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The AAPS Journal

, 21:59 | Cite as

Biodegradable Thermosensitive PLGA-PEG-PLGA Polymer for Non-irritating and Sustained Ophthalmic Drug Delivery

  • Pui Shan Chan
  • Jia Wen Xian
  • Qingqing Li
  • Chun Wai Chan
  • Sharon S. Y. LeungEmail author
  • Kenneth K. W. ToEmail author
Research Article

Abstract

Challenges of ophthalmic drug delivery arise from not only the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of the eyes. Biodegradable thermosensitive polymer, poly(dl-lactide-co-glycolide-b–ethylene glycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) is a desirable ophthalmic drug delivery system because it can be formulated into injectable solution which forms gel in situ to provide prolonged drug release. In this study, excellent biocompatibility of blank PLGA-PEG-PLGA (1800-1500-1800) thermogel was demonstrated with insignificant difference from saline noted in rat eye enucleation test, in vivo inflammation test upon topical instillation, and subconjunctival injection. After subconjunctival injection, thermogel formulations loaded with hydrophilic (rhodamine B) or hydrophobic (coumarin 6) fluorescent dyes were retained up to 4 weeks in eye tissues and significantly higher level was detected than rhodamine B solution or coumarin 6 suspension in weeks 3 and 4. Moreover, in vivo whole body imaging showed that dye-loaded (sulfo-cyanine 7 NHS ester, Cy7; or cyanine 7.5 alkyne, Cy7.5) thermogels had longer retention at the injection site and retarded release to other body parts than dye solutions. Generally, the release rate of hydrophobic dyes (coumarin 6 and Cy7.5) was much slower than that of the hydrophilic dyes (rhodamine B and Cy7) from the thermogel. In summary, the thermogel was safe for ophthalmic drug delivery and could deliver both hydrophobic and hydrophilic compounds for sustained drug release into eye tissues with single subconjunctival injection for better patient compliance and reduced risks on repeated injection.

KEY WORDS

biocompatibility in situ thermosensitive hydrogel ocular delivery PLGA-PEG-PLGA subconjunctival injection 

Notes

Acknowledgments

P.S. Chan and Q. Li were supported by postgraduate studentships provided by The Chinese University of Hong Kong. Substantial contribution by Prof. Thomas Lee in terms of conception of research idea, experimental design, and funding support is greatly acknowledged. Also, precious discussion with Prof. Albert H.L. Chow and Prof. Vincent H.L. Lee is gratefully acknowledged.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12248_2019_326_MOESM1_ESM.docx (504 kb)
ESM 1 (DOCX 504 kb)
12248_2019_326_MOESM2_ESM.docx (114 kb)
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References

  1. 1.
    Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348–60.CrossRefGoogle Scholar
  2. 2.
    Schoenwald RD, Huang H. Corneal penetration behavior of β-blocking agents I: physicochemical factors. J Pharm Sci. 1983;72(11):1266–72.CrossRefGoogle Scholar
  3. 3.
    Schoenwald RD. Ocular drug delivery. Clin Pharmacokinet. 1990;18(4):255–69.CrossRefGoogle Scholar
  4. 4.
    Lang JC. Ocular drug delivery conventional ocular formulations. Adv Drug Deliv Rev. 1995;16(1):39–43.CrossRefGoogle Scholar
  5. 5.
    Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3(2):275–87.CrossRefGoogle Scholar
  6. 6.
    Rong X, Mo X, Ren T, Yang S, Yuan W, Dong J, et al. Neuroprotective effect of erythropoietin-loaded composite microspheres on retinal ganglion cells in rats. Eur J Pharm Sci. 2011;43(4):334–42.CrossRefGoogle Scholar
  7. 7.
    Tanito M, Li F, Elliott MH, Dittmar M, Anderson RE. Protective effect of TEMPOL derivatives against light-induced retinal damage in rats. Invest Ophthalmol Vis Sci. 2007;48(4):1900–5.CrossRefGoogle Scholar
  8. 8.
    Froger N, Cadetti L, Lorach H, Martins J, Bemelmans A, Dubus E, et al. Taurine provides neuroprotection against retinal ganglion cell degeneration. PLoS One. 2012;7(10):e42017.CrossRefGoogle Scholar
  9. 9.
    HS Boddu S, Gupta H, Patel S. Drug delivery to the back of the eye following topical administration: an update on research and patenting activity. Recent Pat Drug Deliv Formul. 2014;8(1):27–36.CrossRefGoogle Scholar
  10. 10.
    Aburahma MH, Mahmoud AA. Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: preparation and in vitro/in vivo evaluation. AAPS PharmSciTech. 2011;12(4):1335–47.CrossRefGoogle Scholar
  11. 11.
    Ghate D, Edelhauser HF. Barriers to glaucoma drug delivery. J Glaucoma. 2008 Mar;17(2):147–56.CrossRefGoogle Scholar
  12. 12.
    Sampat KM, Garg SJ. Complications of intravitreal injections. Curr Opin Ophthalmol. 2010 May;21(3):178–83.CrossRefGoogle Scholar
  13. 13.
    Lallemand F, Schmitt M, Bourges J, Gurny R, Benita S, Garrigue J. Cyclosporine A delivery to the eye: a comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm. 2017;117:14–28.CrossRefGoogle Scholar
  14. 14.
    Weijtens O, Feron EJ, Schoemaker RC, Cohen AF, Lentjes EG, Romijn FP, et al. High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am J Ophthalmol. 1999;128(2):192–7.CrossRefGoogle Scholar
  15. 15.
    Weijtens O, Schoemaker RC, Lentjes EG, Romijn FP, Cohen AF, van Meurs JC. Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose. Ophthalmology. 2000 Oct;107(10):1932–8.CrossRefGoogle Scholar
  16. 16.
    Wakshull E, Quarmby V, Mahler H, Rivers H, Jere D, Ramos M, et al. Advancements in understanding immunogenicity of biotherapeutics in the intraocular space. AAPS J. 2017;19(6):1656–68.CrossRefGoogle Scholar
  17. 17.
    Luo Z, Jin L, Xu L, Zhang ZL, Yu J, Shi S, et al. Thermosensitive PEG–PCL–PEG (PECE) hydrogel as an in situ gelling system for ocular drug delivery of diclofenac sodium. Drug Deliv. 2016;23(1):63–8.CrossRefGoogle Scholar
  18. 18.
    Cho H, Kwon GS. Thermosensitive poly-(d, l-lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly-(d, l-lactide-co-glycolide) hydrogels for multi-drug delivery. J Drug Target. 2014;22(7):669–77.CrossRefGoogle Scholar
  19. 19.
    Qiao M, Chen D, Ma X, Liu Y. Injectable biodegradable temperature-responsive PLGA–PEG–PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int J Pharm. 2005;294(1–2):103–12.CrossRefGoogle Scholar
  20. 20.
    Shim MS, Lee HT, Shim WS, Park I, Lee H, Chang T, et al. Poly (D, L-lactic acid-co-glycolic acid)-b-poly (ethylene glycol)-b-poly (D, L-lactic acid-co-glycolic acid) triblock copolymer and thermoreversible phase transition in water. J Biomed Mater Res A. 2002;61(2):188–96.CrossRefGoogle Scholar
  21. 21.
    Duvvuri S, Janoria KG, Mitra AK. Development of a novel formulation containing poly (d, l-lactide-co-glycolide) microspheres dispersed in PLGA–PEG–PLGA gel for sustained delivery of ganciclovir. J Control Release. 2005;108(2–3):282–93.CrossRefGoogle Scholar
  22. 22.
    Gao Y, Sun Y, Ren F, Gao S. PLGA–PEG–PLGA hydrogel for ocular drug delivery of dexamethasone acetate. Drug Dev Ind Pharm. 2010;36(10):1131–8.CrossRefGoogle Scholar
  23. 23.
    Duvvuri S, Janoria KG, Pal D, Mitra AK. Controlled delivery of ganciclovir to the retina with drug-loaded poly (d, L-lactide-co-glycolide)(PLGA) microspheres dispersed in PLGA-PEG-PLGA gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis. J Ocul Pharmacol Ther. 2007;23(3):264–74.CrossRefGoogle Scholar
  24. 24.
    Pratoomsoot C, Tanioka H, Hori K, Kawasaki S, Kinoshita S, Tighe PJ, et al. A thermoreversible hydrogel as a biosynthetic bandage for corneal wound repair. Biomaterials. 2008;29(3):272–81.CrossRefGoogle Scholar
  25. 25.
    Zhang L, Shen W, Luan J, Yang D, Wei G, Yu L, et al. Sustained intravitreal delivery of dexamethasone using an injectable and biodegradable thermogel. Acta Biomater. 2015;23:271–81.CrossRefGoogle Scholar
  26. 26.
    Xie B, Jin L, Luo Z, Yu J, Shi S, Zhang Z, et al. An injectable thermosensitive polymeric hydrogel for sustained release of Avastin® to treat posterior segment disease. Int J Pharm. 2015;490(1–2):375–83.CrossRefGoogle Scholar
  27. 27.
    Cuming RS, Abarca EM, Duran S, Wooldridge AA, Stewart AJ, Ravis W, et al. Development of a sustained-release voriconazole-containing thermogel for subconjunctival injection in horses. Invest Ophthalmol Vis Sci. 2017;58(5):2746–54.CrossRefGoogle Scholar
  28. 28.
    Kim YJ, Choi S, Koh JJ, Lee M, Ko KS, Kim SW. Controlled release of insulin from injectable biodegradable triblock copolymer. Pharm Res. 2001;18(4):548–50.CrossRefGoogle Scholar
  29. 29.
    Rieke ER, Amaral J, Becerra SP, Lutz RJ. Sustained subconjunctival protein delivery using a thermosetting gel delivery system. J Ocul Pharmacol Ther. 2010;26(1):55–64.CrossRefGoogle Scholar
  30. 30.
    Wang P, Chu W, Zhuo X, Zhang Y, Gou J, Ren T, et al. Modified PLGA–PEG–PLGA thermosensitive hydrogels with suitable thermosensitivity and properties for use in a drug delivery system. J Mater Chem B. 2017;5(8):1551–65.CrossRefGoogle Scholar
  31. 31.
    Wilson SL, Ahearne M, Hopkinson A. An overview of current techniques for ocular toxicity testing. Toxicology. 2015;327:32–46.CrossRefGoogle Scholar
  32. 32.
    Prinsen M, Koëter H. Justification of the enucleated eye test with eyes of slaughterhouse animals as an alternative to the Draize eye irritation test with rabbits. Food Chem Toxicol. 1993;31(1):69–76.CrossRefGoogle Scholar
  33. 33.
    Fujishima H, Toda I, Yamada M, Sato N, Tsubota K. Corneal temperature in patients with dry eye evaluated by infrared radiation thermometry. Br J Ophthalmol. 1996;80(1):29–32.CrossRefGoogle Scholar
  34. 34.
    Purslow C, Wolffsohn JS. Ocular surface temperature: a review. Eye Contact Lens. 2005;31(3):117–23.CrossRefGoogle Scholar
  35. 35.
    Choi S, Baudys M, Kim SW. Control of blood glucose by novel GLP-1 delivery using biodegradable triblock copolymer of PLGA-PEG-PLGA in type 2 diabetic rats. Pharm Res. 2004;21(5):827–31.CrossRefGoogle Scholar
  36. 36.
    Liu CB, Gong CY, Huang MJ, Wang JW, Pan YF, Zhang YD, et al. Thermoreversible gel–sol behavior of biodegradable PCL-PEG-PCL triblock copolymer in aqueous solutions. J Biomed Mater Res B Appl Biomater. 2008;84(1):165–75.CrossRefGoogle Scholar
  37. 37.
    Nagahama K, Takahashi A, Ohya Y. Biodegradable polymers exhibiting temperature-responsive sol–gel transition as injectable biomedical materials. React Funct Polym. 2013;73(7):979–85.CrossRefGoogle Scholar
  38. 38.
    Yuan B, He C, Dong X, Wang J, Gao Z, Wang Q, et al. 5-Fluorouracil loaded thermosensitive PLGA–PEG–PLGA hydrogels for the prevention of postoperative tendon adhesion. RSC Adv. 2015;5(32):25295–303.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Pui Shan Chan
    • 1
  • Jia Wen Xian
    • 2
  • Qingqing Li
    • 1
  • Chun Wai Chan
    • 2
  • Sharon S. Y. Leung
    • 1
    Email author
  • Kenneth K. W. To
    • 1
    Email author
  1. 1.School of Pharmacy, Faculty of MedicineThe Chinese University of Hong KongShatin, N.T.China
  2. 2.School of Chinese Medicine, Faculty of MedicineThe Chinese University of Hong KongShatin, N.T.China

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