ADVANCES IN POLYPHENOL-BASED OCULAR DRUG DELIVERY: MECHANISTIC INSIGHTS, FORMULATION INNOVATIONS, AND TRANSLATIONAL PERSPECTIVES

Authors

  • ASHOK KUMAR JANAKIRAMAN Faculty of Pharmaceutical Sciences, UCSI University-56000 Cheras, Kuala Lumpur, Malaysia. Department of Pharmaceutics, Dr. Kalam College of Pharmacy, Avanam-614623, Thanjavur, Tamil Nadu, India. Faculty of Health and Life Sciences, INTI International University-71800 Nilai, Malaysia https://orcid.org/0000-0002-9670-8323
  • MOUNEESHWARAN MOORTHY Faculty of Pharmaceutical Sciences, UCSI University-56000 Cheras, Kuala Lumpur, Malaysia https://orcid.org/0009-0003-0178-9795
  • MADHAN KUMAR SOUTALLU JANAKIRAM Department of Anatomy, Faculty of Medicine, Manipal University College Malaysia, Melaka-75150, Malaysia https://orcid.org/0000-0002-1395-6453
  • SAMINATHAN KAYAROHANAM Faculty of Bioeconomics, Food and Health Sciences, Universiti Geomatika Malaysia, Kuala Lumpur-54200, Malaysia https://orcid.org/0000-0002-1235-1217
  • CHENG WAN HEE Faculty of Health and Life Sciences, INTI International University-71800 Nilai, Malaysia https://orcid.org/0000-0002-2311-2377
  • MOHAMED SALEEM TS Department of Pharmacology, College of Pharmacy, Riyadh ELM University, Riyadh-12737, Saudi Arabia
  • RAVI SHESHALA Department of Pharmaceutics, School of Pharmacy, Anurag University, Venkatapur, Ghatkesar, Medchal–Malkajgiri District, Hyderabad-500088, Telangana, India. Department of Pharmacology and Life Sciences, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus-42300 Bandar Puncak Alam, Selangor, Malaysia https://orcid.org/0000-0001-5255-3238
  • HANISH SINGH JAYASINGH CHELLAMMAL Department of Pharmacology and Life Sciences, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus-42300 Bandar Puncak Alam, Selangor, Malaysia https://orcid.org/0000-0001-9110-606X

DOI:

https://doi.org/10.22159/ijap.2026v18i3.57271

Keywords:

Polyphenols, Ocular drug delivery, Nanoemulsions, Nanocarriers, Enhanced ocular penetration

Abstract

Polyphenols, a structurally diverse class of plant-derived phytoconstituents, possess potent antioxidant, anti-inflammatory, and vasoprotective properties that make them promising therapeutic candidates for ocular disorders driven by oxidative stress, chronic inflammation, and overall health. Despite this potential, their clinical translation remains restricted due to the inherent limitations of conventional ocular delivery systems, such as low ocular bioavailability, rapid precorneal elimination, poor corneal permeability, and inadequate targeting of posterior ocular tissues. To address these challenges, recent research has focused on advanced formulation approaches designed to enhance polyphenol retention, penetration, and sustained release within ocular tissues. These include nanoemulsions, polymeric micelles lipid and polymer-based nanocarriers, in situ gelling systems, mucoadhesive and stimuli-responsive platforms, and advanced drug delivery platforms for the posterior and anterior ocular segments. Mechanistically, these systems exploit physicochemical and biological strategies such as enhancing mucoadhesion, modulating paracellular transport, and leveraging endocytic uptake to improve drug disposition and therapeutic performance. The review critically examines these innovative formulation platforms, delineates their pharmacokinetic and pharmacodynamic outcomes, and discusses safety, manufacturing challenges, and regulatory considerations that presently influence their clinical progression. Overall, it highlights emerging formulation technologies most likely to facilitate the successful clinical translation of polyphenol-based ocular therapies.

References

1. Ahmed S, Amin MM, Sayed S. Ocular drug delivery: a comprehensive review. AAPS PharmSciTech. 2023; 24 (2):66. doi:10.1208/s12249-023-02516-9.

2. Mitra AK. Ophthalmic drug delivery systems. New York: Marcel Dekker; 2005.

3. Wang C, Liu X, Lv W, Kuang X, Wu F ,Fan X, et al. Long-lasting comfort ocular surface drug delivery by in situ formation of an adhesive lubricative Janus nanocoating. Sci Adv. 2025; 11 (10): eads0282. doi:10.1126/sciadv.ads0282.

4. Yao W, Sun K, Mu H, Liang N, Liu Y, Yao C, et al. Preparation and characterization of puerarin dendrimer complexes as an ocular drug delivery system. Drug Dev Ind Pharm. 2010;36(9):1027-1035. doi:10.3109/03639041003610799.

5. Jani HS, Ranch K, Pandya R, Patel Y, Boddu S, Tiwari A, et al. An update on novel drug delivery systems for the management of glaucoma. Pharmaceutics. 2025;17 (8):1087. doi:10.3390/pharmaceutics17081087.

6. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. doi:10.5497/wjp.v2.i2.47.

7. Mostafa M, Al Fatease A, Alany RG, Abdelkader H. Recent advances of ocular drug delivery systems: prominence of ocular implants for chronic eye diseases. Pharmaceutics. 2023;15(6):1746. doi:10.3390/pharmaceutics15061746.

8. Ung L, Pattamatta U, Carnt N, Wilkinson-Berka JL, Liew G, White AJR. Oxidative stress and reactive oxygen species: a review of their role in ocular disease. Clin Sci (Lond). 2017;131(24):2865-2883. doi:10.1042/CS20171246.

9. Zhang J, Tuo J, Wang Z, Zhu A, Machalińska A, Long Q. Pathogenesis of common ocular diseases. J Ophthalmol. 2015;2015:734527. doi:10.1155/2015/734527.

10. Li Y, Liang L, Snelligen T, Xu K, Gao Y, Zhang F, et al. Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial. Trials. 2021;22(1):69. doi:10.1186/s13063-021-05025-x.

11. Tang KXH, Iqbal T, Lott PPW, Reddy SC. Prevalence of visual impairment and eye diseases in Malaysia: a cross-sectional prospective study at the University of Malaya Medical Centre. Malays Fam Physician. 2024;19:30. doi:10.51866/OA.549.

12. Chew FLM, Salowi M, Mustari Z, HusnM, Hussein E, Adnan T, et al. Estimates of visual impairment and its causes from the national eye survey in Malaysia (NESII). PLoS One. 2018;13(6):e0198799. doi:10.1371/journal.pone.0198799.

13. Zainal M, Ismail SM, Ropilah AR, Elias H, Arumugam G, Alias D, et al. Prevalence of blindness and low vision in Malaysian population: results from the National Eye Survey 1996. Br J Ophthalmol. 2002;86(9):951-956. doi:10.1136/bjo.86.9.951.

14. Rudrapal M, Khairmar S, Khan J, Dukhyil A, Ansari M, Alomary M, et al. Dietary polyphenols and their role in oxidative stress-induced human diseases: insights into protective effects, antioxidant potentials and mechanism(s) of action. Front Pharmacol. 2022;13:806470. doi:10.3389/fphar.2022.806470.

15. Sinha D. Pharmacological importance of polyphenols: a review. Int Res J Pharm. 2019;10(9):13-23. doi:10.7897/2230-8407.1009255.

16. Rasouli H, Farzaei MH, Khodarahmi R. Polyphenols and their benefits: a review. International Journal of Food Properties. 2017: 20(sup2), 1700–1741. 2018;58(4):829-846. doi:10.1080/10942912.2017.1354017.

17. Feng J, Zhang Y. The potential benefits of polyphenols for corneal diseases. Biomed Pharmacother. 2023;169:115862. doi:10.1016/j.biopha.2023.115862.

18. Ng D, Altamirano-Vallejo J, Gonzalez-De la Rosa A, Navarro-Partida J, Valdez-Garcia J, Acosta-Gonzalez R, et al. An oral polyphenol formulation to modulate the ocular surface inflammatory process and to improve the symptomatology associated with dry eye disease. Nutrients. 2022;14(15):3236. doi:10.3390/nu14153236.

19. Bungau S, Abdel-Daim M, Tit D, Ghanem E, Sato S, Maruyama-Inoue M, et al. Health benefits of polyphenols and carotenoids in age-related eye diseases. Oxid Med Cell Longev. 2019; 9783429. doi:10.1155/2019/9783429.

20. Wang Y, Zhang J, Zhao Y, Pu M, Song X, Yu L, et al. Innovations and challenges of polyphenol-based smart drug delivery systems. Nano Res. 2022;15(9):8156-8184. doi:10.1007/s12274-022-4430-3.

21. Rudrapal M, Mishra A, Rani L, Sarwa K, Zothantluanga J, Khan J, et al. Nanodelivery of dietary polyphenols for therapeutic applications. Molecules. 2022;27(24):8706. doi:10.3390/molecules27248706.

22. Tsung TH, Tsai YC, Lee HP, Chen YH, Lu DW. Biodegradable polymer-based drug-delivery systems for ocular diseases. Int J Mol Sci. 2023;24(16):12976. doi:10.3390/ijms241612976.

23. Razavi MS, Ebrahimnejad P, Fatahi Y, D'Emanuele A, Dinarvand R. Recent developments of nanostructures for the ocular delivery of natural compounds. Front Chem. 2022;10:850757. doi:10.3389/fchem.2022.850757.

24. Krstić L, González-García MJ, Diebold Y. Ocular delivery of polyphenols: meeting the unmet needs. Molecules. 2021;26(2):370. doi:10.3390/molecules26020370.

25. Bisen A, Biswas A, Dubey A, Sanap S, Agrawal S, Yadav K, et al. A review on polymers in ocular drug delivery systems. MedComm Biomater Appl. 2024;3(2):e77. doi:10.1002/mba2.77.

26. Sapowadia A, Ghanbariamin D, Zhou L, Zhou Q, Schmidt T, Tamayol A, et al. Biomaterial drug delivery systems for prominent ocular diseases. Pharmaceutics. 2023;15(7):1959. doi:10.3390/pharmaceutics15071959.

27. Lin X, Zhou Y, Lv K, Wu W, Chen C. Nanomedicine-based ophthalmic drug delivery systems for the treatment of ocular diseases. Int J Nanomedicine. 2025;20:9221-9249. doi:10.2147/IJN.S532074.

28. Bhaskar R, Ola M, Madwe V, Tikhe R, Pawar A, Khade S, et al. Eye drops to smart gels: the future of ocular drug delivery. J Drug Deliv Ther. 2025;15(5):181-193. doi:10.22270/jddt.v15i5.7115.

29. Gao Q, Chu X, Yang J, Guo Y, Guo H, Qian S, et al. An antibiotic nanobomb constructed from pH-responsive chemical bonds in metal-phenolic network nanoparticles for biofilm eradication and corneal ulcer healing. Adv Sci (Weinh). 2024;11(22):2309086. doi:10.1002/advs.202309086.

30. Chimento A, De Amicis F, Sirianni R, Sinicropi M, Puoci F, Casaburi I, et al. Progress to improve oral bioavailability and beneficial effects of resveratrol. Int J Mol Sci. 2019;20(6):1381. doi:10.3390/ijms20061381.

31. Fakhri S, Abbaszadeh F, Moradi SZ, Cao H, Khan H, Xiao J. Effects of polyphenols on oxidative stress, inflammation, and interconnected pathways during spinal cord injury. Oxid Med Cell Longevitv. 2022;8100195. doi:10.1155/2022/8100195.

32. Caban M, Owczarek K, Chojnacka K, Lewandowska U. Overview of polyphenols and polyphenol-rich extracts as modulators of inflammatory response in dry eye syndrome. Food Rev Int. 2022;38(Suppl 1):501-528. doi:10.1080/87559129.2021.1874412.

33. Vora D, Heruye S, Kumari D, Opere C, Chauhan H. Preparation, characterization and antioxidant evaluation of poorly soluble polyphenol-loaded nanoparticles for cataract treatment. AAPS PharmSciTech. 2019;20(5):163. doi:10.1208/s12249-019-1379-y.

34. Alabdali AYM, Chinnappan S, Abd Razik BM, et al. Pharmacological activities of curcumin: an update. Res J Pharm Technol. 2022;15(6):2809-2813. doi: 10.52711/0974-360X.2022.00469 .

35. Alkozi HA, Franco R, Pintor JJ. Epigenetics in the eye: an overview of the most relevant ocular diseases. Front Genet. 2017;8:144. doi:10.3389/fgene.2017.00144.

36. Dong Y, Wan G, Yan P, Qian C, Li F, Peng G. Fabrication of resveratrol coated gold nanoparticles and investigation of their effect on diabetic retinopathy in streptozotocin induced diabetic rats. J Photochem Photobiol B. 2019;195:51-57. doi:10.1016/j.jphotobiol.2019.04.012.

37. Wong CN, Lim YM, Liew KB, Chew YL, Chua AL, Lee SK. EGCG as a therapeutic agent: a systematic review of recent advances and challenges in nanocarrier strategies. J Zhejiang Univ Sci B. 2025;26(7):633-656. doi:10.1631/jzus.B2400040.

38. Conte R, De Luca I, Calarco A, Finicelli M, Peluso G. Polyphenol-loaded nanodevices as innovative therapeutic strategies for dry eye disease: advances and perspectives. Antioxidants (Basel). 2025;14(11):1280. doi:10.3390/antiox14111280.

39. Dutta S, Subramanian A, Kumarasamy V, Tamilanban T, Begum M, Sekar M, et al. Network pharmacology of natural polyphenols for stroke: a bioinformatic approach to drug design. Adv Appl Bioinform Chem. 2025;17(0):203-219. doi:10.2147/AABC.S470861.

40. Fanaro G, Marques M, Calaza K, Brito R, Pessoni A, Mendonça H, et al. New insights on dietary polyphenols for the management of oxidative stress and neuroinflammation in diabetic retinopathy. Antioxidants (Basel). 2023;12(6):1237. doi:10.3390/antiox12061237.

41. Zhao J, Xiong J, Ning Y, Zhao J, Wang Z, Long L, et al. A triple crosslinked micelle-hydrogel lacrimal implant for localized and prolonged therapy of glaucoma. Eur J Pharm Biopharm. 2023;185:44-54. doi:10.1016/j.ejpb.2023.02.011.

42. Tsung TH, Chen YH, Lu DW. Updates on biodegradable formulations for ocular drug delivery. Pharmaceutics. 2023;15(3):734. doi:10.3390/pharmaceutics15030734.

43. Wu Y, Wang L, Hu C, Tian R. mPEG-PCL modified caffeic acid eye drops for endotoxin-induced uveitis treatment. Sci Rep. 2025;15(1):9018. doi:10.1038/s41598-025-94296-4.

44. Burgalassi S, Zucchetti E, Birindelli E, Tampucci S, Chetoni P, Monti D. Ocular application of oleuropein in dry eye treatment: formulation studies and biological evaluation. Pharmaceuticals (Basel). 2021;14(11):1151. doi:10.3390/ph14111151.

45. De Luca I, Di Cristo F, Conte R, Peluso G, Cerruti P, Calarco A. In-situ thermoresponsive hydrogel containing resveratrol-loaded nanoparticles as a localized drug delivery platform for dry eye disease. Antioxidants (Basel). 2023;12(5):993. doi:10.3390/antiox12050993.

46. Hu L, Xu Y, Meng H. Development and evaluation of puerarin loaded-albumin nanoparticles thermoresponsive in situ gel for ophthalmic delivery. Drug Des Devel Ther. 2022;16:3315-3326. doi:10.2147/DDDT.S374061.

47. Zhang R, Yang J, Luo Q, Shi J, Xu H, Zhang J. Preparation and in vitro and in vivo evaluation of an isoliquiritigenin-loaded ophthalmic nanoemulsion for the treatment of corneal neovascularization. Drug Deliv. 2022;29(1):2217-2233. doi:10.1080/10717544.2022.2096714.

48. Dinte E, Vostinaru O, Samoila O, Sevastre B, Bodoki E. Ophthalmic nanosystems with antioxidants for the prevention and treatment of eye diseases. Coatings. 2020;10(1):36. doi:10.3390/coatings10010036.

49. Liu R, Liu Z, Zhang C, Zhang B. Nanostructured lipid carriers as novel ophthalmic delivery system for mangiferin: improving in vivo ocular bioavailability. J Pharm Sci. 2012;101(10):3833-3844. doi:10.1002/jps.23251.

50. Ahmed B, Saini N, Barathi VA, Patravale VB, Shah RM, Kaur IP. Innovative solid lipid nanoparticle formulations for ocular therapeutics and related patents: a systematic review. J Control Release. 2025;385:113992. doi:10.1016/j.jconrel.2025.113992.

51. Favero G, Moretti E, Krajčíková K, Tomečková V, Rezzani R. Evidence of polyphenols efficacy against dry eye disease. Antioxidants (Basel). 2021;10(2):190. doi:10.3390/antiox10020190.

52. Zhao L, Song J, Du Y, Ren C, Guo B, Bi H. Therapeutic applications of contact lens-based drug delivery systems in ophthalmic diseases. Drug Deliv. 2023;30(1):2219419. doi:10.1080/10717544.2023.2219419.

53. Vieira L, Moreira C, Castro B, Cotta O, Silva L, Fulgêncio G, et al. Rosmarinic acid intravitreal implants: a new therapeutic approach for ocular neovascularization. Planta Med. 2020;86(17):1286-1297. doi:10.1055/a-1223-2525.

54. Majumdar S, Srirangam R. Potential of the bioflavonoids in the prevention/treatment of ocular disorders. J Pharm Pharmacol. 2010;62(8):951-965. doi:10.1211/jpp.62.08.0001.

55. Kim D, Maharjan P, Jin M, Park T, Maharjan A, Amatya R, et al. Potential albumin-based antioxidant nanoformulations for ocular protection against oxidative stress. Pharmaceutics. 2019;11(7):297. doi:10.3390/pharmaceutics11070297.

56. Jhanji V, Liu H, Law K, Lee V, Huang S, Pang C, et al. Isoliquiritigenin from licorice root suppressed neovascularisation in experimental ocular angiogenesis models. Br J Ophthalmol. 2011;95(9):1309-1315. doi:10.1136/bjophthalmol-2011-300110.

57. Andrade-Arenas L, Yactayo-Arias C. Advances in the diagnosis of ocular diseases: an innovative approach through an expert system. Bull Electr Eng Inform. 2024;13(4):2828-2840. doi:10.11591/eei.v13i4.7971.

Published

27-02-2026

How to Cite

JANAKIRAMAN, A. K., MOORTHY, M., SOUTALLU JANAKIRAM, M. K., KAYAROHANAM, S., HEE, C. W., SALEEM TS, M., … JAYASINGH CHELLAMMAL, H. S. (2026). ADVANCES IN POLYPHENOL-BASED OCULAR DRUG DELIVERY: MECHANISTIC INSIGHTS, FORMULATION INNOVATIONS, AND TRANSLATIONAL PERSPECTIVES. International Journal of Applied Pharmaceutics, 18(3). https://doi.org/10.22159/ijap.2026v18i3.57271

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