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.
Anumolu
SivaNaga S
SS
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8022, USA.
Menjoge
Anupa R
AR
Deshmukh
Manjeet
M
Gerecke
Donald
D
Stein
Stanley
S
Laskin
Jeffrey
J
Sinko
Patrick J
PJ
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