Ocular Compositions and Methods Thereof

a technology of compositions and therapeutic agents, applied in the direction of aerosol delivery, transferases, peptide/protein ingredients, etc., can solve the problems of difficult or impractical treatment of numerous diseases and conditions that affect the eyes, including those for which therapeutic agents are available, and achieve the effect of increasing the ocular residence time and bioavailability of therapeutic agents

Inactive Publication Date: 2017-07-06
UNIV OF MISSISSIPPI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In some embodiments of the presently disclosed subject matter, the compound forms a hydrogel after topical application or intraocular injection. In some embodiments, the compound has a phase transition below the ocular temperature, wherein ocular injection or application induces phase transfer and hydrogel formation. In some embodiments, the hydrogel formation increases ocular residence time and bioavailability of the therapeutic.

Problems solved by technology

Delivery of drugs to the eye via topical application is especially challenging.
Thus, treatment of numerous diseases and conditions that affect the eyes, including those for which therapeutic agents are available, can be difficult or impractical because there exists no simple and effective method for delivering therapeutic agents.
Inhibition of sFlt-1 expression is sufficient to abolish corneal avascularity in mice, but treatment is hampered by the lack of a system to deliver sFlt-1 to the eye.
Persistent pathological NV leads to development and accumulation of blood vessels that are immature and structurally weak, which can then lead to lipid exudation, inflammation, scarring, and ultimately, blindness.
Current treatment strategies are limited to pharmacological interventions, such as steroids, NSAIDs, and anti-angiogenic growth factors, and surgical interventions, such as photodynamic therapy, laser ablation, cautery, and superficial keratectomy.
Similarly, bacterial keratitis can be a severe and sight threatening condition.
However, this strategy is limited by poor penetration of many antibiotics into the cornea, rapid removal of the drugs by the natural formation of tears, and development of antibiotic resistance by the infecting bacteria.

Method used

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  • Ocular Compositions and Methods Thereof
  • Ocular Compositions and Methods Thereof
  • Ocular Compositions and Methods Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0072]This Example characterizes the uptake of elastic-like polypeptides (ELPs) and cell-penetrating peptide ELP fusion polypeptides (CPP-ELPs) in human corneal epithelial cells (HCEs). To determine if CPPs could mediate the uptake of ELP in corneal cells, HCEs grown in culture were exposed to 10 μM fluorescently-labeled ELP, SynB1-ELP, or Tat-ELP. After 24 h incubation with the labeled proteins, the cells were detached and analyzed by flow cytometry. The mean fluorescence intensity was determined for all cells, and the fluorescence value was corrected to account for differences in labeling efficiency among the proteins. As shown in FIG. 1, ELP was detectable over autofluorescence in HCE cells, and the cellular uptake was increased 2.8-fold and 3.9-fold with SynB1 and Tat CPPs, respectively.

[0073]In addition to uptake efficiency, toxicity of ELP or CPP-ELPs to HCE cells was examined. Cells were exposed to varying concentrations of ELP, SynB1-ELP, or Tat-ELP for 72 hours, and cell nu...

example 2

[0074]This Example characterizes the development of a rabbit corneal neovascularization (CN) model. Rabbits were chosen for this model because the thickness of their corneal epithelial layer is similar to that of humans. New Zealand white rabbits were anesthetized with isoflurane, and a corneal burn was induced using a 60 second application of a silver nitrate cautery stick. As shown in FIG. 3, 7 days after corneal injury, the rabbits developed a neovascular response in the injured eye.

example 3

[0075]This Example characterizes penetration of the corneal barrier by ELP and CPP-ELPs, and compares ELP corneal accumulation to a model antibody, immunoglobulin. G (IgG). Fluorescently labeled ELP, SynB1-ELP, Tat-ELP, or IgG was applied topically via eye drops three times over 6 h in rabbits. The contralateral eye was administered saline control. 8 h after the first application, the animals were sacrificed and the eyes removed for ex vivo analysis. As shown in FIG. 4, ELP accumulated in the rabbit cornea at levels over seven-fold higher than IgG. SynB1-ELP and Tat-ELP also accumulated in the cornea much more efficiently than IgG, but the CPP-ELP corneal levels were not enhanced relative to ELP control.

[0076]After total fluorescence analysis, the eyes were frozen and cut using a cryomicrotome. Sagittal sections were used in order to visualize the cornea in cross-section. Sections were stained with DAPI to mark cell nuclei and imaged with an epifluorescence microscope. As shown in F...

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Abstract

Methods and pharmaceutical compositions (or delivering a therapeutic agent, treating a neovascularization disorder, and treating an ocular infection include make use of a compound that includes an clastin-likc polypeptide (ELP) coupled to a therapeutic agent, wherein the ELP comprises at least one repeat of the amino acid sequence VPGXG (SEQ ID NO: 1), and where the composition is suitable for ocular administration.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application Ser. No. 61 / 985,808 filed Apr. 29, 2014, the entire disclosure of which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The presently-disclosed subject matter relates to compositions and methods for ocular delivery of therapeutic agents. In particular, the presently-disclosed subject matter relates to compounds comprising an elastic-like polypeptide (ELP) coupled to a therapeutic agent as well as compositions and methods thereof.INTRODUCTION[0003]Delivery of drugs to the eye via topical application is especially challenging. The corneal barrier consists of tight junction connected epithelial cells over a basement membrane layer that prevent the passage of large or hydrophilic molecules into the eye. Thus, treatment of numerous diseases and conditions that affect the eyes, including those for which therapeutic agents are available, can be difficult or impractical beca...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48A61K9/06A61K38/17A61K9/00A61K38/45
CPCA61K47/48246A61K9/0048A61K38/1703A61K38/45C12Y207/10001A61K9/06A61K38/10A61K38/18C07K14/71C07K14/78C07K2319/10A61K38/179A61K47/64
Inventor BIDWELL, III, GENE L.GEORGE, ERIC M.
Owner UNIV OF MISSISSIPPI MEDICAL CENT
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