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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]

Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM. [Display omitted] • Developed an in-silico model that can simulate drug delivery from ocular implants. • Validated the predicted intra-ocular pressure values with the values reported in the literature. • For lower levels of loaded drug in the implant, bioavailability time period starts reducing as effective diffusivity is reduced below a certain threshold level. • Neglecting Aqueous Humor (AH) flow effects can result in substantially wrong predictions of drug availability at the Trabecular Meshwork. [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]

This study outlines the development of a chitosan/gelatin biopolymer-based ophthalmic drug delivery film, crosslinked by nontoxic citric acid with enhanced mechanical properties attributed to nanocellulose particle reinforcement. Dynamic light scattering analysis indicates the formation of nanocellulose particles with an average diameter of 177.9 nm. Tensile test demonstrates increased strength with the incorporation of nanocellulose (NC) particles from 0 to 1%. UV-transmission analysis indicates a reduction in light transmission by incorporating NC. Puncture test results reveal that 1% NC incorporated sample showed higher puncture force (9.5 kN) and higher toughness than 0% NC incorporated film (7.5 kN). Thermal analysis revealed higher weight reduction (66.85%) of CG-0%NC film compared to CG-1%NC (63.56%) film. Water contact angle measurement indicates that the CG-1%NC film contains less hydrophilic properties than CG-0%NC film. The scanning electron microscopy (SEM) examination shows a homogeneous distribution of nanocellulose in CG film. In vitro drug release studies indicate that the CG-1%NC film shows a more controllable cumulative drug release with a 600-min equilibrium time compared to the CG-0%NC film in laboratory-made aqueous humor media. The antibacterial activity analysis indicates that the CG-1%NC-Rb film exhibits antibacterial behavior against common pathogenic bacterial species such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The film's transparency, controlled drug delivery behavior, and increased mechanical properties make it a promising candidate for an ophthalmic drug delivery system. [ABSTRACT FROM AUTHOR]

Abstract 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.

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 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.

Juan Li,1,* Ziqing Gao,1,* Ning Li,1 Ling Yao,1 Chao Liu,1 Che Xu,1 Xiaohui Ren,1 Aiqin Wang,1 Siqi Gao,2 Miao Wang,2 Xiang Gao,2 Kun Li,3 Jianfeng Wang1 1Department of Ophthalmology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 2School of Clinical Medicine, Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 3School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, 233100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun Li; Jianfeng Wang, Email liangliang2419@126.com; wangjianfeng1969@163.comBackground: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers.Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections.Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities.Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.Keywords: ophthalmic safety, hollow mesoporous silica nanoparticles, ophthalmic drug delivery, tetrasulfur bond

Amid the escalating prevalence of eye diseases and the intricate nature of the eye as a crucial target organ for drug delivery, researchers face significant challenges in developing delivery systems tailored specifically for ocular complications. Addressing the gaps in the current conventional ocular drug delivery system (ODDS) is crucial and this can be achieved by incorporating polymers while designing newer ODDS. This review aims to offer a concise overview of the diverse polymers utilized in the development of ODDS, designed to address various eye conditions and disorders, enhance treatment outcomes, and ensure patient adherence. Introducing the anatomy of the eye and different ocular routes of administration, alongside the barriers encountered, this review presents polymer‐based ODDS, renowned for their unique properties facilitating the engineering of specialized devices for enhanced drug delivery. Further discussions delve into the applications of polymers in ophthalmology. Emphasis is placed on emerging polymer‐based technologies available in the market for treating ocular diseases, underscoring their potential for revolutionizing ocular healthcare. The review also addresses challenges in translating these advancements into clinical practice, while highlighting the versatility of polymers in treating diverse eye diseases and disorders through customizable properties and sustained 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]

This study endeavored to overcome the physiological barriers hindering optimal bioavailability in ophthalmic therapeutics by devising drug delivery platforms that allow therapeutically effective drug concentrations in ocular tissues for prolonged times. Thermosensitive drug delivery platforms were formulated by blending poloxamers (F68 and F127) with low-molecular-weight hyaluronic acid (HA) in various concentrations and loaded with hydrocortisone (HC). Among the formulations examined, only three were deemed suitable based on their desirable gelling properties at a temperature close to the eye's surface conditions while also ensuring minimal gelation time for swift ocular application. Rheological analyses unveiled the ability of the formulations to develop gels at suitable temperatures, elucidating the gel-like characteristics around the physiological temperature essential for sustained drug release. The differential scanning calorimetry findings elucidated intricate hydrogel–water interactions, indicating that HA affects the water–polymer interactions within the gel by increasing the platform hydrophilicity. Also, in vitro drug release studies demonstrated significant hydrocortisone release within 8 h, governed by an anomalous transport mechanism, prompting further investigation for optimized release kinetics. The produced platforms offer promising prospects for efficacious ocular drug delivery, addressing pivotal challenges in ocular therapeutics and heralding future advancements in the domain. [ABSTRACT FROM AUTHOR]

Abstract Amid the escalating prevalence of eye diseases and the intricate nature of the eye as a crucial target organ for drug delivery, researchers face significant challenges in developing delivery systems tailored specifically for ocular complications. Addressing the gaps in the current conventional ocular drug delivery system (ODDS) is crucial and this can be achieved by incorporating polymers while designing newer ODDS. This review aims to offer a concise overview of the diverse polymers utilized in the development of ODDS, designed to address various eye conditions and disorders, enhance treatment outcomes, and ensure patient adherence. Introducing the anatomy of the eye and different ocular routes of administration, alongside the barriers encountered, this review presents polymer‐based ODDS, renowned for their unique properties facilitating the engineering of specialized devices for enhanced drug delivery. Further discussions delve into the applications of polymers in ophthalmology. Emphasis is placed on emerging polymer‐based technologies available in the market for treating ocular diseases, underscoring their potential for revolutionizing ocular healthcare. The review also addresses challenges in translating these advancements into clinical practice, while highlighting the versatility of polymers in treating diverse eye diseases and disorders through customizable properties and sustained drug delivery.

Dry eye disease (DED) is a highly prevalent ocular surface disease that affects life quality and reduces productivity at work. The purpose of this study is to improve the efficacy of tacrolimus (FK506) in the treatment of DED using the special eye surface retention properties of cationic nanoemulsion (CNE) modified by thermosensitive in-situ gel (ISG) (CNE-ISG). The precorneal retention of CNE-ISG containing 0.05% FK506 (50 min) was longer than that of CNE containing 0.05% FK506 (25 min) and commercial suspension containing 0.1% FK506 (Talymus®) (10 min). Successfully modeled dry-eye rabbits were treated with 0.05% CNE-ISG (twice/day), 0.05% CNE and 0.1% suspension (Talymus®) (thrice/day). Schirmer's tear secretion test showed no significant difference between the CNE-ISG group and the healthy group after 5 days of treatment (p > 0.05). The results of a tear ferning test (TFT) showed that the tear-fern-like crystal branches in the CNE-ISG group returned to normal after 5 days of treatment. Histological analysis showed that the number of goblet cells in the CNE-ISG group significantly increased. HET-CAM stimulation test showed that the CNE-ISG group had no ocular irritation. The above results indicated that CNE-ISG might be a promising delivery system and as an effective dosage form was employed for FK506 in the treatment of DED. [Display omitted] [ABSTRACT FROM AUTHOR]

Metformin is known to lower inflammation, independent of its anti-diabetic action. Thus, topical metformin can be a therapeutic strategy for managing ocular inflammation associated with diabetes. To achieve this and address the issues of ocular retention and controlled release an in situ gel of metformin was developed. The formulations were prepared using sodium hyaluronate, hypromellose, and gellan gum. The composition was optimized by monitoring gelling time/capacity, viscosity, and mucoadhesion. MF5 was selected as the optimized formulation. It showed both chemical and physiological compatibility. It was found to be sterile and stable. MF5 exhibited sustained release of metformin for 8h that fitted best with zero-order kinetics. Further, the release mode was found to be close to the Korsmeyer-Peppas model. Supported by an ex vivo permeation study, it showed potential for prolonged action. It showed a significant reduction in ocular inflammation that was comparable to that of the standard drug. MF5 shows translational potential as a safe alternative to steroids for managing ocular inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. Here, we have presented the first of its kind investigation, to study the PK of 4 different size non-binding protein therapeutics in mouse plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) following IVT administration. Administered proteins include trastuzumab (150 kDa) and F(ab) 2 (100 kDa), Fab, and scFv (27 kDa) fragments of trastuzumab. An imaging and injection apparatus suitable for performing small (50 nL) IVT injections in mice was developed, and techniques for enucleation of the eye and dissection of ocular tissues were developed. Furthermore, a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of proteins in very small amounts of ocular tissues were developed. It was observed that elimination from the vitreous chamber was the primary driver of PK in the cornea/ICB, retina, posterior cup, and plasma. Trastuzumab displays first-order kinetics in the vitreous humor with a half-life of 18.8 h. F(ab) 2 , Fab, and ScFv show biphasic PK profiles with distribution phases becoming more rapid as molecular weight decreases, and terminal elimination becoming longer as molecular weight decreases, with terminal half-lives of 16.3, 20.6, and 48.9 h, respectively. The mean residence times of trastuzumab, F(ab) 2 , Fab, and scFv in the vitreous humor were 26.0, 12.2, 10.7, and 8.16 h, respectively. It was found that the mean residence time in vitreous humor doubles with an increase in molecular weight of ∼69 kDa. Interestingly, the PK of proteins measured in the un-injected eye suggest the presence of a pathway for drug transfer between the eyes, which needs to be further validated. Overall, the findings presented here pave the way for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice. [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.

This study endeavored to overcome the physiological barriers hindering optimal bioavailability in ophthalmic therapeutics by devising drug delivery platforms that allow therapeutically effective drug concentrations in ocular tissues for prolonged times. Thermosensitive drug delivery platforms were formulated by blending poloxamers (F68 and F127) with low-molecular-weight hyaluronic acid (HA) in various concentrations and loaded with hydrocortisone (HC). Among the formulations examined, only three were deemed suitable based on their desirable gelling properties at a temperature close to the eye’s surface conditions while also ensuring minimal gelation time for swift ocular application. Rheological analyses unveiled the ability of the formulations to develop gels at suitable temperatures, elucidating the gel-like characteristics around the physiological temperature essential for sustained drug release. The differential scanning calorimetry findings elucidated intricate hydrogel–water interactions, indicating that HA affects the water–polymer interactions within the gel by increasing the platform hydrophilicity. Also, in vitro drug release studies demonstrated significant hydrocortisone release within 8 h, governed by an anomalous transport mechanism, prompting further investigation for optimized release kinetics. The produced platforms offer promising prospects for efficacious ocular drug delivery, addressing pivotal challenges in ocular therapeutics and heralding future advancements in the domain.

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]

To maintain the therapeutic drug concentration for a prolonged period of time in aqueous and vitreous humor is primary challenge for ophthalmic drug delivery. Majority of the locally administered drug into the eye is lost as to natural reflexes like blinking and lacrimation resulting in the short span of drug residence. Consequently, less than 5% of the applied drug penetrate through the cornea and reaches the intraocular tissues. The major targets for optimal ophthalmic drug delivery are increasing drug residence time in cul-de-sac of the eye, prolonging intraocular exposure, modulating drug release from the delivery system, and minimizing pre-corneal drug loss. Development of in situ gel, contact lens, intraocular lens, inserts, artificial cornea, scaffold, etc., for ophthalmic drug delivery are few approaches to achieve these major targeted objectives for delivering the drug optimally. Interpenetrating polymeric network (IPN) or smart hydrogels or stimuli sensitive hydrogels are the class of polymers that can help to achieve the targets in ophthalmic drug delivery due to their versatility, biocompatibility and biodegradability. These novel "smart" materials can alter their molecular configuration and result in volume phase transition in response to environmental stimuli, such as temperature, pH, ionic strength, electric and magnetic field. Hydrogel and tissue interaction, mechanical/tensile properties, pore size and surface chemistry of IPNs can also be modulated for tuning the drug release kinetics. Stimuli sensitive IPNs has been widely exploited to prepare in situ gelling formulations for ophthalmic drug delivery. Low refractive index hydrogel biomaterials with high water content, soft tissue-like physical properties, wettability, oxygen, glucose permeability and desired biocompatibility makes IPNs versatile candidate for contact lenses and corneal implants. This review article focuses on the exploration of these smart polymeric networks/IPNs for therapeutically improved ophthalmic drug delivery that has unfastened novel arenas in ophthalmic drug delivery. [ABSTRACT FROM AUTHOR]

Restrictive barriers and efficient clearance mechanisms make delivery of therapeutics to the back of the eye particularly challenging. An optically transparent, thermally gelling copolymer scaffold that can simply be mixed with an active pharmaceutical ingredient of choice and injected directly into the vitreous chamber has been designed. The poly(N-isopropylacrylamide) (PNIPAAm)-based copolymer possesses a lower critical solution temperature near body temperature. Incorporating acrylic acid and poly(ethylene glycol) methacrylate into the polymer at optimized ratios modulates the lower critical solution temperature to transition the aqueous copolymer solution into a volume-consistent gel, which does not expel water, a common challenge with PNIPAAm-based materials. The addition of acryloyloxy dimethyl-γ-butyrolactone to the copolymer enables the polymer to slowly degrade and be cleared from the body. Herein, the synthesis and characterization of the novel copolymer scaffolds are described. A detailed report is provided on the intraocular biocompatibility profile as assessed via in vivo imaging techniques, histology, and immunostaining. Overall, the scaffolds were well tolerated in the rodent eye for the duration of the 17-day experiment. [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.

[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: Conventional topical dosage forms face with some challenges like low intraocularbioavailability, which could be overcome by application of novel drug delivery systems.Therefore, this study was conducted to prepare azithromycin (AZM)-loaded chitosan/polyvinylalcohol/polyvinyl pyrrolidone (CS/PVA-PVP) nanofibers with the prolonged antibacterialactivity by electrospinning method.Methods: After preparation of nanofibers, they were characterized in terms of physicochemicaland morphological properties. In vitro and in vivo release of the drug from nanofibers wereevaluated using microbial assay against the Micrococcus luteus. Antibacterial efficacy of thenanofibers was assessed. The ophthalmic irritation test was also performed. MTT test wascarried out to evaluate cytotoxicity of the formulations.Results: All the formulations were found to be stable with uniform thickness, weight, and drugcontent. Nanofibers had a diameter range from 119 ± 29 to 171 ± 39 nm. The inserts were nonirritantand non-toxic to the rabbits’ eye. Based on the obtained results, the crosslinked AZMnanofibers showed slower and more controlled drug release in tear fluid compared to the noncrosslinkedones, within 184 hours.Conclusion: Our results revealed that the prepared nanofibers could be considered as suitableand non-invasive inserts for the prolonged ophthalmic delivery of AZM.

The eyes are the most sensitive organ in the human body with complicated physiology, so that any associated dysfunctions or injuries are the leading causes of total blindness. Dynamic barriers of the eyes allow just 5% of medicines of the eye drops to be reached to the eye's aqueous fluids, that's why eye drops shall be administered frequently to keep a drug concentration at the side of action, therefore research hard work focused on developing novel drug delivery system that can overcome problem associated with conventional drug delivery to ocular surfaces subsequently nano-technology based ophthalmic preparations have been extensively studied in the domain of drug administration to the anterior and posterior portions of the eye over the last few decades. Surface active agents (SAAs) have been broadly used for the design of various of the dosage forms targeting of thalmic tissues. Novel ocular carriers employing SAAs were mainly classified into particulate, vesicular, and controlled release drug delivery systems. Depending on their physicochemical properties, Yet, their use is limited by their possible harmfulness and possible interactions with other formulation ingredients. This review offers information about the efficacy and safety of various types of surfactants utilized in nanotechnology(nanomicelles, niosomes, nanoemulsions) for topical ocular medication delivery over the last ten years. Nonionic surfactants were the most commonly utilized surfactant among other types of surfactants (anionic and cationic) because of their safity and effectiveness in the range used for ofthalmic drug delivery of novel nanotechnology. [ABSTRACT FROM AUTHOR]

Background and purpose: Prolonging the drug release can be a suitable approach to overcome the challenges related to topical ophthalmic administration of drugs especially the ones prescribed for chronic ailments. The sustained delivery of the drug would reduce the required frequency of administration which could extremely improve patient compliance and feeling of well-being. This study aimed to develop nanofibrous inserts for sustained ophthalmic delivery of timolol maleate (TIM) for the treatment of glaucoma. Experimental approach: Polycaprolactone-based nanofibers containing TIM were prepared using pure polycaprolactone or a blend of it with cellulose acetate or Eudragit RL100 polymers by the electrospinning method. Following the preparation, polymeric inserts were evaluated for morphological and physicochemical properties. The in vitro drug release was assessed and the in vivo efficacy of a selected insert in decreasing the intraocular pressure (IOP) was also evaluated in the equine eyes. Findings / Results: Prepared nanofibers indicated diameter ranged between 122-174 nm. The formulations showed suitable physicochemical properties and stability for ophthalmic administration. In vitro release study showed prolonged release of drug during more than 3 days. In vivo evaluation revealed that the prepared insert is non-irritant and non-toxic to the equine eyes while having suitable efficacy in decreasing the IOP during 6 days. Conclusions and implication: Prepared TIM inserts indicated a higher efficacy than commercial TIM eye drop in lowering IOP during a prolonged period. Thus, these formulations can be considered suitable for enhancing patient compliance by reducing the frequency of administration in the treatment of glaucoma.

In ophthalmic therapy, drugs of various structures are used, administered into the conjunctival sac or onto the cornea. Novel concepts of technological development of the form of an ophthalmic drug delivery systems include obtaining a higher concentration of the drug in the target tissue of the cornea, while reducing side effects. In recent years, there has been a growing interest in using nanofibers as a dosage forms used in ophthalmic therapy. Nanofibers prepared by the electrospinning method are characterized by high porosity, high surface area/volume ratio and good mechanical properties. For their preparation, biocompatible and biodegradable polymers are used, such as: poly-ɛ-caprolactone, polymers and copolymers of lactic acid, chitosan, gelatin, collagen, polyvinyl alcohol, polyvinylpyrrolidone. They are considered as carriers of a drug substance in order to provide its prolonged or controlled release which is essential in the treatment of chronic diseases. The improvement in the bioavailability of fluocinolone acetonide was achieved after applying inserts containing nanofibers with poly-ɛ-caprolactone prepared using the electrospinning method to the rabbit eye. Poly-ɛ-caprolactone was also used to prepare nanofibers for intravitreal administration of dexamethasone acetate in retinal diseases to achieve controlled release of the drug substance. In order to reduce intraocular pressure in the treatment of glaucoma, contact lenses coated with timolol maleate nanofibers were used. The electrospinning method was also used to prepare nanofibers gelling in situ with gellan gum and pullulan polysaccharide. On the other hand, biodegradable core-shell nanofibers composed of monoclonal antibodies, bevacizumab, may be utilized as a new form of the drug for the ADM. Natural and synthetic polymers or their combinations are also used to prepare electospun nanofibers for the tissue engineering, e.g. in corneal tissues regeneration, for the preparation of cells for implantation or for direct injection of cells into the damaged area, e.g. retina, cornea.

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]

[Display omitted] The present study aimed at developing a potential in situ gellable dexamethasone (DXM) eye drop. Poly(aspartic acid) (PASP) derivatives were synthesized with dual functionality to improve the solubility of DXM, and to achieve in situ gelation. First, amine-modified β-cyclodextrin (CD) was attached to polysuccinimide (PSI), second, thiol functionalities were added by the reaction of cysteamine and succinimide rings. Finally, the PSI derivatives were hydrolysed to the corresponding PASP derivatives to get water-soluble polymers. Phase-solubility studies confirmed the complexation ability of CD-containing PASP derivatives. In situ gelation and the effect of the CD immobilization on this behaviour were characterized by rheological measurements. The solubilizing effect of CD was confirmed by kinetic solubility measurements, whereas in vitro corneal permeability assay (corneal-PAMPA) measurements were performed to determine in vitro permeability and flux values. The effect of the PASP derivatives on permeation strongly depended on chemical composition and polymer concentration. [ABSTRACT FROM AUTHOR]

Purpose: Conventional topical dosage forms face with some challenges like low intraocular bioavailability, which could be overcome by application of novel drug delivery systems. Therefore, this study was conducted to prepare azithromycin (AZM)-loaded chitosan/polyvinyl alcohol/polyvinyl pyrrolidone (CS/PVA-PVP) nanofibers with the prolonged antibacterial activity by electrospinning method. Methods: After preparation of nanofibers, they were characterized in terms of physicochemical and morphological properties. In vitro and in vivo release of the drug from nanofibers were evaluated using microbial assay against the Micrococcus luteus. Antibacterial efficacy of the nanofibers was assessed. The ophthalmic irritation test was also performed. MTT test was carried out to evaluate cytotoxicity of the formulations. Results: All the formulations were found to be stable with uniform thickness, weight, and drug content. Nanofibers had a diameter range from 119 ± 29 to 171 ± 39 nm. The inserts were nonirritant and non-toxic to the rabbits' eye. Based on the obtained results, the crosslinked AZM nanofibers showed slower and more controlled drug release in tear fluid compared to the noncrosslinked ones, within 184 hours. Conclusion: Our results revealed that the prepared nanofibers could be considered as suitable and non-invasive inserts for the prolonged ophthalmic delivery of AZM. [ABSTRACT FROM AUTHOR]

AIM: To compare the differences in kinetics, distribution, and toxicity of triamcinolone acetonide (TA) between the injection methods, sub-Tenon and intravitreal injections in rabbit ocular tissues. METHODS: TA was injected into the vitreous or the sub-Tenon in rabbits. For pharmacokinetic study, rabbits were sacrificed periodically and then TA in blood and ocular tissues (retina/choroids, vitreous, and aqueous humor) were measured over 91d. For toxicological study, clinical signs, slit-lamp microscopic examination, ophthalmological test were performed. The eyeballs and surrounding tissues were collected and fixed with glutaraldehyde-formalin solution, and then paraffin embedded for histological investigation. RESULTS: Higher levels of TA were distributed in the intraocular tissues when injected into the vitreous compared to the sub-Tenon. Conversely, TA level was remarkably lower in the rabbits which received intravitreal TA injections than those treated with sub-Tenon injection throughout the study period in plasma. Optical discharge probably caused by systemic circulation of TA was observed by receiving sub-Tenon TA injection. Meanwhile, technic-associated toxicological ocular symptoms and findings were more frequently observed in intravitreal injection than in sub-Tenon injection. CONCLUSION: There are significant differences in kinetics and distribution of TA in vitreous body, aqueous humor and plasma, between the two injection methods. Although further study is needed to explain the species difference between human and rabbit, it is assumed that the difference in the frequency of intraocular pressure elevation and cataract formation by TA between the two injection methods are directly related to the TA concentrations in aqueous humor and vitreous body in each injection methods. Systemic toxicity and technic-associated toxicity are also closely related to kinetics of TA in plasma and each injection method itself, respectively.

Ocular drug delivery presents significant challenges due to intricate anatomy and the various barriers (corneal, tear, conjunctival, blood-aqueous, blood-retinal, and degradative enzymes) within the eye. Lipid-based nanoparticles (LNPs) have emerged as promising carriers for ocular drug delivery due to their ability to enhance drug solubility, improve bioavailability, and provide sustained release. LNPs, particularly solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and cationic nanostructured lipid carriers (CNLCs), have emerged as promising solutions for enhancing ocular drug delivery. This review provides a comprehensive summary of lipid nanoparticle-based drug delivery systems, emphasizing their biocompatibility and efficiency in ocular applications. We evaluated research and review articles sourced from databases such as Google Scholar, TandFonline, SpringerLink, and ScienceDirect, focusing on studies published between 2013 and 2023. The review discusses the materials and methodologies employed in the preparation of SLNs, NLCs, and CNLCs, focusing on their application as proficient carriers for ocular drug delivery. CNLCs, in particular, demonstrate superior effectiveness attributed due to their electrostatic bioadhesion to ocular tissues, enhancing drug delivery. However, continued research efforts are essential to further optimize CNLC formulations and validate their clinical utility, ensuring advancements in ocular drug delivery technology for improved patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Baig, Karade, Ahmad, Khan, Haque, Webster, Faiyazuddin and Al-Qahtani.)

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]

[Display omitted] • Encapsulation of acetazolamide in ELRs nanoparticles using SAS technique. • ELR-based nanoparticles system offering more permeation ocular of Acetazolamide. • Tests on hypertensive rabbits show high bioavailability and hypotensive effect. Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of –33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance. [ABSTRACT FROM AUTHOR]

Oil-in-water nanoemulsions (NEs) represent one of the formulation approaches to improve eye-related bio-availability of lipophilic drugs. The potential of cationic NEs is pronounced due to the electrostatic interaction of positively charged droplets with negatively charged mucins present in the tear film, providing prolonged formulation residence at the ocular surface. The aim of this study was to develop a cationic ophthalmic NE with cationic lipid stearylamine (SA) as a carrier of a positive charge. The addition of a nonionic surfactant provided the dual electro-steric stabilization of NEs and enabled tuning of SA concentration to achieve an optimal balance between its interaction with mucins and biocompatibility. Physicochemical characterization, stability profile, in vitro mucoadhesion study and biocompatibility study employing 3D HCE-T cell-based model of corneal epithelium pointed out the NE with 0.05 % (m/m) SA as the leading formulation. Minimizing SA content while retaining droplet/mucin interactions is of great importance for efficacy and safety of future ophthalmic drug products.