Doxycycline hydrogels with reversible disulfide crosslinks for dermal wound healing of mustard injuries.

Doxycycline hydrogels containing reversible disulfide crosslinks were investigated for a dermal wound healing application. Nitrogen mustard (NM) was used as a surrogate to mimic the vesicant effects of the chemical warfare agent sulfur mustard. An 8-arm-poly(ethylene glycol) (PEG) polymer containing multiple thiol (-SH) groups was crosslinked using hydrogen peroxide (H(2)O(2) hydrogel) or 8-arm-S-thiopyridyl (S-TP hydrogel) to form a hydrogel in situ. Formulation additives (glycerin, PVP and PEG 600) were found to promote dermal hydrogel retention for up to 24 h. Hydrogels demonstrated high mechanical strength and a low degree of swelling (< 1.5%). Doxycycline release from the hydrogels was biphasic and sustained for up to 10-days in vitro. Doxycycline (8.5 mg/cm(3)) permeability through NM-exposed skin was elevated as compared to non vesicant-treated controls at 24, 72 and 168 h post-exposure with peak permeability at 72 h. The decrease in doxycycline permeability at 168 h correlates to epidermal re-epithelialization and wound healing. Histology studies of skin showed that doxycycline loaded (0.25% w/v) hydrogels provided improved wound healing response on NM-exposed skin as compared to untreated skin and skin treated with placebo hydrogels in an SKH-1 mouse model. In conclusion, PEG-based doxycycline hydrogels are promising for dermal wound healing application of mustard injuries.

Doxycycline loaded poly(ethylene glycol) hydrogels for healing vesicant-induced ocular wounds.

Half mustard (CEES) and nitrogen mustard (NM) are commonly used surrogates and vesicant analogs of the chemical warfare agent sulfur mustard. In the current study, in situ forming poly(ethylene glycol) (PEG)-based doxycycline hydrogels are developed and evaluated for their wound healing efficacy in CEES and NM-exposed rabbit corneas in organ culture. The hydrogels, characterized by UV-Vis spectrophotometry, rheometry, and swelling kinetics, showed that the hydrogels are optically transparent, have good mechanical strength and a relatively low degree of swelling (<7%). In vitro doxycycline release from the hydrogel disks (0.25% w/v) was found to be biphasic with release half times of approximately 12 and 72h, respectively, with 80-100% released over a 7-day period. Permeation of doxycycline through vesicant wounded corneas was found to be 2.5 to 3.4 fold higher than non-wounded corneas. Histology and immunofluorescence studies showed a significant reduction of matrix metalloproteinase-9 (MMP-9) and improved healing of vesicant-exposed corneas by doxycycline hydrogels compared to a similar dose of doxycycline delivered in phosphate buffered saline (PBS, pH 7.4). In conclusion, the current studies demonstrate that the doxycycline-PEG hydrogels accelerate corneal wound healing after vesicant injury offering a therapeutic option for ocular mustard injuries.

Design and evaluation of novel fast forming pilocarpine-loaded ocular hydrogels for sustained pharmacological response.

Fast forming hydrogels prepared by crosslinking a poly(ethylene glycol) (PEG)-based copolymer containing multiple thiol (SH) groups were evaluated for the controlled ocular delivery of pilocarpine and subsequent pupillary constriction. Physical properties of the hydrogels were characterized using UV-Vis spectrophotometry, transmission electron microscopy (TEM), rheometry, and swelling kinetics. Pilocarpine loading efficiency and release properties were measured in simulated tear fluid. The hydrogel formulations exhibited high drug loading efficiency (approximately 74%). Pilocarpine release was found to be biphasic with release half times of approximately 2 and 94 h, respectively, and 85-100% of the drug was released over 8-days. Pilocarpine-loaded (2% w/v) hydrogels were evaluated in a rabbit model and compared to a similar dose of drug in aqueous solution. The hydrogels were retained in the eye for the entire period of the study with no observed irritation. Pilocarpine-loaded hydrogels sustained pupillary constriction for 24 h after administration as compared to 3 h for the solution, an 8-fold increase in the duration of action. A strong correlation between pilocarpine release and pupillary response was observed. In conclusion, the current studies demonstrate that in situ forming PEG hydrogels possess the viscoelastic, retention, and sustained delivery properties required for an efficient ocular drug delivery system.