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The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment.

Polysaccharides, such as cellulose, hyaluronic acid, alginic acid, and chitosan, as well as polysaccharide derivatives, have been successfully used to augment drug delivery in the treatment of ocular pathologies. The properties of polysaccharides can be extensively modified to optimize ocular drug formulations and to obtain biocompatible and biodegradable drugs with improved bioavailability and tailored pharmacological effects. This review discusses the available polysaccharide choices for overcoming the difficulties associated with ocular drug delivery, and it explores the reasons for the dependence between the physicochemical properties of polysaccharide-based drug carriers and their efficiency in different formulations and applications. Polysaccharides will continue to be of great interest to researchers endeavoring to develop ophthalmic drugs with improved effectiveness and safety.

The aim of the present study is to examine the possibility of nephrotoxicity following the intravitreal injection of the antifungal agents voriconazole and micafungin. Μale and female New Zealand white rabbits were divided into the control group C that received no medication and the study groups that underwent either one or two intravitreal injections of voriconazole or micafungin solution, respectively, or one co-administration of the two agents. Euthanasia was performed ten days after the last intravitreal administration, and kidney tissue samples were obtained and prepared for electron microscopy study, as well as immunohistochemical study for EGFR and IL-6 markers. Ultrastructural alterations of the renal tissue were found in places of limited extent, more evident at the level of the proximal tubules. The expression of the two markers was positive, especially in the double and the combined administration of the two drugs, both in the renal corpuscle and the tubules. The finding of the aforementioned histological lesions triggers the need for an additional study of the effect of the specific drugs on the kidney to establish whether these alterations are reversible or not. Redesigning the dosage regimen during intravitreal administration of these agents could be a future therapeutic goal to prevent potential nephrotoxicity. The intravitreal concentrations used in rabbits, particularly for voriconazole, closely approximate those used in humans, supporting the clinical relevance of the findings.

The main purpose of the study was the formulation development of nanogels (NHs) composed of chondroitin sulfate (CS) and low molecular weight chitosan (lCH), loaded with a naringenin-β-cyclodextrin complex (NAR/β-CD), as a potential treatment for early-stage diabetic retinopathy. Different formulations of NHs were prepared by varying polymer concentration, lCH ratio, and pH and, then, characterized for particle size, zeta potential, particle concentration (particles/mL) and morphology. Cytotoxicity and internalization were assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVEC). The NAR/β-CD complex was prepared and evaluated for morphology, complexation efficiency, and solubility. Finally, the most promising NH prototype was loaded with NAR/β-CD (NH@NAR/β-CD) and further characterized for encapsulation efficiency, loading capacity, opacity and cytotoxicity on HUVEC; in vitro release test and DPPH assay were performed to investigate NH capability to sustain NAR release and NH@NAR/β-CD antioxidant properties, respectively. NH properties were influenced by polymer concentration, lCH ratio, and pH. N3 (0.5 mg/mL; lCH=1.5:1; pH = 5) and N9 (0.5 mg/mL; lCH=1:1; pH = 5) showed optimal characteristics, including small size (<350 nm) and positive zeta potential, facilitating cellular uptake. The NAR/β-CD complex showed 71% complexation efficiency and enhanced NAR solubility. Since characterized by superior properties and better in vitro biocompatibility, N3 was loaded with NAR/β-CD. N3@NAR/β-CD capability to sustain in vitro NAR release, radical scavenging activity and in vitro biocompatibility were finally demonstrated. The physico-chemical properties of N3@NAR/β-CD were responsible for their cell uptake, suggesting their potential to target retinal endothelial cells. The high NAR/β-CD complexation efficiency and the sustained NAR release over 72 hours could guarantee the maintenance of an effective drug concentration at the damage site while reducing the injection number. Further studies about the safety and the effectiveness of the intravitreal injection of NHs@NAR/β-CD will be performed on a diabetic animal model.

Compounding drug products is a vital hospital pharmacy feature that requires safe and compatible primary packaging, particularly for prefilled syringes (PFSs). The off-label use of plastic syringes in batch compounding for intravitreal administration has raised concerns over leachables and silicone oil lubricants, which may migrate into drug solutions and potentially cause toxicity. This study evaluated two widely used off-label plastic syringes, BD Plastipak and BBraun Omnifix, for conditioning with topotecan (TPT), a chemotherapeutic used to treat infant retinoblastoma. Leachables were monitored over 12 months via an original LC‒MS method with postcolumn infusion (PCI), including possible detection of silicone degradants. This approach may serve as an indirect method to assess silicone-related contamination due to the spread of free silicone particulates. Both syringes released low overall levels of leachables. However, BD Plastipak emits five oligomeric degradants, two exceeding permitted daily exposure (PDE) limits. In contrast, BBraun Omnifix showed greater chemical stability, releasing only minimal silicone-related compounds and oleamide, suggesting a lower risk for intraocular use. Although these findings support BBraun Omnifix as a safer option, the findings underscore the need for toxicologically assessed, purpose-designed plastic PFSs made from low-extractable materials such as cyclic olefin polymer (COP) or copolymer (COC) for long-term drug storage.

BackgroundIntravitreal and intracameral administration of melphalan and topotecan (TPT) has shown its efficacy in the treatment of retinoblastoma over the last few years. Due to rapid hydrolysis, melphalan must be administered within the hour following reconstitution. With improved stability at room temperature and reduced ocular toxicity, TPT seems to be a promising candidate for production of prefilled syringes in terms of safety and efficiency of preparation and treatment administration. Due to the lack of TPT stability data, the stability of TPT at 20 µg/mL and 200 µg/mL in prefilled syringes was evaluated in three different storage conditions.MethodsThe stability of TPT in prefilled syringes was assessed via reversed-phase liquid chromatography coupled to a diode array detector analytical platform. The physicochemical stability of TPT in prefilled syringes in both concentrations, stored at 30±2°C with a relative humidity (RH) of 65±5%, 5±3°C, and −20±5°C, was evaluated over 12 months including visual inspection and pH measurement.ResultsTPT solution in syringes at 20 µg/mL and 200 µg/mL was stable at 5±3°C and −20±5°C for up to 12 months, with no precipitate and no significant change in pH and concentration. A TPT-related degradant, 8-methoxy-TPT, was detected at <0.5% only in 30±2°C (65±5% RH) after 3 months.ConclusionThis study demonstrated that TPT solutions at 20 µg/mL and 200 µg/mL conditioned in BBraun Omnifix syringes could be stored at 5±3°C for 12 months for safe and secure administration to patients.

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

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.

Mometasone furoate (MF) is a medium-potency synthetic glucocorticosteroid with anti-inflammatory, antipruritic, and vasoconstrictive properties. However, its role in the treatment of ocular inflammation has not yet been explored. This work investigated the anti-inflammatory activity of MF in ocular tissues. First, the in vivo safety of the intravitreal (IVT) injection of MF (80, 160, and 240 µg) was evaluated via clinical examination (including the assessment of intraocular pressure), electroretinography (ERG), and histopathology. Second, MF was tested in an experimental model of bacillus Calmette–Guérin (BCG)-induced uveitis in Wistar rats. Intraocular inflammation was then evaluated via a slit-lamp and fundus examination, ERG, histopathology, and the quantification of pro-inflammatory markers. Intravitreal MF showed no toxicity in all the investigated doses, with 160 µg leading to attenuated disease progression and improvement in clinical, morphological, and functional parameters. There was a significant reduction in the levels of inflammatory markers (myeloperoxidase, interleukins 6 and 1β, CXCL-1, and tumor necrosis factor-alpha) when compared to the levels in untreated animals. Therefore, MF should be further investigated as a promising drug for the treatment of ocular inflammation.

Intravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.