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.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8022, USA.
SivaNaga S
SS
Anumolu
Anupa R
AR
Menjoge
Manjeet
M
Deshmukh
Donald
D
Gerecke
Stanley
S
Stein
Jeffrey
J
Laskin
Patrick J
PJ
Sinko
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry*; D004318:Doxycycline / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry; D007509:Irritants / Q000737:chemistry / Q000494:pharmacology; D008422:Materials Testing; D008466:Mechlorethamine / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009151:Mustard Gas / Q000737:chemistry / Q000494:pharmacology; D016877:Oxidants / Q000737:chemistry; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001672:Biocompatible Materials; D002619:Chemical Warfare Agents; D003432:Cross-Linking Reagents; D004220:Disulfides; D020100:Hydrogels; D007509:Irritants; D016877:Oxidants; D008466:Mechlorethamine; D006861:Hydrogen Peroxide; D004318:Doxycycline; D009151:Mustard Gas