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2000
Volume 25, Issue 7
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

Topical application of ophthalmic drugs remains to be the preferred delivery method. Eye drops lead the pharmaceutical forms due to ease of application. Despite the poor bioavailability of drugs administered topically, especially related to the dilution and excretion by tear fluid, the absence of controlled drug delivery, and the poor compliance within pediatric and senior populations, eye drops and ointments are still the first choices in eye-related disorders management. Only a few studies have explored the eyelid skin as a site for drug application and transdermal delivery as an alternative route of administration of ophthalmic drugs. Such works have validated the delivery of drugs into the ocular tissues through the eyelid barrier. The eyelid represents a differentiated skin barrier concerning the thickness, the structure of the , the vasculature, and the amount of lipids. This work intends to question why the eyelid, being an accessible, non-invasive, comfortable route of administration is not considered a feasible route for ophthalmic drugs. The eyelid structure is presented, and the anatomical and physiological distinctive characteristics are presented. The work also presents the research work on topical drug application to the eyelid skin that has been published so far.

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2025-01-13
2025-07-28

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References

  1. LöscherM. SeizC. HurstJ. SchnichelsS. Topical drug delivery to the posterior segment of the eye.Pharmaceutics202214113410.3390/pharmaceutics14010134 35057030
     [Google Scholar]
  2. IsowakiA. OhtoriA. MatsuoY. TojoK. Drug delivery to the eye with a transdermal therapeutic system.Biol. Pharm. Bull.2003261697210.1248/bpb.26.69 12520176
     [Google Scholar]
  3. BaranowskiP. KarolewiczB. GajdaM. PlutaJ. Ophthalmic drug dosage forms: Characterisation and research methods.Sci. World J.2014201411410.1155/2014/861904 24772038
     [Google Scholar]
  4. LanierO.L. ManfreM.G. BaileyC. LiuZ. SparksZ. KulkarniS. ChauhanA. Review of approaches for increasing ophthalmic bioavailability for eye drop formulations.AAPS Pharm. Sci. Tech.202122310710.1208/s12249‑021‑01977‑0 33719019
     [Google Scholar]
  5. JünemannA.G.M. ChorągiewiczT. OzimekM. GriebP. RejdakR. Drug bioavailability from topically applied ocular drops. Does drop size matter?Ophthalmol. J.201611293510.5603/OJ.2016.0005
     [Google Scholar]
  6. AlkilaniA. McCruddenM.T. DonnellyR. Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum.Pharmaceutics20157443847010.3390/pharmaceutics7040438 26506371
     [Google Scholar]
  7. LeeD.H. LimS. KwakS.S. KimJ. Advancements in skin-mediated drug delivery: Mechanisms, techniques, and applications.Adv. Healthc. Mater.2024137230237510.1002/adhm.202302375 38009520
     [Google Scholar]
  8. PratchyapruitW. KikuchiK. GritiyarangasanP. AibaS. TagamiH. Functional analyses of the eyelid skin constituting the most soft and smooth area on the face: Contribution of its remarkably large superficial corneocytes to effective water‐holding capacity of the stratum corneum.Skin Res. Technol.200713216917510.1111/j.1600‑0846.2007.00183.x 17374058
     [Google Scholar]
  9. WalkerM.K. SchornackM.M. VincentS.J. Anatomical and physiological considerations in scleral lens wear: Eyelids and tear film.Cont. Lens Anterior Eye202144510140710.1016/j.clae.2021.01.002 33468392
     [Google Scholar]
  10. TakahashiY. WatanabeA. MatsudaH. NakamuraY. NakanoT. AsamotoK. IkedaH. KakizakiH. Anatomy of secretory glands in the eyelid and conjunctiva: A photographic review.Ophthalmol. Plast. Reconstr. Surg.201329321521910.1097/IOP.0b013e3182833dee 23381567
     [Google Scholar]
  11. CochranM.L. LopezM.J. CzyzC.N. Anatomy, Head and Neck: Eyelid. StatPearls.StatPearls Publishing2003
     [Google Scholar]
  12. KaplanH.J. Anatomy and function of the eye.Chem. Immunol. Allergy20079241010.1159/000099236 17264478
     [Google Scholar]
  13. BarabinoS. ChenY. ChauhanS. DanaR. Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease.Prog. Retin. Eye Res.201231327128510.1016/j.preteyeres.2012.02.003 22426080
     [Google Scholar]
  14. ProkschE. BrandnerJ.M. JensenJ.M. The skin: An indispensable barrier.Exp. Dermatol.200817121063107210.1111/j.1600‑0625.2008.00786.x 19043850
     [Google Scholar]
  15. van SmedenJ. HoppelL. van der HeijdenR. HankemeierT. VreekenR.J. BouwstraJ.A. LC/MS analysis of stratum corneum lipids: Ceramide profiling and discovery.J. Lipid Res.20115261211122110.1194/jlr.M014456 21444759
     [Google Scholar]
  16. TuckerS.M. LinbergJ.V. Vascular anatomy of the eyelids.Ophthalmology199410161118112110.1016/S0161‑6420(94)31212‑7 8008353
     [Google Scholar]
  17. GroenD. PooleD.S. GoorisG.S. BouwstraJ.A. Is an orthorhombic lateral packing and a proper lamellar organization important for the skin barrier function?Biochim. Biophys. Acta Biomembr.2011180861529153710.1016/j.bbamem.2010.10.015 21036143
     [Google Scholar]
  18. MonizT. Costa LimaS.A. ReisS. Human skin models: From healthy to disease‐mimetic systems; characteristics and applications.Br. J. Pharmacol.2020177194314432910.1111/bph.15184 32608012
     [Google Scholar]
  19. ChenC.P. ChenC.C. HuangC.W. ChangY.C. Evaluating molecular properties involved in transport of small molecules in stratum corneum: A quantitative structure-activity relationship for skin permeability.Molecules201823491110.3390/molecules23040911 29662033
     [Google Scholar]
  20. ShahM. Cabrera-GhayouriS. ChristieL.A. HeldK.S. ViswanathV. Translational preclinical pharmacologic disease models for ophthalmic drug development.Pharm. Res.20193645810.1007/s11095‑019‑2588‑5 30805711
     [Google Scholar]
  21. Benítez-Del-CastilloJ. How to promote and preserve eyelid health.Clin. Ophthalmol.201261689169810.2147/OPTH.S33133 23118519
     [Google Scholar]
  22. AliM. ShahD. PashaZ. JassimS.H. Jassim JabooriA. SetabutrP. AakaluV.K. Evaluation of accessory lacrimal gland in Muller’s muscle conjunctival resection specimens for precursor cell markers and biological markers of dry eye disease.Curr. Eye Res.201742449149710.1080/02713683.2016.1214966 27612554
     [Google Scholar]
  23. MohammedD. MattsP.J. HadgraftJ. LaneM.E. Variation of stratum corneum biophysical and molecular properties with anatomic site.AAPS J.201214480681210.1208/s12248‑012‑9400‑3 22903879
     [Google Scholar]
  24. Varela-FernándezR. Díaz-ToméV. Luaces-RodríguezA. Conde-PenedoA. García-OteroX. Luzardo-ÁlvarezA. Fernández-FerreiroA. Otero-EspinarF. Drug delivery to the posterior segment of the eye: Biopharmaceutic and pharmacokinetic considerations.Pharmaceutics202012326910.3390/pharmaceutics12030269 32188045
     [Google Scholar]
  25. SeeG.L. SagesakaA. TodoH. WierzbaK. SugibayashiK. Pharmacokinetics and tissue distribution of pilocarpine after application to eyelid skin of rats.J. Pharm. Sci.201910892942294810.1016/j.xphs.2019.04.012 31002809
     [Google Scholar]
  26. HwangK. Surgical anatomy of the upper eyelid relating to upper blepharoplasty or blepharoptosis surgery.Anat. Cell Biol.20134629310010.5115/acb.2013.46.2.93 23869256
     [Google Scholar]
  27. KakizakiH. MalhotraR. MadgeS.N. SelvaD. Lower eyelid anatomy: An update.Ann. Plast. Surg.200963334435110.1097/SAP.0b013e31818c4b22 19602948
     [Google Scholar]
  28. HuangC.X. YianniasJ.A. KillianJ.M. ShenJ.F. Seven common allergen groups causing eyelid dermatitis: Education and avoidance strategies.Clin. Ophthalmol.2021151477149010.2147/OPTH.S297754 33880007
     [Google Scholar]
  29. LiuS. LiJ. TanD.T. BeuermanR.W. The eyelid margin: A transitional zone for 2 epithelial phenotypes.Arch. Ophthalmol.2007125452353210.1001/archopht.125.4.523 17420373
     [Google Scholar]
  30. UhmC. JeongH. LeeS.H. HwangJ.S. LimK.M. NamK.T. Comparison of structural characteristics and molecular markers of rabbit skin, pig skin, and reconstructed human epidermis for an ex vivo human skin model.Toxicol. Res.202339347748410.1007/s43188‑023‑00185‑1 37398575
     [Google Scholar]
  31. BarbalhoG.N. FalcãoM.A. LopesJ.M.S. LopesJ.M. ContaratoJ.L.A. GelfusoG.M. Cunha-FilhoM. GratieriT. Dynamic ex vivo porcine eye model to measure ophthalmic drug penetration under simulated lacrimal flow.Pharmaceutics2023159232510.3390/pharmaceutics15092325 37765293
     [Google Scholar]
  32. RodriguesC. CarvalhoF. MarquesM. Upper eyelid blepharoplasty: Surgical techniques and results-Systematic review and meta-analysis.Aesthetic Plast. Surg.20234751870188310.1007/s00266‑023‑03436‑6 37430010
     [Google Scholar]
  33. BosJ.D. MeinardiM.M.H.M. The 500 Dalton rule for the skin penetration of chemical compounds and drugs.Exp. Dermatol.20009316516910.1034/j.1600‑0625.2000.009003165.x 10839713
     [Google Scholar]
  34. AscensoA. BatistaC. CardosoP. MendesT. PraçaF. BentleyV. RaposoS. SimõesS. Development, characterization, and skin delivery studies of related ultradeformable vesicles: Transfersomes, ethosomes, and transethosomes.Int. J. Nanomedicine2015105837585110.2147/IJN.S86186 26425085
     [Google Scholar]
  35. ThorneJ.E. SugarE.A. HolbrookJ.T. BurkeA.E. AltaweelM.M. VitaleA.T. AcharyaN.R. KempenJ.H. JabsD.A. Periocular triamcinolone vs. intravitreal triamcinolone vs. intravitreal dexamethasone implant for the treatment of uveitic macular edema: The PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT) Trial.Ophthalmology2019126228329510.1016/j.ophtha.2018.08.021 30269924
     [Google Scholar]
  36. OPTASEComfort Dry Eye Spray.Available at: https://optase.com/product/comfort-spray/ Assessed April 21, 2024.
  37. Laboratorios ViñasEye hygiene.Available at: https://www.vinas.es/en/indications/eye-care/eye-hygiene Assessed April 21, 2024.
  38. PultH. KhatumF.S. Trave-HuarteS. WolffsohnJ.S. Effect of eye spray phospholipid concentration on the tear film and ocular comfort.Eye Contact Lens202147844544810.1097/ICL.0000000000000788 33813585
     [Google Scholar]
  39. KimuraC. TojoK. Development of a stick-type transdermal eyelid delivery system of ketotifen fumarate for ophthalmic diseases.Chem. Pharm. Bull. (Tokyo)20075571002100510.1248/cpb.55.1002 17603189
     [Google Scholar]
  40. TsubotaK. MondenY. YagiY. GotoE. ShimmuraS. New treatment of dry eye: The effect of calcium ointment through eyelid skin delivery.Br. J. Ophthalmol.199983776777010.1136/bjo.83.7.767 10381659
     [Google Scholar]
  41. TanM.H. LebwohlM. EsserA.C. WeiH. The penetration of 0.005% fluticasone propionate ointment in eyelid skin.J. Am. Acad. Dermatol.200145339239610.1067/mjd.2001.116220 11511836
     [Google Scholar]
  42. BodduS.H.S. GuptaH. BonamS.P. Preclinical evaluation of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery.Int. J. Pharm.20144701-215816110.1016/j.ijpharm.2014.04.057 24813783
     [Google Scholar]
  43. SeeG.L. SagesakaA. SugasawaS. TodoH. SugibayashiK. Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.Int. J. Pharm.2017533119820510.1016/j.ijpharm.2017.09.070 28965801
     [Google Scholar]
  44. EmeriewenK. McAuleyW.J. BeebeejaunM.T. CookM.T. SalehG.M. The permeability of human eyelid skin to topically applied lidocaine.J. Drug Deliv. Sci. Technol.20205510135710.1016/j.jddst.2019.101357
     [Google Scholar]
  45. SeeG.L. ArceF.Jr ItakuraS. TodoH. SugibayashiK. Prolonged distribution of tranilast in the eyes after topical application onto eyelid skin.Chem. Pharm. Bull. (Tokyo)202068877978310.1248/cpb.c20‑00289 32741920
     [Google Scholar]
  46. LalatsaA. PatelP.V. SunY. KiunC.C. KarimiF. ZekonyteJ. EmeriewenK. SalehG.M. Transcutaneous anaesthetic nano-enabled hydrogels for eyelid surgery.Int. J. Pharm.202057711900310.1016/j.ijpharm.2019.119003 31935474
     [Google Scholar]
  47. KamimuraM. OhnishiT. TeradaH. MouriA. NaoiT. TodoH. SugibayashiK. Application of diphenydramine ointment to the eyelids for allergic conjunctivitis.Iberoam. J. Med.202131445010.53986/ibjm.2021.0008
     [Google Scholar]
  48. WangW.J. SniderN. Discovery and potential utility of a novel non-invasive ocular delivery platform.Pharmaceutics2023159234410.3390/pharmaceutics15092344 37765311
     [Google Scholar]
  49. MochizukiT. HataT. MoriN. YamazakiT. NotoT. ManoH. Trans-eyelid distribution of epinastine to the conjunctiva following eyelid application in rabbits.Jpn. J. Ophthalmol.202468559460210.1007/s10384‑024‑01070‑6 38795193
     [Google Scholar]
  50. FujishimaH. ShojiJ. Safety and efficacy of a novel 0.5% epinastine topical eyelid cream in allergic conjunctivitis: A phase 3 trial.Jpn. J. Ophthalmol.20246865165910.1007/s10384‑024‑01108‑9 39259242
     [Google Scholar]
  51. LinJ. BuF. WuD. JiangP. HeQ. YangD. ZhuX. WangY. XiangX. Physiologically based pharmacokinetic modeling and clinical extrapolation for topical application of pilocarpine on eyelids: A comprehensive study.J. Pharm. Sci.202411392861287010.1016/j.xphs.2024.06.004 38857643
     [Google Scholar]
  52. TagawaY. NambaK. NakazonoY. IwataD. IshidaS. Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis.Allergol. Int.201766233834310.1016/j.alit.2016.08.011 27720602
     [Google Scholar]
  53. HadgraftJ. Modulation of the barrier function of the skin.Skin Pharmacol. Physiol.200114Suppl. 1728110.1159/000056393 11509910
     [Google Scholar]
  54. CohenR.G. HartsteinM. LadavM. WoogJ.J. Ocular toxicity following topical application of anesthetic cream to the eyelid skin.Ophthalmic Surg. Lasers Imaging Retina199627537437710.3928/1542‑8877‑19960501‑10 8860604
     [Google Scholar]
  55. WróblewskaK.B. JadachB. Muszalska-KolosI. Progress in drug formulation design and delivery of medicinal substances used in ophthalmology.Int. J. Pharm.202160712101210.1016/j.ijpharm.2021.121012 34400274
     [Google Scholar]
  56. CohenR.G. HartsteinM. LahavM. WoogJ.J. Ocular toxicity following topical application of anesthetic cream to the eyelid skin.Ophthalmic Surg. Lasers199627537437710.3928/1542‑8877‑19960501‑10 8860604
     [Google Scholar]
  57. Nelson O’DonoghueM. Eye cosmetics.Dermatol. Clin.200018463363910.1016/S0733‑8635(05)70214‑X 11059371
     [Google Scholar]
  58. AzariA.A. BarneyN.P. Conjunctivitis.JAMA2013310161721172910.1001/jama.2013.280318 24150468
     [Google Scholar]
  59. HonkilaM. KoskelaU. KontiokariT. MattilaM.L. KristoA. ValtonenR. SarlinS. PaalanneN. IkäheimoI. PokkaT. UhariM. RenkoM. TapiainenT. Effect of topical antibiotics on duration of acute infective conjunctivitis in children: A randomized clinical trial and a systematic review and meta-analysis.JAMA Netw. Open2022510e223445910.1001/jamanetworkopen.2022.34459 36194412
     [Google Scholar]
  60. OliveiraD.S. Sousa-MartinsD. RosaA.I. Cabral-MarquesH. BacalhauC. MartinsD. Eyelid and conjunctiva epithelial tumours: A review of risk factors and primary prevention options.ARC J. Ophthalmol.202152129
     [Google Scholar]
  61. OliveiraD. RibeiroA. BacalhauC. AlmadaS. DinizS. SaramagoA. MarquesH. MartinsD. Are we capable of contributing to the reduction of eyelid basal cell carcinoma? building a healthcare team.J. Opht. Res. Rev. Rep.2023418
     [Google Scholar]
  62. LiuL. ZhaoW. MaQ. GaoY. WangW. ZhangX. DongY. ZhangT. LiangY. HanS. CaoJ. WangX. SunW. MaH. SunY. Functional nano-systems for transdermal drug delivery and skin therapy.Nanoscale Adv.2023561527155810.1039/D2NA00530A 36926556
     [Google Scholar]
  63. MartoJ. VitorC. GuerreiroA. SeverinoC. EleutérioC. AscensoA. SimõesS. Ethosomes for enhanced skin delivery of griseofulvin.Colloids Surf. B Biointerfaces201614661662310.1016/j.colsurfb.2016.07.021 27429295
     [Google Scholar]
  64. SimõesS.I. DelgadoT.C. LopesR.M. JesusS. FerreiraA.A. MoraisJ.A. CruzM.E.M. CorvoM.L. MartinsM.B.F. Developments in the rat adjuvant arthritis model and its use in therapeutic evaluation of novel non-invasive treatment by SOD in Transfersomes.J. Control. Release2005103241943410.1016/j.jconrel.2004.12.008 15763624
     [Google Scholar]
  65. SeeG.L.L. Unlocking the potential of eyelid skin-based drug delivery: A Filipino pharmaceutical scientist’s journey.J. Pharm. Sci. Technol. Jpn.2020804193197
     [Google Scholar]
/content/journals/mrmc/10.2174/0113895575358373241220043138
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Topical Application onto the Eyelid Skin: Is it a Feasible Delivery Route of Ophthalmic Drugs?
Mini Rev Med Chem 25, 521 (2025); https://doi.org/10.2174/0113895575358373241220043138
/content/journals/mrmc/10.2174/0113895575358373241220043138
/content/journals/mrmc/10.2174/0113895575358373241220043138
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  • Article Type:     Review Article
Keyword(s): corneal epithelial cells; eye drops; Eyelid; ophthalmic drugs; stratum corneum; topical and transdermal delivery

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