Ex vivo conjunctival retention and transconjunctival transport of poorly soluble drugs using polymeric micelles
Open accessAbstract
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.
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The amount of drug found in the receptor compartment is the result of two processes: effective release of the drug from the micelle and permeation of the drug across the dialysis membrane.
“Finally, it should be always considered that the amount of drug found in the receptor compartment is the result of two processes: the effective release of the drug from the micelle and the permeation of the drug across the dialysis membrane [120].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [120]
Methods §2.8 (page unavailable) places drug-loaded micelles inside a cellulose dialysis tube and measures drug in the external solution; Results §3.5.3 describes the resulting profile as dexamethasone release from micelles. These passages support the experimental setup behind the claim, but the paper does not explicitly identify release and permeation across the dialysis membrane as two distinct processes determining the measured amount. (LLM, conf=0.78)
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Cites
Wanka, G., Hoffmann, H., & Ulbricht, W. (1994) · Macromolecules · doi:10.1021/ma00093a016 · Cited by 1,506 · see citing works
Guzmán, H. R., Tawa, M. D., Zhang, Z., et al. (2007) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20906 · Cited by 382 · see citing works
Warren, D. B., Benameur, H., Porter, C. J. H., et al. (2010) · Journal of drug targeting · doi:10.3109/1061186x.2010.525652 · Cited by 323 · see citing works
Ophthalmic Drug Dosage Forms: Characterisation and Research Methods
Baranowski, P., Karolewicz, B., Gajda, M., & Pluta, J. (2014) · The Scientific World JOURNAL · doi:10.1155/2014/861904 · Cited by 283 · see citing works
Collnot, E.-M., Baldes, C., Wempe, M. F., et al. (2007) · Molecular Pharmaceutics · doi:10.1021/mp060121r · Cited by 280 · see citing works
Minimizing systemic absorption of topically administered ophthalmic drugs
Urtti, A. O., & Salminen, L. (1993) · Survey of Ophthalmology · doi:10.1016/0039-6257(93)90141-s · Cited by 267 · see citing works
Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera.
Hämäläinen, K. M., Kananen, K., Auriola, S. O. K., Kontturi, K., & Urtti, A. O. (1997) · PubMed · Cited by 266 · see citing works
Polymeric micelles: Basic research to clinical practice
Deshmukh, A. S., Chauhan, P. N., Noolvi, M. N., Chaturvedi, K., Ganguly, K., Shukla, S. S., Nadagouda, M. N., & Aminabhavi, T. M. (2017) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2017.09.005 · Cited by 244 · see citing works
Penetration Enhancers in Ocular Drug Delivery
Moiseev, R. V., Morrison, P. W. J., Steele, D. F., & Khutoryanskiy, V. V. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11070321 · Cited by 242 · see citing works
Cyclosporine A delivery to the eye: A pharmaceutical challenge
Lallemand, F., Felt-Baeyens, O., Besseghir, K., Béhar‐Cohen, F., & Gurny, R. (2003) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/s0939-6411(03)00138-3 · Cited by 239 · see citing works
Physicochemical Determinants of Drug Diffusion Across the Conjunctiva, Sclera, and Cornea
Ahmed, I., Gokhale, R. D., Shah, M. V., & Patton, T. F. (1987) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600760802 · Cited by 197 · see citing works
Hosoya, K.-I., Lee, V. H. L., & Kim, K.-J. (2005) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2004.12.007 · Cited by 194 · see citing works
Paracellular permeability of corneal and conjunctival epithelia.
Huang, A., Tseng, S. C. G., & Kenyon, K. R. (1989) · PubMed · Cited by 190 · see citing works
Fathalla, Z. M. A., Vangala, A., Longman, M. R., Khaled, K. A., Hussein, A. K., El-Garhy, O. H., & Alany, R. G. (2017) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2017.01.008 · Cited by 169 · see citing works
Transscleral drug delivery to the posterior eye: Prospects of pharmacokinetic modeling
Ranta, V., & Urtti, A. O. (2006) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2006.07.025 · Cited by 160 · see citing works
Ramsay, E., del Amo, E. M., Toropainen, E., Tengvall, U., Ranta, V., Urtti, A. O., & Ruponen, M. (2018) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2018.03.034 · Cited by 151 · see citing works
Wang, W., Sasaki, H., Chien, D., & Lee, V. H. L. (1991) · Current Eye Research · doi:10.3109/02713689109001766 · Cited by 142 · see citing works
Poloxamer 407/TPGS mixed micelles as promising carriers for cyclosporine ocular delivery
Grimaudo, M. A., Pescina, S., Padula, C., Santi, P., Concheiro, A., Alvarez-Lorenzo, C., & Nicoli, S. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b00939 · Cited by 138 · see citing works
Self-citationMortensen, K., Batsberg, W., & Hvidt, S. (2008) · Macromolecules · doi:10.1021/ma702269c · Cited by 137 · see citing works
Di Tommaso, C., Bourges, J.-L., Valamanesh, F., Trubitsyn, G., Torriglia, A., Jeanny, J.-C., Behar-Cohen, F., Gurny, R., & Möller, M. (2012) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2012.02.014 · Cited by 128 · see citing works
Liaw, J., Chang, S.-F., & Hsiao, F.-C. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301485 · Cited by 125 · see citing works
Polyhydroxyethylaspartamide-based micelles for ocular drug delivery
Civiale, C., Licciardi, M., Cavallaro, G., Giammona, G., & Mazzone, M. G. (2009) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2009.05.028 · Cited by 120 · see citing works
Overhoff, K. A., McConville, J. T., Yang, W., et al. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9417-y · Cited by 104 · see citing works
Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery
Cholkar, K., Gilger, B. C., & Mitra, A. K. (2015) · Translational Vision Science & Technology · doi:10.1167/tvst.4.3.1 · Cited by 103 · see citing works
How do polymeric micelles cross epithelial barriers?
Pepić, I., Lovrić, J., & Filipović-Grčić, J. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2013.04.012 · Cited by 102 · see citing works
Challenges in the Polyene- and Azole-Based Pharmacotherapy of Ocular Fungal Infections
Lakhani, P. M., Patil, A., & Majumdar, S. (2018) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2018.0089 · Cited by 102 · see citing works
Direct visualisation of micelles of Pluronic block copolymers in aqueous solution by cryo-TEM
Lam, Y. M., Grigorieff, N., & Goldbeck, G. (1999) · Physical Chemistry Chemical Physics · doi:10.1039/a902369k · Cited by 100 · see citing works
Soluplus micelles for acyclovir ocular delivery: formulation and cornea and sclera permeability
Varela-Garcia, A., Concheiro, A., & Alvarez-Lorenzo, C. (2018) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2018.09.053 · Cited by 92 · see citing works
Yu, Y., Chen, D., Li, Y., Yang, W., Tu, J., & Shen, Y. (2018) · Drug Delivery · doi:10.1080/10717544.2018.1458923 · Cited by 85 · see citing works
Sun, F., Zheng, Z., Lan, J., Li, X., Li, M., Song, K., & Wu, X. (2019) · Drug Delivery · doi:10.1080/10717544.2019.1622608 · Cited by 85 · see citing works
Grimaudo, M. A., Pescina, S., Padula, C., Santi, P., Concheiro, A., Alvarez-Lorenzo, C., & Nicoli, S. (2019) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2019.1597848 · Cited by 78 · see citing works
Self-citationKompella, U. B., Sundaram, S., Raghava, S., & Escobar, E. R. (2006) · PubMed · Cited by 77 · see citing works
Prajna, N. V. (2003) · British Journal of Ophthalmology · doi:10.1136/bjo.87.10.1235 · Cited by 76 · see citing works
Ostacolo, C., Caruso, C., Tronino, D., Troisi, S., Laneri, S., Pacente, L., Prete, A., & Sacchi, A. (2012) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2012.09.051 · Cited by 72 · see citing works
Yang, J. J., Kim, K.-J., & Lee, V. H. L. (2000) · Pharmaceutical Research · doi:10.1023/a:1007508714259 · Cited by 70 · see citing works
Existence of a p-glycoprotein drug efflux pump in cultured rabbit conjunctival epithelial cells.
Saha, P., Yang, J. J., & Lee, V. H. L. (1998) · PubMed · Cited by 68 · see citing works
Horibe, Y., Hosoya, K., Kim, K., et al. (1997) · Pharmaceutical Research · doi:10.1023/a:1012123411343 · Cited by 63 · see citing works
Expression, activity and pharmacokinetic impact of ocular transporters
Vellonen, K., Hellinen, L., Mannermaa, E., Ruponen, M., Urtti, A. O., & Kidron, H. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.12.009 · Cited by 63 · see citing works
Ramsay, E., Ruponen, M., Picardat, T., Tengvall, U., Tuomainen, M. H., Auriola, S. O. K., Toropainen, E., Urtti, A. O., & del Amo, E. M. (2017) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.04.061 · Cited by 62 · see citing works
Li, H., Yan, L., Tang, E. K. Y., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00769 · Cited by 61 · see citing works
Novel Dexamethasone-Loaded Nanomicelles for the Intermediate and Posterior Segment Uveitis
Vaishya, R. D., Gokulgandhi, M. R., Patel, S. P., Minocha, M., & Mitra, A. K. (2014) · AAPS PharmSciTech · doi:10.1208/s12249-014-0100-4 · Cited by 58 · see citing works
A Single Drop in the Eye – Effects on the Whole Body?
Vaajanen, A., & Vapaatalo, H. (2017) · The Open Ophthalmology Journal · doi:10.2174/1874364101711010305 · Cited by 57 · see citing works
Sun, D. D., & Lee, P. I. (2015) · Molecular Pharmaceutics · doi:10.1021/mp500711c · Cited by 54 · see citing works
Prima, G. D., Saladino, S., Bongiovì, F., Adamo, G., Ghersi, G., Pitarresi, G. L., & Giammona, G. (2017) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2017.05.005 · Cited by 54 · see citing works
Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin
Lorenzo-Veiga, B., Sigurðsson, H. H., Loftsson, Þ., & Alvarez‐Lorenzo, C. (2019) · Nanomaterials · doi:10.3390/nano9050745 · Cited by 53 · see citing works
Caruso, C., Ostacolo, C., Epstein, R. L., et al. (2015) · Cornea · doi:10.1097/ico.0000000000000699 · Cited by 50 · see citing works
Ophthalmic Econazole Hydrogels for the Treatment of Fungal Keratitis
Díaz-Tomé, V., Luaces-Rodríguez, A., Silva‐Rodríguez, J., Blanco‐Dorado, S., García‐Quintanilla, L., Llovo‐Taboada, J., Blanco-Méndez, J., García‐Otero, X., Varela‐Fernández, R., Herranz, M., et al. (2018) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.12.028 · Cited by 50 · see citing works
Hou, Y., Zhang, F., Lan, J., Sun, F., Li, J., Li, M., Song, K., & Wu, X. (2019) · Drug Delivery · doi:10.1080/10717544.2019.1568624 · Cited by 50 · see citing works
Tırnaksız, F., & Robinson, J. R. (2005) · PubMed · Cited by 47 · see citing works
Bongiovì, F., Prima, G. D., Palumbo, F. S., Licciardi, M., Pitarresi, G. L., & Giammona, G. (2017) · Macromolecular Bioscience · doi:10.1002/mabi.201700261 · Cited by 47 · see citing works
Ahmed, T. A., El‐Say, K. M., Ahmed, O. A. A., & Aljaeid, B. M. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s213086 · Cited by 46 · see citing works
Elmowafy, E. M., Gad, H. A., Biondo, F., Casettari, L., & Soliman, M. E. (2019) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2019.06.011 · Cited by 45 · see citing works
Puig-Rigall, J., Grillo, I., Dreiss, C. A., et al. (2017) · Langmuir · doi:10.1021/acs.langmuir.7b00701 · Cited by 38 · see citing works
Ocular Permeability of FITC-Dextran with Absorption Promoter for Ocular Delivery of Peptide Drug
Sasaki, H., Yamamura, K., Tei, C., et al. (1995) · Journal of drug targeting · doi:10.3109/10611869509059212 · Cited by 35 · see citing works
Cyclosporine A micellar delivery system for dry eyes
Hwang, S., Kang, H. S., Cha, K.-H., Cho, W., Park, J. S., Park, H. J., Sun, B. K., & Hyun, S.-M. (2016) · International Journal of Nanomedicine · doi:10.2147/ijn.s107569 · Cited by 35 · see citing works
Noh, G., Keum, T., Seo, J., Choi, J., Bastola, R., Lamichhane, S., Park, B., Choi, Y. W., & Lee, S. K. (2018) · Pharmaceutics · doi:10.3390/pharmaceutics10040208 · Cited by 30 · see citing works
Ocular Membrane Permeability of Hydrophilic Drugs for Ocular Peptide Delivery
Sasaki, H., Ichikawa, M., Yamamura, K., Nishida, K., & Nakamura, J. (1997) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1997.tb06767.x · Cited by 28 · see citing works
The Conjunctival Barrier in Ocular Drug Delivery
Gukasyan, H. J., Kim, K., & Lee, V. H. L. (2007) · Springer eBooks · doi:10.1007/978-0-387-74901-3_13 · Cited by 23 · see citing works
Modification of Ocular Permeability of Peptide Drugs by Absorption Promoters.
Sasaki, H., Yamamura, K., Mukai, T., et al. (2000) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.23.1524 · Cited by 22 · see citing works
Holland, E. J., Mannis, M. J., & Lee, W. B. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-2876-3.00058-4 · Cited by 22 · see citing works
Clear, Aqueous Topical Drop of Triamcinolone Acetonide
Trinh, H. M., Cholkar, K., Joseph, M. A., Yang, X., & Mitra, A. K. (2017) · AAPS PharmSciTech · doi:10.1208/s12249-017-0714-4 · Cited by 19 · see citing works
Juretić, M., Cetina‐Čižmek, B., Filipović‐Grčić, J., et al. (2018) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2018.04.032 · Cited by 19 · see citing works
Singh, R., Kristensen, S., & Hh, T. (2012) · PubMed · Cited by 16 · see citing works
Conjunctival Anatomy and Physiology
Harvey, T. M., Fernandez, A. G. A., Patel, R. N., et al. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-2876-3.00004-3 · Cited by 15 · see citing works
Pescina, S., Macaluso, C., Gioia, G. A., Padula, C., Santi, P., & Nicoli, S. (2017) · Drug Development and Industrial Pharmacy · doi:10.1080/03639045.2017.1318910 · Cited by 9 · see citing works
Self-citationImidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury
Zeng, S., Wen, K., Workalemahu, G., Sohn, E. H., Wu, M., Chirco, K. R., Flamme‐Wiese, M. J., Liu, X., Stone, E. M., Tucker, B. A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-31846-z · Cited by 9 · see citing works
Dumée, L. F., Lemoine, J.-B., Ancel, A., Hameed, N., He, L., & Kong, L. (2015) · Nanomaterials · doi:10.3390/nano5041766 · Cited by 8 · see citing works
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Ghezzi, M., Pescina, S., Padula, C., Santi, P., Del Favero, E., Cantù, L., & Nicoli, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.02.031 · Cited by 1,135 · see citing works
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- Authors
- Pescina, S., Grolli Lucca, L., Govoni, P., Padula, C., Del Favero, E., Cantù, L., Santi, P., & Nicoli, S.
- Affiliations
- University of Parma (IT)
- Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
- Department of Medical Biotechnologies and Translational Medicine, LITA, University of Milan, 20090 Segrate (MI), Italy
- Corresponding author
- Nicoli, Sara
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2019-09-14
- Volume
- 11
- Issue
- 9
- Pages
- 476
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC6781556
- OpenAlex
- W2973028280
- Cited by
- 38
- References
- 67
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Università degli Studi di Parma (20173ZECCM)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ocular Surface and Contact Lens
- Keywords
- polymeric micelles, ocular drug delivery, poorly water-soluble drugs, TPGS, Pluronic F127, dexamethasone, cyclosporine, econazole nitrate, lipophilic drugs, solubility enhancement
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