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Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery.

ABSTRACT: Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to ~67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 ± 30 nm and 402 ± 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 °C, while in homogenized vitreous at 37 °C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery.

SUBMITTER: Kickova E

PROVIDER: S-EPMC8227697 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PURPOSE:To determine the ocular toxicity, systemic exposure, and amounts of dexamethasone sodium phosphate (DSP) in ocular tissues after administration of DSP with the Visulex system (DSP-Visulex). METHODS:DSP-Visulex was applied onto healthy rabbit eyes. DSP concentrations (4%, 8%, 15%, and 25%) and treatment durations (5, 10, and 20 min) were evaluated for the amounts of DSP in the ocular tissues and in plasma after single administrations of DSP-Visulex. The drug in eye tissues and plasma was analyzed by high-performance liquid chromatography-UV/VIS and by liquid chromatography-mass spectrometry, respectively. The safety and tolerability were ascertained based on clinical observations and histopathological examinations from repeat weekly DSP-Visulex treatments (4%, 8%, 15%, and 25% for 20 min) for 12 weeks. RESULTS:Significant amounts of DSP (ie, higher than 1 μg/g) were found in the anterior chamber, retina-choroid, cornea, vitreous, conjunctiva, and sclera after single applications of DSP-Visulex. The DSP concentrations in the ocular tissues and in plasma increased with increased DSP concentrations in the Visulex applicator and with increased application times. Systemic DSP was rapidly detected. The plasma half-life was 2-3 h. Cmax was 148 and 1,844 ng/mL, and the area under the plasma drug concentration versus time curve (AUC) was 418 and 3,779 ng · h/mL for the low dose (4% DSP-Visulex for 5 min) and the high dose (15% DSP-Visulex for 20 min), respectively. Ocular findings over 12 weeks were mostly conjunctival injection and eye discharge. These were transient and mild. Histopathological examinations indicated the eyes to be normal. CONCLUSIONS:DSP can be administered safely and effectively into the rabbit eye with the Visulex system. Treatment duration and DSP concentration are important factors in achieving therapeutic levels. Repeat applications of DSP-Visulex are safe and well tolerated for weekly administrations over 4-12 weeks. DSP-Visulex has clinical potential for the noninvasive treatment of ocular diseases.

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Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery.

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