Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications
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Publication Number
US-8389021-B2
Publication Date
2013-03-05
Expiration Date
Abstract
Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating acute wounds, chronic wounds and/or a wound or epithelial tissue surface that contains bacterial biofilm, including unexpected synergy between bismuth-thiol (BT) compounds and certain antibiotics, to provide topical formulations including antiseptic formulations, for management and promotion of wound healing and in particular infected wounds. Previously unpredicted antibacterial properties and anti-biofilm properties of disclosed BT compounds and BT compound-plus-antibiotic combinations are also described, including preferential efficacies of certain such compositions for treating gram-positive bacterial infections, and distinct preferential efficacies of certain such compositions for treating gram-negative bacterial infections.
Core Innovation
The disclosed invention relates to bismuth-thiol (BT) antiseptic microparticle compositions. The compositions include a plurality of solid microparticles that exhibit a unimodal size distribution and a volumetric mean diameter of from about 0.4 μm to about 5 μm when analyzed on a particle size analyzer. The BT compound contained in the microparticles is not micronized, milled, or subjected to super-critical fluid processing, and comprises bismuth or a bismuth salt and a thiol-containing compound.
A preparation method is also disclosed for producing the BT microparticles without micronizing, milling, or super-critical fluid processing. An acidic aqueous solution comprising a bismuth salt with bismuth at a concentration of at least 50 mM and lacking a hydrophilic, polar or organic solubilizer is admixed with ethanol to obtain an admixture comprising about 25% ethanol by volume. An ethanolic solution containing a thiol-containing compound is then added such that the thiol-containing compound is present at a molar ratio of from about 1:3 to about 3:1 relative to bismuth to form a precipitate containing the BT microparticles.
The invention further addresses epithelial tissue and bacterial pathogens through contacting an epithelial tissue surface with an effective amount of the BT composition. The stated aim is prevention of infection, inhibition of planktonic cell viability and/or growth, inhibition of biofilm formation, and inhibition of biofilm viability and/or growth. The document emphasizes antibiotic-BT synergy and suppressing biofilm formation/viability, including preferential bacterial activity as between gram-positive and gram-negative bacteria in the reported context.
Claims Coverage
The independent claim content identifies three inventive features: a BT composition, a method for preparing that composition, and a method for protecting epithelial tissue against a bacterial pathogen.
Unimodal non-processed BT microparticles with defined volumetric mean diameter
A BT composition comprising a plurality of solid microparticles that exhibit a unimodal size distribution on a particle size analyzer and comprise a BT compound not micronized, milled or subjected to super-critical fluid processing, substantially all microparticles having a volumetric mean diameter from about 0.4 μm to about 5 μm, wherein the BT compound comprises bismuth or a bismuth salt and a thiol-containing compound.
Acidic bismuth-salt/ethanol admixture with defined bismuth:thiol molar ratio precipitation to form BT microparticles
A method for preparing a BT composition comprising solid microparticles with unimodal size distribution and volumetric mean diameter from about 0.4 μm to about 5 μm, not micronized, milled or subjected to super-critical fluid processing, comprising admixing an acidic aqueous solution of a bismuth salt with ethanol to obtain about 25% ethanol by volume, and adding an ethanolic solution comprising a thiol-containing compound at a molar ratio of from about 1:3 to about 3:1 relative to bismuth to form a precipitate comprising the BT microparticles.
Protecting epithelial tissue surface against bacterial pathogen by inhibiting planktonic and biofilm states
A method for protecting an epithelial tissue surface against a bacterial pathogen by contacting the epithelial tissue surface with an effective amount of a BT composition, under conditions and for a time sufficient for prevention of infection, inhibition of planktonic cell viability and growth, inhibition of biofilm formation, and inhibition of biofilm viability and growth.
The claims center on BT microparticles that are not micronized, milled, or super-critical fluid processed and have a unimodal size distribution with substantially all particles in a volumetric mean diameter range of about 0.4 μm to about 5 μm, plus a precipitation-based preparation using an acidic aqueous bismuth-salt solution admixed with ethanol and a thiol-containing ethanolic solution at a defined bismuth:thiol molar ratio. The claims also include epithelial-contact use targeting planktonic viability/growth and biofilm formation/viability.
Stated Advantages
Prevention of infection.
Inhibition of planktonic cell viability and growth.
Inhibition of biofilm formation.
Inhibition of biofilm viability and growth.
Antibiotic-BT synergy.
Suppressing biofilm formation and viability.
Preferential bacterial activity as between gram-positive and gram-negative bacteria in the reported context.
Documented Applications
Protecting an epithelial tissue surface against a bacterial pathogen by contacting the epithelial tissue surface with an effective amount of the BT composition to prevent infection and inhibit planktonic and biofilm bacterial states.
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