Poly(ethylene glycol) hydrogels for sustained topical drug delivery to the eyes and skin.

摘要

Sulfur mustard (SM) is a potent chemical warfare agent that mainly affects the eyes, lungs and skin. Inflammatory cytokines and Matrix Metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets for SM-induced tissue damage since they quantitatively increase over time in response to SM exposure. Doxycycline is a tetracycline antibiotic with anti-inflammatory properties that acts by inhibiting MMP-9. Currently, neither doxycycline nor doxycycline delivery systems have been investigated for treatment of SM injuries.The objective of this thesis project is to design and fabricate sustained release topical doxycycline delivery systems and evaluate their wound healing efficacy. Fast forming hydrogels were prepared by crosslinking a poly(ethylene glycol) (PEG)-based polymer containing multiple thiol groups with different polymers or crosslinkers. The optical properties of the hydrogels were evaluated by spectrophotometry and the hydrogels that were transparent or close to transparent were chosen for drug delivery to the eye. Physicochemical properties of the hydrogels evaluated by rheometry and swelling kinetics show that the hydrogels have good mechanical strength with a low degree of swelling (8%).In vitro release profiles of doxycycline-loaded hydrogels demonstrated biphasic release with an initial burst phase followed by a sustained phase. Permeation of doxycycline through vesicant wounded corneas was 2.5 to 3.4 fold higher than through unwounded corneas suggesting that the barrier function of the cornea is compromised after vesicant exposure. Doxycycline hydrogels showed a significant improvement in corneal epithelial healing compared to a similar dose of doxycycline solution in a vesicant-exposed rabbit corneal organ culture model.The model vesicant, nitrogen mustard (NM) showed dose and time dependent wound progression in SKH-1 mice. The permeability of NM-exposed skin (5 mumoles) to different molecular markers increased significantly compared to the control suggesting that stratum corneum does not act as a barrier for transdermal drug absorption after vesicant exposure. From histology analyses, it is evident that doxycycline hydrogel treated groups showed significant wound healing efficacy compared to untreated or placebo hydrogel treated groups. In summary, in situ forming topical doxycycline-loaded PEG hydrogels showed superior wound healing efficacy offering a potential therapeutic option for mustard injuries in the eye and skin.