Intraocular Drug Delivery Systems Research Articles

Intraocular drug delivery systems for Diabetic retinopathy: Current and future prospective

In pharmaceutical research and development, novel drug delivery systems represent a significant advancement aimed at enhancing the efficacy of therapeutic agents through innovative delivery mechanisms. The primary objective of these systems is to transport therapeutic compounds to specific target sites, such as tumors and afflicted tissues, with the dual purpose of mitigating side effects and toxicity associated with the drugs while concurrently augmenting therapeutic effectiveness. Numerous innovative drug delivery strategies have been scrutinized for their applicability in the context of targeted ocular drug delivery. Diverse novel carriers, including but not limited to implants, hydrogels, metal nanoparticles, Nano-liposomes, micelles, solid lipid nanoparticles (SLN), emulsions, and biodegradable nanoparticles, have been harnessed to facilitate the controlled release of pharmaceutical agents to the retina and vitreous. These carriers offer distinct advantages, such as enhanced intraocular drug delivery, precise control over drug release kinetics, heightened stability, and superior entrapment efficiency. This comprehensive review seeks to elucidate the current strides made in the realm of carriers and their contemporary applications in treating diabetic retinopathy (DR). Furthermore, it underscores these carriers' pivotal role in achieving efficacious intraocular drug delivery. Additionally, this article explores the various administration routes, potential future advancements, and the multifaceted challenges confronting the domain of novel carriers in treating DR. In conclusion, novel formulations are introduced to surmount the challenges associated with intraocular drug delivery.

Stability of ranibizumab during continuous delivery from the Port Delivery Platform

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system that has the potential to reduce treatment burden in patients with retinovascular diseases. The Port Delivery Platform (PD-P) implant is a permanent, indwelling device that can be refilled in situ through a self-sealing septum and is designed to continuously deliver ranibizumab by passive diffusion through a porous titanium release control element. We present results for the studies carried out to characterize the stability of ranibizumab for use with the PD-P. Simulated administration, in vitro release studies, and modeling studies were performed to evaluate the compatibility of ranibizumab with the PD-P administration components, and degradation and photostability in the implant. Simulated administration studies demonstrated that ranibizumab was highly compatible with the PD-P administration components (initial fill and refill needles) and commercially available administration components (syringe, transfer needle, syringe closure). Subsequent simulated in vitro release studies examining continuous delivery for up to 12 months in phosphate buffered saline, a surrogate for human vitreous, showed that the primary degradation products of ranibizumab were acidic variants. The presence of these variants increased over time and potency remained high. The stability attributes of ranibizumab were consistent across multiple implant refill-exchanges. Despite some degradation within the implant, the absolute mass of variants released daily from the implant was low due to the continuous release mechanism of the implant. Simulated light exposure within the implant resulted in small increases in the relative amount of ranibizumab degradants compared with those seen over 6 months.

Trends in Ophthalmological Patents, 2005-2020.

Purpose: Technological development drives the optimization of therapeutics in ophthalmology, but quantifiable and systematic review of such innovation is lacking. To fill this gap, we characterize trends in ophthalmology-related patents in the United States from 2005 to 2020. Methods: Publicly available patent data from the US Patent and Trademark Office was analyzed with the R programming language. Ophthalmology-related patents were identified with a keyword search of their titles and claims text. Temporal trends were assessed with the Mann-Kendall trend test (α = 0.05, two-sided). Results: Of 4.5 million collected patents, some 21,000 (0.5%) were ophthalmology related. The number of annually granted ophthalmology patents increased over time (Mann-Kendall test: z = 4.91; P < 0.001), from 619 patents released in 2005 to 2,019 patents in 2020. Patent counts also increased over time for all ophthalmic subspecialties except oculoplastics, with steepest rises in retina (z = 4.91; P < 0.001) and cornea (z = 4.64; P < 0.001). The most cited patents were in biocompatible intraocular implants and implantable controlled-release drug delivery systems, which underscores particular advancement in therapeutic efficacy and safety in devices used in the treatment and management of common yet debilitating eye conditions. Conclusion: This exploratory analysis reveals hotspots for ophthalmology-related innovation in the United States that may predict current and future growth trends in device development and pharmacologic advancement in ophthalmology, paving the way for more diverse and effective treatment options for preserving vision.

Novel formulations in the treatment of glaucoma

AbstractNeuroprotective therapy in glaucoma is gaining a lot of interest to be used alone or simultaneously with the control of intraocular pressure (IOP). Neuronal degeneration process occurs through different pathways. For this reason, effective neuroprotection of retinal ganglion cells (RGC) and other retinal cells in glaucoma must be performed according to different targets. Recently, there is special interest in designing treatments able to include a combination of active agents in the same formulation.Treatments destined to lower IOP, in which the target is the anterior segment of the eye are administered topically. By the contrary, neuroprotective therapies require the administration of the active substances close to the retinal tissues as well as their maintenance during long term. Since the last decades the development of intraocular drug delivery systems (IDDS) has emerged as therapeutic tools to provide therapeutic concentrations inside the eye during long term, thus reducing the number of injections. Among the controlled release devices, implants (&gt;1 mm) and microparticles (1–1000 μm), are capable of releasing the active substance during long time. Furthermore, if they are prepared with biodegradable polymers, they have the advantage of disappearing from the site of administration after releasing the drug. There are currently two biodegradable implants in the clinical practice to avoid frequent administrations. One of them is loaded with dexamethasone (Ozurdex®) for intravitreal injection and Durysta™ administered in the anterior chamber. Both devices are prepared from the biopolymers derived from the lactic and glycolic acid poly‐(lactic‐co‐glycolic) acid, named as PLGA. The final products of this biodegradable biomaterial result well tolerated and they are finally eliminated from the body.Despite the advantages of the commercialized biodegradable implants, they did not allow personalized therapy and microparticles (mainly PLGA microspheres) are under investigation as therapeutic platforms for intraocular purposes(1). One of their main advantages is that they can be administered as a suspension in the vitreous using small gauge needles (30‐32G). Another interesting advantage of microspheres is that, by being able to easily modify the amount of microparticles to be administered, they become very useful tools for personalized therapies.Microspheres allow to incorporate several drugs in the same device providing a simultaneous delivery of the active substances, resulting of special interest in multifactorial diseases(2). Furthermore, the amount of injected polymer in the co‐loaded device resulted lower compared to single‐loaded systems.Acknowledgements‐Grant: PID2020‐113281RB‐C21 funded by MCIN/AEI/ 10.13039/501100011033, Research Group UCM 920415 “Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal)” and the ISCII‐FEDER RETICS (OFTARED) (RD16/0008/0004 and RD16/0008/0009).

The Port Delivery System with ranibizumab: a new paradigm for long-acting retinal drug delivery

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system designed for the continuous delivery of ranibizumab into the vitreous for 6 months and beyond. The PDS includes an ocular implant, a customized formulation of ranibizumab, and four dedicated ancillary devices for initial fill, surgical implantation, refill-exchange, and explantation, if clinically indicated. Ranibizumab is an ideal candidate for the PDS on account of its unique physicochemical stability and high solubility. Controlled release is achieved via passive diffusion through the porous release control element, which is tuned to specific drug characteristics to accomplish a therapeutic level of ranibizumab in the vitreous. To characterize drug release from the implant, release rate was measured in vitro with starting concentrations of ranibizumab 10, 40, and 100 mg/mL, with release of ranibizumab 40 and 100 mg/mL found to remain quantifiable after 6 months. Using a starting concentration of 100 mg/mL, active release rate at approximately 6 months was consistent after the initial fill and first, second, and third refills, demonstrating reproducibility between implants and between multiple refill-exchanges of the same implant. A refill-exchange performed with a single 100-µL stroke using the refill needle was shown to replace over 95% of the implant contents with fresh drug. In vitro data support the use of the PDS with fixed refill-exchange intervals of at least 6 months in clinical trials.

Development of the Port Delivery System with ranibizumab for neovascular age-related macular degeneration.

This review provides background on the remaining unmet needs with antivascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (nAMD). We also discuss the developmental story of the Port Delivery System with ranibizumab (PDS; SUSVIMO, Genentech, Inc., South San Francisco, CA, USA). Real-world studies have shown that undertreatment is a major reason for continued vision loss in the anti-VEGF era. As a result, there is a need for long-acting anti-VEGF treatment options for patients with nAMD, diabetic macular edema, and other retinal diseases. The PDS is a solid state, refillable, intraocular long-acting drug delivery system that continuously delivers a customized formulation of ranibizumab into the vitreous for 6 months. In a phase 3 trial, the PDS showed equivalent visual acuity improvements with monthly ranibizumab injections in patients with nAMD and adverse events associated with the PDS were well understood and manageable. The PDS is the first US Food and Drug Administration-approved treatment for nAMD that provides continuous delivery of an anti-VEGF molecule. The PDS offers a unique drug delivery system that has the potential to serve as a platform to be used with other molecules in the future.

Graphene Family Nanomaterials in Ocular Applications: Physicochemical Properties and Toxicity.

Graphene family nanomaterials (GFNs) are rapidly emerging for ocular applications due to their outstanding physicochemical properties. Since the eyes are very sensitive organs and the contact between the eyes and GFNs in eye drops, contact lenses, intraocular drug delivery systems and biosensors and even the workers handling these nanomaterials is inevitable, it is necessary to investigate their ocular toxicities and physiological interactions with cells as well as their toxicity mechanisms. The toxicity of GFNs can be extremely affected by their physicochemical properties, including composition, size, surface chemistry, and oxidation level as well as dose and the time of exposure. Up to now, there are several studies on the in vitro and in vivo toxicity of GFNs; however, a comprehensive review on ocular toxicity and applications of GFNs is missing, and a knowledge about the health risks of eye exposure to the GFNs is predominantly unspecified. This review highlights the ocular applications of GFNs and systematically covers the most recent advances of GFNs’ physicochemical properties, in vitro and in vivo ocular toxicity, and the possible toxicity mechanisms as well as provides some perspectives on the potential risks of GFNs in material development and biomedical applications.

Asymmetry in Drug Permeability through the Cornea.

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.

Co-delivery of glial cell-derived neurotrophic factor (GDNF) and tauroursodeoxycholic acid (TUDCA) from PLGA microspheres: potential combination therapy for retinal diseases.

Retinitis pigmentosa (RP) is a group of genetically diverse inherited disorders characterised by the progressive photoreceptors and pigment epithelial cell dysfunction leading to central vision impairment. Although important advances in the understanding of the pathophysiologic pathways involved in RP have been made, drug delivery for the treatment of ocular disorders affecting the posterior segment of the eye is still an unmet clinical need. In the present study, we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating two neuroprotectants agents (glial cell-line-derived neurotrophic factor-GDNF and Tauroursodeoxycholic acid-TUDCA) as a potential therapeutic tool for the treatment of RP. A solid-in-oil-in-water (S/O/W) emulsion solvent extraction-evaporation technique was employed for MS preparation. A combination of PLGA and vitamin E was used to create the microcarriers. The morphology, particle size, encapsulation efficiency and in vitro release profile of the MSs were studied. Encapsulation efficiencies of GDNF and TUDCA for the initial multiloaded MSs, prepared with methylene chloride (MC) as organic solvent and polyvinyl alcohol (PVA) solution in the external phase, were 28.53±0.36% and 45.65±8.01% respectively. Different technological parameters to optimise the formulation such as the incorporation of a water-soluble co-solvent ethanol (EtOH) in the internal organic phase, as well as NaCl concentration, and viscosity using a viscosizing agent (hydroxypropyl methylcellulose-HPMC) in the external aqueous phase were considered. EtOH incorporation and external phase viscosity of the emulsion were critical attributes for improving drug loading of both compounds. In such a way, when using a methylene chloride/EtOH ratio 75:25 into the inner organic phase and the viscosity agent HPMC (1% w/v) in the external aqueous phase, GDNF and TUDCA payloads resulted 48.86±1.49% and 78.58±10.40% respectively, and a decrease in the initial release of GDNF was observed (22.03±1.41% compared with 40.86±6.66% of the initial multi-loaded formulation). These optimised microparticles exhibited sustained in vitro releases over 91 days. These results suggest that the microencapsulation procedure optimised in this work presents a promising technological strategy for the development of multi-loaded intraocular drug delivery systems (IODDS).

Nuevos sistemas de liberación controlada de sustancias activas de administración intraocular

Neurodegenerative pathologies affecting the posterior segment of the eye such as diabetic retinopathy, age related macular degeneration and glaucoma are among the main causes of blindness in the world. They have in common that are cronic, multifactorial and in some cases related with the elderly. The treatment of these pathologies require to maintain therapeutic concentrations in the posterior segment thanks to the use of successive intraocular injections which are associated to secondary effects being poor tolerated by patients. Intraocular drug delivery systems emerged as an alternative to frequent injections as they are able to deliver the therapeutic agent in a controlled fashion into the eye after a single administration. Depending on the biomaterial these delivery systems are biodegradable or non biodegradable. Attending to their sizes, drug delivery systems are classified in implants (&gt;1mm), microsystems (1-1000μm) y nanosystems (1-1000nm). Biodegradable microspheres emerge as therapeutic tools of great interest for the treatment of neurodegenerative pathologies as they can encapsulate active substances of distinct nature and provide release profiles tailoring with clinical needs. Furthermore, it is possible to administer different amounts of microspheres which correspond to the most adequated doses of the medicine in a personalized therapy. The simultaneous encapsulation of several active substances in the microspheres are of great interest in the treatment of multifactorial diseases covering different therapeutic targets.

A Critical Appraisal of New Developments in Intraocular Lens Modifications and Drug Delivery Systems for the Prevention of Cataract Surgery Complications.

Cataract surgery is the commonest ophthalmic surgery worldwide. The replacement of the diseased lens with a synthetic one (intraocular lens—IOL) remains the treatment of choice, despite its potential complications that include infection, inflammation and posterior capsule opacification. The potential for drug delivery via the IOL has been researched extensively over a period of twenty-five years, yet there is very limited progress in transferring the findings from research to everyday practice. The objective of this review is to assess the progress made in the field of IOL lens modifications and drug delivery systems over the past five years. Thirty-six studies that were conducted during the past five years were identified and deemed suitable for inclusion. They were grouped in three broad categories, studies that described new methods for loading a drug onto the IOL, assessment of the effects of drugs that were loaded to the IOL and studies that assessed the effects of non-pharmaceutical modifications of IOLs. While considerable progress is continually being made with regard to methods and materials, there is still little capitalization upon these research studies, with no commercially available IOL-based drug delivery system being available. Close cooperation between researchers in basic sciences (chemistry, physics, materials science and pharmacy), clinical researchers, IOL manufacturers and the pharmaceutical industry is an important prerequisite for further development.

Design, characterisation and drug release study of polymeric, drug-eluting single layer thin films on the surface of intraocular lenses.

To design, develop and study a novel drug delivery system for intraocular applications. The spin coating technique was applied to develop a polymeric, drug-eluting thin film consisting of a blend of organic polymers [poly (D, L lactide coglycolide) lactide: glycolide 75: 25, PLGA and polycaprolactone, PCL] and dexamethasone on the surface of intraocular lenses (IOLs). The initial durability of the IOLs during spinning was assessed. Information about the structural and optical properties of the modified IOLs was extracted using atomic force microscopy, scanning electron microscopy and spectroscopic ellipsometry. A drug release study was conducted for 8 weeks. The IOLs were durable in spinning speeds higher than the ones used to develop thin films. Single-layer thin films were successfully developed on the optics and the haptics of the lenses. The films formed nanopores with encapsulated aggregates of dexamethasone. The spectroscopic ellipsometry showed an acceptable optical transparency of the lenses regardless of the deposition of the drug-eluting films on their surface. The drug release study demonstrated gradual dexamethasone release over the selected period. In conclusion, the novel drug-eluting IOL system exhibited desired properties regarding its transparency and drug release rate. Further research is necessary to assess their suitability as an intraocular drug delivery system.

Intraocular Distribution and Kinetics of Intravitreally Injected Antibodies and Nanoparticles in Rabbit Eyes

PurposeTo investigate the intraocular distribution and kinetics of antibodies and nanoparticles in the experimental model.MethodsAntibodies (whole IgG 149kDa, antigen-binding fragments 48.39 kDa) and four kinds of nondegradable nanoparticles (25, 50, 200, and 250 nm) were intravitreally injected in the right eye of New Zealand white rabbits. The average optical density and concentration were used to measure intraocular distribution and kinetics.ResultsAfter intravitreal injection, antibodies were distributed throughout the vitreous humor and eliminated gradually into anterior and posterior routes. Fluorescence intensity decreased 1 day after injection and was not detected 25 days after injection. The nondegradable nanoparticles migrated posteriorly to the retina 7 days after injection onward and anteriorly to the aqueous humor from 1 hour to 1 day after injection. The fluorescence intensity of the nanoparticles was relatively stable in the vitreous humor, compared to antibodies. Nanoparticles accumulated on the internal limiting membrane of the retina with no penetration into deeper retinal tissue, whereas the smaller size 25 nm nanoparticles passed across the ciliary body and moved into choroid, retina, and suprachoroidal space. A gradual decrease of nanoparticles by their sizes in the vitreous after 30 days after injection was described as the percentage ratio: 61.1% (25 nm), 69.1% (50 nm), 78.6% (200nm), and 85.3% (250 nm).ConclusionsOur study revealed the in vivo intraocular distribution and kinetics of antibodies and nanoparticles with diverse sizes and the result might help to develop newer intraocular drugs and drug delivery systems to treat retinal diseases.Translational RelevanceThese experimental results can be valuable data for human research.

Intravitreal safety profiles of sol-gel mesoporous silica microparticles and the degradation product (Si(OH)4)

Mesoporous silica has attracted significant attention in the drug delivery area; however, impurities can be a source of toxicity. The current study used commercial microparticles produced at large scale in a well-controlled environment. Micrometer sized mesoporous silica particles were acquired through a commercial vendor and pore structures were characterized by SEM. The three silica particle formulations had a diameter of 15 micrometers and three different pore sizes of 10 nm, 30 nm, and 100 nm. The fourth formulation had particle size of 20–40 micrometers with 50 nm pores. Before in vivo tests, an in vitro cytotoxicity test was conducted with silicic acid, derived from the sol-gel particles, on EA.hy926 cells. Low concentration (2.5 µg/mL) of silicic acid showed no cytotoxicity; however, high concentration (25 µg/mL) was cytotoxic. In vivo intravitreal injection demonstrated that 15 um silica particles with 10 nm pore were safe in both rabbit and guinea pig eyes and the particles lasted in the vitreous for longer than two months. Formulations of with larger pores demonstrated variable localized vitreous cloudiness around the sol-gel particle depot and mild inflammatory cells in the aqueous humor. The incidence of reaction trended higher with larger pores (10 nm: 0%, 30 nm: 29%, 50 nm: 71%, 100 nm: 100%, p < .0001, Cochran Armitage Trend Test). Sol-gel mesoporous silica particles have uniform particle sizes and well-defined pores, which is an advantage for implantation via a fine needle. Selected formulations may be used as an intraocular drug delivery system with proper loading and encapsulation.

Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma

Glaucoma is a multifactorial neurodegenerative disorder and one of the leading causes of irreversible blindness globally and for which intraocular pressure is the only modifiable risk factor. Although neuroprotective therapies have been suggested to have therapeutic potential, drug delivery for the treatment of ocular disorders such as glaucoma remains an unmet clinical need, further complicated by poor patient compliance with topically applied treatments. In the present study we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating three recognised neuroprotective agents (dexamethasone (DX), melatonin (MEL) and coenzyme Q10 (CoQ10)) in a single formulation (DMQ-MSs) to create a novel sustained-release intraocular drug delivery system (IODDS) for the treatment of glaucoma. MSs were spherical, with a mean particle size of 29.04 ± 1.89 μm rendering them suitable for intravitreal injection using conventional 25G–32G needles. >62% incorporation efficiency was achieved for the three drug cargo and MSs were able to co-deliver the encapsulated active compounds in a sustained manner over 30-days with low burst release. In vitro studies showed DMQ-MSs to be neuroprotective in a glutamate-induced cytotoxicity model (IC50 10.00 ± 0.94 mM versus 6.89 ± 0.82 mM in absence of DMQ-MSs) in R28 cell line. In vivo efficacy studies were performed using a well-established rodent model of chronic ocular hypertension (OHT), comparing single intravitreal injections of microspheres of DMQ-MSs to their equivalent individual single-drug loaded MSs mixture (MSsmix), empty MSs, no-treatment OHT only and naïve groups. Twenty one days after OHT induction, DMQ-MSs showed a significantly neuroprotective effect on RGCs compared to OHT only controls. No such protective effect was observed in empty MSs and single-drug MSs treated groups. This work suggests that multi-loaded PLGA MSs present a novel therapeutic approach in the management of retinal neurodegeneration conditions such as glaucoma.

Design and fabrication of drug-eluting polymeric thin films for applications in ophthalmology.

To study the development, characterisation, and drug release of one- and two-layered thin films based on organic polymers [poly(D,L-lactide-co-glycolide) lactide:glycolide (65:35), poly(D,L-lactide-co-glycolide) lactide:glycolide (75:25), and polycaprolactone] and dexamethasone. To examine their applicability for intraocular lenses (IOLs) and function in intraocular drug delivery systems. Four series of thin films, single and double-layer, were prepared by the spin-coating method on a silicon substrate. The films were studied using atomic force microscopy and spectroscopic ellipsometry. The release rate of dexamethasone was studied for a period of ten weeks. Series A and C demonstrated the formation of large dexamethasone aggregates. The monolayer films of series C and D formed pores, in agreement with previous findings. The spectroscopic ellipsometry study demonstrated that the samples were transparent. The drug release study demonstrated that dexamethasone was released during the first 6 weeks at a desirable rate. The films exhibited properties suitable for use in intraocular drug delivery systems. The single-layer thin films demonstrated a sufficient encapsulation of dexamethasone and appropriate release of the therapeutic substance. Further studies are necessary to investigate the possibility of developing the films directly on the surface of the IOL.

7.1 T MRI and T2 mapping of the human and porcine vitreous body post mortem

Numerous literature reports describe the liquefaction of the vitreous body with increasing age. It must be expected that this process also influences drug distribution and elimination following intravitreal application of active pharmaceutical ingredients (APIs). To better understand the impact and extent of the liquefaction a magnetic resonance imaging (MRI) study was performed examining human donor eyes post mortem. For comparison, eyes of juvenile pigs were also examined representing a fully gelled vitreous.7.1Tesla ultra-high field MRI and T2 mapping of the vitreous body were used in this study since it must be expected that age-induced degradation processes and structural changes of the vitreous gel to a liquid state will result in changes of the T2 relaxation time of water proton spins. The vitreous bodies were imaged in 12 axial slices and within each image the T2 relaxation times of water proton spins were determined. It was found that T2 relaxation time increased with increasing age of the donor. Whilst the mean T2 relaxation time (±standard deviation) of water proton spins within the central vitreous body of a juvenile porcine eye was 210.1 ± 31.1 ms, the mean T2 relaxation time within the central vitreous body of the 88-year-old and therefore oldest human donor was 528.0 ± 79.3 ms. Within the vitreous body of a single donor, the T2 relaxation time increased from the anterior to the posterior segment, for example in the vitreous body of the oldest human donor from 388.0 ± 31.1 ms on average in the anterior to 631.7 ± 42.8 ms in the posterior segment, indicating an increase in intravitreal liquefaction respectively inhomogeneity from anterior to posterior regions. Additionally, physicochemical parameters were determined yielding averages of 7.54 ± 0.34 for pH, 1.33629 ± 0.00044 for refractive index, 368.99 ± 26.87 mosmol/kg for osmolality, 97.56 ± 0.43% for drying mass loss and 0.73 ± 0.18 mg/mL for total protein content.The aging process and the liquefaction of the vitreous body are expected to affect the pharmacokinetic profile of intravitreally injected APIs, which is of high relevance to drug release from intravitreal drug delivery systems and the therapeutic concept in the treatment of posterior segment diseases. Our data indicate that such processes are not reflected in animal models. Since there is still a need for valid pharmacokinetic data, invitro test systems for the characterization of intraocular drug delivery systems have to be improved according to the current state of knowledge about the vitreous structure and intravitreal transport phenomena.

Emerging Treatments for Non-infectious Uveitis

The primary goals of treatment in patients with non-infectious uveitis (NIU) are to control ocular inflammation and prevent sight-threatening complications such as macular edema and glaucoma. Systemic corticosteroids are the mainstay of treatment in NIU of the posterior segment (NIU-PS); however, long-term use is associated with treatment-limiting adverse effects. The need for agents with improved safety and tolerability coupled with recent insights into the pathogenesis of NIU-PS have led to the development of novel targeted interventions that potentially reduce or eliminate systemic corticosteroid exposure. Targeted interventions include intraocular drug delivery systems that provide high local concentrations at the site of inflammation with low systemic exposure and therapeutic agents, such as monoclonal antibodies that target specific pro-inflammatory cytokines and cytokine-mediated signaling pathways. The expanding range of therapeutic options enhances the ability to tailor therapy according to individual patient circumstances and optimize outcomes in patients with NIU-PS.

An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration

Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)–polyvalerolactone–poly(ethylene glycol) (PAMAM–PVL–PEG). While the hydrophobic PAMAM–PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-d-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology.

Applications of polymers in intraocular drug delivery systems.

We are entering a new era of ophthalmic pharmacology where new drugs are rapidly being developed for the treatment of anterior and posterior segment of the eye disease. The pharmacokinetics of drug delivery to the eye remains a very active area of ophthalmic research. Intraocular drug delivery systems allow the release of the drug, bypassing the blood-ocular barrier. The main advantage of these preparations is that they can release the drug over a long time with one single administration. These pharmaceutical systems are of great important in the treatment of the posterior segment diseases, and they can be prepared from biodegradable or nonbiodegradable polymers. Biodegradable polymers have the advantage of disappearing from the site of action after releasing the drug. The majority of intraocular devices are prepared from nonbiodegradable polymers, and they can release controlled amounts of drugs for months. Nonbiodegradable polymers include silicone, polyvinyl alcohol, and ethylene-vinyl acetate. The polymers usually employed to prepare nanoparticles for the topical ophthalmic route are poly (acrylic acid) derivatives (polyalquilcyanocrylates), albumin, poly-ε-caprolactone, and chitosan. Dendrimers are a recent class of polymeric materials with unique nanostructure which has been studied to discover their role in the delivery of therapeutics and imaging agents. Hydrogels are polymers that can swell in aqueous solvent system, and they hold the solvents in a swollen cross-linked gel for delivery. This review exhibits the current literature regarding applications of polymers in ophthalmic drug delivery systems including pharmacokinetics, advantages, disadvantages, and indications aimed to obtain successful eye therapy.Method of Literature Search:A systematic literature review was performed using PubMed databases into two steps. The first step was oriented to classification of intraocular polymers implants focusing on their advantages and disadvantages. The second step was focused on the role of polymers therapy for intraocular pathology with clinical examples. The search strategy was not limited by year of publication.