Skip to main content

Advertisement

SpringerLink
Log in

Shear-Thinning Viscous Materials for Subconjunctival Injection of Microparticles

  • Research Article
  • Theme: Ocular Drug Delivery and Ophthalmic Formulations
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

While drug-loaded microparticles (MPs) can serve as drug reservoirs for sustained drug release and therapeutic effects, needle clogging by MPs poses a challenge for ocular drug delivery via injection. Two polymers commonly used in ophthalmic procedures—hyaluronic acid (HA) and methylcellulose (MC)—have been tested for their applicability for ocular injections. HA and MC were physically blended with sunitinib malate (SUN)–loaded PLGA MPs for subconjunctival (SCT) injection into rat eyes. The HA and MC viscous solutions facilitated injection through fine-gauged needles due to their shear-thinning properties as shown by rheological characterizations. The diffusion barrier presented by HA and MC reduced burst drug release and extended overall release from MPs. The significant level of MP retention in the conjunctiva tissue post-operation confirmed the minimal leakage of MPs following injection. The safety of HA and MC for ocular applications was demonstrated histologically.

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

References

  1. Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization. Cornea. 2008;27(2):142–7.

    Article  Google Scholar 

  2. Tan JC, Mann S, Coroneo MT. Successful treatment of conjunctival lymphangiectasia with subconjunctival injection of bevacizumab. Cornea. 2016;35(10):1375–7.

    Article  Google Scholar 

  3. Xu Q, Tan X, Zhang Y, Jie Y, Pan Z. Subconjunctival injection of in vitro transforming growth factor-beta-induced regulatory T cells prolongs allogeneic corneal graft survival in mice. Int J Clin Exp Med. 2015;8(11):20271–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Yoshida J, Wicks RT, Zambrano AI, Tyler BM, Javaherian K, Grossman R, et al. Inhibition of corneal neovascularization by subconjunctival injection of Fc-endostatin, a novel inhibitor of angiogenesis. J Ophthalmol. 2015;2015:137136.

    Article  Google Scholar 

  5. Wang B, Tang Y, Oh Y, Lamb NW, Xia S, Ding Z, et al. Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization. Nanomedicine. 2019;17:119–23.

    Article  CAS  Google Scholar 

  6. Luo L, Yang J, Oh Y, Hartsock MJ, Xia S, Kim YC, et al. Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis. J Control Release. 2019;296:68–80.

    Article  CAS  Google Scholar 

  7. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348–60.

    Article  CAS  Google Scholar 

  8. Xu Q, Kambhampati SP, Kannan RM. Nanotechnology approaches for ocular drug delivery. Middle East Afr J Ophthalmol. 2013;20(1):26–37.

    Article  CAS  Google Scholar 

  9. Lux A, Maier S, Dinslage S, Suverkrup 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  Google Scholar 

  10. Patton TF, Francoeur M. Ocular bioavailability and systemic loss of topically applied ophthalmic drugs. Am J Ophthalmol. 1978;85(2):225–9.

    Article  CAS  Google Scholar 

  11. Kholdebarin R, Campbell RJ, Jin YP, Buys YM. Multicenter study of compliance and drop administration in glaucoma. Can J Ophthalmol. 2008;43(4):454–61.

    Article  Google Scholar 

  12. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13(3–4):135–43.

    PubMed  Google Scholar 

  13. Kadam RS, Tyagi P, Edelhauser HF, Kompella UB. Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide. Int J Pharm. 2012;434(1–2):140–7.

    Article  CAS  Google Scholar 

  14. Pan Q, Xu Q, Boylan NJ, Lamb NW, Emmert DG, Yang JC, et al. Corticosteroid-loaded biodegradable nanoparticles for prevention of corneal allograft rejection in rats. J Control Release. 2015;201:32–40.

    Article  CAS  Google Scholar 

  15. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64.

    Article  CAS  Google Scholar 

  16. Rafiei F, Tabesh H, Farzad F. Sustained subconjunctival drug delivery systems: current trends and future perspectives. Int Ophthalmol. 2020;40:2385–401.

    Article  Google Scholar 

  17. Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 1997;28(1):5–24.

    Article  CAS  Google Scholar 

  18. Alipour S, Montaseri H, Tafaghodi M. Inhalable, large porous PLGA microparticles loaded with paclitaxel: preparation, in vitro and in vivo characterization. J Microencapsul. 2015;32(7):661–8.

    Article  CAS  Google Scholar 

  19. Costa MP, Feitosa AC, Oliveira FC, Cavalcanti BC, da Silva EN, Dias GG, et al. Controlled release of nor-beta-lapachone by PLGA microparticles: a strategy for improving cytotoxicity against prostate cancer cells. Molecules. 2016;21(7):873.

    Article  Google Scholar 

  20. Obayemi JD, Danyuo Y, Dozie-Nwachukwu S, Odusanya OS, Anuku N, Malatesta K, et al. PLGA-based microparticles loaded with bacterial-synthesized prodigiosin for anticancer drug release: effects of particle size on drug release kinetics and cell viability. Mater Sci Eng C Mater Biol Appl. 2016;66:51–65.

    Article  CAS  Google Scholar 

  21. Kohane DS. Microparticles and nanoparticles for drug delivery. Biotechnol Bioeng. 2007;96(2):203–9.

    Article  CAS  Google Scholar 

  22. Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci. 2006;47(3):1149–60.

    Article  Google Scholar 

  23. Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci. 2003;44(3):1192–201.

    Article  Google Scholar 

  24. Tarlan B, Kiratli H. Subconjunctival hemorrhage: risk factors and potential indicators. Clin Ophthalmol. 2013;7:1163–70.

    PubMed  PubMed Central  Google Scholar 

  25. Ballios BG, Cooke MJ, van der Kooy D, Shoichet MS. A hydrogel-based stem cell delivery system to treat retinal degenerative diseases. Biomaterials. 2010;31(9):2555–64.

    Article  CAS  Google Scholar 

  26. Delplace V, Payne S, Shoichet M. Delivery strategies for treatment of age-related ocular diseases: from a biological understanding to biomaterial solutions. J Control Release. 2015;219:652–68.

    Article  CAS  Google Scholar 

  27. Cronau H, Kankanala RR, Mauger T. Diagnosis and management of red eye in primary care. Am Fam Physician. 2010;81(2):137–44.

    PubMed  Google Scholar 

  28. Reed DB, Mannis MJ, Hills JF, Johnson CA. Corneal epithelial healing after penetrating keratoplasty using topical Healon versus balanced salt solution. Ophthalmic Surg. 1987;18(7):525–8.

    CAS  PubMed  Google Scholar 

  29. Tsujinaka H, Fu J, Shen J, Yu Y, Hafiz Z, Kays J, et al. Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles. Nat Commun. 2020;11(1):694.

    Article  CAS  Google Scholar 

  30. Yang J, Luo L, Oh Y, Meng T, Chai G, Xia S, et al. Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats. J Control Release. 2020;327:456–66.

    Article  CAS  Google Scholar 

  31. Rosca ID, Watari F, Uo M. Microparticle formation and its mechanism in single and double emulsion solvent evaporation. J Control Release. 2004;99(2):271–80.

    Article  CAS  Google Scholar 

  32. Benelli U. Systane lubricant eye drops in the management of ocular dryness. Clin Ophthalmol. 2011;5:783–90.

    Article  Google Scholar 

  33. Shastri D, Patel L, Parikh R. Studies on in situ hydrogel: a smart way for safe and sustained ocular drug delivery. J Young Pharm. 2010;2(2):116–20.

    Article  CAS  Google Scholar 

  34. Johansen S, Rask-Pedersen E, Prause JU. An ocular bioavailability comparison in rabbits of prednisolone acetate after repeated topical applications formulated as a high-viscosity gel and as an aqueous suspension. Acta Ophthalmol Scand. 1996;74(3):259–64.

    Article  CAS  Google Scholar 

  35. Shimmura S, Goto E, Shimazaki J, Tsubota K. Viscosity-dependent fluid dynamics of eyedrops on the ocular surface. Am J Ophthalmol. 1998;125(3):386–8.

    Article  CAS  Google Scholar 

  36. Burdick JA, Chung C, Jia X, Randolph MA, Langer R. Controlled degradation and mechanical behavior of photopolymerized hyaluronic acid networks. Biomacromolecules. 2005;6(1):386–91.

    Article  CAS  Google Scholar 

  37. von Schantz L, Schagerlöf H, Karlsson EN, Ohlin M. Characterization of the substitution pattern of cellulose derivatives using carbohydrate-binding modules. BMC Biotechnol. 2014;14(1):1.

    Google Scholar 

Download references

Acknowledgments

The authors are grateful to Kyung Min Park and Sharon Gerecht for offering help with rheometer operation, and thankful for Maria Jose Suarez for help with histology imaging.

Funding

Funding for this study was provided by National Institutes of Health (R01EY027827, P30-EY001765), the George and Lavinia Blick Research Fund, and the Johns Hopkins University Office of the Provost.

Author information

Authors and Affiliations

  1. Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, Maryland, 21231, USA

    Shiyu Xia, Zheng Ding, Lixia Luo, Baiwei Chen, Joanna Schneider, Jin Yang, Walter J. Stark & Qingguo Xu

  2. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland, 21218, USA

    Shiyu Xia & Joanna Schneider

  3. Department of Biomedical Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland, 21218, USA

    Zheng Ding

  4. Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, Maryland, 21231, USA

    Lixia Luo, Jin Yang, Charles G. Eberhart, Walter J. Stark & Qingguo Xu

  5. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21231, USA

    Charles G. Eberhart

  6. Departments of Pharmaceutics and Ophthalmology, Virginia Commonwealth University, Richmond, Virginia, 23298, USA

    Qingguo Xu

Authors
  1. Shiyu Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zheng Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lixia Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Baiwei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joanna Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles G. Eberhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Walter J. Stark
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qingguo Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qingguo Xu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Guest Editors: Qingguo Xu and Iok-Hou Pang

Publisher’s Note

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

Supplementary Information

ESM 1

(DOCX 1604 kb)

(MP4 3418 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xia, S., Ding, Z., Luo, L. et al. Shear-Thinning Viscous Materials for Subconjunctival Injection of Microparticles. AAPS PharmSciTech 22, 8 (2021). https://doi.org/10.1208/s12249-020-01877-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-01877-9

KEY WORDS

Search

Navigation