In Vivo Drug Delivery of Low Solubility Drugs from Biodegradable Hydrogel Punctum Plugs

摘要

?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. ?View OriginalDownload SlideView OriginalDownload Slide?View OriginalDownload SlideView OriginalDownload Slide? Keywords: 487 corticosteroids ? 557 inflammation ? 445 cataract ?.