Hot-Melt Extrusion-Based Dexamethasone-PLGA Implants: Physicochemical, Physicomechanical, and Surface Morphological Properties and In Vitro Release Corrected for Drug Degradation.

Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% w/w of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R2 = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R2 ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products.

Nanotechnology-based ocular drug delivery systems: recent advances and future prospects.

Ocular drug delivery has constantly challenged ophthalmologists and drug delivery scientists due to various anatomical and physiological barriers. Static and dynamic ocular barriers prevent the entry of exogenous substances and impede therapeutic agents' active absorption. This review elaborates on the anatomy of the eye and the associated constraints. Followed by an illustration of some common ocular diseases, including glaucoma and their current clinical therapies, emphasizing the significance of drug therapy in treating ocular diseases. Subsequently, advances in ocular drug delivery modalities, especially nanotechnology-based ocular drug delivery systems, are recommended, and some typical research is highlighted. Based on the related research, systematic and comprehensive characterizations of the nanocarriers are summarized, hoping to assist with future research. Besides, we summarize the nanotechnology-based ophthalmic drugs currently on the market or still in clinical trials and the recent patents of nanocarriers. Finally, inspired by current trends and therapeutic concepts, we provide an insight into the challenges faced by novel ocular drug delivery systems and further put forward directions for future research. We hope this review can provide inspiration and motivation for better design and development of novel ophthalmic formulations.

Vitreous Humor: Composition, Characteristics and Implication on Intravitreal Drug Delivery.

Purpose: Intravitreal administration of drug molecules is one of the most common routes for treating posterior segment eye diseases. However, the properties of vitreous humour changes with the time. A number of ocular complications such as liquefaction of the vitreous humour, solidification of the vitreous humour in the central vitreous cavity and detachment of the limiting membrane due to the shrinking of vitreous humour are some of the factors that can drastically affect the efficacy of therapeutics delivered via intravitreal route. Although significant research has been conducted for studying the properties of vitreous humour and its changes during the ageing process, there have been limited work to understand the effect of these changes on therapeutic efficacy of intravitreal drug delivery systems. Therefore, in this review we discussed both the coomposition and characteristics of the vitreous humour, and their subsequent influence on intravitreal drug delivery.Methods: Articles were searched on Scopus, PubMed and Web of Science up to March 2022.Results: In this review, we discussed the biological composition and biomechanical properties of vitreous humour, methods to study the properties of vitreous humour and the changes in these properties and their relevance in ocular drug delivery field, with the aim to provide a useful insight into these aspects which can aid the process of development of novel intravitreal drug delivery systems.Conclusions: The composition and characteristics of the vitreous humour, and how these change during natural aging processes, directly influence intravitreal drug delivery. This review therefore highlights the importance of understanding the properties of the vitreous and identifies the need to achieve greater understanding of how changing properties of the vitreous affect the therapeutic efficacy of drugs administered for the treatment of posterior eye diseases.

More than Antibiotics: Latest Therapeutics in the Treatment and Prevention of Ocular Surface Infections.

Ocular surface infections have been common issues for ophthalmologists for decades. Traditional strategies for infection include antibiotics, antiviral agents, and steroids. However, multiple drug-resistant bacteria have become more common with the prevalence of antibiotic use. Furthermore, an ideal treatment for an infectious disease should not only emphasize eliminating the microorganism but also maintaining clear and satisfying visual acuity. Immunogenetic inflammation, tissue fibrosis, and corneal scarring pose serious threats to vision, and they are not attenuated or prevented by traditional antimicrobial therapeutics. Herein, we collected information about current management techniques including stem-cell therapy, probiotics, and gene therapy as well as preventive strategies related to Toll-like receptors. Finally, we will introduce the latest research findings in ocular drug-delivery systems, which may enhance the bioavailability and efficiency of ocular therapeutics. The clinical application of improved delivery systems and novel therapeutics may support people suffering from ocular surface infections.

First Real-World, Multicenter, Post-Marketing, Retrospective Study of Dexamethasone Intraocular Suspension for Inflammation After Cataract Surgery.

Purpose: To evaluate dexamethasone intraocular suspension 9% (intraocular DXM) in real-world clinical use to manage inflammation associated with cataract surgery. Setting: Patients who underwent cataract surgery and received intraocular DXM at 22 outpatient eye surgery centers in the US. Design: Retrospective, observational chart review. Methods: Records of all patients who received intraocular DXM from March to December 2019 at participating centers were reviewed. Main Outcome Measures: Outcomes included anterior chamber cell (ACC) grades, anterior chamber flare (ACF) grades, and visual acuity, as well as intraocular pressure (IOP) and adverse events (AEs) at postoperative days (PODs) 1, 8, 14, 30. Descriptive statistics were generated. Results: The study population included 527 patients (641 eyes), with glaucoma history in 66 patients (80 eyes). Among eyes with recorded ACC grades, the percentage with grade 0 increased from 40% at POD 1 to 89.7% at POD 30, with similar results in eyes with glaucoma history. Among eyes with recorded ACF grades, the percentage with grade 0 increased from 78.4% at POD 1 to 97.1% at POD 30. At POD 30, 96.6% eyes with recorded results achieved target acuity. Mean IOP was 18.6 mmHg at POD 1 but declined to ≤15.2 mmHg thereafter. Investigators reported 22 AEs in 20 patients, all reported mild or moderate, the most common: IOP increase (7 events). Conclusion: Patients undergoing cataract surgery and treated with intraocular DXM showed favorable inflammatory and visual outcomes, without unanticipated safety problems, consistent with results of previous controlled clinical trials.

Posaconazole micelles for ocular delivery: in vitro permeation, ocular irritation and antifungal activity studies.

Posaconazole (PSC) is a triazole group anti-fungal agent with the widest spectrum. Although there is no commercially available ocular dosage form, its diluted oral suspension preparation (Noxafil®) is used as off-label in topical treatment of severe keratitis and sclerokeratitis in the clinic. However, ocular bioavailability of PSC suspension form is extremely low due to its highly lipophilic character. Thus, there is a clinical need to improve its ocular bioavailability and to develop novel delivery system for the treatment of ocular fungal infections. Herein, we studied ex vivo permeation, penetration, anti-fungal activity, and Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) toxicity tests in order to assess ocular targeting of PSC micelles, which were optimized in our previous study. The results indicated that micellar carrier system increased the permeability of PSC to eye tissues. Micelles showed higher affinity to ocular tissues than that of commercial oral suspension of PSC (Noxafil®). In vitro anti-fungal activity data also confirmed the efficacy of PSC loaded micellar formulations against Candida. albicans strains. The relative safety of the optimized micelles on the ocular tissue was shown with the HET-CAM toxicity test. In conclusion, micellar systems could be a promising strategy for the effective and safe delivery of PSC in the treatment of ocular fungal infections.

Novel Drug Delivery Systems Fighting Glaucoma: Formulation Obstacles and Solutions.

Glaucoma is considered to be one of the biggest health problems in the world. It is the main cause of preventable blindness due to its asymptomatic nature in the early stages on the one hand and patients' non-adherence on the other. There are several approaches in glaucoma treatment, whereby this has to be individually designed for each patient. The first-line treatment is medication therapy. However, taking into account numerous disadvantages of conventional ophthalmic dosage forms, intensive work has been carried out on the development of novel drug delivery systems for glaucoma. This review aims to provide an overview of formulation solutions and strategies in the development of in situ gel systems, nanosystems, ocular inserts, contact lenses, collagen corneal shields, ocular implants, microneedles, and iontophoretic devices. The results of studies confirming the effectiveness of the aforementioned drug delivery systems were also briefly presented.

Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations.

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.

Turning the screw even further to increase microparticle retention and ocular bioavailability of associated drugs: The bioadhesion goal.

Ocular drug delivery is one of the most fascinating and challenging tasks facing pharmaceutical researchers. Improving drug ocular residence time and/or penetration is complex. Microparticles (MP) provide interesting opportunities to increase ocular bioavailability of drugs and patient compliance brought about by decreased frequency of dosing. However, sustained-release microsphere formulation would fail to accomplish the task of long-lasting drug release unless microspheres remained for a prolonged period at the site of action. Some strategies have been assessed to retain MP at the target site. Among them, improving bioadhesion properties is possibly the one that offers the best technical features to date. In this review, we present the latest scientific communications in the field of MP development and coating to increase bioavailability when MP are destined for ocular treatment. All of these are more or less useful tools that must be considered as an important part of the development process for ocular medication optimization.

Ciprofloxacin-imprinted hydrogels for drug sustained release in aqueous media.

In this study several ciprofloxacin (CFX) imprinted and non-imprinted hydrogels were prepared and evaluated as ocular drug delivery systems in aqueous media. 2-Hydroxyethyl methacrylate (HEMA) was used as a solvent and backbone monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker, methacrylic acid (MAA) as a functional monomer and CFX as the template molecule. CFX-imprinted hydrogels (MIPs) were prepared applying different CFX:MAA molar ratios (1:16, 1:20 and 1:32) in feed composition of monomer solutions. Thermal polymerization was applied and hydrogels were synthesized in a polypropylene mold (0.4 mm thickness). Swelling and binding properties of hydrogels were evaluated in water. Release profile of the MIPs was evaluated in NaCl (0.9%) and artificial tears. The data showed that enhancing the MAA concentration, as a co-monomer, and using molecular imprinting improved binding properties of the synthesized hydrogels. The optimized MIPs with 400 mM MAA and CFX: MAA molar ratio of 1:20 and 1:16 showed the greatest affinity for CFX and the highest ability to control drug release. In vitro antibacterial activity of hydrogels was studied and demonstrated the effect of CFX-loaded hydrogels against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) isolated from patients' eyes. This study indicated antibacterial efficacy of CFX-loaded MIP hydrogels.

Influence of different surfactants on the technological properties and in vivo ocular tolerability of lipid nanoparticles.

Addition of one or more surfactant agents is often necessary for the production of nanostructured lipid and polymeric systems. The removal of residual surfactants is a required step for technological and toxicological reasons, especially for peculiar applications, such as the ophthalmic field. This study was planned to assess the technological properties of some surfactants, commonly used for the production of lipid nanoparticles, as well as their ocular safety profile. Stable and small-size solid lipid nanoparticles were obtained using Dynasan(®) 114 as the lipid matrix and all the tested surfactants. However, from a toxicological point of view, the nanocarriers produced using Kolliphor(®) P188 were the most valuable, showing no irritant effect on the ocular surface up to the highest tested surfactant concentration (0.4%, w/v). The SLN produced using Cremophor(®) A25 and Lipoid(®) S100 were tolerated up to a surfactant concentration of 0.2% by weight, while for Tween(®) 80 and Kolliphor(®) HS 15 a maximum concentration of 0.05% can be considered totally not-irritant.

The PLGA implant as an antimitotic delivery system after experimental trabeculectomy.

PURPOSE: To investigate the effect of poly (lactic-co-glycolic acid) (PLGA) implants loaded with mitomycin C (MMC) and with different adjuvant treatments after glaucoma filtration surgery (GFS), in comparison to standard treatments. METHODS: Forty-two New Zealand White rabbits underwent bilateral GFS and received different treatments: topical MMC (group 1); topical 5-fluorouracil (5-FU; group 2); PLGA implant (group 3); MMC-loaded and -coated PLGA implant (group 4); MMC-loaded and 5-FU-coated PLGA implant (group 5); subconjunctival bevacizumab (group 6); MMC-loaded PLGA implant and subconjunctival bevacizumab (group 7); and no treatment (right eye of all animals; control group). Intraocular pressure (IOP) and filtering bleb were evaluated on different days after GFS. Histology was performed to examine the conjunctiva, sclerotomy, filtering bleb, and persistence of the implant. RESULTS: The best hypotensive results were achieved in the MMC-loaded and -coated PLGA implant group, which presented the lowest IOP values on days 1, 5, 7, 14, and 28 after GFS. Excluding the implant groups, in which the bleb could not be properly measured, bleb survival was superior to controls in groups 1, 2 and lower in group 6. Group 7 presented greater extension, height, and vascularization of the bleb. Epithelial thinning and lymphoplasmacytic infiltrate were observed in groups 1, 2, 4, 5, and 7. The rates of closure of the sclerotomy and bleb were 100% and 76%, respectively, and implant persistence was 95%. CONCLUSIONS: MMC-loaded and -coated implants have optimal surgical results, followed by topical MMC application. In this experimental model, bevacizumab could interact with MMC.