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New vehicle based on a microemulsion for topical ocular administration of dexamethasone

Aim: Eye drops are the most used dosage form by the ocular route, in spite of their low bioavailability. Due to their properties and numerous advantages, microemulsions are promising systems for topical ocular drug delivery. They can increase water solubility of the drug and enhance drug absorption into the eye. The present study describes the development and characterization of an oil‐in‐water microemulsion containing dexamethasone and the evaluation of its pharmacokinetics in rabbits after topical ocular application.

Manufacturing Techniques of Biodegradable Implants Intended for Intraocular Application

Polylactic acid and polylactic-co-glycolic acid are biocompatible and biodegradable polymers with wide utility for the design of controlled release systems for drugs. Regarding intraocular application, polymeric sustained-drug release systems are being studied to treat vitreoretinal diseases. Our work aimed to compare the influence of two implant manufacturing techniques, compression and hot molding, on the in vitro degradation of the polymeric matrices and on the release of dexamethasone acetate. The results showed that the manufacturing technique highly influences degradation and drug release processes. The compressed systems degraded faster and allowed one faster release of the drug.

Microemulsões como veículo de drogas para administração ocular tópica

The conventional ophthalmic dosage forms are relatively simple: usually, water-soluble drugs are delivered in aqueous solution and water-insoluble drugs are prepared as suspensions or ointments. However, these delivery systems currently used present very low corneal bioavailability, systemic exposure because of nasolacrimal drainage and lack of efficiency in the posterior segment of ocular tissue. Recent research efforts have focused on the development of new ophthalmic drug delivery systems. As a result of these efforts, microemulsions are promising dosage forms for ocular use. These delivery systems are dispersions of water and oil that require surfactant and co-surfactant agents in order to stabilize the interfacial area. The microemulsions have a transparent appearance, thermodynamic stability and small droplet size of the dispersed fase (<1,0 mm), providing them with the capacity of being sterilized by filtration. Furthermore, these systems offer additional advantages that include: low viscosity, great ability as drug delivery vehicles, widened properties as absorption promoters and easiness of preparation, which do not require much energy and the use of special equipments. In this review, we present the technology and some preliminary studies of microemulsions in relation to ocular drug delivery systems.

Pharmacokinetic and toxicity investigations of a new intraocular lens with a dexamethasone drug delivery system : A pilot study

Aim: To investigate the short-term safety and pharmacokinetic behavior of a new intraocular lens containing a dexamethasone drug delivery system (IOL-DDS) in rabbit eyes. Methods: A modified polymethylmethacrylate IOL containing a biodegradable dexamethasone DDS was implanted into the posterior chamber of the right eyes of 9 New Zealand white rabbits. Serial slitlamp and indirect ophthalmoscopic examinations (including grading of intraocular inflammation) were performed. After 3, 6 and 9 days, the rabbits were euthanized and the globes were removed for histological examination and for determination of dexamethasone levels in the aqueous humor and in the vitreous. Analysis of dexamethasone concentrations was performed by ELISA. Results: Therapeutic concentrations of dexamethasone were detectable in the aqueous and vitreous of the study eyes throughout the 9-day period in all tested animals. The mean aqueous dexamethasone concentration (ng/ml, ±SD) was 1,015.42 (±43.05), 970.11 (±32.47) and 757.58 (±30.19) and the mean vitreous concentration (ng/ml, ±SD) was 399.82 (±38.05), 287.38 (±34.47) and 268.15 (±32.00) at 3, 6 and 9 days after the surgical procedure, respectively. No corneal or retinal histological changes were observed during the study period. Conclusion: The IOL-DDS is effective in delivering therapeutic concentrations of dexamethasone to the aqueous and vitreous, without acute damage to the cornea and retina. Further controlled studies in the same animal model are under way to determine the potential value of this lens in the prevention and treatment of inflammation following cataract surgery.

Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.

Implants as drug delivery devices for the treatment of eye diseases

The treatment of diseases affecting the posterior segment of the eye is limited by the difficulty in transporting effective doses of drugs to the vitreous, retina, and choroid. Topically applied drugs are poorly absorbed due to the low permeability of the external ocular tissues and tearing. The blood-retina barrier limits drug diffusion from the systemic blood to the posterior segment, thus high doses of drug are needed to maintain therapeutic levels. In addition, systemic side effects are common. Intraocular injections could be an alternative, but the fast flowing blood supply in this region, associated with rapid clearance rates, causes drug concentration to quickly fall below therapeutic levels. To obtain therapeutic levels over longer time periods, polymeric sustained-drug release systems implanted within the vitreous are being studied for the treatment of vitreoretinal disorders. These systems are prepared using different kinds of biodegradable or non-biodegradable polymers. This review aims to demonstrate the main characteristics of these drug delivery implants and their potential for clinical application.

Implantes biodegradáveis destinados à administração intra-ocular

O tratamento de doencas oculares que acometem o vitreo e a retina tem sido um problema devido a dificuldade de penetracao das drogas no segmento posterior do bulbo ocular. A administracao de colirios apresenta efeito terapeutico minimo nessa regiao do olho, que, geralmente, e mantido com a administracao de doses frequentes do medicamento. Uma alternativa seria a injecao intra-ocular; entretanto, a rapida circulacao sanguinea nesses locais promove uma reducao da meia-vida das drogas, diminuindo, rapidamente, suas concentracoes a niveis subterapeuticos. Visando a obtencao de niveis terapeuticos adequados de drogas no segmento posterior do bulbo ocular por longos periodos, sistemas de liberacao polimericos implantados intravitreo estao sendo investigados para o tratamento de varias doencas vitreo-retinianas. Esses implantes sao preparados a partir de diferentes polimeros, os quais podem ser biodegradaveis ou nao biodegradaveis. Os polimeros derivados dos acidos latico e glicolico tem se revelados bastante promissores devido, principalmente, as suas caracteristicas de biocompatibilidade e biodegradabilidade. De acordo com os estudos realizados ate o momento, os implantes podem se apresentar na forma de bastao, de discos ou de membranas e ser obtidos pelos metodos de moldagem, de extrusao ou de preparacao de filmes. O presente artigo objetiva uma revisao de literatura abordando o tema e os principais estudos relacionados com a utilizacao de implantes polimericos como sistemas transportadores de drogas para aplicacao intra-ocular.

Evaluation of water-in-oil-in-water multiple emulsion and microemulsion as potential adjuvants for immunization with rabies antigen

Water-in-oil-in-water (W/O/W) multiple emulsions and microemulsions have been studied as potential candidates to be formulated as adjuvants. In this work their application as adjuvants for rabies virus immunization was studied. The humoral response, the effective dose 50 and histology for the developed formulations were evaluated in mice and compared with those from traditional adjuvants. The microemulsion and W/O/W multiple emulsion adjuvants developed were able to induce humoral response in mice and the serum showed good in vivo protection. Compared to the other adjuvants evaluated, microemulsion was shown to be the best candidate for rabies immunization as it presented good potency against the virus and did not appear to cause any local reaction.

Sistemas de transporte de drogas para o segmento posterior do olho: bases fundamentais e aplicações

The diseases of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These conditions stimulate the development of new modalities of treatment for vitreoretinal diseases. The success in the treatment aims, mainly, the delivery of effective doses of pharmacological agents directly to the target sites. Because of the difficulties in delivering drugs to the posterior segment of the eye, the development of intraocular delivery systems that allow the delivery of therapeutic concentrations of drugs for long periods are being studied. These systems offer many advantages, such as increase in drug bioavailability, obtaining constant and sustained drug release, to achievement of elevated local concentrations of drugs without systemic side effects, targeting one specific tissue or cell type, reducing the frequency of intraocular injections. These advantages can increase the comfort of the patient and reduce the complications observed with intraocular injections. Several drug delivery systems are being developed with the above described purposes. These systems may be prepared with biodegradable or non-biodegradable polymers or they may be lipid formulations. The drug delivery systems are represented, mainly, by micro- e nanoparticles and implants, composed of different polymers; by liposomes, which are made of lipids and surfactants; and by iontophoresis, that is based on the application of an electric current. In this review, the main characteristics of the different drug delivery systems will be shown, with their potentialities of clinical application.

Tacrolimus-loaded PLGA implants: in vivo release and ocular toxicity.

Abstract Purpose: To evaluate the in vivo release and ocular toxicity of a tacrolimus-loaded PLGA intravitreal implant. Methods: Tacrolimus-loaded PLGA implants were inserted into the vitreous cavity of rabbits’ eye. At different time points, the vitreous was retrieved and the concentration of tacrolimus released from the implants was determined. Clinical examination was performed to evaluate the implant tolerance. Results: PLGA implants provided controlled and prolonged release of tacrolimus. Approximately 99.97% of the drug was released from the devices at 6 weeks. Ophthalmic examination revealed no evidence of toxic effects of implants. Conclusions: Tolerance and feasibility of the tacrolimus-loaded PLGA implants, as sustained intraocular drug delivery systems, were demonstrated.