for ocular drug delivery. Biomacromolecules. 2016;17(2):485–95. https://doi.org/10.1021/acs.biomac.5b01387.

    Article  CAS  PubMed  Google Scholar 

  47. Lin MC, Svitova TF. Contact lenses wettability in vitro: effect of surface-active ingredients. Optom Vis Sci. 2010;87(6):440–7.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Campbell D, Carnell SM, Eden RJ. Applicability of contact angle techniques used in the analysis of contact lenses, part 1: comparative methodologies. Eye Contact Lens. 2013;39:254–62.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Scientific Research Project of Liaoning Province Education Department (2020LJC16).

Author information

Author notes

  1. Hongyu Yang and Faxing Zhang contributed to the work equally.

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, People’s Republic of China

    Hongyu Yang, Faxing Zhang, Yingzhen Fan, Jian Zhang, Ting Fang, Dandan Xing, Yanli Zhen, Zhihao Nie, Yaming Liu, Dongkai Wang & Ji Li

Authors
  1. Hongyu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faxing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingzhen Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ting Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dandan Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yanli Zhen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhihao Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yaming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dongkai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ji Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dongkai Wang or Ji Li.

Ethics declarations

Competing interests

The authors have declared no conflicts of interest.

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 srrupplementary material.

Supplementary file1 (DOCX 156 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

Yang, H., Zhang, F., Fan, Y. et al. Co-delivery of Brinzolamide and Timolol from Micelles-laden Contact Lenses: In vitro and In Vivo Evaluation. Pharm Res 41, 531–546 (2024). https://doi.org/10.1007/s11095-024-03672-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-024-03672-8

Keywords

Search

Navigation