Pharmacokinetics Demonstrating Sustained Dexamethasone Delivery from a Punctum Plug in a Canine Model

Abstract

 

Purpose

 

To examine the dose-dependent pharmacokinetics of dexamethasone delivered from a biodegradable hydrogel punctum plug in a canine model.

 

Methods

 

Micronized dexamethasone (Dex) was suspended in a multi-arm PEG solution at two different levels (high and low dose) and injected into small bore tubing prior to cross-linking. Fluorescein was conjugated into the hydrogel to aid plug visualization through the tissue using the blue light from a slit lamp. The Dex hydrogel matrix was dried and cut into punctum plugs. The Dex plugs were inserted into the inferior canaliculus of beagles and a subset was removed each week for imaging. Tear fluid samples were collected at weekly intervals and dexamethasone concentration was determined by LC/MS. The high dose was evaluated in a toxicology study and the low dose is a clinically representative dose designed for four weeks of tapered release that was assessed in a PK study.

 

Results

 

The Dex plug demonstrated a sustained drug release profile in tear fluid with a tapering effect over the treatment period. Explanted plugs (Figure Two) of the low dose formulation illustrate the drug release over time, with full drug clearance from the plug at four weeks.

 

Conclusions

 

Topical corticosteroids, such as dexamethasone, are used to treat inflammation for various ophthalmic conditions including post-operative inflammation. Many therapies require multiple daily administrations (up to hourly for severe conditions) for the first several weeks followed by tapering to a lesser frequency as the inflammation subsides and the condition resolves. A single-dose dexamethasone punctum plug which biodegrades may provide a more convenient option to help eliminate patient compliance with stringent dosing requirements, and help ensure appropriate treatment and resolution of the condition.

 

 

 

Keywords: 487 corticosteroids • 557 inflammation • 669 quality of life