Use of CPG oligonucleotides co-formulated with an antibiotic to accelerate wound healing
Inventors
KLINMAN, DENNIS M. • Ito, Hiroyasu
Assignees
US Department of Health and Human Services
Publication Number
US-10076535-B2
Publication Date
2018-09-18
Expiration Date
2033-03-29
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Abstract
Pharmaceutical compositions are provided that include an antibiotics, but that include ingredients that counteract the effect of that antibiotic on wound healing, without altering the bactericidal properties of the antibiotic. These pharmaceutical compositions include an effective amount of 1) an imidazoquinoline having toll-like receptor 7 (TLR7) ligand activity, 2) an immunostimulatory K-type CpG oligodeoxynucleotide (ODN) comprising an unmethylated CpG motif, 3) an antibiotic, and 4) a surfactant, wherein the composition is formulated for topical administration. Methods for accelerating wound healing are also provided. These methods include topically administering the disclosed compositions. The wound can be in the skin or in the eye.
Core Innovation
The invention provides pharmaceutical compositions comprising an antibiotic combined with an imidazoquinoline having toll-like receptor 7 (TLR7) ligand activity, an immunostimulatory K-type CpG oligodeoxynucleotide (ODN) with an unmethylated CpG motif, and a surfactant. These compositions are formulated for topical administration and include amounts of the ODN and imidazoquinoline sufficient to counteract the wound healing delay caused by the antibiotic without altering its bactericidal properties.
The invention addresses the problem that although antibiotics reduce bacterial contamination in wounds, their use delays wound healing by reducing pathogen-associated molecular patterns (PAMPs) that stimulate the innate immune response and accelerate repair. The compositions counteract this adverse consequence of antibiotics by stimulating innate immune pathways via TLR7 and TLR9 ligands, namely imidazoquinolines and K-type CpG ODNs, restoring or accelerating wound healing while maintaining antibiotic efficacy.
Claims Coverage
The patent includes multiple independent claims covering pharmaceutical compositions combining specific components for topical use and methods for accelerating wound healing using these compositions. The main inventive features focus on the composition components, their specified structures and properties, and the therapeutic methods applying these compositions.
Pharmaceutical composition comprising a TLR7 ligand, immunostimulatory K-type CpG oligodeoxynucleotide, antibiotic, and surfactant
A pharmaceutical composition formulated for topical administration that includes an effective amount of (1) an imidazoquinoline with TLR7 ligand activity, (2) an immunostimulatory K-type CpG ODN containing an unmethylated CpG motif of formula 5′-N1N2N3D-CpG-WN4N5N6-3′, (3) an antibiotic, and (4) a surfactant, wherein the amounts of the K-type ODN and imidazoquinoline counteract wound healing delay caused by the antibiotic.
Pharmaceutical composition comprising multiple immunostimulatory K-type CpG oligodeoxynucleotides
A pharmaceutical composition with the components as above, wherein the K-type CpG ODN includes multiple CpG motifs separated by at least one nucleotide and sequences selected from SEQ ID NOs: 3-33.
Specified concentrations of K-type CpG ODN and imidazoquinoline
Compositions comprising about 250 to 750 μg/gm of immunostimulatory K-type CpG ODN, about 5 mg/gm imiquimod or resiquimod as the TLR7 ligand, and specified antibiotics including polymyxin B, bacitracin, and/or neomycin sulfate.
Specific antibiotic components and concentrations
Compositions including polymyxin B sulfate from about 5,000 to 10,000 units/gm, neomycin sulfate from about 1.75 to 3.5 mg/gm, and zinc bacitracin from about 400 to 500 units/gm, in combination with the other components.
Use of polysorbate surfactants in topical formulations
The inclusion of surfactants specifically polysorbates such as polysorbate 20 at concentrations ranging 4% to 6% v/v in the topical composition.
Methods of accelerating wound healing by topical administration
Methods for accelerating wound healing in a subject by topically administering a therapeutically effective amount of the disclosed pharmaceutical compositions to skin or eye wounds, including surgical wounds and skin grafts, thereby improving healing relative to antibiotic treatment alone.
The claims cover pharmaceutical compositions containing an antibiotic combined with a TLR7 ligand, K-type CpG ODN, and a surfactant formulated topically to counteract antibiotic-induced wound healing delay, including specified sequence and dosage ranges, surfactants, and antibiotics. They also encompass methods of use of these compositions to accelerate healing of various wound types by topical application.
Stated Advantages
The compositions counteract the delay in wound healing caused by antibiotic treatment without impairing the antibiotic's bactericidal activity.
The co-administration of TLR7 and TLR9 ligands accelerates wound healing more rapidly than either ligand alone.
The compositions reduce bacterial burden at the wound site while simultaneously promoting inflammation and production of cytokines and growth factors involved in wound repair.
Documented Applications
Topical treatment of wounds in the skin or eye to accelerate wound healing while controlling bacterial infections.
Treatment of surgical wounds and skin grafts, including improving adherence and acceptance of the graft.
Treatment of corneal abrasions and epithelial wounds of the eye.
Promotion of healing for diabetic ulcers, dermal ulcers, burns, blisters, ischemic wounds, anastomotic wounds, and other wounds caused by trauma or surgery.
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