ABSTRACT
The permeation and pharmacodynamics of ocular drugs are influenced by the corneal barrier. Here, a hard-soluble drug, brinzolamide, was selected as the model drug and used for preparation of minimally invasive dissolving microneedles. Brinzolamide was dissolved in ethanol and polyvinylpyrrolidone (PVP) K90 was added and dissolved. The mixture solution was casted into the dissolving microneedles mold and dried and brinzolamide dissolving microneedles (BMN) were obtained after demolding. The stereoscopic and scanning electron microscopic images showed that BMN were conical needles with the height of 750 μm, the bottom diameter of 300 μm, and the inter-tip distance of 500 μm. The dissolving microneedles patch was composed of 10×10 arrays with the area of 1 cm2 and the high drug load of 7.3 mg·cm-2. BMN showed a rapid in vitro drug release with 93% accumulative release at 2 h and the high drug corneal permeation amount of 877 ± 105 μg. BMN exhibited the high mechanical strength of 0.32 N/needle, leading to easy rat corneal insertion with the depth of 200 μm. Moreover, BMN were rapidly dissolved in the cornea, and more importantly, the damaged cornea were quickly self-healed within 24 h. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical and the experiments were conducted in accordance with relevant guidelines and regulations. Ocular minimally invasive dissolving microneedles have the advantages of corneal minimal wounds and rapid healing, high drug loading, and high permeability, favoring the treatment of ocular diseases.
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Ocular toxoplasmosis is caused by Toxoplasma gondii, inducing retinochoroiditis. It is the leading cause of infectiousposterior uveitis worldwide. Its treatment is based on oral drug administration. However, the blood–ocular barriersystems make the penetration of therapeutic drug concentrations within the eye difficult, limiting the effectiveness oftreatments. In this context, ocular drug delivery systems represent therapeutic alternative for the treatment of oculartoxoplasmosis. In this study, a review of clinical manifestations, diagnosis, treatment, and perspectives regardingthe treatment of ocular toxoplasmosis was conducted. A search was carried out on ScienceDirect, Scopus, Webof Science, PubMed, and SciELO, and the following keywords were used: toxoplasmosis, ocular toxoplasmosis,toxoplasmic retinochoroiditis, and congenital toxoplasmosis; and Boolean operators, associated with other keywords,such as epidemiology, ocular toxoplasmosis diagnosis, ocular toxoplasmosis treatment, and ocular toxoplasmosisperspectives, were applied. In conclusion, ocular toxoplasmosis still lacks effective treatment. Therefore, it is essentialto develop new molecules and/or new drug delivery systems capable of releasing therapeutic doses of anti-Toxoplasmadrugs directly in the posterior segment of the eye, for an extended period, since complications resulting from thedisease may shorten the productive life of individuals and may even lead to blindness
ABSTRACT
Diabetes is a worldwide prevalent disease and diabetic retinopathy (DR) is one of the common complications, which is vision threatening and even leading to blindness.The current management of DR includes laser retina photocoagulation, vitrectomy, and frequent intravitreal anti-vascular endothelial growth factor (VEGF) agents.However, these measures do not target the root cause and their efficacy is limited.Fenofibrate is a blood lipid lowering therapeutics and its metabolite, fenofibric acid, is responsible for the pharmacology effect.Two large clinical trials (FIELD and ACCORD-Eye) have demonstrated oral fenofibrate retarded progression of DR and the needs for laser retinopexy.The animal and cell researches have revealed that fenofibric acid attenuated overexpression of basement membrane and VEGF, protected the tight junctions of endothelial cells and vascular permeability, as well as inhibited cells migration and neovascularization via suppression of inflammatory cytokines.These pharmacological effects might be materialized through several pathways, such as PPAR-α, MAPK and nuclear factor-κB (NF-кB). Blood-ocular barrier is a significant limiting factor for therapeutics reaching retina after systemic administration.Local ocular application of fenofibric acid may achieve better efficacy through improving therapeutic concentration in the eye.This drug may be delivered either by eye drop formulation or a sustained delivery device under conjunctiva or sub-Tenon.
ABSTRACT
Diabetes is a worldwide prevalent disease and diabetic retinopathy ( DR) is one of the common complications,which is vision threatening and even leading to blindness. The current management of DR includes laser retina photocoagulation,vitrectomy,and frequent intravitreal anti-vascular endothelial growth factor ( VEGF) agents. However,these measures do not target the root cause and their efficacy is limited. Fenofibrate is a blood lipid lowering therapeutics and its metabolite, fenofibric acid, is responsible for the pharmacology effect. Two large clinical trials ( FIELD and ACCORD-Eye) have demonstrated oral fenofibrate retarded progression of DR and the needs for laser retinopexy. The animal and cell researches have revealed that fenofibric acid attenuated overexpression of basement membrane and VEGF,protected the tight junctions of endothelial cells and vascular permeability,as well as inhibited cells migration and neovascularization via suppression of inflammatory cytokines. These pharmacological effects might be materialized through several pathways, such as PPAR-α, MAPK and nuclear factor-κB ( NF-кB ) . Blood-ocular barrier is a significant limiting factor for therapeutics reaching retina after systemic administration. Local ocular application of fenofibric acid may achieve better efficacy through improving therapeutic concentration in the eye. This drug may be delivered either by eye drop formulation or a sustained delivery device under conjunctiva or sub-Tenon.
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The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation, resulting in low ocular bioavailability. Mucoadhesive chitosan (CS)/ tripolyphosphatesodium (TPP) and chitosan (CS)/ tripolyphosphatesodium (TPP)-alginate (ALG) nanoparticles were investigated for the prolonged topical ophthalmic delivery of ofloxacin. A modified ionotropic gelation method was used to produce ofloxacin-loaded nanoreservoir systems. The ofloxacin-loaded CS/TPP and CS/TPP-ALG nanoparticles were characterized for particle size, morphology, zeta potential, encapsulation efficiency, subsequent release and corneal penetration study. The designed nanoparticles have a particle size from 113.8 nm to 509 nm and zeta potential from 16.2 mV to 40.3 mV and encapsulation efficiency values ranging from 19.7% to 33.1%. Nanoparticles revealed a release during the first hours, followed by a more gradual drug release. The ofloxacin-loading CS/TPP or CS/TPP-ALG NPs developed are pronounced penetration enhancing effect as compared to OFX solution (5-6.5 times). Thus, these nanoparticles have a strong potential for ocular drug delivery.
Subject(s)
Ofloxacin/analysis , Chitosan/analysis , Nanoparticles/analysis , Administration, Ophthalmic , Ocular Physiological Phenomena , Eye Infections/classification , Chromatography, High Pressure Liquid/methods , CorneaABSTRACT
Contact lenses have good biocompatibility and long wearing duration, and can be used as promising ocular drug delivery system. Drug loading contact lenses can retain the drug on the surface of eye and thus improve the bioavailability. In this review, we summarized the advantage of contact lenses as ocular drug delivery system, mechanism of improving drug absorption, drug loading method and release behavior, and influence of drug loading on physical properties of contact lenses.
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Ocular diseases include various anterior and posterior segment diseases. Due to the unique anatomy and physiology of the eye, efficient ocular drug delivery is a great challenge to researchers and pharmacologists. Although there are conventional noninvasive and invasive treatments, such as eye drops, injections and implants, the current treatments either suffer from low bioavailability or severe adverse ocular effects. Alternatively, the emerging nanoscience and nanotechnology are playing an important role in the development of novel strategies for ocular disease therapy. Various active molecules have been designed to associate with nanocarriers to overcome ocular barriers and intimately interact with specific ocular tissues. In this review, we highlight the recent attempts of nanotechnology-based systems for imaging and treating ocular diseases, such as corneal d iseases, glaucoma, retina diseases, and choroid diseases. Although additional work remains, the progress described herein may pave the way to new, highly effective and important ocular nanomedicines.
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Ophthalmic formulations in terms of eye drops are more frequently used formulation for ocular disorders. But unfortunately this mode of drug instillation into the cul-de-sac of eye shows very poor ocular bioavailability (less than 5%). A large number of carrier systems have been investigated to overcome this problem. In the present study a novel nano-carrier system (Ketorolac loaded cubosomes) is developed and evaluated for the safe and enhance ocular bioavailability. Cubosomes were developed and optimized by utilizing glyceryl mono-oleate, poloxamer 407 and initial drug concentration. Finally developed formulation was evaluated for various In vitro characteristics i.e. particles size, size distribution, shape and morphology, in-vitro release profile, corneal permeation, corneal retention, and ocular tolerance study. The optimized drug loaded cubosomal formulation showed mean particle size, polydispersity index, and entrapment efficiency 127.3±12.23 nm, 0.205±0.011, and 53.27±5.23 %, respectively. Transmission electron microscopic analysis revealed a cubic shape of developed formulation. Further, developed formulation exhibited biphasic release profile. Significant high transcorneal permeation (2.07 folds) and corneal retention (2.24 folds) of ketorolac was observed with cubosomal formulation correspond to Ketorolac solution (p< 0.01). Further safety profile of optimized formulation was evaluated by histopathology of corneal membrane. The developed novel ocular carrier system (cubosomes) might be a promising platform as a vehicle for effective ocular drug delivery.
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Efflux protein is an active transport protein family located on cell membranes of various human tissues,including ocular tissues.Efflux proteins can transport exogenous molecules out of the cells to function as a protective mechanism.Scientists have revealed these proteins in various human eye tissues,including cornea,iris and ciliary body,retina,as well as retinal pigment epithelium.Many studies have demonstrated that these efflux proteins have their own unique substrates and inhibitors.The effects of these efflux proteins and inhibitors can alter ocular pharmacokinetics as well as pharmacodynamics of a given therapeutics.Better understanding of the efflux proteins and their functions can provide scientific insight and guideline for development of optimal ocular drug delivery strategy.
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Drug deliver to the posterior eye segment (retinal tissue and vitreous) via systemic administration is constrained due to the presence of blood-retinal barrier (BRB) ,which regulates the permeation of many substances from blood to retina selectively.Two major transporters have been identified in the human genome,and they are solute carrier superfamilies and ATP-binding cassette.As the function of transporters is being revealed,it has been clarifed that the transporters are very important in pharmacokinetics.This article reviewed the expression and functional activity of various BRB transporters, including amino acid, oligopeptide, monocarboxylate, folate, nucleoside transporters etc.,updated the current knowledge about the BRB transporters and elucidated the urgent need for the development of optimal and efficient drug delivery systems.Any approach to further improving the ocular bioavailability of drugs will be of significant clinical relevance.
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In situ gel is liquid upon instillation and undergo phase transition under physiological conditions to form visco-elastic gel with dual advantages of liquid and gel. Ordinary eye drops exist a problem of short residence time with low bioavailability. In recent years, an impressive number of novel in situ gel systems have been reported for ocular drug delivery to increase bioavailability with the extension of corneal residence time. In this article, the classification and application about in situ gel for ocular drug delivery are reviewed, then the study status and the key technical problem of the in situ ophthalmic gel in detail are described. In addition, the future advancement of this field is also discussed.
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Carriage of medicaments assigned in the forms of conventional dosage is restricted to the eye; moreover, favorable drug concentrations in the destination tissues are not kept up for an extended time spread given that the eyes are escorted via an inimitable anatomy, physiology and biochemistry. The clearcut aim of designing a therapeutic system is to attain a desirable concentration of a drug at the active site for the relevant duration. A successful design of a drugdelivery system, therefore, desires an integrated knowledge of the drug molecule and the restrictions offered by the ocular route of administration. In last decade, with the emergence of miscellaneous powerful and multifaceted medicinal substitutes, the assortment of traditional ophthalmic preparations has progressively developed; drawing out considerably apart from ordinary solutions, suspensions and ointments, presently comprises a diversity of drug administration formats. Present communication echoes miscellaneous barriers and successive blossoms in the field of ocular therapeutics.
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The aim of this research is to develop thermo sensitive drug vehicles for glaucoma therapy in in-situ form to overcome the problems of poor bioavailability, naso lachrymal drainage and rapid precorneal elimination exhibited by conventional eye drops. Thermo sensitive ophthalmic drop was prepared using cold method by mixing thermo sensitive polymer pluronic F-127, viscosifying agent HPMC-E 50 LV and antiglaucoma drug (betaxolol hydrochloride). Prepared in situ gels were evaluated for physical parameters like appearance, gelation temperature, pH, drug content, rheological properties, isotonicity, sterility test, in vitro permeation and in-vivo ocular irritation study. The drug released from selected batch provides sustained release of betaxolol over 7 hours period and showed excellent ocular tolerance. The overall results of this study supports that the Pluronic/HPMC based vehicle could be used for controlled drug release that exhibits a greater potential for glaucoma therapy.
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OBJECTIVE: To develop an appropriate nanostructured lipid carrier (CsA-NLC) for ocular drug delivery of cyclosporine A and its in vitro physicochemical properties and ocular irritation studies were investigated. METHODS: The melt-emulsification method was chosen to prepare CsA-NLC. The formulation was optimized by orthogonal design. The morphology of CsA-NLC was observed by transmission electron microscopy (TEM). The mean particle size and Zeta potential were measured by laser particle size analyzer. The state of drug in NLC was confirmed by DSC. Drug loading and encapsulation efficiency were determined by HPLC. Dialysis method at 34°C was employed to investigate the in vitro release of CsA-NLC. The topical ocular irritation study of CsA-NLC was made in rabbits. RESULTS: The obtained CsA- NLC was approximately spherical in shape with average particle size of (35.9 ± 0.21) nm and zeta potential of (- 13.9 ± 0.21) mV. The drug loading and encapsulation efficiency were (16.2 ± 0.09)% and (97.5 ± 0.58)%, respectively. The in vitro release of CsA-NLC was slowed down and fitted well single exponential distribution model. There was no irritation for CsA-NLC to rabbits eye. CONCLUSION: CsA-NLC with small particle sizes and high drug loading, slow release would be a promising nanocarrier for ocular drug delivery to improve drugs bioavailability. Copyright 2012 by the Chinese Pharmaceutical Association.
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OBJECTIVE: To develop a bioadhesive nanostructured lipid carrier (P407-NLC) for ocular delivery of cyclosporine A and investigate its ocular distribution in rabbits. METHODS: Melt-emulsification method was chosen to prepare CsA-NLC. Poloxamer 407 (P407) was dissolved in borate buffer solution (pH 8.0), then added into CsA-NLC to prepare P407-NLC. The morphology of P407-NLC was observed by transmission electron microscopy (TEM). The mean particle size and Zeta potential were measured by laser particle size analyzer. The viscosity was measured by rheometer. Dialysis method was employed to investigate the in vitro release of CsA from P407-NLC at 34°C. The concentrations of CsA in ocular tissues were studied by RP-HPLC, and the pharmacokinetic parameters were calculated by linear trapezoidal method. The topical ocular irritation study of P407-NLC was carried out in rabbits. RESULTS: The obtained P407-NLC was approximately spherical in shape with average particle size of (41.2 ± 0.2) nm and Zeta potential of (-15.2 ± 0.21) mV, and P407 was coated on the appearance of NLC. P407-NLC was non-newtonian fluids. The in vitro release of CsA from P407-NLC was slowed down and fitted well with single exponential distribution model. AUC0-24h of CsA in cornea, aqueous humor and iris after ocular administration of P407-NLC containing 6.0% P407 were 10.75, 4.45 and 4.62 times higher than that of CsA oil solution, and 2.77, 1.22 and 1.54 times higher than that of CsA-NLC, respectively. MRTs in aqueous humor, cornea and iris were 3.28, 2.26 and 3.46 times higher, respectively, than that of CsA oil solution, and 1.69, 1.50 and 1.62 times higher than CsA-NLC, respectively. There was no irritation for P407-NLC to rabbit eyes. CONCLUSION: P407-NLC can be used to increase the level of CsA in ocular tissues and would be a promising nanocarrier for ocular drug delivery. Copyright 2012 by the Chinese Pharmaceutical Association.
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PURPOSE: The purpose of this study was to evaluate the effect of transscleral pressure on the thickness and hydration of the human sclera. METHODS: Scleral sections excised from moist-chamber-stored human globes were mounted in a perfusion chamber that can create transscleral pressure. The scleral thickness was measured at 15-minute intervals using ultrasonic pachymetry with pressure changes of 15, 30, and 60 mmHg every 2 hours. The scleral hydration was measured by maintaining a constant pressure (15, 30, and 60 mmHg) for 4 hours, weighing the hydrated tissue, then drying for 24 hours at 120degrees C, and finally weighing the dry tissue. RESULTS: The changes of scleral thickness from the initial control thickness in the 7-mm perfusion chamber (n=6) were -0.38+/-2.11%, 0.26+/-2.99 %, and -3.92+/-3.40% at 15, 30, and 60 mmHg, respectively. In the 10-mm perfusion chamber (n=5), the thickness changes were -0.56+/-1.35%, -1.05+/-1.63%, and -2.71+/-1.60% at 15, 30, and 60 mmHg, respectively. Scleral thickness was slightly decreased with the increase of transscleral pressure. There was a statistically significant decrease in scleral thickness from 30 mmHg to 60 mmHg in the 7-mm perfusion chamber (p0.10). CONCLUSIONS: The scleral hydration remained essentially unchanged with the transscleral pressure change of 0 ~ 60 mmHg, whereas the scleral thickness showed a slight decrease with the increase of transscleral pressure. Further histologic studies will be needed to assess the ultrastructural change of human sclera in the future.
Subject(s)
Humans , Perfusion , Sclera , UltrasonicsABSTRACT
PURPOSE: The purpose of this study was to evaluate the effect of two sustained release systems (Pluronic F-127 gel and Fibrin glue) on the diffusion of dexamethasone across the human sclera. METHODS: Scleral sections excised from moist-chamber-stored human globes were mounted in a perfusion chamber that can create transscleral pressure. In the sustained release study, sample (100 muL) of 3H-dexamethasone in Pluronic F-127 gel or Fibrin glue was added to the episcleral side of the tissue, while BSS plusR was perfused across the uveal side at an transscleral pressure of 15 mmHg. Perfusate fractions were collected and measured using scintillation spectrometry and scleral permeability was calculated. RESULTS: The apparent permeability constants of the human sclera to 3H-dexamethasone in BSS plus(R) (the control value), Pluronic F-127 gel, and Fibrin glue were 1.15+/-0.11x10(-5) cm/s (n=5), 1.49+/-0.33x10-6 cm/s (n=5), and 7.32+/-0.98x10(-6) cm/s (n=7), respectively. The permeability values of Pluronic F-127 gel and Fibrin glue were relatively lower than the control value. Pluronic F-127 gel and Fibrin glue showed a uniform sustained release characteristic during a 24-hour period. The cumulative release rates of dexamethasone through the human sclera from BSS plus(R) (the control value), Pluronic F-127 gel, and Fibrin glue were 84.0+/-1.5% (n=5), 29.3+/-5.8% (n=5), and 61.5+/-5.9% (n=4) at 20 hours, respectively. There were significant differences in the human scleral permeability constants and cumulative release rates among the three vehicles (p<0.0001). CONCLUSIONS: Pluronic F-127 gel and Fibrin glue provided a slow, uniform sustained release during a 24- hour period. This study established a strong possibility of the new transscleral drug delivery in vitro using the sustained release systems of Pluronic F-127 gel and Fibrin glue. This may be a good experimental tool in the future development of a practical drug delivery system across the sclera for the treatment of a variety of chorioretinal disorders.