Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents

Abstract

The present invention is directed to compositions comprising at least one nitric oxide donor and at least one second therapeutically active agent with antimicrobial or wound healing capability. In one embodiment, the nitric oxide donor is a nanoparticle which is designed to control for the amount and duration of release of nitric oxide. The nanoparticle may further comprise the additional therapeutically active agent. The composition is useful for enhancing wound healing and for treating and preventing microbial infection. In one embodiment, the composition is directed toward reducing oral bacteria or dental plaque. The combination of one or more nitric oxide donors and one or more additional therapeutically active agent results in unexpected synergistic effects, wherein both the antimicrobial efficacy of the nitric oxide and the antimicrobial or wound healing efficacy of the second therapeutically active agent are enhanced. As a result, a patient may benefit from reduced dosage requirements and a reduced likelihood of antimicrobial resistance. The composition may be formulated for local or systemic administration, for topical applications as well as for use in coatings for medical supplies and devices.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a NO donor and one or more antimicrobial agents, wherein said NO donor and said one or more antimicrobial agents are each present in a concentration that is less than a concentration that provides a 3 log microbial kill in 120 minutes (MBC 120 ). 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said NO donor and said one or more antimicrobial agents in combination provide a fractional bactericidal concentration (NBC) of 0.5 or less. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein said NO donor comprises a compound containing a functional group selected from the group consisting of
 diazeniumdiolates, S-nitrosothiols, metal coordination complexes, hydroxyureas, nitrosamines,   hydroxyl nitrosamines, and hydroxylamines.   
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said NO donor is a diazeniumdiolate. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein said NO donor provides a maximum NO flux of at least about 21,700 ppb/mg upon exposure to physiological conditions. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein said one or more antimicrobial agents is selected from the group consisting of clindamycin, erythromycin, and any combination thereof. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein said composition is in the form of a paste, oral rinse, cream, gel, salve, foam, aerosol, spray, lotion, ointment, soap, or shampoo. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein each of said NO donor and said one or more antimicrobial agents is applied to a subject in a separate composition to form said composition. 
     
     
         9 . A pharmaceutical composition comprising a NO donor and one or more antimicrobial agents, wherein said composition reduces the likelihood of antimicrobial resistance and said NO donor and said one or more antimicrobial agents are each present in a sub-bactericidal concentration. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said NO donor comprises a compound containing a functional group selected from the group consisting of
 diazeniumdiolates, S-nitrosothiols, metal coordination complexes, hydroxyureas, nitrosamines,   hydroxyl nitrosamines, and hydroxylamines.   
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said NO donor is a diazeniumdiolate. 
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein said NO donor provides a maximum NO flux of at least about 21,700 ppb/mg upon exposure to physiological conditions. 
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein said one or more antimicrobial agents is each independently selected from the group consisting of topical antibiotics, systemic antibiotics, topical antiseptics, and any combination thereof. 
     
     
         14 . The pharmaceutical composition of  claim 9 , wherein said composition is in the form of a paste, oral rinse, cream, gel, salve, foam, aerosol, spray, lotion, ointment, soap, or shampoo. 
     
     
         15 . The pharmaceutical composition of  claim 9 , wherein each of said NO donor and said one or more antimicrobial agents is applied to a subject in a separate composition to form said composition. 
     
     
         16 . A pharmaceutical composition comprising a NO donor and one or more of clindamycin or erythromycin, wherein said one or more of clindamycin or erythromycin and said NO donor in combination provide a fractional bactericidal concentration (FBC) of 0.5 or less. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein said composition is in the form of a paste, oral rinse, cream, gel, salve, foam, aerosol, spray, lotion, ointment, soap, or shampoo. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein each of said NO donor and said one or more of clindamycin or erythromycin is applied to a subject in a separate composition to form said composition. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein said NO donor is a diazeniumdiolate.