Ocular Formulations Research Articles

Preparation and functional evaluation of electrospun polymeric nanofibers as a new system for sustained topical ocular delivery of itraconazole

Due to the rapid clearance of external agents from the surface of the cornea, conventional ocular formulations usually require frequent and long duration of administration to achieve a therapeutic level of the drug on the cornea which can be conquered using prolonged-release nanofibrous inserts. In the present study, for the first time, polymeric nanofibers of itraconazole (ITZ), a potent triazole antifungal agent, were prepared as ocular inserts to enhance the topical ocular delivery of the drug. Three different nanofibers were prepared by electrospinning using polyvinyl alcohol-cellulose acetate and polycaprolactone-polyethylene glycol 12 000 polymeric blends. Nanofibers indicated uniform structures with the mean diameter ranging between 137 and 180 nm. Differential scanning calorimetry and Fourier-transform infrared spectroscopy confirmed the amorphous state of the drug in the formulations and the no drug-polymer interaction. Appropriate stability, suitable flexibility, and 2.2–3.9 MPa tensile strength were observed. Formulations indicated antifungal efficacy against Candida albicans and Aspergillus fumigatus and cell viability >70% at different concentrations. Results of bioassay against Candida albicans exhibited prolonged in vitro release of 50–70% of ITZ for almost 55 days. The results suggested that the nanofibers could be considered suitable for prolonged delivery of the ITZ as an antifungal requiring frequent and long duration of administration.

Strengthened rebamipide ocular nanoformulation to effectively treat corneal alkali burns in mice through the HMGB1 signaling pathway

Corneal alkali burns are a major ophthalmic emergency, as current therapeutic treatments are limited. Novel treatment targets and new potential agents are required to combat this severe ocular injury. Glycyrrhizin and rebamipide (RBM) are both FDA-approved drugs with potential effects against corneal alkali burns, but RBM is limited by its low aqueous solubility and low bioavailability. This study aimed to utilize dipotassium glycyrrhizinate (DG, a dipotassium salt of glycyrrhizin) as a nanocarrier encapsulating RBM to formulate an ophthalmic solution (marked DG-RBM) with strengthened activities to treat corneal alkali burns. Results showed that an easy DG-RBM preparative process generated particles with high encapsulation efficacy and ultra-small micellar size. The solubility of RBM in DG-RBM in aqueous solution was 3.1 × 105-fold enhanced than its free solution. DG-RBM exhibited excellent storage stability. In vitro cytotoxicity, ex vivo conjunctival responses, and rabbit eye tolerance tests showed that DG-RBM possessed good ocular safety profiles. DG-RBM exhibited improved in vivo corneal permeation profiles and demonstrated a strong effect against H2O2-induced oxidative damage, with a significant effect on promoting epithelial wound healing in corneal cells in vitro. As expected, in a mouse model of corneal alkali burns, the topical administration of DG-RBM achieved a strengthened efficacy against alkali burn damages. The mechanism of this therapeutic effect involved regulating high-mobility group box 1 (HMGB1) signaling and its related angiogenic and proinflammatory cytokines. These findings demonstrate the ease of preparing DG-RBM and its great potential as a novel ocular topical formulation to treat corneal alkali burns by regulating HMGB1 signaling.

Super aggregated amphotericin B with a thermoreversible in situ gelling ophthalmic system for amoebic keratitis treatment

Acanthamoeba spp. are the causative agents of a sight-threatening infection of the cornea known as Acanthamoeba keratitis (AK). Amphotericin B - deoxycholate (AB) is used in the treatment of infectious keratitis, however, its topical administration has side effects as blepharitis, iritis, and painful instillation. In this context, the preheating of AB can decrease its toxicity by the formation of super aggregates (hAB). hAB associated with a thermoreversible in situ gelling ophthalmic system is a promising option due to the latter biocompatibility, low toxicity, and high residence time on the ocular surface. Our objective was to develop a topical ocular formulation of hAB for the treatment of AK. After heating at 70°C for 20 min, hAB was incorporated into a thermoreversible gelling system. The amebicidal activity of AB and hAB was evaluated against trophozoites and cysts of A. castellanii (ATCC 50492) and a regional clinical isolate (IC01). The results showed that the preheating of AB did not change the pharmacological action of the drug, with the amebicidal effect of AB and hAB under trophozoites and cysts of Acanthamoeba spp. The thermoreversible system remained stable, allowing the increase of drug retention time. For assessment of cytotoxicity, HUVEC (ATCC® CRL-1730) cells were challenged with AB and hAB for 48h. Cell viability was assessed, and hAB did not show cytotoxicity for HUVEC cells. As far as we know this was the first study that showed the preheated AB associated with a thermoreversible in situ gelling ophthalmic system as a promising system for topical ocular topical administration of hAB for AK therapy.

Development and Optimization of Chitosan-Hydroxypropyl Methylcellulose In Situ Gelling Systems for Ophthalmic Delivery of Bupivacaine Hydrochloride

The aim of this study was the development and optimization of chitosan and hydroxypropyl methylcellulose (HPMC) in situ gelling systems, loaded with bupivacaine hydrochloride for topical ocular administration. This study is based on the properties of two polymers: chitosan, which has mucoadhesive action and is a pH-sensitive polymer, but also the cellulose derivative hydroxypropyl methylcellulose, a thermosensitive polymer which has mucoadhesive properties and increases the viscosity of systems. The analysis and optimization of in situ gelling systems were performed based on an experimental design and response surface methodology. The following formulation parameters were considered: X1 = chitosan concentration (0.5%, 1%), X2 = HPMC E 5 LV concentration (2%, 5%) and X3 = Chitosan/HPMC E 5 LV ratio (1/1, 2/1). In addition, the parameters to be optimized were represented by the contact angle (CA (°)), viscosity and cumulative percentage of bupivacaine hydrochloride released in vitro. The results indicate that the designed in situ gelling systems are suitable for bupivacaine prolonged ophthalmic release and overcome the principal disadvantages of the liquid’s ocular formulations. An immediate therapeutic effect corresponding to ocular anesthetic installation was assured in the first stage: burst bupivacaine release. In the second phase, the gradual drug release was assured for over 6 h. This drug release profile, together with the corresponding rheological profile and a collection of superficial properties for good ocular adhesion balanced with an adequate hydrophilic character, assured the desired quality of the attributes for the proposed systems. The system, based on chitosan 1%, HPMC E 5 LV 5% and a 1/1 polymer ratio, could be a solution for the proposed formulation of in situ gelling colloidal systems, since the viscosity of the system was within the range of the optimal viscosity of the eye, and the amount of bupivacaine hydrochloride released after 6 h was the highest at 69.55%.

Research Progress of Nanostructured Lipid Carriers in Ocular Drug Delivery

: The eye is the most important sensory organ, which restricts most of the active substances due to its static and dynamic barriers. The application of conventional eye drop is still popular, but it was found to be less permeable to both anterior and posterior eye portions, requiring more frequent administration. It seems to be a great challenge for the researcher to fabricate an ocular formulation that crosses the barriers and achieves an optimal therapeutic concentration at the ocular globe. Recent studies revealed that a nanostructured lipid carrier has great potential in ophthalmic use and has become more popular due to its permeability in the eye cavity. : This review describes the nanostructured lipid carriers with respect to the mechanism of ocular permeation, structural feature, manufacturing process, characterization, and its merits over other nanocarriers. In recent years, newly nanostructured-based ocular formulations have been developed, like surface-modified with various cationic compounds and their integration with different polymeric systems, to enhance ocular bioavailability in both regions of the eye. Newly developed nanostructured lipid carriers include surface modified cationic lipid, polymers, and thiolated compounds, etc., that increases mucoadhesive property. Finally, nanostructured incorporated forms, in situ gel, and hydrogel increase permeation in the posterior region of the eye.

Vildagliptin plasticized hydrogel film in the control of ocular inflammation after topical application: study of hydration and erosion behaviour

Abstract Vildagliptin (VID) is a dipeptidyl peptidase-4 (DPP-4) inhibitor used in controlling blood glucose level in type 2 diabetes. Vildagliptin improves beta cells function and is also suggested to effectively control the inflammation. The possible ocular anti-inflammatory property of vildagliptin has been explored using topically applied plasticized ocular film formulation. Film formulation was prepared by solvent cast and evaporation method using triethanolamine (TEA), dimethyl sulphoxide (DMSO), and polyethylene glycol 400 (PEG 400) as the plasticizer in HPMC hydrogel matrix base. Anti-inflammatory study was carried out in the carrageenan induced ocular rabbit model. Analytical methods confirmed that the drug was present almost in completely amorphized form in the film formulation. Level of hydration, swelling and erosion rate of the film played the controlling factor in the process of drug release, ocular residence and permeation. Maximum swelling rate of 363 h−1 has been shown by VHT compared to other formulation of VHD and VHP (174 and 242 h−1 respectively). Film containing DMSO exhibited highest in vitro release as well as ex vivo ocular permeation. Film formulation has shown a fast recovery of ocular inflammation in contrast to the untreated eye after inducing inflammation. Plasticized vildagliptin hydrogel film formulation could be utilized in the management and control of ocular inflammation particularly with diabetic retinopathy after proper clinical studies in higher animal and human individuals.

Ocular microemulsion of brinzolamide: Formulation, physicochemical characterization, and in vitro irritation studies based on EpiOcular™ eye irritation assay

In recent years, the hydrophobic active substances have led researchers to develop new formulations to enhance bioavailability and dissolution rate; brinzolamide, a lipophilic drug belongs to carbonic anhydrase inhibitors, which cause reduction of intraocular pressure in patients suffering from glaucoma. Currently, the marketed product of brinzolamide is in the form of ocular drops; nonetheless, the conventional drops provide decreased therapeutic efficacy owing to their low bioavailability and pulsed drug release. Thus, the development of novel ocular formulations such as topical microemulsions is of high importance. In this work, the preparation of new microemulsions containing brinzolamide (0.2, 0.5 and 1% w/w) and comprised from isopropyl myristate, tween 80 and span 20 and Cremophor EL was performed. The obtained microemulsions were further characterized for their physicochemical properties. In addition, Fourier Transformed-Infrared spectroscopy was used touate the compatibility of active ingredients and components. In vitro release studies along with kinetic modeling were performed using the dialysis membrane method in simulated tear fluid. Bioadhesion studies were performed using Texture analysis. Finally, in vitro ocular irritation based on EpiOcular™ Eye Irritation Test and cytocompatibility studies was performed to examine any possible harm on ocular cells and predict in vivo safety profile.

Formulation of Ocular In Situ Gels with Lithuanian Royal Jelly and Their Biopharmaceutical Evaluation In Vitro.

Royal jelly is a natural substance produced by worker bees that possesses a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and protective. Although fresh royal jelly is kept at low temperatures, to increase its stability, it needs to be incorporated into pharmaceutical formulations, such as in situ gels. The aim of this study was to formulate in situ ocular gels containing Lithuanian royal jelly for topical corneal use in order to increase the retention time of the formulation on the ocular surface and bioavailability. Gels were evaluated for physicochemical characteristics (pH, rheological properties, refractive index) and in vitro drug release measuring the amount of 10-hydroxy-2-decenoic acid (10-HDA). An ocular irritation test and cell viability tests were performed using the SIRC (Statens Seruminstitut Rabbit Cornea) cell culture line. Results indicated that all the in situ gels were within an acceptable pH and refractive index range close to corneal properties. Rheology studies have shown that the gelation temperature varies between 25 and 32 °C, depending on the amount of poloxamers. The release studies have shown that the release of 10-HDA from in situ gels is more sustained than royal jelly suspension. All gel formulations were non-irritant according to the short-time exposure test (STE) using the SIRC cell culture line, and long-term cell viability studies indicated that the formulations used in small concentrations did not induce cell death. Prepared in situ gels containing royal jelly have potential for ocular drug delivery, and they may improve the bioavailability, stability of royal jelly, and formation of non-irritant ocular formulations.

Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure.

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC0–24 levels were 25,780 ng.h g−1, 12,046 ng.h g−1 and 5879 ng.h g−1, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.

Potential of Stimuli-Responsive In Situ Gel System for Sustained Ocular Drug Delivery: Recent Progress and Contemporary Research.

Eyesight is one of the most well-deserved blessings, amid all the five senses in the human body. It captures the raw signals from the outside world to create detailed visual images, granting the ability to witness and gain knowledge about the world. Eyes are exposed directly to the external environment; they are susceptible to the vicissitudes of diseases. The World Health Organization has predicted that the number of individuals affected by eye diseases will rise enormously in the next decades. However, the physical barriers of the eyes and the problems associated with conventional ocular formulations are significant challenges in ophthalmic drug development. This has generated the demand for a sustained ocular drug delivery system, which serves to deliver effective drug concentration at a reduced frequency for consistent therapeutic effect and better patient treatment adherence. Recent advancement in pharmaceutical dosage design has demonstrated that a stimuli-responsive in situ gel system exhibits the favorable characteristics for providing sustained ocular drug delivery and enhanced ocular bioavailability. Stimuli-responsive in situ gels undergo a phase transition (solution–gelation) in response to the ocular environmental temperature, pH, and ions. These stimuli transform the formulation into a gel at the cul de sac to overcome the shortcomings of conventional eye drops, such as rapid nasolacrimal drainage and short contact time with the ocular surface This review highlights the recent successful research outcomes of stimuli-responsive in situ gelling systems in treating in vivo models with glaucoma and various ocular infections. Additionally, it also presents the mechanism, recent development, and safety considerations of stimuli-sensitive in situ gel as the potential sustained ocular delivery system for treating common eye disorders.

Next-generation contact lenses: Towards bioresponsive drug delivery and smart technologies in ocular therapeutics

In contrast to the conventional ocular formulations, contact lenses are well known for their diverse applications ranging from bio-sensing, prevention of myopia, cosmetics, and drug delivery. With a tremendous change in the lifestyle, contact lenses for therapeutic purposes have increased several fold. Contact lenses as medicated lenses suffer from several disadvantages, and to overcome the same numerous approaches have been explored. Researches worldwide have come a long way from cyclodextrin-based and vitamin E-based modified contact lenses to bioinspired approaches to enhance the effectiveness of the drug-eluting contact lenses. The bioinspired approach exploits bioinspired polymeric systems to enhance biocompatibility, specific molecule recognition technique by molecular imprinting, or stimuli-responsive system to improve the biocompatibility, drug loading, and drug delivery efficacy of the drug-eluting contact lenses. Moreover, recent innovations in ocular therapeutics such as nanowafers and microneedle contact lenses, and ocular patches have gained tremendous attention in ocular therapeutics. Another potential application of the contact lenses are smart lenses applied in the biosensing and diagnosis of various ocular disorders. The review summarizes and discusses the widespread therapeutic applications of next-generation contact lenses and various fabrication approaches, including its clinical implications, efforts taken by researchers in exploring the novel materials and diverse forms of the lenses, mechanisms of drug release, clinical trials, and their toxicity and safety concerns.

A polymeric aqueous tacrolimus formulation for topical ocular delivery

Tacrolimus (TAC) suspension is used to treat moderate to severe atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). The objectives of this study were to formulate the hydrophobic compound TAC (TAC) in an aqueous eye drop formulation and study its ocular biodistribution on topical ocular application to a healthy rabbit model, with the overall aim of using the formulation to treat AKC and VKC. A thin-film hydration method was used to encapsulate TAC within the chitosan-based amphiphile: N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (Molecular Envelope Technology – MET) in an aqueous formulation. The formulation was characterized, and its stability studied under three storage conditions for one month. The ocular distribution of the formulation was studied in healthy rabbits and the ocular tissues and the whole blood analyzed by LC-MS/MS. A 200 nm nanoparticle formulation (MET-TAC) containing 0.1 ± 0.002% w/v TAC was produced with viscosity, osmolarity and pH within the ocular comfort range, and the formulation was stable on refrigeration for one month. On topical application, the TAC concentrations in rabbit cornea and conjunctiva one hour after dosing were 4452 ± 2289 and 516 ± 180 ng/g of tissue, respectively. A topical ocular aqueous TAC eye drop formulation has been prepared with the ability to deliver sufficient drug to the relevant ocular surface tissues.

Hydroxypropyl methylcellulose: Physicochemical properties and ocular drug delivery formulations

Hydroxypropyl methylcellulose (HPMC) is a cellulose ether widely used in drug formulations due to its biocompatibility, uncharged nature, solubility in water and thermoplastic behavior. Particularly for ocular and ophthalmic formulations, HPMC is applied as viscosity enhancer agent in eye drops, gelling agent in injections, and polymeric matrix in films, filaments and inserts. The different therapeutic approaches are necessary due to the complex anatomic structure of the eye. The natural ocular barriers and the low drug permeation into the circulatory system make the drug administration challenging. This review presents the eye anatomy and the usual local routes of drugs administration, which are facilitated by the physicochemical properties of HPMC. The relationship between chemical structure and physicochemical properties of HPMC is displayed. The different types of formulations (local application) including HPMC for ocular drug delivery are discussed with basis on recent literature reports and patents.

Review on Conventional and Novel Topical Ocular Drug Delivery System

Ocular drug delivery is a very challenging area for ophthalmologists and drug delivery scientists due to the structural and barrier complexity of the eye. Barriers such as different layers of cornea, sclera, conjunctival blood flow, and tear dilution limit the efficacy of drug delivery to the anterior part of the eye in addition to more barriers present to the posterior part. Due to these, scientists have designed and studied various delivery systems to increase drug delivery and treatment efficacy to the eye. Among conventional ocular drug delivery systems, ophthalmic solution or eye drop is widely used and preferred by consumers. Conventional dosage forms available in the market are emulsion, suspension, ointment and polymeric gels. Several ocular formulations such as nano-formulations, liposomes, ocular inserts, and ocular mini-tablets are also being widely studied as future treatments to improve ocular drug delivery and as an alternative to conventional drug delivery. This review intends to summarise several conventional and novel topical formulations for ocular drug delivery.

Preparation and in vitro/in vivo evaluations of novel ocular micelle formulations of hesperetin with glycyrrhizin as a nanocarrier

The purpose of this study was to explore the potential of formulating hesperetin into an ophthalmic solution with dipotassium glycyrrhizinate (DG) as a micelle nanocarrier. A DG-based micelle ophthalmic solution encapsulating hesperetin (DG-Hes) was developed and its in vitro/in vivo characterizations were evaluated. The optimal formulation featured a DG/hesperetin (Hes) weight ratio of 12:1 and an encapsulation efficiency of 90.4 ± 1.7%; The optimized DG-Hes was characterized as small uniform spheres with an average micelle size of 70.93 ± 3.41 nm, a polydispersity index of 0.11 ± 0.02, and an electrically negative surface (−36.12 ± 2.79 mV). The DG-Hes ophthalmic solution had good tolerance in rabbit eyes. DG-Hes significantly improved the in vitro passive permeation, ex vivo corneal permeation, and in vivo ocular bioavailability of Hes. DG-Hes showed markedly increases in in vitro antioxidant activity. In vitro antibacterial activity tests revealed a lower minimum inhibitory concentration and lower minimum bactericidal concentration for DG-Hes ophthalmic solution were lower than for free Hes. DG-Hes ophthalmic solution also significantly reduced symptoms of eye infection in the rabbit bacterial keratitis model when compared to a Hes suspension. These results suggest that DG-Hes eye drops may be useful as a new ophthalmic preparation for the treatment of ocular diseases, especially bacterial ophthalmopathy.

Promising bioadhesive ofloxacin-loaded polymeric nanoparticles for the treatment of ocular inflammation: formulation and in vivo evaluation.

Our work tackles the combined advantages of both nanotechnology and the bioadhesive gel properties which were utilized to design an ocular drug delivery system that is capable to treat ocular inflammation. Nanoparticles encapsulating an antibiotic drug, ofloxacin, were fabricated using emulsion solvent evaporation technique adopting 23 full factorial design to evaluate the effect of formulation parameters: that is to say, the molecular weight of the polymer (polycaprolactone), amount of Kolliphor P188, and presence of the charge inducer (chitosan hydrochloride) on the measured responses: drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The results show that the optimized LPCL-NP2 formulation (composed of low molecular weight polycaprolactone, 500mg of Kolliphor P188, 0.25% chitosan hydrochloride, and 50mg ofloxacin) displayed a sphere shape with EE%, PS, PDI, and ZP values of 89.73 ± 0.04%, 195.4 ± 13.17nm, 0.323 ± 0.01, and 55.4 ± 0.66mV, respectively. DSC study confirmed the amorphous nature of the drug. The optimized nanoparticle formulation was then further incorporated into the following two ocular formulations: gel (LPCL-NP2-G4) and in situ forming gel (LPCL-NP2-ISG4). The penetration of optimized ocular formulations was assessed by confocal laser scanning microscopy. The antimicrobial study was conducted for the following three ocular formulations: LPCL-NP2 presented as eye drops, LPCL-NP2-G4, and LPCL-NP2-ISG4 as well as the market product using rabbits which were infected in their eyeswith Escherichia coli. Results revealed that rabbits treated with LPCL-NP2-ISG4 demonstrated a remarkable antibacterial efficacy and evident low bacterial growth which was additionally assuredby the histopathological examination of eye biopsies compared with the other investigated groups. Thus, a novel ofloxacin-loaded nanoparticle formulation based on polycaprolactone is presented in the form of mucoadhesive non-irritatingin situ forming ocular gel possessing a superior antibacterial activity. Graphical abstract.

Ex-Vivo Trans-Corneal and Trans-Scleral Diffusion Studies with Ocular Formulations of Glutathione as an Antioxidant Treatment for Ocular Diseases.

Exposure to sunlight and contact with atmospheric oxygen makes the eye particularly susceptible to oxidative stress, which can potentially produce cellular damage. In physiological conditions, there are several antioxidant defense mechanisms within the eye. Glutathione (GSH) is the most important antioxidant in the eye; GSH deficit has been linked to several ocular pathologies. The aim of this study was to explore the potential for newly developed formulations allowing controlled delivery of antioxidants such as GSH and vitamin C (Vit C) directly to the eye. We have investigated the stability of antioxidants in aqueous solution and assessed ex-vivo the diffusion of GSH through two ocular membranes, namely cornea and sclera, either in solution or included in a semisolid insert. We have also carried out the hen’s egg-chlorioallantoic membrane test (HET-CAM) to evaluate the ocular irritancy of the different antioxidant solutions. Our results showed that GSH is stable for up to 30 days at 4 °C in darkness and it is not an irritant to the eye. The diffusion studies revealed that the manufactured formulation, a semisolid insert containing GSH, could deliver this tripeptide directly to the eye in a sustained manner.

Rebaudioside A/TPGS mixed nanomicelles as promising nanocarriers for nimodipine ocular delivery.

Nimodipine (NMD), a calcium channel blocker, has demonstrated benefits in treating glaucoma. However, its ocular therapeutic application remains limited due to its poor aqueous solubility, which restrains the development of an ophthalmic formulation. Thus, the present study aimed to formulate an NMD micelle ophthalmic solution to enhance the potential of NMD in an ocular topical formulation to treat glaucoma. The NMD micelle ophthalmic solution was formulated with nanocarriers composed of rebaudioside A and D-α-tocopheryl polyethylene glycol 1000 succinate. Spherical mixed micelles were optimized and obtained at a small micelle size 13.429 ± 0.181nm with a narrow size distribution (polydispersity index 0.166 ± 0.023) and high encapsulation efficiency rate (99.59 ± 0.09%). Compared with free NMD, NMD in micelles had much greater in vitro membrane permeability and antioxidant activity. The NMD micelle ophthalmic solution was well tolerated in rabbit eyes. It profoundly improved the in vivo intraocular permeation of NMD, and in vivo intraocular pressure reduction and improved miosis were also observed. Accordingly, this NMD micelle ophthalmic solution might be a promising ocular formulation to treat glaucoma. Graphical abstract.

Studying Angiogenesis in the Rabbit Corneal Pocket Assay.

The rabbit corneal micropocket assay uses the avascular cornea as a substrate to study angiogenesis in vivo. The continuous monitoring of neovascular growth in the same animal allows for the evaluation of drugs acting as suppressors or stimulators of angiogenesis. Through the use of standardized slow-release pellets, a predictable angiogenic response can be quantified over the course of 1-2weeks. Uniform slow-release pellets are prepared by mixing purified angiogenic growth factors such as basic fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) and a synthetic polymer to allow for their slow release. A micropocket is surgically created in the cornea thickness under anesthesia and in sterile conditions. The angiogenesis stimulus (growth factor but also tissue fragment or cell suspension) is placed into the pocket in order to induce vascular outgrowth from the limbal capillaries where vessels are preexisting. On the following days, the neovascular development and progression are measured and qualified using a slit lamp, as well as the concomitant vascular phenotype or inflammatory features. The results of the assay allow to assess the ability of potential therapeutic molecules to modulate angiogenesis in vivo, both when released locally or given by ocular formulations or through systemic treatment. In this chapter the experimental details of the avascular rabbit cornea assay, the technical challenges, advantages, and limitations are discussed.

Chitosan and its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments.

Chitosan (CS) is a hemi-synthetic cationic linear polysaccharide produced by the deacetylation of chitin. CS is non-toxic, highly biocompatible, and biodegradable, and it has a low immunogenicity. Additionally, CS has inherent antibacterial properties and a mucoadhesive character and can disrupt epithelial tight junctions, thus acting as a permeability enhancer. As such, CS and its derivatives are well-suited for the challenging field of ocular drug delivery. In the present review article, we will discuss the properties of CS that contribute to its successful application in ocular delivery before reviewing the latest advances in the use of CS for the development of novel ophthalmic delivery systems. Colloidal nanocarriers (nanoparticles, micelles, liposomes) will be presented, followed by CS gels and lenses and ocular inserts. Finally, instances of CS coatings, aiming at conferring mucoadhesiveness to other matrixes, will be presented.