Download In Vivo Drug Delivery of Low Solubility Drugs from Biodegradable

In Vivo Drug Delivery of Low Solubility Drugs from Biodegradable Hydrogel
Punctum Plugs
Author Block: M. McGrath, C. Blizzard, A. Desai, M. Bassett, P. Jarrett, A. Driscoll, A. Sawhney. All of
Ocular Therapeutix, Inc., Bedford, MA.
Purpose: To examine the pharmacokinetics of various corticosteroid drugs released from hydrogel
punctum plugs on the basis of aqueous solubility and drug dose in a preclinical animal model.
Methods: Four different topical ophthalmic
corticosteroids (dexamethasone-DX,
prednisolone-PD, prednisolone acetate – PA
and loteprednol etabonate – LE) were
individually suspended in a multi-arm PEG
precursor solution and injected into small bore
tubing prior to cross-linking. The steroid
loaded hydrogel matrix was dried and cut into
punctum plugs containing approximately 800
µg of each steroid per plug. The DX plug was
additionally prepared at a lower 200 µg dose
to study the influence of dose. The plugs were
inserted into the inferior canaliculus of beagles
and explanted after 7 days to analyze the
average drug content released from the plug
on a per day basis. A subset was left in place
and explanted after 21 days for imaging.
Results: The steroid plugs demonstrated an in
vivo daily drug release consistent with their
aqueous solubility, as is shown in Figure One.
Increasing the dose per plug didn’t change the
amount released per day indicating drug
saturation in tear fluid drives the kinetics of
release from the hydrogel plug. Explanted plug
images, as shown in Figure Two, demonstrate
that the most soluble drug (PD) completely
cleared from the matrix whereas the less
soluble drugs (PA and LE) had no visual
hydrogel clearance even after 21 days. The DX
plug when constrained in the canaliculus
demonstrates an in vivo directional drug
release from the portion facing the punctal
opening which is capable of lavage with
replenishing tear fluid.
Conclusions: Preclinical studies of steroid release from punctum plugs demonstrate that plugs
containing a higher dose of a given steroid will release the same amount per day and will release drug
for a longer duration. Once zone clearance begins at the hydrogel interface then diffusion path length
limits saturation solubility creating a tapering effect which is beneficial in corticosteroid therapy and is
consistent with eye drop therapy regimens. This understanding of in vivo drug release from
biodegradable punctum plugs on the basis of aqueous solubility can be applied to other corticosteroids
and many other classes of low solubility drugs currently prescribed as eye drop suspensions.