Oküler ilaç uygulamaları, gözün yapısal karmaşıklığı ve savunma mekanizmaları nedeniyle oftalmologlar ve oküler ilaç taşıyıcı sistemler üzerine çalışan bilim insanları için çok zorlu bir alandır. Farklı kornea katmanları, sklera, konjonktival kan akışı, gözyaşı seyreltmesi ve kan retina bariyeri gibi engeller, gözün anterior ve posterior kısımlarına ilaç uygulanması etkinliğini sınırlamaktadır. Konvansiyonel oküler ilaç uygulama şekilleri arasında oküler göz damlası tüketiciler tarafından yaygın olarak tercih edilmektedir. Fakat bu göz damlalarının oküler bariyerlerden emilimi sınırlı olduğu için düşük biyoyararlanıma sahiptir bu sebeple sık uygulama gerektirmektedir. Bu durum ise hasta uyuncunu azaltmaktadır. Ayrıca bazı durumlarda etkin maddenin çözelti şeklinde hazırlanması mümkün olmamaktadır. Bu sebeple yine damla şeklinde kullanılabilen süspansiyon, emülsiyon gibi farklı dozaj şekilleri de geliştirilmeye çalışılmaktadır. Fakat bu tarz formülasyonlar da formülasyona bağlı stabilite ve yüksek viskozite gibi ciddi sıkıntılar barındırmaktadır. Hem gözün yapısal sorunları hem de dozaj şekillerinde istenilen etkilerin elde edilememesi araştırmacıları farklı çalışmalara itmektedir. Bu nedenle bilim insanları, göze ilaç verme potansiyelini ve dolayısıyla tedavi etkinliğini artırmak için çeşitli ilaç taşıyıcı sistemleri tasarlamış ve incelemişlerdir. Nanopartikül, lipozom, mikroemülsiyon, insert ve ilaç yüklü kontakt lens gibi yeni ilaç taşıyıcı sistemler son zamanlarda geleneksel ilaç taşıyıcı sistemlere alternatif olarak araştırılmaktadır. Bu tarz yeni ilaç taşıyıcı sistemler oküler ilaç uygulama açısından umut verici olsa da üstesinden gelinmesi gereken sorunlar da bulunmaktadır. Bu derlemede çeşitli geleneksel ve yeni ilaç taşıyıcı formülasyonlar özetlenmeye çalışılmıştır.
Anahtar Kelimeler: Göz; göz damlası; oküler ilaç taşıyıcı sistemler
Ocular drug applications are a challenging area for ophthalmologists and scientists developing drug delivery systems due to the structural and barrier complexity of the eye. Obstacles such as different corneal layers, sclera, conjunctival blood flow, tear dilution, and blood retinal barrier limit the effectiveness of drug administration to the anterior and posterior parts of the eye. Among the conventional ocular drug administration forms, ocular eye drops are widely preferred by patients. However, these eye drops have low bioavailability due to the ocular barrier and therefore require frequent application. This situation reduces patient compliance. In addition, in some cases, it isn't possible to prepare the active substance in solution form. For this reason, different dosage forms such as suspension and emulsion, which can be used in drops form, are also being developed. However, such formulations also have serious problems such as formulation-related stability and high viscosity. Both the structural problems of the eye and the inability to achieve the desired effects in dosage forms push researchers to different studies. For this reason, scientists have designed and studied various drug delivery systems to increase the drug delivery potential to the eye and thus the treatment efficacy. New drug delivery systems such as nanoparticles, liposomes, microemulsions, inserts, and drug-loaded contact lenses have recently been investigated as an alternative to conventional drug delivery systems. Although such new drug delivery systems provide a glimmer of hope for ocular drug delivery, there are still problems to be overcome. In this review, various traditional and new drug delivery formulations have been tried to be summarized.
Keywords: Eye; eye drop; ocular drug delivery systems
- Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131-5. [Crossref] [PubMed]
- Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems--recent advances. Prog Retin Eye Res. 1998;17(1):33-58. [Crossref] [PubMed]
- Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47-64. [Crossref] [PubMed] [PMC]
- Qamar Z, Qizilbash FF, Iqubal MK, Ali A, Narang JK, Ali J, et al. Nano-based drug delivery system: recent strategies for the treatment of ocular disease and future perspective. Recent Pat Drug Deliv Formul. 2019;13(4):246-54. [Crossref] [PubMed] [PMC]
- Aksu B, Mesut B. Quality by design (QbD) for pharmaceutical area. J Pharm Istanbul Univ. 2015;45(2):233-51. [Link]
- Bozdag S, Weyenberg W, Adriaens E, Dhondt MM, Vergote V, Vervaet C, et al. In vitro evaluation of gentamicin- and vancomycin-containing minitablets as a replacement for fortified eye drops. Drug Dev Ind Pharm. 2010;36(11):1259-70. [Crossref] [PubMed]
- Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3(2):275-87. [Crossref] [PubMed]
- Gote V, Sikder S, Sicotte J, Pal D. Ocular drug delivery: present innovations and future challenges. J Pharmacol Exp Ther. 2019;370(3):602-24. [Crossref] [PubMed]
- Patel P, Shastri D, Shelat P, Shukla A. Ophthalmic drug delivery system: challenges and approaches. Sys Rev Pharm. 2010;1(2):113-20. [Crossref]
- Vandamme TF. Microemulsions as ocular drug delivery systems: recent developments and future challenges. Prog Retin Eye Res. 2002;21(1):15-34. [Crossref] [PubMed]
- Liang H, Brignole-Baudouin F, Rabinovich-Guilatt L, Mao Z, Riancho L, Faure MO, et al. Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits. Mol Vis. 2008;14:204-16. [PubMed] [PMC]
- Yamaguchi M, Ueda K, Isowaki A, Ohtori A, Takeuchi H, Ohguro N, et al. Mucoadhesive properties of chitosan-coated ophthalmic lipid emulsion containing indomethacin in tear fluid. Biol Pharm Bull. 2009;32(7):1266-71. [Crossref] [PubMed]
- Polat HK, Kurt N, Aytekin E, Bozdağ Pehlivan S, Çalış S. Novel drug delivery systems to improve the treatment of keratitis. J Ocul Pharmacol Ther. 2022;38(6):376-95. [Crossref] [PubMed]
- Rozi MF, Sabere ASM. A Review on conventional and novel topical ocular drug delivery system. J Pharm Pharmacol. 2021;1(1):19-26. [Crossref]
- Kaur IP, Kanwar M. Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002;28(5):473-93. [Crossref] [PubMed]
- Gaballa SA, Kompella UB, Elgarhy O, Alqahtani AM, Pierscionek B, Alany RG, et al. Corticosteroids in ophthalmology: drug delivery innovations, pharmacology, clinical applications, and future perspectives. Drug Deliv Transl Res. 2021;11(3):866-93. [Crossref] [PubMed]
- Scoper SV, Kabat AG, Owen GR, Stroman DW, Kabra BP, Faulkner R, et al. Ocular distribution, bactericidal activity and settling characteristics of TobraDex ST ophthalmic suspension compared with TobraDex ophthalmic suspension. Adv Ther. 2008;25(2):77-88. [Crossref] [PubMed]
- Sasaki H, Yamamura K, Mukai T, Nishida K, Nakamura J, Nakashima M, et al. Enhancement of ocular drug penetration. Crit Rev Ther Drug Carrier Syst. 1999;16(1):85-146. [Crossref] [PubMed]
- Baranowski P, Karolewicz B, Gajda M, Pluta J. Ophthalmic drug dosage forms: characterisation and research methods. ScientificWorldJournal. 2014;2014:861904. [Crossref] [PubMed] [PMC]
- Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev. 2006;58(11):1258-68. [Crossref] [PubMed]
- Sheshala R, Kok YY, Ng JM, Thakur RR, Dua K. In situ gelling ophthalmic drug delivery system: an overview and its applications. Recent Pat Drug Deliv Formul. 2015;9(3):237-48. [Crossref] [PubMed]
- Ishibashi T, Yokoi N, Bron AJ, Tiffany JM, Komuro A, Kinoshita S. Retention of reversibly thermo-gelling timolol on the human ocular surface studied by video meniscometry. Curr Eye Res. 2003;27(2):117-22. [Crossref] [PubMed]
- Whitson JT, Ochsner KI, Moster MR, Sullivan EK, Andrew RM, Silver LH, et al; Brimonidine 0.15% Study Group. The safety and intraocular pressure-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1. Ophthalmology. 2006;113(8):1333-9. [Crossref] [PubMed]
- Ranch K, Patel H, Chavda L, Koli A, Maulvi F, Parikh RK. Development of in situ ophthalmic gel of dexamethasone sodium phosphate and chloramphenicol: a viable alternative to conventional eye drops. J Appl Pharm Sci. 2017;7(3):101-8. [Crossref]
- Kaur IP, Singh M, Kanwar M. Formulation and evaluation of ophthalmic preparations of acetazolamide. Int J Pharm. 2000;199(2):119-27. [Crossref] [PubMed]
- Polat HK. In situ gels triggered by temperature for ocular delivery of dexamethasone and dexamethasone/SBE-β-CD complex. J Res Pharm. 2022;26(4):873-83. [Crossref]
- Fang G, Yang X, Wang Q, Zhang A, Tang B. Hydrogels-based ophthalmic drug delivery systems for treatment of ocular diseases. Mater Sci Eng C Mater Biol Appl. 2021;127:112212. [Crossref] [PubMed]
- Sahoo SK, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discov Today. 2008;13(3-4):144-51. [Crossref] [PubMed]
- Wadhwa S, Paliwal R, Paliwal SR, Vyas SP. Nanocarriers in ocular drug delivery: an update review. Curr Pharm Des. 2009;15(23):2724-50. [Crossref] [PubMed]
- Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26(5):1197-216. [Crossref] [PubMed] [PMC]
- Sakurai E, Ozeki H, Kunou N, Ogura Y. Effect of particle size of polymeric nanospheres on intravitreal kinetics. Ophthalmic Res. 2001;33(1):31-6. [Crossref] [PubMed]
- de Campos AM, Diebold Y, Carvalho EL, Sánchez A, Alonso MJ. Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability, in vivo fate, and cellular toxicity. Pharm Res. 2004;21(5):803-10. Erratum in: Pharm Res. 2005;22(6):1007. [Crossref] [PubMed]
- Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK. Chitosan-sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitro characterisation. Eur J Pharm Biopharm. 2008;68(3):513-25. [Crossref] [PubMed]
- Seyfoddin A, Shaw J, Al-Kassas R. Solid lipid nanoparticles for ocular drug delivery. Drug Deliv. 2010;17(7):467-89. [Crossref] [PubMed]
- Seyfoddin A, Al-Kassas R. Development of solid lipid nanoparticles and nanostructured lipid carriers for improving ocular delivery of acyclovir. Drug Dev Ind Pharm. 2013;39(4):508-19. [Crossref] [PubMed]
- Cavalli R, Gasco MR, Chetoni P, Burgalassi S, Saettone MF. Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin. Int J Pharm. 2002;238(1-2):241-5. [Crossref] [PubMed]
- Polat HK, Kurt N, Aytekin E, Akdağ Çaylı Y, Bozdağ Pehlivan S, Çalış S. Design of besifloxacin hcl-loaded nanostructured lipid carriers: in vitro and ex vivo evaluation. J Ocul Pharmacol Ther. 2022;38(6):412-23. [Crossref] [PubMed]
- Aytekin E, Öztürk N, Vural İ, Polat HK, Çakmak HB, Çalış S, et al. Design of ocular drug delivery platforms and in vitro - in vivo evaluation of riboflavin to the cornea by non-interventional (epi-on) technique for keratoconus treatment. J Control Release. 2020;324:238-49. [Crossref] [PubMed]
- Elmowafy M, Al-Sanea MM. Nanostructured lipid carriers (NLCs) as drug delivery platform: advances in formulation and delivery strategies. Saudi Pharm J. 2021;29(9):999-1012. [Crossref] [PubMed] [PMC]
- Andrade LM, Rocha KA, De Sá FA, Marreto RN, Lima EM, Gratieri T, et al. Voriconazole-loaded nanostructured lipid carriers for ocular drug delivery. Cornea. 2016;35(6):866-71. [Crossref] [PubMed]
- Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev. 2000;45(1):89-121. [Crossref] [PubMed]
- Bharti SK, Kesavan K. Phase-transition W/O microemulsions for ocular delivery: evaluation of antibacterial activity in the treatment of bacterial keratitis. Ocul Immunol Inflamm. 2017;25(4):463-74. [Crossref] [PubMed]
- Üstündağ Okur N, Çağlar EŞ, Siafaka PI. Novel ocular drug delivery systems: an update on microemulsions. J Ocul Pharmacol Ther. 2020;36(6):342-54. [Crossref] [PubMed]
- Kassem MA, Abdel Rahman AA, Ghorab MM, Ahmed MB, Khalil RM. Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int J Pharm. 2007;340(1-2):126-33. [Crossref] [PubMed]
- Ali HS, York P, Ali AM, Blagden N. Hydrocortisone nanosuspensions for ophthalmic delivery: a comparative study between microfluidic nanoprecipitation and wet milling. J Control Release. 2011;149(2):175-81. [Crossref] [PubMed]
- Zhang L, Zhang Q, Wang X, Zhang W, Lin C, Chen F, et al. Drug-in-cyclodextrin-in-liposomes: a novel drug delivery system for flurbiprofen. Int J Pharm. 2015;492(1-2):40-5. [Crossref] [PubMed]
- Gan L, Wang J, Jiang M, Bartlett H, Ouyang D, Eperjesi F, et al. Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug Discov Today. 2013;18(5-6):290-7. [Crossref] [PubMed]
- Chetoni P, Burgalassi S, Monti D, Najarro M, Boldrini E. Liposome-encapsulated mitomycin C for the reduction of corneal healing rate and ocular toxicity. J Drug Deliv Sci Technol. 2007;17(1):43-8. [Crossref]
- Budai L, Hajdú M, Budai M, Gróf P, Béni S, Noszál B, et al. Gels and liposomes in optimized ocular drug delivery: studies on ciprofloxacin formulations. Int J Pharm. 2007;343(1-2):34-40. [Crossref] [PubMed]
- Shen Y, Tu J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007;9(3):E371-7. [Crossref] [PubMed] [PMC]
- Habib FS, Fouad EA, Abdel-Rhaman MS, Fathalla D. Liposomes as an ocular delivery system of fluconazole: in-vitro studies. Acta Ophthalmol. 2010;88(8):901-4. [Crossref] [PubMed]
- Zhang J, Wang S. Topical use of coenzyme Q10-loaded liposomes coated with trimethyl chitosan: tolerance, precorneal retention and anti-cataract effect. Int J Pharm. 2009;372(1-2):66-75. [Crossref] [PubMed]
- Mehanna MM, Elmaradny HA, Samaha MW. Mucoadhesive liposomes as ocular delivery system: physical, microbiological, and in vivo assessment. Drug Dev Ind Pharm. 2010;36(1):108-18. [Crossref] [PubMed]
- Yavuz B, Pehlivan SB, Unlü N. Dendrimeric systems and their applications in ocular drug delivery. ScientificWorldJournal. 2013;2013:732340. [Crossref] [PubMed] [PMC]
- Abdelkader H, Alany RG. Controlled and continuous release ocular drug delivery systems: pros and cons. Curr Drug Deliv. 2012;9(4):421-30. [Crossref] [PubMed]
- Vandamme TF, Brobeck L. Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide. J Control Release. 2005;102(1):23-38. [Crossref] [PubMed]
- Kalomiraki M, Thermos K, Chaniotakis NA. Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications. Int J Nanomedicine. 2015;11:1-12. [Crossref] [PubMed] [PMC]
- Gupta H, Aqil M. Contact lenses in ocular therapeutics. Drug Discov Today. 2012;17(9-10):522-7. [Crossref] [PubMed]
- Kim J, Chauhan A. Dexamethasone transport and ocular delivery from poly(hydroxyethyl methacrylate) gels. Int J Pharm. 2008;353(1-2):205-22. [PubMed]
- Gulsen D, Li CC, Chauhan A. Dispersion of DMPC liposomes in contact lenses for ophthalmic drug delivery. Curr Eye Res. 2005;30(12):1071-80. [Crossref] [PubMed]
- White CJ, Byrne ME. Molecularly imprinted therapeutic contact lenses. Expert Opin Drug Deliv. 2010;7(6):765-80. [Crossref] [PubMed]
- Tieppo A, White CJ, Paine AC, Voyles ML, McBride MK, Byrne ME. Sustained in vivo release from imprinted therapeutic contact lenses. J Control Release. 2012;157(3):391-7. [Crossref] [PubMed]
- Donnelly RF, Raj Singh TR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv. 2010;17(4):187-207. [Crossref] [PubMed] [PMC]
- Bhatnagar S, Saju A, Cheerla KD, Gade SK, Garg P, Venuganti VVK. Corneal delivery of besifloxacin using rapidly dissolving polymeric microneedles. Drug Deliv Transl Res. 2018;8(3):473-83. [Crossref] [PubMed]
- Jiang J, Gill HS, Ghate D, McCarey BE, Patel SR, Edelhauser HF, et al. Coated microneedles for drug delivery to the eye. Invest Ophthalmol Vis Sci. 2007;48(9):4038-43. [Crossref] [PubMed]
- Jiang J, Moore JS, Edelhauser HF, Prausnitz MR. Intrascleral drug delivery to the eye using hollow microneedles. Pharm Res. 2009;26(2):395-403. [Crossref] [PubMed] [PMC]
- Patel SR, Lin AS, Edelhauser HF, Prausnitz MR. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm Res. 2011;28(1):166-76. [Crossref] [PubMed] [PMC]
- Grass GM, Cobby J, Makoid MC. Ocular delivery of pilocarpine from erodible matrices. J Pharm Sci. 1984;73(5):618-21. [Crossref] [PubMed]
- Saettone MF, Salminen L. Ocular inserts for topical delivery. Adv Drug Deliv Rev. 1995;16(1):95-106. [Crossref]
- Üstündağ-Okur N, Gökçe EH, Bozbıyık Dİ, Eğrilmez S, Ertan G, Özer Ö. Novel nanostructured lipid carrier-based inserts for controlled ocular drug delivery: evaluation of corneal bioavailability and treatment efficacy in bacterial keratitis. Expert Opin Drug Deliv. 2015;12(11):1791-807. [Crossref] [PubMed]
- Polat HK, Bozdağ Pehlivan S, Özkul C, Çalamak S, Öztürk N, Aytekin E, et al. Development of besifloxacin HCl loaded nanofibrous ocular inserts for the treatment of bacterial keratitis: In vitro, ex vivo and in vivo evaluation. Int J Pharm. 2020;585:119552. [Crossref] [PubMed]
.: Process List