Advances in Ocular Drug Delivery Systems

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 34133

Special Issue Editor


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Guest Editor
Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
Interests: ocular drug delivery; drug delivery to the posterior segment of the eye; drug delivery to the anterior segment of the eye; nanomedicine for eye diseases; ophthalmic medical devices

Special Issue Information

Dear Colleagues,

There have been major advances in the treatment of eye diseases over the last years. Novel therapeutic agents, ranging from small molecules to gene therapies, are available in the market to treat diseases that affect both the anterior and posterior segments of the eye, while several other drugs are at different phases of clinical trials. Simultaneously new drug delivery systems that allow the transport of therapeutic concentrations of substances to specific targets of the eye are under studies. Despite these advances, the main challenge remains in the need of alternatives for the treatment of chronic eye diseases that could increase the log-term efficacy and avoid the inconvenient of monthly intravitreal injections or daily and repeated administrations of eye drops. Therefore, this Special Issue intends to collect papers focusing on the latest developments in ocular drug delivery, specifically related to sustained delivery systems.

Prof. Dr. Armando Da Silva Cunha Júnior
Guest Editor

Manuscript Submission Information

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Keywords

  • therapy for eye diseases
  • ocular barriers of drug permeation
  • intravitreal route of drug administration
  • transporters in eye
  • ocular drug delivery
  • nanomedicine for eye diseases
  • ophthalmic medical devices
  • new treatments for chronic eye disorders
  • ocular drug bioavailability
  • ocular drug pharmacokinetics

Published Papers (8 papers)

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Editorial

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4 pages, 174 KiB  
Editorial
Advances in Ocular Drug Delivery Systems
by Armando Silva-Cunha
Pharmaceutics 2021, 13(9), 1383; https://doi.org/10.3390/pharmaceutics13091383 - 1 Sep 2021
Cited by 2 | Viewed by 1728
Abstract
There have been major advances in the treatment of eye diseases over the last years [...] Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)

Research

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11 pages, 2164 KiB  
Article
Artificial Protein Coronas Enable Controlled Interaction with Corneal Epithelial Cells: New Opportunities for Ocular Drug Delivery
by Carlo Astarita, Sara Palchetti, Mina Massaro-Giordano, Marina Di Domenico, Francesco Petrillo, Silvia Boffo, Giulio Caracciolo and Antonio Giordano
Pharmaceutics 2021, 13(6), 867; https://doi.org/10.3390/pharmaceutics13060867 - 12 Jun 2021
Cited by 8 | Viewed by 3118
Abstract
Topical administration is the most convenient route for ocular drug delivery, but only a minor fraction is retained in the precorneal pocket. To overcome this limitation, numerous drug delivery systems (DDS) have been developed. The protein corona (PC) is the layer of biomolecules [...] Read more.
Topical administration is the most convenient route for ocular drug delivery, but only a minor fraction is retained in the precorneal pocket. To overcome this limitation, numerous drug delivery systems (DDS) have been developed. The protein corona (PC) is the layer of biomolecules (e.g., proteins, sugars, lipids, etc.) that forms around DDS in physiological environments by non-covalent interaction. The PC changes the DDS physical–chemical properties, providing them with a completely novel biological identity. The specific involvement of PC in ocular drug delivery has not been addressed so far. To fulfill this gap, here we explored the interaction between a library of four cationic liposome-DNA complexes (lipoplexes) and mucin (MUC), one of the main components of the tear film. We demonstrate that MUC binds to the lipoplex surface shifting both their size and surface charge and reducing their absorption by primary corneal epithelial cells. To surpass such restrictions, we coated lipoplexes with two different artificial PCs made of Fibronectin (FBN) and Val-Gly-Asp (VGA) tripeptide that are recognized by receptors expressed on the ocular surface. Both these functionalizations remarkedly boosted internalization in corneal epithelial cells with respect to pristine (i.e., uncoated) lipoplexes. This opens the gateway for the exploitation of artificial protein corona in targeted ocular delivery, which will significantly influence the development of novel nanomaterials. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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18 pages, 2987 KiB  
Article
Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration
by Marcela Coelho Silva Ribeiro, Marcelo Coutinho de Miranda, Pricila da Silva Cunha, Gracielle Ferreira Andrade, Gustavo de Oliveira Fulgêncio, Dawidson Assis Gomes, Sílvia Ligorio Fialho, Frederico Pittella, Christine Charrueau, Virginie Escriou and Armando Silva-Cunha
Pharmaceutics 2021, 13(6), 845; https://doi.org/10.3390/pharmaceutics13060845 - 8 Jun 2021
Cited by 7 | Viewed by 3569
Abstract
Since the possibility of silencing specific genes linked to retinal degeneration has become a reality with the use of small interfering RNAs (siRNAs), this technology has been widely studied to promote the treatment of several ocular diseases. Despite recent advances, the clinical success [...] Read more.
Since the possibility of silencing specific genes linked to retinal degeneration has become a reality with the use of small interfering RNAs (siRNAs), this technology has been widely studied to promote the treatment of several ocular diseases. Despite recent advances, the clinical success of gene silencing in the retina is significantly reduced by inherent anatomical and physiological ocular barriers, and new strategies are required to achieve intraocular therapeutic effectiveness. In this study, we developed lipoplexes, prepared with sodium alginate as an adjuvant and strategically coated with hyaluronic acid (HA-LIP), and investigated the potential neuroprotective effect of these systems in a retinal light damage model. Successful functionalization of the lipoplexes with hyaluronic acid was indicated in the dynamic light scattering and transmission electron microscopy results. Moreover, these HA-LIP nanoparticles were able to protect and deliver siRNA molecules targeting caspase-3 into the retina. After retinal degeneration induced by high light exposure, in vitro and in vivo quantitative reverse transcription-PCR (RT-qPCR) assays demonstrated significant inhibition of caspase-3 expression by HA-LIP. Furthermore, these systems were shown to be safe, as no evidence of retinal toxicity was observed by electroretinography, clinical evaluation or histology. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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19 pages, 3413 KiB  
Article
Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery
by Eva Kicková, Stefano Salmaso, Francesca Mastrotto, Paolo Caliceti and Arto Urtti
Pharmaceutics 2021, 13(6), 791; https://doi.org/10.3390/pharmaceutics13060791 - 26 May 2021
Cited by 13 | Viewed by 3507
Abstract
Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug [...] Read more.
Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to ~67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 ± 30 nm and 402 ± 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 °C, while in homogenized vitreous at 37 °C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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17 pages, 17138 KiB  
Article
A New Bevacizumab Carrier for Intravitreal Administration: Focus on Stability
by Daniela Chirio, Elena Peira, Simona Sapino, Giulia Chindamo, Simonetta Oliaro-Bosso, Salvatore Adinolfi, Chiara Dianzani, Francesca Baratta and Marina Gallarate
Pharmaceutics 2021, 13(4), 560; https://doi.org/10.3390/pharmaceutics13040560 - 15 Apr 2021
Cited by 10 | Viewed by 2618
Abstract
Bevacizumab (BVZ) is a monoclonal antibody that binds to human vascular endothelial growth factor A (VEGF-A) and inhibits the interaction between VEGF-A and VEGF receptors, thus blocking the angiogenesis. Repeated intravitreal injections of BVZ for the treatment of ocular pathologies that present an [...] Read more.
Bevacizumab (BVZ) is a monoclonal antibody that binds to human vascular endothelial growth factor A (VEGF-A) and inhibits the interaction between VEGF-A and VEGF receptors, thus blocking the angiogenesis. Repeated intravitreal injections of BVZ for the treatment of ocular pathologies that present an excessive proliferation results in a low patience compliance. BVZ is specially indicated for the treatment of diabetic and degenerative retinopathy. In the present study, we designed lipid nanoparticles (NPs) as a BVZ sustained drug delivery system for reducing the frequency of administration. We used a simple and highly efficient procedure, “Cold dilution of microemulsions”, to obtain spherical NPs with mean diameters of 280–430 nm, Zeta potentials between −17 and −31 mV, and drug entrapment efficiencies between 50 to 90%. This study focused on the biochemical and biophysical stabilities of BVZ after entrapment in NPs. SDS-PAGE electrophoretic analysis and circular dichroism, dynamic light scattering, and scanning electron microscopy were used to characterize BVZ-loaded NPs. The biocompatibility was assessed by in vitro cell compatibility studies using the ARPE-19 cell line. Thus, in this work, a stable BVZ-loaded system was obtained. In addition, several studies have shown that BVZ is released slowly from the lipid matrix and that this system is biocompatible. The results are promising and the developed NPs could be exploited to create a new, potentially effective and minimally invasive treatment of intraocular diseases. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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13 pages, 5284 KiB  
Article
Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region
by Vijayabhaskarreddy Junnuthula, Amir Sadeghi Boroujeni, Shoupeng Cao, Shirin Tavakoli, Roxane Ridolfo, Elisa Toropainen, Marika Ruponen, Jan C. M. van Hest and Arto Urtti
Pharmaceutics 2021, 13(4), 445; https://doi.org/10.3390/pharmaceutics13040445 - 26 Mar 2021
Cited by 28 | Viewed by 5623
Abstract
Posterior eye tissues, such as retina, are affected in many serious eye diseases, but drug delivery to these targets is challenging due to various anatomical eye barriers. Intravitreal injections are widely used, but the intervals between invasive injections should be prolonged. We synthesized [...] Read more.
Posterior eye tissues, such as retina, are affected in many serious eye diseases, but drug delivery to these targets is challenging due to various anatomical eye barriers. Intravitreal injections are widely used, but the intervals between invasive injections should be prolonged. We synthesized and characterized (1H NMR, gel permeation chromatography) block copolymers of poly(ethylene glycol), poly(caprolactone), and trimethylene carbonate. These polymers self-assembled to polymersomes and polymeric micelles. The mean diameters of polymersomes and polymeric micelles, about 100 nm and 30–50 nm, respectively, were obtained with dynamic light scattering. Based on single particle tracking and asymmetric flow field-flow fractionation, the polymeric micelles and polymersomes were stable and diffusible in the vitreous. The materials did not show cellular toxicity in cultured human umbilical vein endothelial cells in the Alamar Blue Assay. Pharmacokinetics of the intravitreal nanocarriers in the rabbits were evaluated using in vivo fluorophotometry. The half-lives of the polymersomes (100 nm) and the micelles (30 nm) were 11.4–32.7 days and 4.3–9.5 days. The intravitreal clearance values were 1.7–8.7 µL/h and 3.6–5.4 µL/h for polymersomes and polymeric micelles, respectively. Apparent volumes of distribution of the particles in the rabbit vitreous were 0.6–1.3 mL for polymeric micelles and 1.9–3.4 mL for polymersomes. Polymersomes were found in the vitreous for at least 92 days post-dosing. Furthermore, fundus imaging revealed that the polymersomes accumulated near the optic nerve and retained there even at 111 days post-injection. Polymersomes represent a promising technology for controlled and site-specific drug delivery in the posterior eye segment. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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31 pages, 6463 KiB  
Article
Self-Assembling Tacrolimus Nanomicelles for Retinal Drug Delivery
by Vrinda Gote, Abhirup Mandal, Meshal Alshamrani and Dhananjay Pal
Pharmaceutics 2020, 12(11), 1072; https://doi.org/10.3390/pharmaceutics12111072 - 10 Nov 2020
Cited by 20 | Viewed by 3217
Abstract
Neovascular age-related macular degeneration (AMD) is characterized by an increase in reactive oxygen species (ROS) and pro-inflammatory cytokines in the retinal pigment epithelium cells. The primary purpose of this study was the development of a clear, tacrolimus nanomicellar formulation (TAC-NMF) for AMD. The [...] Read more.
Neovascular age-related macular degeneration (AMD) is characterized by an increase in reactive oxygen species (ROS) and pro-inflammatory cytokines in the retinal pigment epithelium cells. The primary purpose of this study was the development of a clear, tacrolimus nanomicellar formulation (TAC-NMF) for AMD. The optimized formulation had a mean diameter of 15.41 nm, a zeta potential of 0.5 mV, and an entrapment efficiency of 97.13%. In-vitro cytotoxicity studies revealed the dose-dependent cytotoxicity of TAC-NMF on various ocular cell lines, such as human retinal pigment epithelium (D407), monkey retinal choroidal endothelial (RF/6A) cells, and human corneal epithelium (CCL 20.2) cells. Cellular uptake and in-vitro distribution studies using flow cytometry and confocal microscopy, respectively, indicated an elevated uptake of TAC-NMF in a time-dependent manner. Biocompatibility assay using macrophage RAW 264.7 cell line resulted in low production of inflammatory cytokines such as IL-6, IL-1β and TNF-α after treatment with TAC-NMF. There was a decrease in ROS in D407 cells pre-treated with sodium iodate (ROS inducing agent) after treating with TAC-NMF and tacrolimus drug. Similarly, there was a reduction in the pro-inflammatory cytokines and VEGF-A in D407 cells pretreated with sodium iodate. This indicates that TAC-NMF could lower pro-inflammatory cytokines and ROS commonly seen in AMD. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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Review

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19 pages, 2444 KiB  
Review
Formulation Considerations for the Management of Dry Eye Disease
by Priyanka Agarwal, Jennifer P. Craig and Ilva D. Rupenthal
Pharmaceutics 2021, 13(2), 207; https://doi.org/10.3390/pharmaceutics13020207 - 3 Feb 2021
Cited by 63 | Viewed by 9568
Abstract
Dry eye disease (DED) is one of the most common ocular surface disorders characterised by a deficiency in quality and/or quantity of the tear fluid. Due to its multifactorial nature involving several inter-related underlying pathologies, it can rapidly accelerate to become a chronic [...] Read more.
Dry eye disease (DED) is one of the most common ocular surface disorders characterised by a deficiency in quality and/or quantity of the tear fluid. Due to its multifactorial nature involving several inter-related underlying pathologies, it can rapidly accelerate to become a chronic refractory condition. Therefore, several therapeutic interventions are often simultaneously recommended to manage DED efficiently. Typically, artificial tear supplements are the first line of treatment, followed by topical application of medicated eyedrops. However, the bioavailability of topical eyedrops is generally low as the well-developed protective mechanisms of the eye ensure their rapid clearance from the precorneal space, thus limiting ocular penetration of the incorporated drug. Moreover, excipients commonly used in eyedrops can potentially exhibit ocular toxicity and further exacerbate the signs and symptoms of DED. Therefore, formulation development of topical eyedrops is rather challenging. This review highlights the challenges typically faced in eyedrop development, in particular, those intended for the management of DED. Firstly, various artificial tear supplements currently on the market, their mechanisms of action, as well as their application, are discussed. Furthermore, formulation strategies generally used to enhance ocular drug delivery, their advantages and limitations, as well as their application in commercially available DED eyedrops are described. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery Systems)
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