Silk Fibroin Formed Bioadhesive Ophthalmic Gel for Dry Eye Syndrome Treatment.

Publisher: Springer Country of Publication: United States NLM ID: 100960111 Publication Model: Electronic Cited Medium: Internet ISSN: 1530-9932 (Electronic) Linking ISSN: 15309932 NLM ISO Abbreviation: AAPS PharmSciTech Subsets: MEDLINE

Publication: New York : Springer
Original Publication: Arlington, VA : American Association of Pharmaceutical Scientists, c2000-

Fibroins*/chemistry ; Cyclosporine*/administration & dosage ; Cyclosporine*/pharmacokinetics ; Cyclosporine*/chemistry ; Dry Eye Syndromes*/drug therapy ; Ophthalmic Solutions*/administration & dosage ; Gels* ; Biological Availability*; Rabbits ; Animals ; Drug Delivery Systems/methods ; Administration, Ophthalmic ; Solubility ; Male ; Emulsions/chemistry ; Cornea/metabolism ; Cornea/drug effects ; Disease Models, Animal

Purpose: Dry eye syndrome (DES), arising from various etiologic factors, leads to tear film instability and ocular surface damage. Given its anti-inflammatory effects, cyclosporine A (CsA) has been widely used as a short-term treatment option for DES. However, poor bioavailability and solubility of CsA in aqueous phase make the development of a cyclosporine A-based eye drop for ocular topical application a huge challenge.
Methods: In this study, a novel strategy for preparing cyclosporine A-loaded silk fibroin nanoemulsion gel (CsA NBGs) was proposed to address these barriers. Additionally, the rheological properties, ocular irritation potential, tear elimination kinetics, and pharmacodynamics based on a rabbit dry eye model were investigated for the prepared CsA NBGs. Furthermore, the transcorneal mechanism across the ocular barrier was also investigated.
Results: The pharmacodynamics and pharmacokinetics of CsA NBGs exhibited superior performance compared to cyclosporine eye drops, leading to a significant enhancement in the bioavailability of CsA NBGs. Furthermore, our investigation into the transcorneal mechanism of CsA NBGs revealed their ability to be absorbed by corneal epithelial cells via the paracellular pathway.
Conclusion: The CsA NBG formulation exhibits promising potential for intraocular drug delivery, enabling safe, effective, and controlled administration of hydrophobic drugs into the eye. Moreover, it enhances drug retention within the ocular tissues and improves systemic bioavailability, thereby demonstrating significant clinical translational prospects.
(© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Hakim FE, Farooq AV. Dry eye disease: an update in 2022. Jama. 2022;327(5):478–9. (PMID: 3510378110.1001/jama.2021.19963)
Huang R, Su C, Fang L, et al. Dry eye syndrome: comprehensive etiologies and recent clinical trials. International ophthalmology. 2022;42(10):3253–72. (PMID: 35678897917831810.1007/s10792-022-02320-7)
Zemanová M. Dry eye disease. A review. Ceska a slovenska oftalmologie: casopis Ceske oftalmologicke spolecnosti a Slovenske oftalmologicke spolecnosti. 2021;77(3):107–19. https://doi.org/10.31348/2023/27 .
de Paiva CS. Effects of Aging in Dry Eye. Int Ophthalmol Clin. 2017;57(2):47–64. (PMID: 28282314534747910.1097/IIO.0000000000000170)
Yao W, Davidson RS, Durairaj VD, et al. Dry eye syndrome: an update in office management. Am J Med. 2011;124(11):1016–8. (PMID: 2194416010.1016/j.amjmed.2011.01.030)
Shen Y, Yu Y, Chaurasiya B, et al. Stability, safety, and transcorneal mechanistic studies of ophthalmic lyophilized cyclosporine-loaded polymeric micelles. Int J Nanomed. 2018;13:8281–96. (PMID: 10.2147/IJN.S173691)
Trier AM, Kim BS. Insights into atopic dermatitis pathogenesis lead to newly approved systemic therapies. Br J Dermatol. 2023;188(6):698–708. (PMID: 3676370310.1093/bjd/ljac016)
Schmidt V, Lalevée S, Traidl S, et al. Intravenous immunoglobulins, cyclosporine, and best supportive care in epidermal necrolysis: diverse effects on systemic inflammation. Allergy. 2023;78(5):1280–91. (PMID: 3646348810.1111/all.15608)
Liddicoat AM, Lavelle EC. Modulation of innate immunity by cyclosporine A. Biochem Pharmacol. 2019;163:472–80. (PMID: 3088006110.1016/j.bcp.2019.03.022)
TöNSHOFF B. Immunosuppressants in organ transplantation. Handbook Exp Pharmacol. 2020;261:441–69. (PMID: 10.1007/164_2019_331)
Mason L, Jafri S, Dortonne I, et al. Emerging therapies for dry eye disease. Expert Opin Emerg Drugs. 2021;26(4):401–13. (PMID: 3484697810.1080/14728214.2021.2011858)
Qian L, Wei W. Identified risk factors for dry eye syndrome: a systematic review and meta-analysis. PloS one. 2022;17(8): e0271267. (PMID: 35984830939093210.1371/journal.pone.0271267)
O’Neil EC, Henderson M, Massaro-Giordano M, et al. Advances in dry eye disease treatment. Curr Opin Ophthalmol. 2019;30(3):166–78. (PMID: 30883442698637310.1097/ICU.0000000000000569)
Periman LM, Perez VL, Saban DR, et al. The immunological basis of dry eye disease and current topical treatment options. J Ocular Pharmacol Ther Off J Assoc Ocular Pharmacol Ther. 2020;36(3):137–46. (PMID: 10.1089/jop.2019.0060)
Nguyen DD, Lai J-Y. Advancing the stimuli response of polymer-based drug delivery systems for ocular disease treatment. Poly Chem. 2020;11(44):6988–7008. (PMID: 10.1039/D0PY00919A)
Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–25. (PMID: 1087828610.1016/S0162-3109(00)00192-2)
Tong L, Sun CC, Yoon KC, et al. Cyclosporine anionic and cationic ophthalmic emulsions in dry eye disease: a literature review. Ocular Immunol Inflam. 2021;29(7–8):1606–15. (PMID: 10.1080/09273948.2020.1757121)
Zghal I, Fekih O, Zgolli HM, et al. Cyclosporin A eye drop and subepithelial adenoviral keratoconjunctivitis infiltrates. La Tunisie Med. 2019;97(5):639–43.
Patocka J, Nepovimova E, Kuca K, et al. Cyclosporine A: chemistry and toxicity - a review. Curr Med Chem. 2021;28(20):3925–34. (PMID: 3302342810.2174/0929867327666201006153202)
Patel D, Wairkar S. Recent advances in cyclosporine drug delivery: challenges and opportunities. Drug Del Trans Res. 2019;9(6):1067–81. (PMID: 10.1007/s13346-019-00650-1)
Periman LM, Mah FS, Karpecki PM. A review of the mechanism of action of cyclosporine A: The role of cyclosporine A in dry eye disease and recent formulation developments. Clin Ophthalmol (Auckland, NZ). 2020;14:4187–200. (PMID: 10.2147/OPTH.S279051)
Wolska E, Sznitowska M, Chorążewicz J, et al. Ocular irritation and cyclosporine A distribution in the eye tissues after administration of solid lipid microparticles in the rabbit model. Eur J Pharm Sci Off J Eur Federation Pharm Sci. 2018;121:95–105.
Parrilha LR, Nai GA, Giuffrida R, et al. Comparison of 1% cyclosporine eye drops in olive oil and in linseed oil to treat experimentally-induced keratoconjunctivitis sicca in rabbits. Arquivos Brasileiros De Oftalmologia. 2015;78(5):295–9. (PMID: 2646622810.5935/0004-2749.20150078)
Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Trans Vis Sci Technol. 2015;4(3):1. (PMID: 10.1167/tvst.4.3.1)
Maïssa C, Guillon M, Simmons P, et al. Effect of castor oil emulsion eyedrops on tear film composition and stability. Contact Lens Anter Eye J Br Contact Lens Assoc. 2010;33(2):76–82. (PMID: 10.1016/j.clae.2009.10.005)
Lallemand F, Schmitt M, Bourges JL, et al. Cyclosporine A delivery to the eye: a comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik eV. 2017;117:14–28.
Yan R, Xu L, Wang Q, et al. Cyclosporine A nanosuspensions for ophthalmic delivery: a comparative study between cationic nanoparticles and drug-core mucus penetrating nanoparticles. Mol Pharm. 2021;18(12):4290–8. (PMID: 3473157110.1021/acs.molpharmaceut.1c00370)
Yu H, Xia D, Zhu Q, et al. Supersaturated polymeric micelles for oral cyclosporine A delivery. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik eV. 2013;85(3 Pt B):1325–36.
Quintana-Hau JD, Cruz-Olmos E, LóPEZ-SáNCHEZ MI, et al. Characterization of the novel ophthalmic drug carrier Sophisen in two of its derivatives: 3A Ofteno and Modusik-A Ofteno. Drug Devel Ind Pharm. 2005;31(3):263–9. (PMID: 10.1081/DDC-52058)
Rhim JW, Eom Y, Yoon EG, et al. Efficacy of a 0.05% cyclosporine a topical nanoemulsion in dry eyes with obstructive meibomian gland dysfunction. Japan J Ophthalmol. 2022;66(3):254–63. (PMID: 10.1007/s10384-022-00906-3)
Gomes GS, Frank LA, Contri RV, et al. Nanotechnology-based alternatives for the topical delivery of immunosuppressive agents in psoriasis. Int J Pharm. 2023;631:122535. (PMID: 3656682610.1016/j.ijpharm.2022.122535)
Jo YJ, Lee JE, Lee JS. Clinical efficacy of 0.05% cyclosporine nano-emulsion in the treatment of dry eye syndrome associated with meibomian gland dysfunction. Int J Ophthalmol. 2022;15(12):1924–31. (PMID: 36536967972909210.18240/ijo.2022.12.05)
Huang L, Liang W, Zhou K, et al. Therapeutic effects of fenofibrate nano-emulsion eye drops on retinal vascular leakage and neovascularization. Biology. 2021;10(12):1328. (PMID: 34943243869846010.3390/biology10121328)
Alvarez-Figueroa MJ, Abarca-Riquelme JM, González-Aramundiz JV. Influence of protamine shell on nanoemulsions as a carrier for cyclosporine-A skin delivery. Pharm Devel Technol. 2019;24(5):630–8. (PMID: 10.1080/10837450.2018.1550789)
Binyamin O, Keller G, Frid K, et al. Continues administration of Nano-PSO significantly increased survival of genetic CJD mice. Neurobiol Dis. 2017;108:140–7. (PMID: 2884756710.1016/j.nbd.2017.08.012)
Patnaik SK, Halder N, Chawla B, et al. Comparison of ocular pharmacokinetics of etoposide and its nanoemulsion after subtenon administration in rabbits. J Basic Clin Physiol Pharmacol. 2019;30(5). https://doi.org/10.1515/jbcpp-2018-0108 .
Dong Y, Dong P, Huang D, et al. Fabrication and characterization of silk fibroin-coated liposomes for ocular drug delivery. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik eV. 2015;91:82–90.
Wang X, Anton H, Vandamme T, et al. Updated insight into the characterization of nano-emulsions. Expert Opinion Drug Del. 2023;20(1):93–114. (PMID: 10.1080/17425247.2023.2154075)
Jain AK, Thareja S. In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Art Cells Nanomed Biotechnol. 2019;47(1):524–39. (PMID: 10.1080/21691401.2018.1561457)
Doghish AS, Shehabeldine AM, El-Mahdy HA, et al. Thymus vulgaris oil nanoemulsion: synthesis, characterization, antimicrobial and anticancer activities. Molecules. 2023;28(19):6910. https://doi.org/10.3390/molecules28196910 . (PMID: 10.3390/molecules281969103783675310574288)
Sah MK, Gautam B, Pokhrel KP, et al. Quantification of the Quercetin nanoemulsion technique using various parameters. Molecules (Basel, Switzerland). 2023;28(6):2540. (PMID: 3698551110.3390/molecules28062540)
Fu X, Gao Y, Yan W, et al. Preparation of eugenol nanoemulsions for antibacterial activities. RSC Advances. 2022;12(6):3180–90. (PMID: 35425353897927610.1039/D1RA08184E)
Indrati O, Martien R, Rohman A, et al. Development of nanoemulsion-based hydrogel containing andrographolide: physical properties and stability evaluation. J Pharm Bioal Sci. 2020;12(Suppl 2):S816-s20.
Senapati S, Youssef AAA, Sweeney C, et al. Cannabidiol loaded topical ophthalmic nanoemulsion lowers intraocular pressure in normotensive Dutch-belted rabbits. Pharmaceutics. 2022;14(12):2585. (PMID: 36559077978184010.3390/pharmaceutics14122585)
Singh M, Bharadwaj S, Lee KE, et al. Therapeutic nanoemulsions in ophthalmic drug administration: concept in formulations and characterization techniques for ocular drug delivery. J Control Rel Off J Control Rel Soc. 2020;328:895–916. (PMID: 10.1016/j.jconrel.2020.10.025)
Ng SH, Woi PM, Basri M, et al. Characterization of structural stability of palm oil esters-based nanocosmeceuticals loaded with tocotrienol. J Nanobiotechnol. 2013;11:27. (PMID: 10.1186/1477-3155-11-27)
Kimura S, Mori S, Yokoya M, et al. Multiple stimuli-responsive supramolecular gel formed from modified adenosine. Chem Pharm Bull. 2022;70(6):443–7. (PMID: 10.1248/cpb.c22-00134)
Jiang L, Sun S, Chen J, et al. Random forest algorithm-based ultrasonic image in the diagnosis of patients with dry eye syndrome and its relationship with tear osmotic pressure. Comput Math Methods Med. 2022;2022:9437468. (PMID: 352651748901303)
Dutescu RM, Panfil C, Schrage N. Osmolarity of prevalent eye drops, side effects, and therapeutic approaches. Cornea. 2015;34(5):560–6. (PMID: 2578969310.1097/ICO.0000000000000368)
Vicario-De-La-Torre M, Caballo-González M, Vico E, et al. Novel nano-liposome formulation for dry eyes with components similar to the preocular tear film. Polymers. 2018;10(4):425. (PMID: 30966460641527610.3390/polym10040425)
Hotujac GM, Juretić M, Hafner A, et al. Tear fluid-eye drops compatibility assessment using surface tension. Drug Devel Ind Pharm. 2017;43(2):275–82. (PMID: 10.1080/03639045.2016.1238924)
Chen BH, Stephen IB. Nanoemulsion and nanoliposome based strategies for improving anthocyanin stability and bioavailability. Nutrients. 2019;11(5):1052. (PMID: 31083417656675310.3390/nu11051052)
Mozafarpour R, Koocheki A, Sani MA, et al. Ultrasound-modified protein-based colloidal particles: interfacial activity, gelation properties, and encapsulation efficiency. Adv Colloid Interf Sci. 2022;309:102768. (PMID: 10.1016/j.cis.2022.102768)
Lv Y, He H, Qi J, et al. Visual validation of the measurement of entrapment efficiency of drug nanocarriers. Int J Pharm. 2018;547(1–2):395–403. (PMID: 2989475710.1016/j.ijpharm.2018.06.025)
Dong Y, Hengst L, Hunt R, et al. Evaluating drug distribution and release in ophthalmic emulsions: impact of release conditions. J Control Rel Off J Control Rel Soc. 2020;327:360–70. (PMID: 10.1016/j.jconrel.2020.08.020)
Mochizuki H, Yamada M, Hatou S, et al. Turnover rate of tear-film lipid layer determined by fluorophotometry. Br J Ophthalmol. 2009;93(11):1535–8. (PMID: 1969236510.1136/bjo.2008.156828)
Qamar Z, Qizilbash FF, Iqubal MK, et al. Nano-based drug delivery system: recent strategies for the treatment of ocular disease and future perspective. Recent Patents Drug Del Formulation. 2019;13(4):246–54. (PMID: 10.2174/1872211314666191224115211)

Keywords: cyclosporine a; dry eye syndrome; eye irritation; ophthalmic nanoemulsion with silk fibroin gel; transcorneal mechanism

9007-76-5 (Fibroins)
83HN0GTJ6D (Cyclosporine)
0 (Ophthalmic Solutions)
0 (Gels)
0 (Emulsions)

Date Created: 20240429 Date Completed: 20240429 Latest Revision: 20240429

20240501

10.1208/s12249-024-02792-z

38684590