Ocular Drug Delivery Applications Research Articles

Advancements in Nanogels for Enhanced Ocular Drug Delivery: Cutting-Edge Strategies to Overcome Eye Barriers.

Nanomedicine in gel or particle formation holds considerable potential for enhancing passive and active targeting within ocular drug delivery systems. The complex barriers of the eye, exemplified by the intricate network of closely connected tissue structures, pose significant challenges for drug administration. Leveraging the capability of engineered nanomedicine offers a promising approach to enhance drug penetration, particularly through active targeting agents such as protein peptides and aptamers, which facilitate targeted release and heightened bioavailability. Simultaneously, DNA carriers have emerged as a cutting-edge class of active-targeting structures, connecting active targeting agents and illustrating their potential in ocular drug delivery applications. This review aims to consolidate recent findings regarding the optimization of various nanoparticles, i.e., hydrogel-based systems, incorporating both passive and active targeting agents for ocular drug delivery, thereby identifying novel mechanisms and strategies. Furthermore, the review delves into the potential application of DNA nanostructures, exploring their role in the development of targeted drug delivery approaches within the field of ocular therapy.

Neuroprotective Nanoparticles Targeting the Retina: A Polymeric Platform for Ocular Drug Delivery Applications.

Neuroprotective drug delivery to the posterior segment of the eye represents a major challenge to counteract vision loss. This work focuses on the development of a polymer-based nanocarrier, specifically designed for targeting the posterior eye. Polyacrylamide nanoparticles (ANPs) were synthesised and characterised, and their high binding efficiency was exploited to gain both ocular targeting and neuroprotective capabilities, through conjugation with peanut agglutinin (ANP:PNA) and neurotrophin nerve growth factor (ANP:PNA:NGF). The neuroprotective activity of ANP:PNA:NGF was assessed in an oxidative stress-induced retinal degeneration model using the teleost zebrafish. Upon nanoformulation, NGF improved the visual function of zebrafish larvae after the intravitreal injection of hydrogen peroxide, accompanied by a reduction in the number of apoptotic cells in the retina. Additionally, ANP:PNA:NGF counteracted the impairment of visual behaviour in zebrafish larvae exposed to cigarette smoke extract (CSE). Collectively, these data suggest that our polymeric drug delivery system represents a promising strategy for implementing targeted treatment against retinal degeneration.

Pickering emulsions stabilised with oligoglycine-functionalised nanodiamond as a model system for ocular drug delivery applications.

Oil-in-water emulsions, stabilised with conventional surfactants, are commonly used in eye drops for ocular drug delivery. However, the presence of surfactants can sometimes irritate tissues. Furthermore, conventional emulsions often have poor retention on ocular tissue. Pickering emulsions stabilised with nanoparticles have been gaining attention in recent years for a range of biomedical applications because of their biocompatibility. Here, Pickering emulsions were evaluated for the first time for the confinement of organic components for potential application in ocular drug delivery. For a model system, we used nanodiamond (ND) nanoparticles functionalised with covalently-bonded two-tail (2T) oligoglycine C10(NGly4)2 to make Pickering oil-in-water emulsions, which were stable over three months of storage under neutral pH. We proved the non-toxicity of ND-2T Pickering emulsions, comparable to buffer solution, via an ex vivo bovine corneal permeability and opacity test. The retention of the oil phase in the ND-2T stabilised emulsions on corneal tissue is significantly increased because of the mucoadhesive properties arising from the positively-charged terminal amino groups of 2T. Our formulated emulsions have a surface tension, pH and salt concentration comparable to that of tear fluid. The high retention of the ND-2T-stabilised emulsions on the corneal surface, in combination with their non-toxicity, gives them distinct advantages for ocular drug delivery. The principles of this model system could be applied in the future design of a range of formulations for drug delivery.

Development of Dexamethasone Loaded Nanomicelles Using a 3d Printed Microfluidic Device for Ocular Drug Delivery Applications

Development of Dexamethasone Loaded Nanomicelles Using a 3d Printed Microfluidic Device for Ocular Drug Delivery Applications

PEG-containing siloxane materials by metal-free click-chemistry for ocular drug delivery applications

Metal-free click-chemistry can be used to create silicone hydrogels for ocular drug delivery applications, imparting the benefits of silicones without catalyst contamination. Previous work has demonstrated the capacity for these materials to significantly reduce protein adsorption. Building upon this success, the current work examines and optimizes different materials in terms of their protein adsorption and drug release capabilities. Specifically, incorporating lower molecular weight poly-ethylene glycol (PEG) is better able to reduce protein adsorption. However, with higher molecular weight PEG, the materials exhibit excellent water content and better drug release profiles. The lower molecular weight PEG is also able to deliver the drug over a period in excess of four months, with the amount of crosslinking having the greatest impact on the amount of drug release. Overall, these materials show great promise for ocular applications.

Hydrogel Biomaterials for Application in Ocular Drug Delivery.

There are many challenges involved in ocular drug delivery. These are a result of the many tissue barriers and defense mechanisms that are present with the eye; such as the cornea, conjunctiva, the blinking reflex, and nasolacrimal drainage system. This leads to many of the conventional ophthalmic preparations, such as eye drops, having low bioavailability profiles, rapid removal from the administration site, and thus ineffective delivery of drugs. Hydrogels have been investigated as a delivery system which is able to overcome some of these challenges. These have been formulated as standalone systems or with the incorporation of other technologies such as nanoparticles. Hydrogels are able to be formulated in such a way that they are able to change from a liquid to gel as a response to a stimulus; known as “smart” or stimuli-responsive biotechnology platforms. Various different stimuli-responsive hydrogel systems are discussed in this article. Hydrogel drug delivery systems are able to be formulated from both synthetic and natural polymers, known as biopolymers. This review focuses on the formulations which incorporate biopolymers. These polymers have a number of benefits such as the fact that they are biodegradable, biocompatible, and non-cytotoxic. The biocompatibility of the polymers is essential for ocular drug delivery systems because the eye is an extremely sensitive organ which is known as an immune privileged site.

Neem seed oil and gum arabic-based oil-in-water emulsions as potential ocular drug delivery system

The present study deciphers the synthesis and characterization of the neem seed oil (NSO) and gum arabic (GA) based emulsion. The synthesized emulsions were thoroughly characterized for probable application in ocular drug delivery. The synthesized emulsions were white in color. The FTIR spectroscopy divulged that the glycoprotein complex of GA retained its functional architecture. The formation of the oil-in-water emulsion was confirmed by confocal microscopy. The NSO droplets in the emulsions behaved as capacitive elements whose properties altered as the composition of the emulsions were varied. The mechanical studies suggested that the interactions within the emulsion components tailored the polymer-polymer integrity under stress. The drug release and corneal permeation studies using ciprofloxacin HCl-loaded emulsions indicated that the ciprofloxacin molecules were released from the emulsions, and the emulsions were able to deliver the drug across the corneal tissue. The prepared emulsions were nonirritant to the ocular tissues. The released drug was capable of inhibiting the growth of the model bacteria (Staphylococcus aureus). In gist, the prepared emulsions were suitable for ocular drug delivery applications.

Chitosan/poly(2-ethyl-2-oxazoline) films for ocular drug delivery: Formulation, miscibility, in vitro and in vivo studies

Polymeric films were prepared based on chitosan and its blends with poly(2-ethyl-2-oxazoline) by casting from aqueous solutions. These materials were characterised using a number of physicochemical techniques, including Fourier-transform infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, wide angle x-ray diffraction, tensile testing and scanning electron microscopy. All these studies indicate that there is a weak intermacromolecular hydrogen bonding between these polymers, which facilitates their complete miscibility in solid state. These films were formulated with sodium fluorescein as a model drug and were evaluated for their potential application in ocular drug delivery both in vitro and in vivo. It was established that the films are biocompatible and mucoadhesive; they are capable of providing a sustained drug release when administered topically on the cornea.

A hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier ocular drug delivery platform

The objective of this study was to develop a novel hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier (NLC) drug delivery platform. An ophthalmic anti-inflammatory drug, baicalin (BN) was chosen as the model drug. BNNLC was prepared using melt-emulsification combined with ultra-sonication technique. Additionally, a dual pH- and thermo-sensitive hydrogel composed of carboxymethyl chitosan (CMCS) and poloxamer 407 (F127) was fabricated by a cross-linking reaction with a nontoxic crosslinker genipin (GP). GP-CMCS/F127 hydrogel was characterized by FTIR, NMR, XRD and SEM. The swelling studies showed GP-CMCS/F127 hydrogel was both pH- and thermo-sensitive. The results of in vitro release suggested BNNLC gel can prolong the release of baicalin comparing with BN eye drops and BNNLC. Ex vivo cornea permeation study was evaluated using Franz diffusion cells. The apparent permeability coefficient (Papp) of BNNLC gel was much higher (4.46-fold) than that of BN eye drops. Through the determination of corneal hydration levels, BNNLC gel was confirmed that had no significant irritation to cornea. Ex vivo precorneal retention experiments were carried out by a flow-through approach. The results indicated that the NLC-based hydrogel can prolong precorneal residence time. In conclusion, the hybrid NLC-based hydrogel has a promising potential for application in ocular drug delivery.

ZnO/PVP nanoparticles induce gelation in type I collagen

Collagen based hydrogels have similar properties to native cornea and play an important role in ocular drug delivery. Here we report the preparation of zinc oxide nanoparticle/collagen hydrogels (collagen ZnO/PVP) without the need of an external cross-linking agent. The resulting hydrogels had sufficient mechanical strength to be manipulated and transferred without damaging its structure. Differential scanning calorimetry showed an increase in the denaturation temperature on increasing the ZnO/PVP NPs ratio. Whilst rheological measurements of the collagen hydrogels suggest that strong hydrogels were formed, at high concentration of ZnO/PVP NPs a decrease in G′ can be observed. The responses of retinal epithelial cells (ARPE-19) to the collagen ZnO/PVP hydrogels were examined by cell viability assays and exhibited minimal cytotoxicity. The collagen ZnO/PVP hydrogel might be an excellent candidate for ocular drug delivery applications.

Microfluidic in vitro Drug Release from Contact Lens Materials

PurposeOver 90% of ophthalmic drugs are commonly applied as eye drops. However, drug tear film residence time is less than 5 min, and only 5% of the administered drug is absorbed, leading to a final poor drug bioavailability and eventual side effects Efforts have been made to develop more effective drug delivery systems. Therapeutic contact lenses (CLs) have demonstrated to be a good vehicle for a controlled release of a variety of drugs owing to their biocompatibility, high degree of comfort, and prolonged contact with the eye.MethodsCLs materials were prepared as a) a conventional hydroxyethylmethacrylate (HEMA) based hydrogel and as b) a silicone based hydrogel. The different materials were loaded with an antibiotic‐ levofloxacin (LVF), and one of two non‐steroidal anti‐inflammatory drugs (NSAID) ‐diclofenac (DCF) and ketorolac (KET). To simulate physiological human eye conditions such as temperature, tear volume and flow rate, drug release tests were carried out in a novel microfluidic cell.ResultsResults showed that a) HEMA based hydrogel allows a drug release up to 10 hours with predicted concentrations in the eye as >129 µg/mL for LVF, >918 µg/mL for DCF and > 251 µg/mL for KET whereas b) Silicone based hydrogel releases both NSAID for at least 4 days, with concentrations >163 µg/mL for DCF and >31 µg/mL for KET.ConclusionsDrug eluted CLs biomaterials can be used as a platform for ocular drug delivery applications.

Hyaluronic acid‐based nanocomposite hydrogels for ocular drug delivery applications

Hyaluronic acid‐based nanocomposite hydrogels for ocular drug delivery applications

Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System.

In extended ocular drug delivery applications, it is necessary to exert control over the release characteristics of the drug. Design considerations must be made to limit the initial burst (IB) and ensure complete release of drug from the drug delivery system (DDS). In this study, ovalbumin was used as a model protein to explore the effects on release of polymer formulation and fabrication technique in poly(lactic-co-glycolic acid) (PLGA) microspheres. Furthermore, the effect on release of suspending these microspheres in an injectable, thermo-responsive poly(N-isopropylacrylamide)-based hydrogel was determined. To characterize release, ovalbumin was radiolabeled with iodine-125. Regardless of polymer formulation or fabrication technique, pulsatile release was achieved with a second burst occurring after ~70 days for microspheres alone. Suspending PLGA 75:25 microspheres within hydrogel reduced the IB by ~75%, delayed the second burst by 28 days, and extended release out to ~200 days with steadier, consistent release throughout compared to microspheres alone. The combined microsphere-hydrogel DDS remains injectable through small-gauge needles and may have many applications, namely ocular drug delivery to the posterior segment.

Development of a Layer-by-Layer Assembled Film on Hydrogel for Ocular Drug Delivery

Hydrogel is a kind of attractive drug carriers because of its good biocompatibility and transparency. But traditional hydrogel showed some restrictions in its application in ocular drug delivery. A simple surface modification technique based on layer-by-layer (LbL) self-assembled multilayer for ocular drug delivery was developed in this work. Polycarboxymethyl-β-cyclodextrin (poly(CM-β-CD))/poly-l-lysine (PLL) multilayer film was designed and constructed for ocular drug delivery, sinceβ-CD showed good drug delivery property. The properties such as the contact angle and transparency varied a little with the deposition of poly(CM-β-CD)/PLL multilayer. Orfloxacin and puerarin were loaded into multilayer during the self-assembly procedure by two methods, which were tracked by the largest drug absorbance of UV spectrum. The loaded drug amount by incorporating drugs into poly(CM-β-CD) solution was larger than that by incorporating drugs into PLL solution. The loaded drug in the multilayer could gradually be released from multilayer in some period either for orfloxacin or for puerarin. The drug release behavior was influenced by drug loading method and pH value of released medium. Moreover, the balanced released drug amount by incorporating drugs into poly(CM-β-CD) solution is much smaller than that by incorporating drugs into PLL solution.

In situ covalently cross-linked PEG hydrogel for ocular drug delivery applications.

Avastin(®) has been clinically proved to be effective in the treatment of intraocular neovascularization diseases. However, the short half-life of Avastin(®) need frequent administration to maintain its therapeutic efficiency. In this paper, we attempted to develop an in situ PEG hydrogels with great biocompatibility for sustained release of Avastin(®) to inhibit the corneal neovascularization. PEG hydrogels was formed via thiol-maleimide reaction using 4-arm PEG-Mal and 4-arm PEG-SH. The transparent hydrogel was rapidly formed under physiological conditions. By varying the concentration of 4-arm PEG-SH, PEG hydrogel with different gelling time, pore size, swelling ratio and mechanical property could be obtained. In vitro cytotoxicity indicated that the developed PEG hydrogel had no apparent cytotoxicity on L-929 cells after 7 days of incubation. In vitro release study showed the encapsulated Avastin(®) was sustained release from PEG hydrogels within a period of 14 days study. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis further confirmed that the released Avastin(®) did not undergo apparent hydrolysis within 14 days. As a conclusion, we could conclude that the developed PEG hydrogels as an injectable hydrogels might be suitable for extended Avastin(®) release to treat the corneal neovascularization.

Hyaluronic acid‐based nanocomposite hydrogels for ocular drug delivery applications

Hyaluronic acid (HA) is a widely investigated biomaterial for many therapeutic applications owing to its unique properties of biocompatibility, biodegradation, and viscoelasticity. HA being a natural component of eye tissue with significant role in wound healing is a natural choice as a carrier for ocular drug delivery, provided the incorporated drugs are released in a sustained manner. However, localized sustained release of drugs inside eye has been difficult to achieve because of the inability to retain carriers for long periods in the eye. Using noncrosslinked (soluble) HA offers limited control over site retention of drugs. In order to obtain prolonged sustained delivery, two HA-based composite hydrogels incorporating nanocarriers, have been synthesized and characterized for swelling, rheology, degradation, and in vitro release of latanoprost, a drug used to reduce intraocular pressure. The HA is first chemically modified, mixed with drug-loaded liposomes, and then crosslinked to obtain nanocomposite hydrogels. In vitro release study shows longer sustained release of latanoprost from composite hydrogels as compared to liposomes or hydrogels alone indicating additional resistance to drug diffusion because of the incorporation of liposomes inside the hydrogels. It is believed that these nanocomposite hydrogels, with controlled degradation properties and sustained release, could serve as potential drug delivery systems for many ocular diseases.

In vivo performance of a drug-eluting contact lens to treat glaucoma for a month

For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery, but achieving controlled drug release has been a significant challenge. We have developed a drug-eluting contact lens designed for prolonged delivery of latanoprost for the treatment of glaucoma, the leading cause of irreversible blindness worldwide. Latanoprost-eluting contact lenses were created by encapsulating latanoprost–poly(lactic-co-glycolic acid) films in methafilcon by ultraviolet light polymerization. In vitro and in vivo studies showed an early burst of drug release followed by sustained release for one month. Contact lenses containing thicker drug–polymer films demonstrated released a greater amount of drug after the initial burst. In vivo, single contact lenses were able to achieve, for at least one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with topical latanoprost solution, the current first-line treatment for glaucoma. The lenses appeared safe in cell culture and animal studies. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications.

Development and evaluation of fast forming nano-composite hydrogel for ocular delivery of diclofenac

In this paper, a fast forming nano-composite hydrogel was developed for potential application in ocular drug delivery. The optical transmission (OT) as well as rheological properties of nano-composite hydrogel was characterized. The developed nano-composite hydrogel given a high diclofenac micelles loading and provided a sustained release manner of diclofenac within 6h. The developed nano-composite hydrogel formulation was administrated into the eye as flowable solution, quickly forming a hydrogel that is able to resist of the blinking and flushing of tear, yet resulting in the prolonged residence time of pre-corneal. In vivo eye irritation test suggested that the developed nano-composite hydrogel was none-eye irritation might be suitable for various ocular applications. In vivo pharmacokinetic study indicated that the developed nano-composite hydrogel could significantly increase the bioavailability of diclofenac and maintain the concentration of diclofenac in aqueous humor above MEC at least 24h after administration as compared with that of the commercial diclofenac sodium eye drops, which might be able to reduce the frequency of administration for patients.

Design of an Implantable Device for Ocular Drug Delivery

Ocular diseases, such as, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting million of adults in USA and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This study focuses on the design, simulation, and development of an implantable ocular drug delivery device consisting of micro-/nanochannels embedded between top and bottom covers with a drug reservoir made from polydimethylsiloxane (PDMS) which is silicon-based organic and biodegradable polymer. Several simulations were carried out with six different micro-channel configurations in order to see the feasibility for ocular drug delivery applications. Based on the results obtained, channel design of osmotic I and osmotic II satisfied the diffusion rates required for ocular drug delivery. Finally, a prototype illustrating the three components of the drug delivery design is presented. In the future, the device will be tested for its functionality and diffusion characteristics.

Effect of cucurbit[n]urils on tropicamide and potential application in ocular drug delivery

The supramolecular interactions of the ocular drug tropicamide (TR) with cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8) were investigated in aqueous solutions by using 1H NMR, ESI-MS and UV–vis spectroscopic techniques. The results indicate a 1:1 binding stoichiometry of TR with CB7 and CB8. The binding constants of TR in its protonated form were higher (e.g. K = 4 × 106 M− 1 with CB8) than in its neutral form (e.g. K = 1.4 × 104 M− 1 with CB8), which led to a complexation-induced increase in its pK a value of ca. 0.5 and 2 units with CB7 and CB8, respectively. In the presence of about 1% (w/v) CB8, the ionisation degree of 0.1% (w/v) TR was increased from 2% to 62% at neutral pH. The increase in the pK a value and thus stabilisation of the protonated TR species at neutral pH is discussed in the context of supramolecular drug delivery of ophthalmologic drugs.