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Purpose: Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique. Methods: Different strategies to approach the optic nerve head were investigated, including standard intravitreal and retroorbital injections. A novel SupraChoroidal-to-Optic-NervE (SCONE) delivery was optimized by creating a sclerotomy and introducing a catheter into the suprachoroidal space. Under direct visualization, the catheter was guided to the optic nerve head. India ink was injected. The suprachoroidal approach was performed in New Zealand White rabbit eyes in vivo (25 animals total). Parameters, including microneedle size and design, catheter design, and catheter tip angle, were optimized ex vivo and in vivo. Results: Out of the candidate optic nerve head approaches, intravitreal, retroorbital, and suprachoroidal approaches were able to localize India ink to within 2 mm of the optic nerve. The suprachoroidal approach was further investigated, and after optimization, was able to deposit India ink directly within the optic nerve head in up to 80% of attempts. In eyes with successful SCONE delivery, latency and amplitude of visual evoked potentials was not different than the naïve untreated eye. Conclusions: SCONE delivery can be used for targeted drug delivery to the optic nerve head of rabbits without measurable toxicity measured anatomically or functionally. Successful development of this system may yield novel opportunities to study optic nerve head-specific drug delivery in animal models, and paradigm-shifting management strategies for treating optic neuropathies. Translational Relevance: Here we demonstrate data on a new method for targeted delivery to the optic nerve head, addressing a significant unmet need in therapeutics for optic neuropathies. [ABSTRACT FROM AUTHOR]

Ophthalmic treatment demands precision and consistency in delivering therapeutic agents over extended periods to address many conditions, from common eye disorders to complex diseases. This diversity necessitates a range of delivery strategies, each tailored to specific needs. We delve into various delivery cargos that are pivotal in ophthalmic care. These cargos encompass biodegradable implants that gradually release medication, nonbiodegradable implants for sustained drug delivery, refillable tools allowing flexibility in treatment, hydrogels capable of retaining substances while maintaining ocular comfort, and advanced nanotechnology devices that precisely target eye tissues. Within each cargo category, we explore cutting-edge research-level approaches and FDA-approved methods, providing a thorough overview of the current state of ophthalmic drug delivery. In particular, our focus on nanotechnology reveals the promising potential for gene delivery, cell therapy administration, and the implantation of active devices directly into the retina. These advancements hold the key to more effective, personalized, and minimally- invasive ophthalmic treatments, revolutionizing the field of eye care. [ABSTRACT FROM AUTHOR]

Exploiting a convenient and highly bioavailable ocular drug delivery approach is currently one of the hotspots in the pharmaceutical industry. Eyelid topical application is seen to be a valuable strategy in the treatment of chronic ocular diseases. To further elucidate the feasibility of eyelid topical administration as an alternative route for ocular drug delivery, pharmacokinetic and pharmacodynamic studies of pilocarpine were conducted in rabbits. Besides, a novel physiologically based pharmacokinetic (PBPK) model describing eyelid transdermal absorption and ocular disposition was developed in rabbits. The PBPK model of rabbits was extrapolated to human by integrating the drug-specific permeability parameters and human physiological parameters to predict ocular pharmacokinetic in human. After eyelid topical application of pilocarpine, the concentration of pilocarpine in iris peaked at 2 h with the value of 18,724 ng/g and the concentration in aqueous humor peaked at 1 h with the value of 1,363 ng/mL. Significant miotic effect were observed from 0.5 h to 4.5 h after eyelid topical application of pilocarpine in rabbits, while that were observed from 0.5 h to 3.5 h after eyedrop instillation. The proposed eyelid PBPK model was capable of reasonably predicting ocular exposure of pilocarpine after application on the eyelid skin and based on the PBPK model, the human ocular concentration was predicted to be 10-fold lower than that in rabbits. And it was suggested that drugs applied on the eyelid skin could transfer into the eyeball through corneal pathway and scleral pathway. This work could provide pharmacokinetic and pharmacodynamic data for the development of eyelid drug delivery, as well as the reference for clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Brinzolamide (BRI) suspensions are used for the treatment of glaucoma; however, sufficient drug delivery to the target tissue after eye drop administration is hampered by poor solubility. To address this issue, we focused on nanocrystal technology, which is expected to improve the bioavailability of poor-solubility drugs, and investigated the effect of BRI nanocrystal formulations on corneal permeability and intraocular pressure (IOP)-reducing effect. Methods: BRI nanocrystal formulations were prepared by the wet-milling method with beads and additives. The particle size was measured by NANOSIGHT LM10, and the morphology was determined using a scanning probe microscope (SPM-9700) and a scanning electron microscope (SEM). Corneal permeability was evaluated in vitro using a Franz diffusion cell with rat corneas and in vivo using rabbits, and the IOP-reducing effect was investigated using a rabbit hypertensive model. Results: The particle size range for prepared BRI nanocrystal formulation was from 50 to 300 nm and the mean particle size was 135 ± 4 nm. The morphology was crystalline, and the nanoparticles were uniformly dispersed. In the corneal permeability study, BRI nanocrystallization exhibited higher corneal permeability than non-milled formulations. This result may be attributed to the increased solubility of BRI by nanocrystallization and the induction of energy-dependent endocytosis by the attachment of BRI nanoparticles to the cell membrane. Furthermore, the addition of tyloxapol to BRI nanocrystal formulation further improved the intraocular penetration of BRI and showed a stronger IOP-reducing effect than the commercial product. Conclusions: The combination of BRI nanocrystallization and tyloxapol is expected to be highly effective in glaucoma treatment and a useful tool for new ophthalmic drug delivery. [ABSTRACT FROM AUTHOR]

Purpose: Chronic ailments usually decrease the quality of life due to the requirement for repetitive administration of drugs. Glaucoma is a chronic eye disease occurred because of increased intraocular pressure (IOP). Controlled-release inserts can overcome this challenge by a gradual release of the antiglaucoma drugs. This study aimed to fabricate ocular inserts of brimonidine tartrate (BMD) for the management of glaucoma. Methods: Different polymers including poly (D, L-lactide), polycaprolactone, cellulose acetate, and Eudragit RL100® were used to develop the BMD-loaded nanofibrous inserts by electrospinning technique. The inserts were characterized. The morphology and drug-polymer compatibility were examined by scanning electron microscopy (SEM), and Fourier-transform infrared (FTIR) spectroscopy and in vitro drug release in PBS. The IOP-lowering efficacy and irritancy of optimized formulation were assessed in the caprines. Results: SEM images demonstrated nanofibers with uniform morphology and a mean diameter<300 nm were fabricated. The nanofibers were high-strength and flexible enough to be placed in the conjunctival sac. FTIR showed drug-polymer compatibility. In vitro release study indicated a sustained-release profile of the drug during 6 days for inserts. In vivo evaluation indicated that the optimized formulation is capable of maintaining the IOP in a non-glaucomatous range for an extended duration of 6 days. In addition, the formulation was non-irritant to the caprine eye. Conclusion: Due to the prolonged IOP-lowering efficiency, BMD-loaded nanofibrous inserts can be considered suitable for the controlled release of drugs and thus enhance patient compliance by reducing the frequency of administration. [ABSTRACT FROM AUTHOR]

In this study, we aimed to develop thermosensitive and bioadhesive in situ gelling systems containing solid dispersions of flurbiprofen (FB-SDs) using poloxamer 407 (P407) and 188 (P188) for ophthalmic delivery. FB-SDs were prepared with the melt method using P407, characterized by solubility, stability, SEM, DSC, TGA, and XRD analyses. Various formulations of poloxamer mixtures and FB-SDs were prepared using the cold method and P407/P188 (15/26.5%), which gels between 32 and 35 °C, was selected to develop an ophthalmic in situ gelling system. Bioadhesive polymers Carbopol 934P (CP) or carboxymethyl cellulose (CMC) were added in three concentrations (0.2, 0.4, and 0.6% (w/w)). Gelation temperature and time, mechanical properties, flow properties, and viscosity values were determined. The in vitro release rate, release kinetics, and the release mechanism of flurbiprofen (FB) from the ophthalmic formulations were analyzed. The results showed that FB-SDs' solubility in water increased 332-fold compared with FB. The oscillation study results indicated that increasing bioadhesive polymer concentrations decreased gelation temperature and time, and formulations containing CP gel at lower temperatures and in a shorter time. All formulations except F3 and F4 showed Newtonion flow under non-physiological conditions, while all formulations exhibited non-Newtonion pseudoplastic flow under physiological conditions. Viscosity values increased with an increase in bioadhesive polymer concertation at physiological conditions. Texture profile analysis (TPA) showed that CP-containing formulations had higher hardness, compressibility, and adhesiveness, and the gel structure of formulation F4, containing 0.6% CP, exhibited the greatest hardness, compressibility, and adhesiveness. In vitro drug release studies indicated that CP and CMC had no effect below 0.6% concentration. Kinetic evaluation favored first-order and Hixson–Crowell kinetic models. Release mechanism analysis showed that the n values of the formulations were greater than 1 except for formulation F5, suggesting that FB might be released from the ophthalmic formulations by super case II type diffusion. When all the results of this study are evaluated, the in situ gelling formulations prepared with FB-SDs that contained P407/P188 (15/26.5%) and 0.2% CP or 0.2% CMC or 0.4 CMC% (F2, F5, and F6, respectively) could be promising formulations to prolong precorneal residence time and improve ocular bioavailability of FB. [ABSTRACT FROM AUTHOR]

Liposome, as a drug delivery vehicle, entraps drugs, releases them sustainably, and modifies release patterns. This entrapment has diminished exposure of the drug to the eye medium, which could minimize adverse effects. In this investigation, 18 formulations in 3 key categories (liposome, gel and lipogel) of cromolyn sodium (CS) were prepared and evaluated as a water‐soluble drug. Then, liposome formulations (L1‐L6) were developed using the thin‐film hydration method. The macroscopic and microscopic assessments comprised drug entrapment efficiency, release rate, release mechanism, liposome stability, and vesicle size were evaluated to evaluate liposomes and lipogel. The results revealed that applying cholesterol in formulations ranging from 33 % to 44 % w/w increased the liposome drug entrapment efficiency, stability, and release time. The optimum phosphatidylcholine (PC) ratio to cholesterol in the L4 formulation was 2 : 1, which prolonged drug release time by up to 5 hours. The carbomer® 934 containing lipogel (0.5 % w/v) showed the longest release time (9 hours) with a zero‐order release. CS release from HPMC (2 % w/v) lipogel was assumed to follow first‐order release kinetics. The prolongation of drug release time in a carboxymethylcellulose lipogels was shorter than carbomer® 934 (5 hours). Finally, a sustained release formulation of CS liposome was produced; it was developed as lipogels to enhance its release duration; finally, release kinetic were modified. [ABSTRACT FROM AUTHOR]

[Display omitted] Dexamethasone (DXM) is a commonly used corticosteroid in the treatment of ocular inflammatory conditions that affect more and more people. The aim of this study was to evaluate the effect of the combination of hydroxypropyl-β-cyclodextrin (HPBCD), in situ gelling formulations, and other mucoadhesive polymers, i.e., hydroxypropyl methylcellulose (HPMC) and zinc-hyaluronate (ZnHA), on permeation by applying in vitro and ex vivo ophthalmic permeation models. Additionally, gelling properties, in vitro drug release, and mucoadhesion were measured to determine the impact of these factors on permeation and ultimately on bioavailability. The results showed that GEL1 and GEL2 had an optimal gelling temperature, 36.3 ℃ and 34.6 ℃, respectively. Moreover, the combination of Poloxamer 407 (P407) with other polymers improved the mucoadhesion (GEL1: 1333.7 mN) compared with formulations containing only P407 (P12: 721.8 mN). Both HPBCD and the gel matrix had a considerable influence on the drug release and permeability of DXM, and the combination could facilitate the permeation into the aqueous humor. After 30 min of treatment, the DXM concentration in the aqueous humor was 1.16–1.37 µg∕mL in case of the gels, whereas DXM could not be detected when treated with the DXM suspension. The results of the experiments using an in vitro cell line indicated that the formulations could be considered safe for topical treatment of the eye. In conclusion, with application of a small amount of HPMC (0.2 % w∕w), the concentration of P407 could be reduced to 12 % w/w while maintaining the ideal gelling properties and gel structure without negatively affecting permeability compared with the formulation containing a higher amount of P407. Furthermore, the gel matrix may also provide programmed and elongated drug release. [ABSTRACT FROM AUTHOR]

Purpose: To overcome the challenges caused by the use of conventional ophthalmic dosageforms such as the fast elimination of the drug from the surface of the eye, in this study, dualdrug-loaded nanofibers were developed for sustained ophthalmic delivery of gentamicin (GNT)and methylprednisolone (MP). Moreover, the solvent effects, polymer mixtures, and method ofpreparation on the release profile of the prepared nanofibers, were evaluated.Methods: The nanofibers were prepared using polycaprolactone (PCL), poly (lactic-co-glycolicacid) (PLGA), and polyvinyl alcohol (PVA) using electrospinning technique. Thereafter,seven optimized formulations were developed with different solvent mixtures and polymerconcentrations using various electrospinning methods. The physicochemical and mechanicalproperties of nanofibers were also evaluated, and the morphology of formulations wasobserved. The antibacterial efficacy was investigated and the in vitro release amounts of GNTand MP from nanofibers were estimated using the bioassay and ultraviolet-visible (UV-Vis)spectroscopy.Results: The developed G1, G4, G5, G6, and G7 had suitable mechanical properties andmorphologies with diameter ranging between 70-350 nm. The 1:1 v/v ratio of DMF/DCM inthe solvent mixture and using core-shell technique for the preparation, formed nanofibers withmore favorable release profiles. The optimized formulations indicated sustained-release mannerfor both drugs during 3-9 days and the antibacterial efficacy against Staphylococcus aureus.Conclusion: Among all the prepared formulations, the nanofiber with core-shell structurepossessed the best sustained-release profiles of GNT and MP. The obtained results suggest thatthese nanofibers have a potential to be used as an insert in the eye for long-term release of thedrug. [ABSTRACT FROM AUTHOR]

The study objective was to investigate molecular thermodynamic properties of approved ophthalmic drugs and derive a framework outlining physicochemical design space for product development. Unlike the methodology used to obtain molecular descriptors for assessment of drug-like properties by Lipinski's Rule of 5 (Ro5), this work presents a retrospective approach based on in silico analysis of molecular thermodynamic properties beyond Ro5 parameters (ie, free energy of distribution/partitioning in octanol/water, dynamic polar surface area, distribution coefficient, and solubility at physiological pH) by using 145 marketed ophthalmic drugs. The study's focus was to delineate inherent molecular parameters explicitly important for ocular permeability and absorption from topical eye drops. A comprehensive parameter distribution analysis on ophthalmic drugs' molecular properties was performed. Frequencies in distribution analyses provided groundwork for physicochemical parameter limits of molecular thermodynamic properties having impact on corneal permeability and topical ophthalmic drug delivery. These parameters included free energy of partitioning (ΔGo/w) calculated based on thermodynamic free energy equation, distribution coefficient at physiological pH (clog DpH7.4), topological polar surface area (TPSA), and aqueous solubility (Sint, SpH7.4) with boundaries of clog DpH7.4 ≤4.0, TPSA ≤250 Å2, ΔGo/w ≤20 kJ/mol (4.8 kcal/mol), and solubility (Sint and SpH7.4) ≥1 μM, respectively. The theoretical free energy of partitioning model streamlined calculation of changes in the free energy of partitioning, Δ(ΔGo/w), as a measure of incremental improvements in corneal permeability for congeneric series. The above parameter limits are proposed as "rules of thumb" for topical ophthalmic drugs to assess risks in developability. [ABSTRACT FROM AUTHOR]

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[Display omitted] This review article provides a comprehensive overview of the advancements in using nanosuspensions for controlled drug delivery in ophthalmology. It highlights the significance of ophthalmic drug delivery due to the prevalence of eye diseases and delves into various aspects of this field. The article explores molecular mechanisms, drugs used, and physiological factors affecting drug absorption. It also addresses challenges in treating both anterior and posterior eye segments and investigates the role of mucus in obstructing micro- and nanosuspensions. Nanosuspensions are presented as a promising approach to enhance drug solubility and absorption, covering formulation, stability, properties, and functionalization. The review discusses the pros and cons of using nanosuspensions for ocular drug delivery and covers their structure, preparation, characterization, and applications. Several graphical representations illustrate their role in treating various eye conditions. Specific drug categories like anti-inflammatory drugs, antihistamines, glucocorticoids, and more are discussed in detail, with relevant studies. The article also addresses current challenges and future directions, emphasizing the need for improved nanosuspension stability and exploring potential technologies. Nanosuspensions have shown substantial potential in advancing ophthalmic drug delivery by enhancing solubility and absorption. This article is a valuable resource for researchers, clinicians, and pharmaceutical professionals in this field, offering insights into recent developments, challenges, and future prospects in nanosuspension use for ocular drug delivery. [ABSTRACT FROM AUTHOR]

Pharmaceuticals delivery to the eye sites of interest via the means of contact lenses (CLs) has attracted significant research attention in recent years. Compared with the conventional formulation in eye treatment such as eye drops, CLs administration has shown remarkable advantages in overcoming the challenges involved in ocular drug delivery such as higher bioavailability, longer drug residence and better medication compliance. This review will first detail each of the material components which have been used in the context of CLs, including HEMA, MAA, DMA, NVP, EGDMA, TRIS and PDMS. The pros and cons of each material in tailoring drug release rates of different encapsulated payloads will be discussed, with special focus on their impact on the therapeutic efficiency. In addition, the advancement of recent emerging copolymer CLs hydrogels, originated from these sophisticated monomers with distinct functions, are further summarized into several synthetic strategies in the means of copolymer architecture design and function‐performance relationship in ophthalmic applications. Finally, the possible considerations for future design of multifunctional CLs hydrogels by combing material selection rationales with biological interface science are proposed. [ABSTRACT FROM AUTHOR]

The eye is the specialized part of the body and is comprised of numerous physiological ocular barriers that limit the drug absorption at the action site. Regardless of various efforts, efficient topical ophthalmic drug delivery remains unsolved, and thus, it is extremely necessary to advance the contemporary treatments of ocular disorders affecting the anterior and posterior cavities. Nowadays, the advent of nanotechnology-based multicomponent nanoemulsions for ophthalmic drug delivery has gained popularity due to the enhancement of ocular penetrability, improve bioavailability, increase solubility, and stability of lipophilic drugs. Nanoemulsions offer the sustained/controlled drug release and increase residence time which depend on viscosity, compositions, and stabilization process, etc.; hence, decrease the instillation frequency and improve patient compliance. Further, due to the nanosized of nanoemulsions, the sterilization process is easy as conventional solutions and cause no blur vision. The review aims to summarizes the various ocular barriers, manufacturing techniques, possible mechanisms to the retention and deep penetration into the eye, and appropriate excipients with their under-lying selection principles to prevent destabilization of nanoemulsions. This review also discusses the characterization parameters of ocular drug delivery to spike the interest of those contemplating a foray in this field. Here, in short, nanoemulsions are abridged with concepts to design clinically advantageous ocular drug delivery. Unlabelled Image [ABSTRACT FROM AUTHOR]

• Solubility of dexamethasone in the polymeric solution was increased by 5.2-fold. • The thermogel solution form a rigid gel at physiological temperature at eyes. • Dexamethasone was released in a sustained manner from the thermogel over 28 days. • Subconjunctivally injected DEX-thermogel could suppress the CNV development. Challenges of ophthalmic drug delivery arise not only from the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of eyes. Excellent biocompatibility of a thermosensitive polymer, PLGA-PEG-PLGA (1800–1500–1800, LA:GA ratio = 3:1), as an ophthalmic delivery system was demonstrated in our previous work. In this study, delivery of dexamethasone using this thermogel via a single subconjunctival injection for prolonged treatment was evaluated with corneal neovascularization using an alkali-burn diseased model in rat. Solubility of dexamethasone in the polymeric solution was increased by 5.2-fold and the resulting drug-loaded solution formed in situ rigid gel at body temperature. Prolonged in vitro release of dexamethasone from the gel structure was noted. Dexamethasone gel formulation was demonstrated to be more effective in reducing the burn stimulus and neovascularization in the rat diseased model. The findings suggest the PLGA-PEG-PLGA in situ gelling system can be applied for ophthalmic drug delivery to achieve sustained drug release and improved efficacy. [ABSTRACT FROM AUTHOR]

The aim of the present research work was to prepare and evaluate in situ gel forming ophthalmic drug delivery system loaded with brimonidine tartarate (BT). In this work, carbopol and hydroxy propyl methyl cellulose (HPMC), ophthalmic gel-forming mucoadhesive polymers, which gets converted to gel in the lachrymal fluid were used as in the preparation of pH t riggered in situ gel formulation. The formulations were then autoclaved at 121°C for 15 min and evaluated for pH, clarity, gelling capacity, drug content, viscosity, and in vitro release. The developed formulations exhibited extended release of drug over a period of 8 hours in in vitro studies and therefore it could increase the residence time in eye. The optimized formulations were finally tested for its ability to cause irritation in male albino rabbits. The results indicated that the formulations did not irritate or damage the cornea, iris and conjunctiva. [ABSTRACT FROM AUTHOR]

Eye drop solutions are widely used by the ophthalmologist to treat the anterior segment eye diseases. However, eye drop solutions have many limitations including low bioavailability, high dose requirements, and poor patient compliance. Contact lenses are used to deliver the ocular drugs with high ocular bioavailability due to its immediate location to cornea. To attend controlled and prolonged drug release from the contact lenses, scientists are working on various systems including polymeric nanoparticles, molecular imprinting, microemulsion, micelles, liposomes, implantation, supercritical fluids, and use of vitamin E. However, the changes in the critical lens properties like swelling, optical transparency, ion permeability, tensile strength, oxygen permeability, high burst release, issues during monomer extraction, sterilization and storage are yet to address. The review is focused on the commercial challenges with different methodologies to develop therapeutic contact lenses for commercial market. Many animal and clinical studies are under pipeline and it is likely that the therapeutic contact lenses will be commercialized in next few years. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to improve the ocular delivery for ketorolac tromethamine (KT) used to treat inflammation of the eye. Methods: Eudragit nanoparticles loaded with KT were prepared and incorporated in polyvinyl alcohol (PVA) and hydroxyethyl cellulose (HEC) films. Nanoparticles were characterized by Fourier transform-infrared (FT-IR), scanning electron microscopy (SEM). Physicochemical properties and encapsulation effciency were investigated for nanoparticles. Also, the inserts were evaluated for their physiochemical parameters like percentage moisture absorption, percentage moisture loss, thickness and folding endurance. Results: Mean particle size and zeta potential were in range of 153.8-217 nm and (-10.8) - (-40.7) mV, respectively. The results show that the use of a surfactant has not led to any major change on drug loading. The loading increases with the amount of polymer. The insert had a thickness varying from 0.072 ± 0.0098 to 0.0865 ± 0.0035 mm. The thicknesses of the inserts and the folding endurance increased with the total polymer concentration. The physicochemical properties showed that the Eudragit® L-100 nanoparticles loaded PVA-HEC films could be an effective carrier for KT. Conclusion: For the first time, inserts of Eudragit nanoparticles were successfully prepared for ophthalmic drug delivery system to prevent frequent drug administration and enhance patient compliance. [ABSTRACT FROM AUTHOR]

Abstract Triblock poloxamer copolymer (PM) has been extensively utilized to deliver various ophthalmic pharmaceutical compounds. The aim of efficient ophthalmic drug delivery strategy is to attain the longer precorneal resident time and good bioavailability of drugs. In this pursuit, the influence of cellulose nanocrystals (CNC) on the in situ gelation behavior of PM and in vitro release of pilocarpine hydrochloride from the nanocomposites formulations was studied. The critical concentration of gelation of PM being 18% (wt/v) was dropped to 16.6% (wt/v) by the addition of a very low percentage of CNC. The reinforcing nature of CNC via H-bonding in the in situ nanocomposite gel also led to an increase in gel strength along with the sustained release of loaded drugs when compared with the pure PM gel. All formulations revealed that the drug release mechanism is controlled by the Fickian diffusion. Thus, the CNC has a significant effect on the gelation behavior, gel strength, and drug release kinetics of PM-CNC formulations. Graphical abstract Unlabelled Image Highlights • Reduced critical concentration of thermo-responsive gelation of poloxamer gel. • Cellulose nanocrystals influenced the in situ gelation behavior of poloxamer gel. • Increased poloxamer gel strength via H-bonds in the in situ nanocomposite gel. • Sustained release of loaded drugs from the nanocomposite gel. • Non-cytotoxic ODDS with reduced dissolution properties. [ABSTRACT FROM AUTHOR]

A hollow cylinder intravitreal implant was developed to achieve sustained release of protein to the retina for the treatment of retinal diseases. Hollow cylinders were fabricated by molding and cross-linking hyaluronic acid, the major component of the vitreous humor. Hollow cylinders were filled with a concentrated protein solution, and the properties of the cylinder walls were tested. Cross-linked hyaluronic acid hydrogels with swelling degrees as low as 2.7 were achieved as a means to extend the release of protein. Hollow cylinders were capable of releasing an antigen-binding fragment for over 4 months at a maximum release rate of 4 μg per day. Protein release from hollow cylinders was modeled using COMSOL Multiphysics ® software, and diffusion coefficients between 1.0 × 10 −11 and 3.0 × 10 −11 cm 2 /s yielded therapeutically effective levels of protein. Cylinders with a 1 mm outer radius were capable of loading >1 mg of protein while releasing at least 2.5 μg a day for over 4.5 months. Although smaller cylinders facilitate intravitreal placement, decreasing the cylinder radius severely limited drug loading. Design of hollow cylinder intravitreal implants must balance high drug loading to reduce device size with control of the diffusion coefficient to sustain protein release. [ABSTRACT FROM AUTHOR]

Glaucoma is characterized by increased intraocular pressure (IOP) that results in blindness if it remains untreated. Acetazolamide (AZM) is a carbonic anhydrase inhibitor, mainly used to reduce IOP in the treatment of glaucoma. However, the potential of topical treatment is limited, due to its low permeability across the ocular epithelium. An alternative to overcome this limitation is the incorporation of AZM in nanoparticulate systems, such as polymeric nanocapsules (NCs). In this way, the aim of this work was to prepare and characterize NC formulations containing AZM, using ethylcellulose (EC) and Eudragit ® RS100 (EUD) as encapsulating polymers. The formulations showed high encapsulation efficiency. Particle size measurements showed that NCs are in the nanometric range. Comparing both groups of formulations, the NCEC proved to be smaller than those prepared with EUD. The formulations prepared with EC showed negative zeta potentials, while NCs of EUD were positively charged. For both groups of formulations, no more than 30% of drug was released in 120 min. Ex vivo and in vivo studies evidenced that the NCEC formulations were the most efficient, because an increased amount of permeated drug was observed, along with a greater IOP decrease and longer duration of the effect in normotensive rabbits. [ABSTRACT FROM AUTHOR]

The pharmacokinetic behaviors of novel ophthalmic drugs are often preliminarily investigated in preclinical studies using ex vivo animal cornea or corneal cell culture models. During transcorneal passage, topically applied drugs may be affected by drug metabolizing enzymes. The knowledge regarding the functional expression of metabolic enzymes in corneal tissue is marginal; thus, the aim of this study was to investigate cytochrome P450 activity in an organotypic three-dimensional human cornea construct and to compare it with porcine and rabbit corneas, which are commonly used ex vivo cornea models. The total cytochrome P450 activity was determined by measuring the transformation of 7-ethoxycoumarin. Furthermore, the expression of the cytochrome P450 enzyme 2D6 (CYP2D6) was investigated at the protein level using immunohistochemistry and western blotting. CYP2D6 activity measurements were performed using a d -luciferin-based assay. In summary, similar levels of the total cytochrome P450 activity were identified in all 3 cornea models. The protein expression of CYP2D6 was confirmed in the human cornea construct and porcine cornea, whereas the signals in the rabbit cornea were weak. The analysis of the CYP2D6 activity indicated similar values for the human cornea construct and porcine cornea; however, a distinctly lower activity was observed in the rabbit cornea. [ABSTRACT FROM AUTHOR]

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug–resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. Afterin vitrodrug release study and corneal permeation study were performed,in vivostudies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 μm and drug loading at 43.00 ± 0.09 %. The results indicate that drug released from the drug–resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug–resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption. [ABSTRACT FROM PUBLISHER]

In this research, the potential of soy protein (SPI) based-films as drug delivery devices for ocular therapy was developed. Hence, crosslinked films with a natural and non-cytotoxic crosslinking agent, genipin (Gen), coated with poly(lactic acid) (PLA), were prepared. Filmogenic solutions were loaded with timolol maleate (TM) as a model drug, to be used as drug delivery devices, a novel application for this material. The mechanical properties of the films were studied, observing that with the presence of PLA coating, more rigid materials with improved properties were obtained. Furthermore, the release behavior of TM was evaluated in aqueous medium, it being influenced by the degree of film crosslinking. Furthermore, it was determined that PLA coating decreased TM release rate compared to that of uncoated films. Similarly, this behavior was observed via indirect estimation of the release by assessing the hypotensive effectiveness of the films by in-vivo assays. Through intraocular pressure (IOP) determination tests in rabbits, it was demonstrated that, through the use of high crosslinked and coated films, a significant decrease in IOP could be achieved for prolonged time periods. These results suggest that the use of soy protein-based films as drug delivery systems is highly suitable. [ABSTRACT FROM AUTHOR]

The topically applied drugs as drops are washed off from the eye in very short period, resulting in low ocular bioavailability of drugs. Number of approaches have been attempted to increase the bioavailability and the duration of action of ocular drugs. This review provides an insight into various novel approaches; hydrophilic nanogels, solid lipid nanoparticles, and nanosponges applied very recently in the delivery of insoluble drugs, prolonging the ocular residence time, minimize pre-corneal drug loss and, therefore, bioavailability and therapeutic efficacy of the drugs. Despite various scientific approaches, efficient ocular drug delivery remains a challenge for pharmaceutical scientists. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the in vivo release, retinal safety and antiangiogenic effect of a thalidomide-loaded poly-lactide-co-glycolide intravitreal implant. Methods: New Zealand white rabbits, divided into two groups, I and II, received an intravitreal implant containing or not thalidomide, respectively ( n = 12). Intravitreal drug levels were determined during a six-week study period. The potential for toxicity associated with the implants was evaluated by electroretinography and light microscopy ( n = 8). Twelve chorioallantoic membranes (CAMs) from chicken eggs were incubated with thalidomide dispersion, implants containing or not thalidomide and vitreous samples and analyzed after two days regarding the percentage of vessels regression. Results: Intravitreal concentrations of thalidomide (ng/ml) were 690.21 ± 177.95, 372.51 ±185.56, 240.59 ± 133.48, 327.54 ± 169.71, 294.26 ± 142.41 and 465.18 ± 157.51 at 1, 2, 3, 4, 5 and 6 weeks, respectively, after implantation in group I rabbits. No drug was detected in group II samples. Electroretinography and histological evaluations did not show any sign of retina toxicity. There was significant regression of vessels in CAM incubated with thalidomide dispersion, thalidomide-loaded implants and vitreous samples from group I when compared to control. Conclusion: The intravitreal implants delivered safe doses of thalidomide that were also effective to induce vessels regression in CAMs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Determination of Mycophenolic acid in vitreo. [•] A sensitive LC–ESI-MS/MS method for the determination of MPA. [•] Intraocular pharmacokinetics study. [•] Ophthalmic drug delivery. [•] Ophthalmic implantable device. [Copyright &y& Elsevier]

Previous magnetic resonance imaging (MRI) studies to investigate the routes of penetration and barriers in ocular delivery have provided insights into the mechanisms of transscleral and intraocular drug delivery. The objective of the present study was to investigate ocular penetration and clearance after subconjunctival and intravitreal injections using a contrast agent at concentrations higher than those in the previous studies. This high concentration approach was hypothesized to allow the visualization of the contrast agent in the eye that could not be achieved previously. Subconjunctival and intravitreal injections of contrast agent Magnevist, a model hydrophililc probe, were performed in rabbits, and the distribution and clearance of the probe after the injections were examined by MRI. After subconjunctival injection in vivo, significant contrast agent penetration into the anterior chamber was observed but not into the vitreous. A clearance pathway of the hydrophilic probe from the subconjunctival depot to the regions near the periocular fat behind the eye was found. After intravitreal injection in vivo, the contrast agent was observed in the anterior chamber, optic nerve, and tissues surrounding the eye during clearance. MRI continues to provide insights into the transport barriers and clearance pathways of hydrophilic molecules in ocular delivery. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2353-2363, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Cyclosporine A (CyA) is effective in treating chronic dry eyes and contact lens mediated dry eyes. CyA is delivered through eye drops of an oil-in-water emulsion, which has a small residence time in the eyes, leading to low bioavailability. Here we explore delivery of CyA from contact lenses to provide controlled and extended drug delivery with an increased bioavailability due to enhanced ocular residence time. Loading and release profiles of CyA from commercial contact lenses are presented to show that 1-DAY ACUVUE® releases CyA for about a day and extended wear silicone hydrogel (SiH) lenses release CyA for about 2-weeks. The longer duration from SiH lenses compared to the 1-DAY ACUVUE®lens is due to larger partition coefficients in the gel. A novel approach is presented for increasing release duration from the SiH lenses to the desired 1-month through incorporation of Vitamin E. The results show that Vitamin E loaded lenses can provide CyA release within the therapeutic window for a period of about a month. This pilot study demonstrates the promising potential of delivering CyA from contact lens for treatment of chromic dry eyes and contact lens mediated dry eyes. [Copyright &y& Elsevier]

Abstract: Dry eyes are treated by instillation of eye drops of cyclosporine A emulsion or by punctal plug insertion in canaliculus to block tear drainage. This paper focuses on a novel approach of developing a punctal plug that can also release cyclosporine A to provide a dual mechanism for treating dry eyes. The punctal plug consists of a cylindrical hydroxy ethyl methacrylate core containing drug microparticles surrounded by an impermeable silicone shell that covers about 50% of the core, with the uncovered part directed towards the eyes. The geometry of this design is significantly different from those in patent literature, which are mostly designed to be rods. Plugs release cyclosporine A for a period of about 3months at zero-order at a rate of about 3μg/day. The in vivo release rates are expected to be about half of this value. A mathematical model is presented that provides an accurate estimate of the release without any fitting parameter. Pharmacokinetic models are also developed for drug delivered through Restasis® and punctal plugs, and based on these models the release rate of about 1.5μg/day may be therapeutically effective. The predictions of the ocular pharmacokinetic model are in reasonable agreement with reported measurements in humans. [Copyright &y& Elsevier]

Aim: The aim of the present study was to develop biosynthetic hybrid polymer-based ocular insert for topical administration of antibiotics for treatment of ocular infections. Methods: Ciprofloxacin hydrochloride-loaded three different inserts were prepared by solution casting method by esterification of a biopolymer (gelatin) with a synthetic polymer (polyvinyl alcohol, PVA). Esterification between PVA and gelatin was confirmed by Fourier transform infrared spectroscopy. Results: Inserts were found to be wettable and swellable with simulated tear fluid and had a contact angle <50° with simulated tear fluid. Mechanical properties of PVA-gelatin (10:3 wt%) inserts included a maximal tensile strength of 8.6 ± 2 MPa and the inserts showed adequate mucoadhesion with reconstituted mucin. In vitro drug release of ciprofloxacin hydrochloride for up to 24 hours was observed from the inserts. Inserts were found to be biocompatible using SIRC rabbit corneal epithelial cell line by sulforhodamine B assay and by Draize test in albino rabbits. Further inserts showed higher ocular penetration of sodium fluorescein in goat eye as compared to eyedrop solution. Conclusions: In brief, the study suggests that PVA-gelatin polymeric blends are promising as ocular inserts for prolonged release of antibiotic in the eye as compared to eyedrops. Such inserts may also be therapeutically beneficial for treatment of corneal ulcers and external ocular infections. [ABSTRACT FROM AUTHOR]

Abstract: This paper focuses on exploring the mechanism of cyclosporine A transport in hydroxyethyl methacrylate (HEMA) rods to develop conjunctival inserts for extended ocular delivery. Cylindrical conjunctival HEMA inserts were prepared by thermal polymerization in presence of drug at high loadings to create rods containing particles of drug dispersed in the matrix. The drug release rates were measured to explore the effect of length, drug loading, crosslinking, and mixing in the release medium. Also microstructure of the inserts was characterized by SEM imaging. The inserts release the drug for a period of about a month at therapeutic rates. The rates of drug release are zero order and independent of drug loading and crosslinking for certain period of time. These effects were shown to arise due to a mass-transfer boundary layer in the fluid and a mathematical model was developed by coupling mass transfer in the insert with that in the boundary layer in the surrounding fluid. The model with diffusivity in the insert and boundary layer thickness as parameters fits the experimental data and explains all trends in release kinetics. The fitted diffusivity is about twice that obtained by direct measurements, which agreed well with the value obtained by using the Brinkman’s equation but only after accounting for drug binding to the polymer. [Copyright &y& Elsevier]

Promising management of eye ailments take off effective concentration of drug at the eye for sufficient period of time. Ocular drug delivery is hampered by the barriers protecting the eye. The bioavailability of the active drug substance is often the major hurdle to overcome. Conventional ocular dosage form, including eye drops, are no longer sufficient to combat ocular diseases. This article reviews the constraints with conventional ocular therapy, essential factors in ocular pharmacokinetics, and explores various approaches like eye ointments, gel, viscosity enhancers, prodrug, penetration enhancers, microparticles, liposomes, niosomes, ocular inserts, implants, intravitreal injections, nanoparticles, nanosuspension, microemulsion, in situ-forming gel, iontophoresis, and periocular injections to improve the ocular bioavailability of drug and provide continuous and controlled release of the drug to the anterior and posterior chamber of the eye and selected pharmacological future challenges in ophthalmology. In near future, a great deal of attention will be paid to develop noninvasive sustained drug release for both anterior and posterior segment eye disorders. Current momentum in the invention of new drug delivery systems hold a promise toward much improved therapies for the treatment of visionthreatening disorders. [ABSTRACT FROM AUTHOR]

Abstract: This paper proposes an approach for increasing drug release durations from contact lenses and other biomedical devices by in situ creation of transport barriers of Vitamin E that force drug molecules to diffuse through long tortuous path. Results show that the increase in release duration is quadratic in Vitamin E loading, which is consistent with proposed mathematical models. Loadings of 10 and 40% Vitamin E increase release time of timolol by a factor of about 5 and 400, respectively for NIGHT&DAY™ lens. Similar results have been obtained for other hydrophilic drugs including fluconazole and dexamethasone 21-disodium phosphate (DXP). Vitamin E loading in the NIGHT&DAY™ lens leads to slight increase in lens sizes (6.5% increase for 30% loading), a slight reduction in oxygen diffusion (about 40% reduction for 75% loading), and a more significant reduction in the ion permeability (50% reduction for 10% loading). Additionally, Vitamin E loading has a beneficial effect of blocking UV radiation which will reduce the corneal damage due to UV light. [Copyright &y& Elsevier]

To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of such in situ gel ophthalmic formulations, were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. It was also shown that the drug concentration had no obvious effect on drug release. The release rates of drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount increased by 4-fold and 1.2-fold for in situ gel compared with eye drops. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. The results showed that the Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: Supercritical fluid impregnation was tested to prepare a new ophthalmic drug delivery device. Poly(methylmethacrylate-co-ethylhexylacrylate-co-ethyleneglycoldimethacrylate), P(MMA-EHA-EGDMA) has been proposed by Mariz [M. Mariz, Preparação de uma lente intra-ocular dotada de um sistema de libertação controlada de fármaco, Master Thesis, Universidade de Coimbra, 1999] as a promising matrix to be used for intraocular delivery of anti-inflammatory drugs used in eye surgery. This matrix was successfully impregnated with flurbiprofen, a non-steroidal anti-inflammatory agent. The success of the impregnation was evaluated by scanning electron microscopy (SEM) analysis and also by in vitro drug release studies. The effect of some operating parameters was evaluated, namely, pressure and contact time. The operating pressure will influence both the solubility of the drug in the supercritical fluid but also the sorption degree of the polymeric matrix in the presence of carbon dioxide. The solubility of the drug in carbon dioxide and the sorption degree are reported in previous studies. A comparison between the batch and the semi-continuous impregnation process is also presented. The supercritical fluid impregnation proved to be feasible for the preparation of a new ophthalmic drug delivery system. The drug release profiles suggest that the drug can be released up to three months, which is a major advantage for the prevention of the inflammatory response after ophthalmic surgery. [Copyright &y& Elsevier]

Abstract: Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The conventional ocular drug delivery systems like solutions, suspensions, and ointments show drawbacks such as increased precorneal elimination, high variability in efficiency, and blurred vision respectively. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form visco-elastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. The choice of a particular hydrogel depends on its intrinsic properties and envisaged therapeutic use. This review includes various temperature, pH, and ion induced in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increase their bioavailability. [Copyright &y& Elsevier]

A liquid atomiser composed of a piezoelectric transducer and a metal plate with numerous micro-apertures is studied to identify the most influential factors on its atomising performance. The Taguchi method is employed in the experiment design and analysis of the study on how each factor acts in the atomising process. An optimal condition is determined for producing a stream of droplets. The study shows that the droplet size and the spraying velocity are suitable for ophthalmic drug delivery application, with an even distribution of the drug over most of the eyeball surface area due to the controllable cross-sectional area of the droplet stream. This greatly improves the treatment effectiveness and efficiency of eye therapy. Finally, a structure of the ophthalmic drug delivery system is proposed. [ABSTRACT FROM AUTHOR]

Poly(lactic/glycolic) acid nanoparticles incorporating flurbiprofen (FB) were prepared by the solvent displacement technique using poloxamer 188 as a stabilizer to improve the availability of the drug for the prevention of the inflammation caused by ocular surgery. A 23 + star design was applied to investigate the influence of several factors such as the pH of the aqueous phase, the initial concentration of the stabilizer, and the drug used to prepare the nanoparticles (NPs) on the physicochemical properties (particle size analysis, zeta potential, and drug loading efficiency) of the colloidal system. The best formulations were those prepared at pH 3.5 with a concentration of 1.5 mg/mL of FB and 10 or 20 mg/mL of poloxamer 188. These formulations showed an appropriate average size for ophthalmic administration (232.8 and 277.6 nm, respectively) and a good yield of entrapment efficiency (94.60% and 93.55%, respectively). The release behavior of FB from the developed NPs was complete and exhibited a biphasic pattern. Formulations did not show toxicity on ocular tissues. In vivo anti-inflammatory efficacy was assessed in the rabbit eye after topical instillation of sodium arachidonate (SA). A higher decrease of the SA-induced inflammation was obtained for the NP formulations. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2393–2405, 2006 [ABSTRACT FROM AUTHOR]

To determine the intraocular bioavailability of a novel embodiment for vitamin B12 delivered to the ocular surface by a piezo-electric ultrasonic nebulizer. The semisolid embodiment contained 0.02% (w/w) vitamin B12 in 1 g of ointment, which was immiscible and insoluble in 5 mL sterilized warm water. To confirm in vitro functionality, nebulized mist particles of the embodiment were collected and analysed for vitamin B12 content. The in vivo arm of the study was designed as randomization of 23 patients who were scheduled to undergo cataract surgery in hospital. Fourteen patients were treated with nebulized vitamin B12, five patients had one drop of 0.02% vitamin B12 instilled in the conjunctival cul de sac, and four control patients had no medication. Twelve hours after the vitamin was delivered, the patients underwent the cataract procedure and a sample of aqueous humour was collected from each. High performance liquid chromatography was used for detection of vitamin B12 in all samples. The in vitro analysis of mist particles showed increasing concentrations of vitamin B12. In the patient tests, analysis of the aqueous humour samples showed that none of the controls or those receiving eye drops had detectable vitamin B12 in the aqueous humour. However, 4 of 14 in the nebulizer group had vitamin B12 detected in the aqueous humour in the amount of 10−7 mol. The small-volume nebulizer system might provide another method of ophthalmic drug delivery. [ABSTRACT FROM AUTHOR]

The system was designed to use Poloxamer as a vehicle for ophthalmic drug delivery using in situ gel formation property. To enhance the wound healing and cell adhesion as well as transparency of Poloxamer hydrogel, chondroitin 6-sulfate (C6S) was introduced into Poloxamer. For this purpose, mono amine-terminated Poloxamer (MATP), which was end-capped with ethylene amine group only in one side of terminal hydroxyl groups of Poloxamer, was synthesized. Subsequently, C6S-graft-Poloxamer copolymer (C6S- g -Poloxamer) was prepared by reaction between the amine groups of MATP and carboxyl groups of C6S in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carboimide (EDC). The coupling of MATP with C6S was clarified by 1 H-NMR and FT-IR spectroscopy. The gelation temperature of graft copolymers was determined by measuring the temperature at which immobility of the meniscus in each solution was first noted. Release behavior of ciprofloxacin from C6S- g -Poloxamer hydrogel in vitro was investigated as a function of C6S content in the graft copolymer by a spectrophotometric assay at 287 nm using an UV spectrophotometer. Differences in the adhesion and morphology of human lens cell between Poloxamer- and C6S- g -Poloxamer-coated surfaces were also investigated. The gelation temperatures of C6S- g -Poloxamer copolymers were lowered with increasing of the concentration of the copolymer and decreasing of C6S content. The release of ciprofloxacin from the graft copolymer was sustained compared with Poloxamer itself and decreased with increasing the content of C6S in the copolymer due to the in situ gel formation of the copolymer and viscous properties of C6S. Human lens cells (B3) adhered to C6S- g -Poloxamer-coated surface were observed as transformed shapes after 2 days. The bioadhesive and thermally gelling of these graft copolymers will be expected to be an excellent drug carrier for the prolonged delivery to surface of the eye. [ABSTRACT FROM AUTHOR]

We have developed a new mucoadhesive drug delivery formulation based on an ionic complex of partially neutralized poly(acrylic acid) (PAA) and a highly potent beta blocker drug, levobetaxolol · hydrochloride (LB · HCl), for use in the treatment of glaucoma. PAA was neutralized with sodium hydroxide to varying degrees of neutralization. Aqueous solutions containing concentrations of LB · HCl equivalent to the degree of PAA neutralization were added to the PAA solutions and formed insoluble complexes, which were isolated. The complex formation was followed by turbidimetric titration, and the complexes were characterized by IR and [sup 1]H NMR spectroscopy. Complexes were prepared with varying degrees of drug loading, such that the same PAA chain would have free COOH groups for mucoadhesion along with ionic complexes of LB · H[sup +] with COO[sup -] groups. Thin films of the complexes dissociated to release the drug by ion exchange with synthetic tear fluid. The films shrunk continuously during release of the drug and dissolved completely in 1 h. Solid inserts of these films could be useful as a mucoadhesive ophthalmic drug delivery system. [ABSTRACT FROM AUTHOR]

Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed. [ABSTRACT FROM AUTHOR]

Therapeutic ophthalmic contact lenses with prolonged drug release and improved bioavailability have been developed to circumvent tedious eye drop instillation. In this work, zwitterionic nanogels based on poly(sulfobetaine methacrylate) (PSBMA) were easily fabricated by one-step reflux-precipitation polymerization, with the advantages of being surfactant-free and morphology controlled. Then, the ophthalmic drug levofloxacin (LEV) was encapsulated into the nanogels. A set of contact lenses with varied nanogel-loading content was fabricated by the cast molding method, with the drug-loaded nanogels dispersed in pre-monomer solutions composed of 2-hydroxyethyl methacrylate (HEMA) and N-vinyl-2-pyrrolidone (NVP). The structure, surface morphology, water contact angle (WCA), equilibrium water content (EWC), transmittance, and mechanical properties of the contact lenses were subsequently investigated, and in vitro drug release and biocompatibility were further evaluated. As a result, the optimized contact lens with nanogel-loading content of 8 wt% could sustainably deliver LEV for ten days, with critical lens properties within the range of recommended values for commercial contact lenses. Moreover, cell viability assays revealed that the prepared contact lenses were cytocompatible, suggesting their significant potential as an alternative to traditional eye drops or ointment formulations for long-term oculopathy treatment. [ABSTRACT FROM AUTHOR]

An increasing number of people worldwide are affected by eye diseases, eventually leading to visual impairment or complete blindness. Conventional treatment involves the use of eye drops. However, these formulations often confer low ocular bioavailability and frequent dosing is required. Therefore, there is an urgent need to develop more effective drug delivery systems to tackle the current limitations. Hydrogels are multifunctional ophthalmic drug delivery systems capable of extending drug residence time and sustaining release of drugs. In this review, common ocular diseases and corresponding therapeutic drugs are briefly introduced. In addition, various types of hydrogels reported for ophthalmic drug delivery, including in-situ gelling hydrogels, contact lenses, low molecular weight supramolecular hydrogels, cyclodextrin/poly (ethylene glycol)-based supramolecular hydrogels and hydrogel-forming microneedles, are summarized. Besides, marketed hydrogel-based opthalmic formulations and clinical trials are also highlighted. Finally, critical considerations regarding clinical translation of biologics-loaded hydrogels are discussed. [Display omitted] • Conventional eye drops often confer low ocular bioavailability. • Hydrogels are capable of extending drug residence time and sustaining release of drugs. • Many small molecular drug-containing ophthalmic hydrogels are in the market. • Discussion the opportunities and challenges toward regarding clinical translation of biologics-loaded hydrogels. [ABSTRACT FROM AUTHOR]

• Dasatinib-loaded micelles showed remarkable safety profiles at cellular levels. • The micelles caused negligible ocular toxicity post-intravitreal injection. • The micelles did not insult the cornea, as proved by slit-lamp biomicroscopy. • The micelles did not insult the retina, as demonstrated by Histology & OCT study. • The micelles caused negligible apoptosis and stresses to the retina. Ocular safety/biocompatibility is an essential element of ophthalmic drug delivery. We previously applied poly(ethylene glycol)-block-poly(ɛ-caprolactone) (PEG-b-PCL) micelles to deliver dasatinib for the management of proliferative vitreoretinopathy (PVR) in vitro. Herein, we seek to ascertain the ocular safety/compatibility of blank and dasatinib loaded PEG-b-PCL micelles, which will set the stage for the future in vivo efficacy evaluations and/or clinical translation for PVR or other eye diseases. To access the safety of blank and dasatinib loaded micelles, in vitro cell based assays (LDH cell membrane damage test, SRB cytotoxicity, TEER and permeability of RPE tight junctions), in vivo slit lamp biomicroscopy and optical coherence tomography, Ex vivo histology (H&E staining, GFAP immunofluorescence staining and TUNEL assay) were undertaken. Both blank and dasatinib loaded micelles showed remarkable safety profiles at cellular levels. They also caused negligible ocular toxicity/abnormalities up to 28 days post-intravitreal injection in mice. The micelles did not insult the cornea, as demonstrated by slit-lamp biomicroscopy. Ex vivo histology and in vivo optical coherence tomography revealed a normal retinal structure with minimal apoptosis and stresses. Taken together, both blank and dasatinib loaded micelles appear to be safe and their applications in drug delivery for eye diseases should be explored. [ABSTRACT FROM AUTHOR]

Self-assembly of drug-polysacrrides conjugates forming nanostructures provides a simple and promising strategy for the extension of precorneal retention and enhancement of corneal permeability. In the present study, a series of dexamethasone-glycol chitosan (Dex-GCS) conjugates were synthesized and thoroughly characterized by Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and ultraviolet–visible (UV–Vis) spectroscopy. The resulting Dex-GCS conjugates were able to self-assemble into nanoparticles spontaneously with particle sizes in the range of 277–289 nm and a positive charge of approximately +15 mV. Roughly spherical nanoparticles were observed by transmission electron microscopy (TEM). The in vitro mucoadhesive properties of Dex-GCS nanoparticles were evaluated by recording the variations in the zeta potential after incubation with different concentrations of mucin. In vitro release studies performed in phosphate-buffered saline (PBS, pH = 7.4) indicated progressive Dex release up to 8 h, followed by a plateau up to 48 h. Dex-GCS nanoparticles caused slight cytotoxicity against L929, HCEC and RAW 264.7 cells after 24 h of incubation and displayed a nearly identical anti-inflammatory efficacy to dexamethasone sodium phosphate (Dexp) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. More importantly, the proposed Dex-GCS nanoparticles showed good ocular tolerance and provided a relatively longer precorneal duration compared with that of the aqueous solution formulation, which suggested that the self-assembled Dex-GCS nanoparticle might be a promising candidate for ophthalmic drug delivery. [ABSTRACT FROM AUTHOR]

To enhance ocular drug bioavailability, a rapidly dissolving dry tablet containing alginate and drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles was proposed. For hygienic and easy administration of an accurate drug-dose with this tablet, the use of a preocular applicator was suggested. Herein, a dry tablet was prepared by embedding dexamethasone-loaded PLGA nanoparticles in alginate, which was deposited on the tip of the applicator. The nanoparticles were loaded with 85.45 μg/mg drug and exhibited sustained drug release for 10 h. To evaluate in vivo efficacy, dexamethasone concentration in the aqueous humor was measured after topical administration of the dry tablet, with the applicator, to rabbit eyes and was compared to that achieved with Maxidex®, a commercially-available dexamethasone eye drops. When applied with the preocular applicator, the dry tablet containing alginate could be fully detached and delivered to the eye surface. In fact, it showed up to 2 h of nanoparticle retention on the preocular surface due to tear viscosity enhancement, causing an estimated 2.6-fold increase in ocular drug bioavailability compared to Maxidex®. Therefore, the preocular applicator combined with a dry alginate tablet containing PLGA nanoparticles can be a promising system for aseptically delivering an accurate dose of ophthalmic drug with enhanced bioavailability. [ABSTRACT FROM AUTHOR]