Sustained release of brimonidine from conjunctival sac insert to reduce intraocular pressure for glaucoma treatment.

BACKGROUND: Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance. METHODS: A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed. RESULTS: The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro. Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion. CONCLUSIONS: The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without need for invasive procedures.

Combined Therapy of Experimental Autoimmune Uveitis by a Dual-Drug Nanocomposite Formulation with Berberine and Dexamethasone.

Purpose: Autoimmune uveitis is a kind of sight-threatening ocular and systemic disorders. Recent treatments on autoimmune uveitis still remain many limitations due to extreme complexity and undetermined pathogenesis. In this study, a novel dual-drug nanocomposite formulation is developed to treat experimental autoimmune uveitis by a combined and sustained therapy method. Methods: The dual-drug nanocomposite formulation is constructed by integrating berberine (BBR)-loaded mesoporous silica nanoparticles (MSNs) into dexamethasone (DEX)-loaded thermogel (BBR@MSN-DEX@Gel). The BBR@MSN-DEX@Gel is characterized by transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectrometer and rheometer. The in vitro drug release profile, cytotoxicity and anti-inflammation effectiveness of BBR@MSN-DEX@Gel on lipopolysaccharide-stimulated human conjunctival epithelial cells are investigated. After the in vivo drug release profile and biosafety of the dual-drug nanocomposite formulation are confirmed, its treatment effectiveness is fully assessed based on the induced experimental autoimmune uveitis (EAU) Lewis rat's model. Results: The dual-drug nanocomposite formulation has good injectability and thermosensitivity, suitable for administration by an intravitreal injection. The BBR@MSN-DEX@Gel has been found to sustainably release both drugs for up to 4 weeks. The carrier materials have minimal in vitro cytotoxicity and high in vivo biosafety. BBR@MSN-DEX@Gel presents obviously anti-inflammatory effectiveness in vitro. After administration of BBR@MSN-DEX@Gel into Lewis rat's eye with EAU by an intravitreal injection, the nanocomposite formulation significantly suppresses inflammatory reaction of autoimmune uveitis via a dual-drug combined and sustained therapy method, compared with the equivalent dose of single-component formulations. Conclusion: BBR@MSN-DEX@Gel serves as a promising dual-drug nanocomposite formulation for future treatment of autoimmune uveitis.

Sustained release of brimonidine from polydimethylsiloxane-coating silicone rubber implant to reduce intraocular pressure in glaucoma.

Glaucoma is the leading cause of irreversible blindness, affecting 111 million people by 2040 worldwide. Intraocular pressure (IOP) is the only controllable risk factor for the disease and current treatment options seek to reduce IOP via daily taking eye drops. However, shortcomings of eye drops, such as poor bioavailability and unsatisfied therapeutic effects, may lead to inadequate patient compliance. In this study, an effective brimonidine (BRI)-loaded silicone rubber (SR) implant coated with polydimethylsiloxane (BRI@SR@PDMS) is designed and fully investigated for IOP reduction treatment. The in vitro BRI release from BRI@SR@PDMS implant reveals a more sustainable trend lasting over 1 month, with a gradually declined immediate drug concentration. The carrier materials show no cytotoxicity on human corneal epithelial cells and mice corneal epithelial cells in vitro. After administrated into rabbit's conjunctival sac, the BRI@SR@PDMS implant releases BRI in a sustained fashion and effectively reduces IOP for 18 days with great biosafety. In contrast, BRI eye drops only maintain IOP-lowering effect for 6 h. Therefore, as a substitute of eye drops, the BRI@SR@PDMS implant can be applied as a promising non-invasive platform to achieve long-term IOP-lowering in patients suffering from ocular hypertension or glaucoma.

Sustained release of brimonidine from BRI@SR@TPU implant for treatment of glaucoma.

Glaucoma is the leading cause of irreversible vision loss worldwide, and reduction of intraocular pressure (IOP) is the only factor that can be interfered to delay disease progression. As the first line and preferred method to treat glaucoma, eye drops have many shortcomings, such as low bioavailability, poor patient compliance, and unsustainable therapeutic effect. In this study, a highly efficient brimonidine (BRI) silicone rubber implant (BRI@SR@TPU implant) has been designed, prepared, characterized, and administrated for sustained relief of IOP to treat glaucoma. The in vitro BRI release from BRI@SR@TPU implants shows a sustainable release profile for up to 35 d, with decreased burst release and increased immediate drug concentration. The carrier materials are not cytotoxic to human corneal epithelial cells and conjunctival epithelial cells, and show good biocompatibility, which can be safely administrated into rabbit's conjunctival sac. The BRI@SR@TPU implant sustainably released BRI and effectively reduced IOP for 18 d (72 times) compared to the commercial BRI eye drops (6 h). The BRI@SR@TPU implant is thus a promising noninvasive platform product for long-term IOP-reducing in patients with glaucoma and ocular hypertension.

[Absence of BAX differentially affects astrocyte density in the mouse cortex and hippocampus].

Astrocytes are a heterogenous group of macroglia present in all regions of the brain and play critical roles in many aspects of brain development, function and disease. Previous studies suggest that the B-cell lymphoma-2 associated X protein (BAX)-dependent apoptosis plays essential roles in regulating neuronal number and achieving optimal excitation/inhibition ratio. The aim of the present paper was to study whether BAX regulates astrocyte distribution in a region-specific manner. Immunofluorescence staining of SOX9 was used to analyze and compare astrocyte density in primary somatosensory cortex, motor cortex, retrosplenial cortex and hippocampus in heterozygous and homozygous BAX knockout mice at age of six weeks when cortical development has finished and glia development has reached a relatively steady state. The results showed that astrocyte density varied significantly among different cortical subdivisions and between cortex and hippocampus. In contrast to the significant increase in GABAergic interneurons, the overall and region-specific astrocyte density remained unchanged in the cortex when BAX was absent. Interestingly, a significant reduction of astrocyte density was observed in the hippocampus of BAX knockout mice. These data suggest that BAX differentially regulates neurons and astrocytes in cortex as well as astrocytes in different brain regions during development. This study provided important information about the regional heterogeneity of astrocyte distribution and the potential contribution of BAX gene during development.