Liposomal Drugs in Ophthalmotherapy: Development and Clinical Translation
DOI:
https://doi.org/10.60988/p.v38i2.149Keywords:
drug delivery system, Liposomes, emulsion, bioavailability, ophthalmology, eye dropsAbstract
The success of ophthalmotherapy depends significantly on the physicochemical affinity or antagonism of the eye structures and the drug. The pronounced hydrophobicity of the corneal epithelium promotes the delivery of lipophilic drugs to the eye and limits the penetration of hydrophilic systems. The translation of active pharmaceutical ingredients incorporated into drug delivery systems can be a targeted approach to the optimization of the ophthalmotherapy. Liposomal systems have an uncontested status among known drug delivery systems due to a complex of sought-after characteristics of liposomal nanoparticles.
The aim of this article is to review the knowledge accumulated to date on the use of liposomal forms in ophthalmological clinical practice as well as perspective composition under development. An analysis of the market of liposomal ophthalmic drugs, well-established in clinical practice, has been conducted. In particular, the liposomal form of verteporphyrin, vitamins A and E, the bioflavonoid quercetin, as well as drugs based on "empty" liposomes were discussed. In addition, data on promising liposomal ophthalmic drugs that are under development are provided.
The results of current clinical and experimental studies reflect the advantages of the effectiveness of action, safety and targeting of ocular transport of liposomal forms of drugs of variable nature in the prevention and treatment of a wide range of common ophthalmological pathologies. Optimized pharmacotoxicological profile and verification of ophthalmological quality of liposomal preparations in combination with a favorable pharmacoeconomic basis substantiate the irreplaceable role of the liposomal factor in modern ophthalmotherapy technologies.
References
1. Rommasi F., Esfandiari N. Liposomal Nanomedicine: Applications for Drug Delivery in Cancer Therapy. Nanoscale research letters. 16(1), 95, 2021. https://doi.org/10.1186/s11671-021-03553-8
2. Amin M., Seynhaeve A.L.B., Sharifi M., Falahati M., Ten Hagen T.L.M. Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience. Pharmaceutics. 14(10), 2165, 2022. https://doi.org/10.3390/pharmaceutics14102165
3. Krasnopolsky Y., Pylypenko D. Licensed liposomal vaccines and adjuvants in the antigen delivery system. Biotechnologia. 103(4), 409–423, 2022. https://doi.org/10.5114/bta.2022.120709
4. Dubald M., Bourgeois S., Andrieu V., Fessi H. Ophthalmic Drug Delivery Systems for Antibiotherapy-A Review. Pharmaceutics. 10(1), 10, 2018. https://doi.org/10.3390/pharmaceutics10010010
5. Visudyne. Annex 1. Summary of product Characteristics, 2010. EPAR, 27.
6. Ebrahim S., Peyman G.A., Lee P.J. Applications of liposomes in ophthalmology. Survey of ophthalmology. 50(2), 167–182, 2005. https://doi.org/10.1016/j.survophthal.2004.12.006
7. Lindner L.H., Eichhorn M.E., Eibl H., Teichert N., Schmitt-Sody M., Issels R.D., Dellian M. Novel temperature-sensitive liposomes with prolonged circulation time. Clinical cancer research : an official journal of the American Association for Cancer Research. 10(6), 2168–2178, 2004. https://doi.org/10.1158/1078-0432.ccr-03-0035
8. Liu L.C., Chen Y. H., Lu D.W. Overview of Recent Advances in Nano-Based Ocular Drug Delivery. International journal of molecular sciences. 24(20), 15352, 2023. https://doi.org/10.3390/ijms242015352
9. Meng T., Kulkarni V., Simmers R., Brar V., Xu Q. Therapeutic implications of nanomedicine for ocular drug delivery. Drug discovery today. 24(8), 1524–1538, 2019. https://doi.org/10.1016/j.drudis.2019.05.006
10. Grzella A.N., Schleicher S., Shah-Hosseini K., Astvatsatourov A., Raskopf E., Allekotte S., Mösges R. Liposomal Eye Spray Is as Effective as Antihistamine Eye Drops in Patients with Allergic Rhinoconjunctivitis Induced by Conjunctival Provocation Testing. International archives of allergy and immunology. 179(2), 123–131, 2019. https://doi.org/10.1159/000496938
11. Wang T.Z., Liu X.X., Wang S.Y., Liu Y., Pan X.Y., Wang J.J., Nan K.H. Engineering Advanced Drug Delivery Systems for Dry Eye: A Review. Bioengineering (Basel, Switzerland), 10(1). 53, 2022. https://doi.org/10.3390/bioengineering10010053
12. Grigoryeva G.S., Кrasnopolsky Yu.М. Liposomes per se: pharmacotherapeutical status. Pharmacology and Drug Toxicology. 14(4), 264-271, 2020. https://doi.org/10.33250/14.04.264
13. Stefanov O.V., Grigorieva G.S., Solovyov A.I., Pasechnikova N.V., Khromov A.S., Konakhovich N.F., Krasnopolsky Yu.M. Method for producing a liposomal preparation containing quercetin. Ukraine Patent 76393. 2006.
14. Grigorieva G.S., Krasnopolsky Yu.M., Konakhovich N.F., Pasechnikova N.V. Method for producing a pharmacologically active liposomal agent containing quercetin. Ukraine Patent 111762. 2016.
15. Qi W., Qi W., Xiong D., Long M. Quercetin: Its Antioxidant Mechanism, Antibacterial Properties and Potential Application in Prevention and Control of Toxipathy. Molecules (Basel, Switzerland), 27(19). 6545, 2022. https://doi.org/10.3390/molecules27196545
16. Anand David A.V., Arulmoli R., Parasuraman S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacognosy reviews. 10(20), 84–89, 2016. https://doi.org/10.4103/0973-7847.194044
17. Pylypenko D.M., Gorbach T.V., Katsai O.G., Grigoryeva A.S., Krasnopolsky Yu.M. A study of oxidative stress markers when using the liposomal antioxidant complex. Pharmakeftiki. 31(1), 40–47, 2019.
18. Pylypenko D., Gorbach T., Krasnopolsky Y. Study of antioxidant activity of liposomal forms of quercetin and curcumin in ischemic heart disease. BioTechnologia. 101(4), 273-282, 2020. https://doi.org/10.5114/bta.2020.100420
19. Pescosolido N., Giannotti R., Plateroti A., Pascarella A., Nebbioso M. Curcumin: Therapeutical Potential in Ophthalmology. Planta Medica. 80(4), 249–254, 2013. http://doi.org/10.1055/s-0033-1351074
20. Nebbioso M., Franzone F., Greco A., Gharbiya M., Bonfiglio V., Polimeni A. Recent Advances and Disputes About Curcumin in Retinal Diseases. Clinical ophthalmology (Auckland, N.Z.). 15, 2553–2571, 2021. https://doi.org/10.2147/OPTH.S306706
21. Zhao L., Wang H., Du X. The therapeutic use of quercetin in ophthalmology: recent applications. Biomedicine & pharmacotherapy. 137, 111371, 2021. https://doi.org/10.1016/j.biopha.2021.111371
22. Mikheytseva I.N., Pasechnikova N.V. Flavonoids in ophthalmology — new strategy of pharmacological influence. Journal of the National Academy of Medical Sciences of Ukraine. 21(1), 45-53, 2015.
23. Agarwal R., Iezhitsa I., Agarwal P., Abdul Nasir N.A., Razali N., Alyautdin R., Ismail N.M. Liposomes in topical ophthalmic drug delivery: an update. Drug delivery. 23(4), 1075–1091, 2016. https://doi.org/10.3109/10717544.2014.943336
24. Chen W., Zou M., Ma X., Lv R., Ding T., Liu D. Co-Encapsulation of EGCG and Quercetin in Liposomes for Optimum Antioxidant Activity. Journal of food science. 84(1), 111–120, 2019. https://doi.org/10.1111/1750-3841.14405
25. Petrunya A.M., Zadorozhnaya A.I. The effect of lipoflavon eye drops in the treatment of patients with primary open-angle glaucoma. Ophthalmological journal. 4, 43-46, 2009.
26. Petrunya A.M., Spector A.V. Effectiveness of the use of eye drops and the injectable form of the drug "Lipoflavon" in patients with non-proliferative diabetic retinopathy. Ophthalmological journal. 2, 36-39, 2007.
27. Pasechnikova N.V., Horshkova R.A., Haydamaka T.B. Preliminary assessment of the anti-inflammatory effect of the drug "Lipoflavon" in patients after extracapsular cataract extraction. Ophthalmological journal. 2, 36-39, 2007.
28. Pasechnikova N.V., Horshkova R.A. Clinical and biochemical justification of the use of the drug "Lipoflavon" in patients with age-related cataract after cataract extraction and IOL implantation. Ukrainian medical almanac. 9(1), 219-221, 2006.
29. Umanskaya Yu.V., Putienko A.A. Results of lipoflavone application in patients with age-related maculopathy. Ophthalmological journal. 1, 36-40, 2011.
30. Rafaliuk S.Ya., Gaydamaka T.B. The effectiveness of the bioflavonoid quercetin in the treatment of herpetic keratitis in patients with dry eye syndrome. Ophthalmological Journal. 5, 15-19, 2018.
31. Hreben N.K. Effect of treatment and rehabilitation of patients with chorioretinal eye burns. Pharmacology and medicinal toxicology. 1(42), 36-40, 2015.
32. Fesyunova O.G., Vit V.V., Molchanyuk N.I., Grigorieva G.S. Experimental verification of the safety of periocular methods of application of liposomal form of quercetin in ophthalmology. Pharmaceutical and medical toxicology. 4(48), 94–100, 2016.
33. Honda M., Asai T., Oku N., Araki Y., Tanaka M., Ebihara N. Liposomes and nanotechnology in drug development: focus on ocular targets. International journal of nanomedicine. 8, 495–503, 2013. https://doi.org/10.2147/IJN.S30725
34. Liu Y.C., Lin M.T., Ng A.H.C., Wong T.T., Mehta J. S. Nanotechnology for the Treatment of Allergic Conjunctival Diseases. Pharmaceuticals (Basel, Switzerland). 13(11), 351, 2020. https://doi.org/10.3390/ph13110351
35. Arroyo C.M., Quinteros D., Cózar-Bernal M.J., Palma S.D., Rabasco A.M., González-Rodríguez M.L. Ophthalmic administration of a 10-fold-lower dose of conventional nanoliposome formulations caused levels of intraocular pressure similar to those induced by marketed eye drops. European journal of pharmaceutical sciences. 111, 186–194, 2018. https://doi.org/10.1016/j.ejps.2017.09.024
36. Zhang J., Jiao J., Niu M., Gao X., Zhang G., Yu H., Yang X., Liu L. Ten Years of Knowledge of Nano-Carrier Based Drug Delivery Systems in Ophthalmology: Current Evidence, Challenges, and Future Prospective. International journal of nanomedicine. 16, 6497–6530, 2021. https://doi.org/10.2147/IJN.S329831
37. Natarajan J.V., Ang M., Darwitan A., Chattopadhyay S., Wong T.T., Venkatraman S.S. Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye. International journal of nanomedicine. 7, 123–131, 2012. https://doi.org/10.2147/IJN.S25468
38. Lai S., Wei Y., Wu Q., Zhou K., Liu T., Zhang Y., Jiang N., Xiao W., Chen J., Liu Q., Yu Y. Liposomes for effective drug delivery to the ocular posterior chamber. Journal of nanobiotechnology. 17(1), 64, 2019. https://doi.org/10.1186/s12951-019-0498-7
39. Wong T.T., Novack G.D., Natarajan J.V., Ho C.L., Htoon H.M., Venkatraman S.S. Nanomedicine for glaucoma: sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops. Drug delivery and translational research. 4(4), 303–309, 2014. https://doi.org/10.1007/s13346-014-0196-9
40. Fahmy H.M., Saad E.A.E.S., Sabra N.M., El-Gohary A.A., Mohamed F.F., Gaber M.H. Treatment merits of Latanoprost/Thymoquinone - Encapsulated liposome for glaucomatus rabbits. International journal of pharmaceutics. 548(1), 597–608, 2018. https://doi.org/10.1016/j.ijpharm.2018.07.012
41. Dubey A., Prabhu P., Beladiya K., Nair N., Ghate V. Development and investigation of timolol maleate and latanoprost combination liposomes for the treatment of glaucoma. International Research Journal of Pharmacy. 6(4), 256-264, 2015. http://dx.doi.org/10.7897/2230-8407.06457
42. Singh R.B., Ichhpujani P., Thakur S., Jindal S. Promising therapeutic drug delivery systems for glaucoma: a comprehensive review. Therapeutic advances in ophthalmology. 12, 2515841420905740, 2020. https://doi.org/10.1177/2515841420905740
43. Pylypenko O.Ya., Grigor'eva G.S., Krasnopolsky Yu.M., Konakhovich N.F., Mikheytseva I.M., Pasechnikova N.V., Prokhorov V.V. Method for obtaining a liposomal composition containing latanoprost, and a pharmacologically active liposomal composition for ophthalmotherapy obtained by this method. Ukraine Patent 124724С2. 2021.
44. Pylypenko O.Ya, Grygorieva G.S., Krasnopolsky Yu.M., Konachovych N.F., Myheytseva I.M., Pasechnikova N.V., Prokhorov V.V. Method for preparing a liposomal composition comprising latanoprost, and the pharmacologically active liposomal composition for ophthalmotherapy prepared by this method. US Patent US20220305028A1, 2022.
45. Mikheytseva I.M., Grygorieva G.S., Pasyechnikova N.V., Kolomiichuk S.G., Siroshtanenko T.I., Konakhovych N.F. Ocular hypotensive efficacy of a new liposomal latanoprost formulation administered by different routes for experimental ocular hypertension. Journal of Ophthalmology (Ukraine). 2, 37-41, 2022. http://doi.org/10.31288/oftalmolzh202223741
46. Grygorieva G.S., Mikheytseva I.M., Medvedovska N.V., Kolomiychuk S.G., Konakhovich N.F., Siroshtanenko T.I., Shayachmetova G.M. An experimental study of the safety of the novel latanoprost liposomal composition at different methods of administration. Pharmacology and Drug Toxicology. 16(3), 195-204, 2022. https://doi.org/10.33250/16.03.195
47. Brugnera M., Vicario-de-la-Torre M., González-Cela Casamayor M. A., López-Cano J. J., Bravo-Osuna I., Huete-Toral F., González Rubio M.L., Carracedo G., Molina-Martínez I.T., Andrés-Guerrero V., Herrero-Vanrell R. Enhancing the hypotensive effect of latanoprost by combining synthetic phosphatidylcholine liposomes with hyaluronic acid and osmoprotective agents. Drug Delivery and Translational Research. 14(10), 2804–2822. 2024. https://doi.org/10.1007/s13346-024-01584-z
48. Brugnera M., Vicario-de-la-Torre M., González-Cela-Casamayor M.A., González-Fernández F.M., Ferraboschi I., Andrés-Guerrero V., Nicoli S., Sissa C., Pescina S., Herrero-Vanrell R., Bravo-Osuna I. Disclosing long-term tolerance, efficacy and penetration properties of hyaluronic acid-coated latanoprost-loaded liposomes as chronic glaucoma therapy. Journal of controlled release : official journal of the Controlled Release Society. 379, 730–742. 2025. https://doi.org/10.1016/j.jconrel.2025.01.041
49. Tan G., Yu S., Pan H., Li J., Liu D., Yuan K., Yang X., Pan W. Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate. International journal of biological macromolecules. 94(PtA), 355–363, 2017. https://doi.org/10.1016/j.ijbiomac.2016.10.035
50. Pontillo A., Detsi A. Nanoparticles for ocular drug delivery: modified and non-modified chitosan as a promising biocompatible carrier. Nanomedicine. 14, 1889–1909, 2019. https://doi.org/10.2217/nnm-2019-0040
51. Zhang J., Guan P., Wang T., Chang D., Jiang T., Wang S. Freeze-dried liposomes as potential carriers for ocular administration of cytochrome c against selenite cataract formation. The Journal of pharmacy and pharmacology. 61(9), 1171–1178, 2009. https://doi.org/10.1211/jpp/61.09.0006
52. Kajimoto K., Katsumi T., Nakamura T., Kataoka M., Harashima H. Liposome Microencapsulation for the Surface Modification and Improved Entrapment of Cytochrome c for Targeted Delivery. Journal of the American Oil Chemists Society. 95(1), 101-109, 2018. https://doi.org/10.1002/aocs.12026
53. Mishra G.P., Bagui M., Tamboli V., Mitra A.K. Recent applications of liposomes in ophthalmic drug delivery. Journal of drug delivery. 2011, 863734, 2011. https://doi.org/10.1155/2011/863734
54. Patel A., Cholkar K., Agrahari V., Mitra A.K. Ocular drug delivery systems: An overview. World journal of pharmacology. 2(2), 47–64, 2013. https://doi.org/10.5497/wjp.v2.i2.47
55. Honary S., Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems - a review (Part 2). Tropical Journal of Pharmaceutical Research. 12, 265–273, 2013. http://dx.doi.org/10.4314/tjpr.v12i2.20
56. Hossen M.N., Kajimoto K., Akita H., Hyodo M., Ishitsuka T., Harashima H. Therapeutic assessment of cytochrome C for the prevention of obesity through endothelial cell-targeted nanoparticulate system. Molecular therapy : the journal of the American Society of Gene Therapy. 21(3), 533–541, 2013. https://doi.org/10.1038/mt.2012.256
57. Kumara S., Phanindra A., Nagaraj A., Anilgoud K., Shiva Kumar R. Liposomes as ocular drug delivery platforms: A review. Saudi Journal of Medical and Pharmaceutical Sciences. 3(7), 808-812, 2017. https://doi.org/10.36348/sjmps.2017.v03i07.023
58. Grigorieva G.S., Katsai O.G., Krasnopolsky Y.M., Prokhorov V.V., Khromov O.S., Pasechnikova N.V., Dobrelya N.V. Method for obtaining a pharmacologically active liposomal composition containing cytochrome C, and liposomal composition obtained by this method. Ukraine Patent 118583. 2019.
59. Katsai O.G., Ruban O.A., Krasnopolskyi Yu.M. "Quality-by-Design" approach to the development of a dosage form for the liposomal delivery system of cytochrome С. Pharmakeftiki. 30(2), 76-87, 2018.
60. Katsai O., Ruban O., Krasnopolskyi Y. The influence of the composition of liposomes on the encapsulation efficiency and the particle size when creating the liposomal form of cytochrome C. ScienceRise: Pharmaceutical Science. 4(8), 32–36, 2017. https://doi.org/10.15587/2519-4852.2017.109003
61. Katsai O.G., Ruban O.A., Krasnopolskyi Y.M. Preparation and in-vivo evaluation of cytochrome-C-containing liposomes. Die Pharmazie. 72(12), 736–740, 2017. https://doi.org/10.1691/ph.2017.7072
62. Al-Amin M.D., Mastrotto F., Subrizi A., Sen M., Turunen T., Arango-Gonzalez B., Ueffing M., Malfanti A., Urtti A., Salmaso S., Caliceti P. Tailoring surface properties of liposomes for dexamethasone intraocular administration. Journal of controlled release : official journal of the Controlled Release Society. 354, 323–336, 2023. https://doi.org/10.1016/j.jconrel.2023.01.027
63. Wijesooriya C., Budai M., Budai L., Szilasi M. E., Petrikovics I. Optimization of liposomal encapsulation for ceftazidime for developing a potential eye drop formulation. Journal of basic and clinical pharmacy. 4(3), 73–75, 2013. https://doi.org/10.4103/0976-0105.118810
