Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2000-04-06
2001-06-19
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C514S706000
Reexamination Certificate
active
06248371
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition and a method for the amelioration and inhibition of bacterial, viral and other microbial activity, and more particularly, to certain metal:thiol complexes and metal/thiol mixtures, and their uses. Bacteriocidal and bacteriostatic properties are demonstrated, as are anti-biofilm properties. The present invention also relates to anti-biofilm use of certain metal:pyrithione complexes and metal/pyrithione mixtures.
DESCRIPTION OF THE RELATED ART
Infectious diseases of the digestive tract constitute a major health problem throughout the world. Infectious diarrheal disease is one of the leading causes of morbidity and mortality in developing countries. In developed countries, diarrhea and colitis are frequent symptoms during antibiotic therapy. Food contamination with Salmonella, Shigella, Campylobacter, or
E. coli
poses a major health problem. Diarrhea is the most frequent discomfort among travelers. Even ulcers are now considered an infectious disease.
The finding in 1983 that
Helicobacter pylori
was the probable cause of ulcers has precipitated intense activity in developing therapies to eradicate this organism from the gastrointestinal (GI) tract. Therapies have emerged, involving combinations of antibiotics, H
2
-inhibitors and bismuth compounds. These therapies rely heavily on bismuth to prevent recurrence. At present, the preferred form to administer bismuth is as the subcitrate (colloidal bismuth subcitrate or CBS) or as the subsalicylate (BSS, available commercially as Pepto-Bismol®).
The mechanisms by which colloidal bismuth subcitrate or Bismuth subsalicylate help to eradicate
H. pylori
are not fully understood and are currently under investigation. For a review of the properties of colloidal bismuth subcitrate, see Wagstaff, et al., Drugs 36:132-157 (1988). Apparently no single mechanism of bismuth activity can account for all of the anti-ulcer effects suggested in the literature. Indeed a number of therapeutic activities may be involved. Experiments recently performed by Beil et. al., Pharmacology; 47:135-140 (1993) investigated the interactions between colloidal bismuth subcitrate (CBS) and sulfhydryls and their results indicated that dithiothreitol did not enhance the antibacterial activity of colloidal bismuth subcitrate.
Bismuth compounds are also used in numerous other medical applications. For example, they are used orally as anti-diarrheal agents, for an upset stomach, nausea, vomiting, and as an internal deodorant, and as skin antiseptics. Bismuth compounds are also used prophylactically for Traveler's diarrhea, and as an iodoform paraffin paste, they are used to limit infection of surgical wounds. In general, bismuth has antibacterial properties with proven medical usefulness. However, the potency of bismuth compounds is relatively low, especially when iron is present. In addition, one of the major problems with using bismuth is its insolubility in aqueous solutions.
Bismuth also has selective effects on expression of virulence factors in bacteria. Concentrations below that which inhibited bacterial growth nevertheless repressed the expression of capsular polysaccharide (CPS) from
K. pneumoniae
and other members of its family Enterobacteriaciae. It also represses the expression of certain pili involved in adherence. The antibacterial potency of bismuth is especially strong under low iron conditions. Increasing iron negates the inhibitory effects of bismuth on bacteria. In addition to bismuth, antimony and arsenic also exhibit modest antibacterial activity which necessitates the use of large doses. This is not always feasible due to their general toxicity and their lack of solubility in water.
Most prior art antibacterial agents suffered from significantly reduced utility when confronted with biofilm. “Biofilm” is a symbiotic community of bacteria (and sometimes other microbes including yeast) in which the entire community (which may also include different types of bacteria) acts, at least in part, as a single unit. Significant amounts of capsular polysaccharide is secreted and binds the organisms together. Metabolism and reproduction slow significantly relative to ordinary bacterial colonies. Biofilm is relatively unresponsive to most chemotactic intervention. The capsular polysaccharide prevents access of antibiotics to bacteria below the surface. Also, antibiotic mediated lysing of surface bacteria undesirably provide food for sub-surface bacteria. Antibiotics that function by attacking cell division and multiplication have little affect on biofilm bacteria which do very little dividing and multiplying.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide more effective compositions and methods for broad antimicrobial applications, including prevention or inhibition of bacterial, fungal, or viral infection.
It is another object of the present invention to eradicate bacteria.
It is yet another object of the present invention to prevent spoilage.
It is yet another object of the present invention to provide methods and components for preventing the formation or growth of biofilm, and for reducing already-formed biofilm.
It is yet another object of the invention to treat psoriasis.
It is yet another object of the invention to treat thrush.
It is yet another object of the invention to treat Candida and Cryptococcal infections.
In one embodiment, the invention provides a method of suppressing bacterial growth comprising the step of supplying to a region for which said suppression is desired, an anti-bacterial agent comprising an antibacterial formulation selected from the group consisting of:
(A) a mixture comprising (i) a non-pyrithione complexing agent having at least one thiol group, and (ii) a group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, antimony and arsenic;
(B) a complex whose molecular structure includes (i) a non-pyrithione complexing agent having at least one thiol group, (ii) a Group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, arsenic and antimony; and (iii) a coordinate bond linking at least one sulfur atom of the thiol-containing complexing agent of subparagraph (B) (i) to the metal of subparagraph (B)(ii); and
(C) a combination comprising the complex of paragraph (B) and at least one specie selected from the group consisting of (i) a thiol-containing complexing agent and (ii) a Group V metal or compound thereof, said Group V metal, being selected from the group consisting of bismuth antimony and arsenic.
The term “thiol” is used herein to refer to a compound that contains one or more sulfur atoms capable of existing in the form of sulfhydryl groups under appropriate pH conditions, e.g. significantly below the lowest pKa of the compound, regardless of whether such sulfur atoms are deprotonated or fully or partially protonated under conditions in which the thiol is used. “Thiol group” means a sulfur or an -SH group of a “thiol”.
The terms “mixture” and “combination” encompass the use of two or more components in sufficiently close proximity to each other that they may interact with each other under conditions of end use for the antimicrobial agent of the invention, or for products which include said agent in accordance with the invention. Patients in need of treatment for a particular disease are those displaying symptoms or responding to diagnostic tests indicating presence of the disease in question. Patients in need of prophylactic intervention are those who through exposure or otherwise are at higher risk of contracting the disease in question than is the general population.
Antimicrobial agents described herein may be used to suppress microbial growth, reduce microbial infestation, treat products or surfaces to improve product resistance to microbial infestation, reduce biofilm, prevent conversion of bacteria to biofilm, prevent or inhibit microbial infection, prevent spoilage, and any other use described herein. It is also usef
Ostrolenk Faber Gerb & Soffen, LLP
Spivack Phyllis G.
Winthrop University Hospital
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