Topical Ocular Delivery Research Articles

Development of gentamicin bilosomes laden in-situ gel for topical ocular delivery: optimization, in-vitro characterization, toxicity, and anti-microbial evaluation

Purpose: The eye drops are the prominent preparation used to treat surface eye disease (bacterial conjunctivitis). However, they have some limitations i.e., short corneal residence, resulting in low ocular bioavailability and necessitating frequent dose administration. The present study developed gentamicin (GE) bilosomes (BM)- laden in-situ gel to improve therapeutic activity. The in-situ gel system is initially in sol form before administration and converted into gel form in physiological eye conditions. Method: The GE-BM was developed using the thin film hydration technique and optimized by D-optimal design. GE-BM was characterized for vesicle size, entrapment efficiency, zeta potential, morphology, and FTIR. The optimized GE-BM (GE-BMopt) was incorporated into an in-situ gel and assessed for physicochemical characteristics. GE-BMopt in-situ gel was evaluated for in-vitro release, ex-vivo permeation, toxicity, and antimicrobial study. Result: GE-BMopt has a vesicle size of 185.1±4.8nm, PDI of 0.254, zeta potential of 27.6 mV, entrapment efficiency of 81.86±1.29 %, and spherical morphology. The FTIR study presented no chemical interactions between GE and excipients. GE-BMopt in-situ gel (GE-BMoptIG4) showed excellent viscosity, gelling strength, and ex-vivo bio-adhesion. GE-BMopt-IG4 showed significant high and sustained release of GE (78.08± 4.73% in 12h). GE-BMopt-IG4 displayed 3.27-fold higher ex-vivo goat corneal permeation than a pure GE solution. GE-BMopt-IG4 showed good corneal tolerance without any damage or irritation. GE-BMopt-IG4 showed significantly (P<0.05) higher anti-bacterial activity (ZOI) against Staphylococcus aureus and Escherichia coli than pure GE solution. Conclusion: The study determined that the BM in-situ gel system can serve as a substitute carrier for GE to enhance its therapeutic effectiveness, and further preclinical studies are required.

Application of sphingolipid-based nanocarriers in drug delivery: an overview.

Sphingolipids (SL) are well recognized for their cell signaling through extracellular and intracellular pathways. Based on chemistry different types of SL are biosynthesized in mammalian cells and have specific function incellular activity. SL has an ampiphilic structure with have hydrophobic body attached to the polar head enables their use as a drug delivery agent in the form of nanocarriers. SL-based liposomes can improve the solubility of lipophilic drugs through host and drug complexes and are more stable than conventional liposomal formulations. Preclinical studies of SL nanocarriers are reported on topical delivery, oral delivery, ocular delivery, chemotherapeutic delivery, cardiovascular delivery and Alzheimer's disease. The commercial challenges and patents related to SL nanoformulations are highlighted in this article.

Design of liposomal nanocarriers with a potential for combined dexamethasone and bevacizumab delivery to the eye

Clinicians face numerous challenges when delivering medications to the eyes topically because of physiological barriers, that can inhibit the complete dose from getting to the intended location. Due to their small size, the ability to deliver drugs of different polarities simultaneously, and their biocompatibility, liposomes hold great promise for ocular drug delivery. This study aimed to develop and characterise a dual loaded liposome formulation encapsulating Bevacizumab (BEV) and Dexamethasone (DEX) that possessed the physicochemical attributes suitable for topical ocular delivery. Liposomes were prepared by using thin film hydration followed by extrusion, and the formulations were optimised using a design of experiments approach. Physicochemical characterisation along with cytocompatibility and bioactivity of the formulations were assessed. Liposomes were successfully prepared with a particle size of 139 ± 2 nm, PDI 0.03 ± 0.01 and zeta potential −2 ± 0.7 mV for the optimised formulation. BEV and DEX were successfully encapsulated into the liposomes with an encapsulation efficiency of 97 ± 0.5 % and 26 ± 0.5 %, respectively. A sustained release of BEV was observed from the liposomes and the bioactivity of the formulation was confirmed using a wound healing assay. In summary, a potential topical eye drop drug delivery system, which can co-load DEX and BEV was developed and characterised for its potential to be used in ocular drug delivery.

Chitosan-based Nanomedicine in the Management of Age-related Macular Degeneration: A Review

Abstract: Age-related macular degeneration (AMD) is a leading cause of permanent blindness globally. Due to the various obstacles, highly invasive intravitreal (IVT) injections are the prima-ry method used to deliver medications to the tissues of the posterior eye. An utmost patient-friendly topical ocular delivery approach has been extensively researched in recent years. Muco-adhesive compositions extend precorneal residence time while reducing precorneal clearance. They increase the likelihood of adhesion to corneal and conjunctival surfaces and, as a result, al-low for enhanced delivery to the posterior eye segment. Due to its remarkable mucoadhesive characteristics, chitosan (CS) has undergone the most extensive research of any mucoadhesive polymer. Drug delivery to the front and back of the eye is still difficult. The pharmaceutical in-dustry has shown greater interest in drug delivery systems (DDSs) based on nanotechnology (NT) in recent years, particularly those made from natural polymers like chitosan, alginate, etc. Be-cause of their incredible adaptability, higher biological effects, and favourable physicochemical properties, CS-oriented nanomaterials (NMs) are explored by researchers as prospective nanocar-riers. CS are the right substrates to develop pharmaceutical products, such as hydrogels, nanopar-ticles (NP), microparticles, and nanofibers, whether used alone or in composite form. CS-based nanocarriers deliver medicine, such as peptides, growth factors, vaccines, and genetic materials in regulated and targeted form. This review highlights current developments and challenges in chi-tosan-mediated nano therapies associated with AMD.

Protein Nanoparticles Laden In situ Gel for Topical Ocular Drug Delivery.

Topical ocular delivery of drugs is most commonly preferred route by the patient and physician for the treatment of ocular diseases. The topical route is always followed with the disadvantages like tear turnover, nasolacrimal drainage, reduction in precorneal residence time, etc</i>. To overcome these hindrances associated with topical ocular route, a novel drug delivery system is used for targeting the drug at a specific site. In the Novel Drug delivery System, protein-based nanoparticles are an attractive class of nanoparticles designed to deliver the drug at targeted site in slow and sustained release manner. They have a size in the range of 1-100 nm. Protein nanoparticles are leading, particularly for the topical ocular delivery like reduction in intra ocular pressure, providing sustained release and targeted drug delivery at the site of its action. Various methods are used for formulation of protein nanoparticles like desolvation, emulsification, complex coacervation, electrospray techniques. The characterization parameters include particle size, surface morphology, drug loading and entrapment efficiency. Protein nanoparticles can also be loaded in to the in situ</i> gel forming polymers for increasing precorneal residence time of nanoparticles. The characterization parameters of in situ</i> gelling systems are gelling time, rheological properties, gel strength. The review mainly describes the use of various proteins in preparation of protein nanoparticles, methods for preparation of protein nanoparticles, polymers used in in situ</i> gelling system and evaluation as well as characterization parameters of protein nanoparticles, in situ</i> gelling systems & patented information related to protein nanoparticles and in situ</i> gelling system for ocular drug delivery.

Carboxymethylcellulose/layered double hydroxide dispersions for topical ocular delivery of non-steroidal anti-inflammatory drugs

Drug delivery to ocular tissues is hindered by anatomical and physiological barriers that diminish their bioavailability. LDH/CMC dispersions are promising due to their sustained drug release and mucoadhesive ability.

Design, optimization and pharmacokinetic evaluation of PLGA phosphatidylcholine hybrid nanoparticles of triamcinolone acetonide loaded in situ gel for topical ocular delivery

Posterior uveitis (PU), which often has an autoimmune origin, can be treated effectively with synthetic glucocorticoid triamcinolone acetonide (TAA). Due to the limitations of topical TAA administration reaching the posterior segment of the eye, the drug is injected directly into the eye through an intravitreal injection. In this study, we prepared TAA loaded poly(lactic-co-glycolic acid) phosphatidylcholine hybrid nanoparticles (TAA-PLHNPs) using the principles of design of experiments (DoE) for topical ocular administration. The mean particle size (nm) and drug loading efficiency (LE%) for the optimized formulations were 163 ± 2.8 nm and 39 ± 1.9%, respectively. The TAA-PLHNPs were then loaded into the dual responsive in situ gel that we reported in our previous work. In vitro assessments were done to show that the formulations are safe for ocular administration. Finally, in vivo ocular pharmacokinetic studies were performed to compare pharmacokinetic parameters of TAA-PLHNPs and TAA-PLHNPs loaded in situ gel with each other and with the previously reported conventional formulation of TAA (aqueous suspension of TAA with 20% hydroxypropyl β-cyclodextrin (TAA-HP-β-CD-Susp)). TAA-PLHNPs loaded dual responsive in situ gel (TAA-PLHNP-ISG) achieved higher concentrations of TAA in the vitreous humor (Cmax of 946.53 ng/mL) and sustained (MRT0–∞ of 16.26 h) the drug concentrations for longer period of time compared to aqueous suspension of TAA-PLHNPs (TAA-PLHNP-Susp) and TAA-HP-β-CD-Susp.

Discovery and Potential Utility of a Novel Non-Invasive Ocular Delivery Platform.

To this day, the use of oily eye drops and non-invasive retinal delivery remain a major challenge. Oily eye drops usually cause ocular irritation and interfere with the normal functioning of the eye, while ocular injections for retinal drug delivery cause significant adverse effects and a high burden on the healthcare system. Here, the authors report a novel topical non-invasive ocular delivery platform (NIODP) through the periorbital skin for high-efficiency anterior and posterior ocular delivery in a non-human primate model (NHP). A single dose of about 7 mg JV-MD2 (omega 3 DHA) was delivered via the NIODP and reached the retina at a Cmax of 111 µg/g and the cornea at a Cmax of 66 µg/g. The NIODP also delivered JV-DE1, an anti-inflammatory agent in development for dry eye diseases, as efficiently as eye drops did to the anterior segments of the NHP. The topical NIODP seems to transport drug candidates through the corneal pathway to the anterior and via the conjunctiva/sclera pathway to the posterior segments of the eye. The novel NIODP method has the potential to reshape the landscape of ocular drug delivery. This is especially the case for oily eye drops and retinal delivery, where the success of the treatment lies in the ocular tolerability and bioavailability of drugs in the target tissue.

Design, optimization, in vitro and in vivo evaluation of triamcinolone acetonide nanocrystals loaded in situ gel for topical ocular delivery

Triamcinolone acetonide (TAA), a long-acting synthetic glucocorticoid, is commonly used for the management of posterior uveitis (PU) because of its anti-inflammatory and immunosuppressive characteristics. The commercially available formulation is in the suspension form advised for intravitreal injection, which has a number of serious problems. In the present research work, we prepared TAA nanocrystals (TAA-NCs) using the principles of design of experiments (DoE). The optimized TAA-NCs had a particle size of 243.0 ± 6.5 nm and a yield (%) of 89.4 ± 4.3%. The optimized TAA-NCs were suspended in a dual-responsive in situ gelling system, which has been previously reported by our team. The TAA-NCs loaded in situ gel (TAA-NC-ISG) formulations were evaluated for rheology, stability, in vitro and in vivo characteristics. The ocular pharmacokinetic investigations revealed that TAA-NCs loaded in situ gel achieved higher concentrations (Cmax of TAA-NC-ISG = 854.9 ng/mL) of the drug in vitreous humor and sustained (MRT0–∞ of TAA-NC-ISG = 11.2 h) the drug concentrations for longer duration compared to aqueous suspension of TAA-NCs (TAA-NC-Susp) and aqueous suspension of TAA with 20% hydroxypropyl β-cyclodextrin(TAA-HP-β-CD-Susp) reported in our previous work. This higher exposure of TAA by TAA-NC-ISG is due to the combined effect of the nanometric size of the TAA nanocrystals and the in situ gelling properties of the formulation.

Topical ocular protein delivery based on protein powder suspensions in semifluorinated alkanes

The field of ocular diseases, specifically retinal diseases is a successful target area for protein drugs with various marketed products. Besides the intraocular treatment of the retina, the topical treatment of corneal or conjunctival diseases is a promising approach. Topical ocular protein formulations face the challenges of poor penetration and potentially low stability. In this study we tested suspensions based on the semifluorinated alkane F6H8 to improve the topical ocular protein delivery. Such suspensions are well known for the increased protein stability compared to aqueous solutions. Furthermore, F6H8 is well known as vehicle for ocular delivery due to its easy spreading on the cornea.Penetration of a model mAb and its Fab fragment was tested in an ex vivo corneal penetration test. The amount of penetrated protein was increased when the protein powder suspensions were used compared to the respective aqueous solutions. Sodium caprate as penetration enhancer at 5 mg/ml substantially increased the Fab fragment (7-fold) and the mAB (3-fold) concentration in the corneal tissue when applied as an aqueous solution. The effect was surprisingly more pronounced, when Fab fragment (31-fold) or mAb (13-fold) and the penetration enhancer were formulated as F6H8 suspensions. The same penetration enhancement from suspensions could be achieved with 2.5 mg/ml, but the penetration was reduced compared to 2.5 mg/ml in the aqueous solution. A test based on stratified human keratinocytes did not indicate eye irritation by the tested formulations.Furthermore, stability studies for bevacizumab suspensions in semifluorinated alkanes were investigated and showed superior long-term stability compared to the marketed aqueous solution. Overall results demonstrate the high potential of topical ocular protein delivery using powder suspensions in non-aqueous vehicles based on semifluorinated alkanes.

Development of Forskolin and rutin-loaded polymeric nanoparticles for enhancement of topical ocular delivery: Optimization, in-vitro, ex-vivo, and toxicity evaluation

Development of Forskolin and rutin-loaded polymeric nanoparticles for enhancement of topical ocular delivery: Optimization, in-vitro, ex-vivo, and toxicity evaluation

Topical ocular delivery of nanoparticles with epoetin beta in Wistar Hannover rats

Topical instillation of drugs targeting the posterior ocular segment is an expanding area of research. Chitosan and hyaluronic acid have remarkable mucoadhesive properties and potentially enhance pre-corneal retention time after topical instillation. Bearing this in mind, we explored the possibility of delivering epoetin beta (EPOβ) to the posterior segment of the eye in a chitosan-hyaluronic acid (CS/HA-EPOβ) nanoparticulate system using the topical route of administration. Complete ophthalmological examinations, electroretinography and microhematocrit evaluations were performed in Wistar Hannover (WH) rats, before and after topical administration of nanoparticles. The right eye received CS/HA-EPOβ and the left eye received only empty nanocarriers (control). Animals were split into 6 groups and at designated timepoints, all animals from each group (n = 3) were euthanized and both eyes enucleated. Retinal morphology and EPOβ ocular distribution were assessed, respectively, through hematoxylin and eosin (HE) and immunofluorescence staining. After topical administration, no adverse ocular signs were noted and no significant changes either in microhematocrits nor in electroretinographies were detected. During the study, intraocular pressure (IOP) was always kept within physiological range bilaterally. No histological changes were detected in any of the ocular globes. Immunofluorescence enabled the identification of EPOβ in the retina 12 h after the administration, its presence still being detectable at day 21. In conclusion, CS/HA nanoparticles could efficiently deliver EPOβ to the retina of WH rats after topical instillation, being considered biologically safe. Topical administration of this nanoformulation could be a valuable tool for retinal neuroprotection, decreasing risks associated with more invasive routes of administration, being cost effective and also increasing long-term patients’ compliance.

Optimization of hyaluronan-enriched cubosomes for bromfenac delivery enhancing corneal permeation: characterization, ex vivo, and in vivo evaluation

To design and evaluate hyaluronan-based cubosomes loaded with bromfenac sodium (BS) for ocular application to enhance the corneal permeation and retention in pterygium and cataract treatment. BS-loaded cubosomes were prepared by the emulsification method, employing 23 full factorial design using Design-Expert® software. Glycerol monoolein (GMO) and poloxamer 407 (P407) as lipid phase and polyvinyl alcohol (PVA) as stabilizer were the used ingredients. The optimized formulation (OBC; containing GMO (7% w/w), P407 (0.7% w/w) and PVA (2.5% w/w)) was further evaluated. OBC had an entrapment efficiency of 61.66 ± 1.01%, a zeta potential of −30.80 ± 0.61 mV, a mean particle size of 149.30 ± 15.24 nm and a polydispersity index of 0.21 ± 0.02. Transmission electron microscopy confirmed its cubic shape and excellent dispersibility. OBC exhibited high stability and no ocular irritation that was ensured by histopathology. Ex vivo permeation study showed a significant increase in drug deposition and permeability parameters through goat cornea, besides, confocal laser microscopy established the superior permeation capability of OBC, as compared to drug solution. In vivo pharmacokinetics in aqueous humor indicated higher AUC0-tlast (18.88 µg.h/mL) and mean residence time (3.16 h) of OBC when compared to the marketed eye drops (7.93 µg.h/mL and 1.97 h, respectively). Accordingly, hyaluronan-enriched cubosomes can be regarded as a promising carrier for safe and effective topical ocular delivery.

Biocompatible phospholipid-based mixed micelles for posaconazole ocular delivery: Development, characterization, and in - vitro antifungal activity.

Current study intended to prepare and evaluate phospholipid-based, mixed micelles (MMs) to improve the ocular delivery of posaconazole (POS), a broad-spectrum antifungal drug. For this, MMs based on egg phosphatidylcholine (EPC), as the main component, in combination with various bile salts (sodium cholate (NaC), sodium deoxycholate (NaDC), sodium taurocholate (NaTC)) or non-ionic surfactants (Pluronic® F-127, Pluronic® F-68, Tween 80, Labrasol® ALF, and d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)) were prepared. Particle size, polydispersity index, zeta potential and entrapment efficiency were evaluated to optimize the composition and preparation method of the MMs. Finally, morphology, stability, in vitro release pattern, and in vitro antifungal activity of the optimized formulation were investigated. Among the prepared MMs, vesicles composed of EPC: TPGS with a molar ratio of 70:30, prepared by the thin-film hydration method, showed more appropriate features. Among the prepared MMs, vesicles composed of EPC: TPGS with a molar ratio of 70:30 showed more appropriate features, including an entrapment efficiency (EE) greater than 80%, spherical shape morphology, an average particle size of about 58nm, desirable stability over a month, slow-release without a noticeable initial burst, and a significantly higher in vitro antifungal activity in comparison with the drug suspension. Therefore, this formulation was selected as the optimal MMs and could be considered as a promising carrier for topical ocular delivery of POS.

PREPARATION AND EVALUATION OF TMC LOADED VORICONAZOLE NANOPARTICLES

Objective: Ocular diseases affect a growing number of people across the globe. Hence, the present research work focused to prepare and evaluate voriconazole (VCZ) nanoparticles containing trimethyl chitosan (TMC) for ophthalmic drug delivery with primary goal is to develop topical ocular delivery systems with improved ocular bioavailability and reduced systemic side effects while maintaining the dosage form’s simplicity and convenience. Methods: In the present study, the nanoparticles are prepared using ionotropic gelation method. The physiochemical interactions between drugs and selected excipients were studied using various techniques such as FTIR, DSC, XRD, and H-NMR. The physiochemical properties of the nanoparticles such as size, PDI, pH, and drug content/entrapment efficiency were determined. The in-vitro drug release properties were characteristics and examined for the formulations. The synthesize form of chitosan, that is, tri-methyl chitosan is used due to solubility issue. Result: The comparative study was done using TMC and cyclodextrin as a polymer out of which TMC polymer gives better results. The optimization is done using 32 factorial design using design expert software. The optimized batch follows the zero order release kinetics. Conclusion: TMC loaded VCZ nanoparticles show better result with improved solubility and permeability.

Linoleic Acid-Based Transferosomes for Topical Ocular Delivery of Cyclosporine A.

Delivering high-molecular-weight hydrophobic peptides, such as cyclosporine A, across the corneal epithelium remains a challenge that is complicated by other physio-anatomical ocular structures that limit the ocular bioavailability of such peptides. Transferosomes have previously been used to improve transdermal permeability, and have the potential for improving the ocular corneal permeability of applicable drugs. In this study, transferosomes for the potential ocular delivery of cyclosporine A were investigated. Linoleic acid was evaluated for its effect on the stability of the transferosomes and was substituted for a portion of the cholesterol in the vesicles. Additionally, Span® 80 and Tween® 80 were evaluated for their effect on transferosome flexibility and toxicity to ocular cells as edge activators. Attenuated Total Reflectance–Fourier Transform Infrared spectroscopy (ATF-FTIR), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) were used to evaluate the physicochemical parameters of the blank and the cyclosporine A-loaded transferosomes. Cyclosporine A release and corneal permeability were studied in vitro and in a New Zealand albino rabbit corneal model, respectively. The linoleic acid contributed to improved stability and the nano-size of the transferosomes. The Tween®-based formulation was preferred on the basis of a more favorable toxicity profile, as the difference in their corneal permeability was not significant. There was an initial burst release of cyclosporine A in the first 24 h that plateaued over one week. The Tween®-based formulation had a flux of 0.78 µg/cm2/h. The prepared transferosomes demonstrated biocompatibility in the ocular cell line, adequately encapsulated cyclosporine A, ensured the corneal permeability of the enclosed drug, and were stable over the period of investigation of 4 months at −20 °C.

Eudragit® L100/Polyvinyl Alcohol Nanoparticles Impregnated Mucoadhesive Films as Ocular Inserts for Controlled Delivery of Erythromycin: Development, Characterization and In Vivo Evaluation.

The fast elimination of drugs from the cornea is one of many challenges associated with the topical administration of conventional dosage forms. The present manuscript aimed to prepare modified-release inserts containing erythromycin (ERY) to enhance drug delivery and address the aforementioned limitation. Film formulations were developed using Eudragit® L100 (EUD) and Polyvinyl Alcohol (PVA) polymers. ERY-loaded EUD-based nanoparticles were developed by the colloidal dispersion method using PVA as the emulsifier. The film-casting method was applied to form the mucoadhesive films using sodium alginate, gelatin, cyclodextrin-α, and β as polymeric film matrices. Different physicochemical properties of the optimized formulations and in vitro release profiles were evaluated. The in vivo evaluation was performed by collecting tear samples of rabbits using a novel, non-invasive method following the administration of inserts in the cul-de-sac. The ERY amount was assayed using a microbiological assay. The developed films showed prolonged in vitro and in vivo release profiles over five to six days; they had suitable physicochemical properties and a tensile strength of 2–3 MPa. All formulations exhibited antibacterial efficacy against E. coli and S. aureus with more than 20 mm diameter of inhibited growth zones. None of the formulations caused irritation to the rabbit’s eye. The inserts showed promising pharmacokinetics with AUC0–120 of 30,000–36,000 µg·h/mL, a Cmax of more than 1800 µg/mL at 4 h, and maintained drug concentration over the threshold of 5 µg/mL during the following 120 h of study. Nanoparticle-containing, mucoadhesive films could be fabricated as ocular inserts and can prolong the topical ocular delivery of ERY.

In situ gelling microemulsion for topical ocular delivery of moxifloxacin and betamethasone

This article proposes an in situ gelling microemulsion for the ocular delivery of moxifloxacin (MOX) combined with betamethasone (BET) for use as a topical formulation throughout the postoperative period following eye surgery. Thermal analyses indicated compatibility between the drugs and the selected excipients. The microemulsion presented parameters that guarantee ocular tolerability: a droplet size of 28.0 ± 0.1 nm (polydispersity index = 0.11 ± 0.01), a zeta potential of −10.3 ± 0.1 mV, a pH of 7.1 ± 0.1, and osmolarity of 579.0 ± 9.4 mOsmol kg−1. The formulation had an ideal gelling temperature for the ocular surface (32.8 ± 0.9 °C), which allowed precise dosing due to its liquid state at storage temperatures. When the drugs’ release was assessed in vitro, the microemulsion was shown to prolong both drugs’ release compared with controls. Last, ex vivo drug penetration tests were performed in porcine corneas under static conditions (i.e., left in contact with the corneal surface) or with a simulated tear flow. In static conditions, the microemulsion increased MOX’s penetration into the cornea but decreased BET’s compared with the control. However, when the formulation was subjected to a simulated tear flow throughout its corneal application, the microemulsion made MOX’s penetration statistically similar to that in static conditions, which was 2–3 times (p less than 0.05) greater than that provided by the control, while maintaining the same BET penetration level as the control. Altogether, the proposed in situ gelling microemulsion seems to be a convenient, effective alternative for use following intraocular surgery.

The topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal inflammatory disease

Treatment of posterior eye diseases with intravitreal injections of drugs, while effective, is invasive and associated with side effects such as retinal detachment and endophthalmitis. In this work, we have formulated a model compound, rapamycin (RAP), in nanoparticle-based eye drops and evaluated the delivery of RAP to the posterior eye tissues in a healthy rabbit. We have also studied the formulation in experimental autoimmune uveitis (EAU) mouse model with retinal inflammation. Aqueous RAP eye drops were prepared using N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (Molecular Envelope Technology – MET) containing 0.23 ± 0.001% w/v RAP with viscosity, osmolarity, and pH within the ocular comfort range, and the formulation (MET-RAP) was stable in terms of drug content at both refrigeration and room temperature for one month. The MET-RAP eye drops delivered RAP to the choroid-retina with a Cmax of 145 ± 49 ng/g (tmax = 1 h). The topical application of the MET-RAP eye drops to the EAU mouse model resulted in significant disease suppression compared to controls, with activity similar to dexamethasone eye drops. The MET-RAP eye drops also resulted in a reduction of RORγt and an increase in both Foxp3 expression and IL-10 secretion, indicating a mechanism involving the inhibition of Th17 cells and the up-regulation of T-reg cells. The MET-RAP formulation delivers RAP to the posterior eye segments, and the formulation is active in EAU.

Chitosan-coated bovine serum albumin nanoparticles for topical tetrandrine delivery in glaucoma: in vitro and in vivo assessment

Glaucoma is one of the leading causes of blindness. Therapies available suffer from several drawbacks including low bioavailability, repeated administration and poor patient compliance with adverse effects thereafter. In this study, bovine serum albumin nanoparticles (BSA-NPs) coated with chitosan(CS) were developed for the topical delivery of tetrandrine (TET) for glaucoma management. Optimized nanoparticles were prepared by desolvation. pH, BSA, CS and cross-linking agent concentrations effects on BSA-NPs colloidal properties were investigated. CS-BSA-NPs with particle size 237.9 nm and zeta potential 24 mV was selected for further evaluation. EE% exceeded 95% with sustained release profile. In vitro mucoadhesion was evaluated based on changes in viscosity and zeta potential upon incubation with mucin. Ex vivo transcorneal permeation was significantly enhanced for CS coated formulation. In vitro cell culture studies on corneal stromal fibroblasts revealed NPs biocompatibility with enhanced cellular uptake and improved antioxidant and anti-proliferative properties for the CS-coated formulation. Moreover, BSA-NPs were nonirritant as shown by HET-CAM test. Also, bioavailability in rabbit aqueous humor showed 2-fold increase for CS-TET-BSA-NPs compared to TET with a sustained reduction in intraocular pressure in a rabbit glaucoma model. Overall, results suggest CS-BSA-NPs as a promising platform for topical ocular TET delivery in the management of glaucoma.