Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2000-06-06
2002-08-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S486000, C424S719000, C424SDIG001, C564S281000
Reexamination Certificate
active
06440405
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to quaternary ammonium functionalized dendrimers and methods of use therefor. Particularly, functionalized dendrimers comprised of Formula I are the object of the invention as well as their use as antimicrobial agents.
BACKGROUND OF THE INVENTION
Jacobs and coworkers first described the antimicrobial activity of many quaternary ammonium compounds (QACs) in 1915. Jacobs, W. A.; Heidelberger, M.
J. Biol. Chem.
1915, 20, 659-683, 685-694; Jacobs, W. A.; Heidelberger, M.
J. Biol. Chem
1915, 21, 103-143, 145-152, 403-407, 439-453, 455-464, 465-475. The second, and most important event in the development of quaternary ammonium biocides occurred in 1935 when Domagk reported that the antibacterial activity of long-chain quaternary ammonium salts was significantly more potent than their short chain counterparts. Domagk,
G. Deut. Med. Wochs.,
61, 829 (1935). The markedly improved antimicrobial activity that occurred when a large aliphatic residue was attached to the quaternary nitrogen atom established the practicality and utility of these compounds, first in medicine, and later in many industrial applications. This important disclosure stimulated further research in synthesis and antimicrobial testing of QACs. It was shown that quaternary ammonium salts are most effective when one substituent is an alkyl chain with at least eight carbon atoms. Rahn, O.; Van Wseltine, W.
Annual Review of Microbiology
1947, 1, 173. The issue of alkyl chain length was considered again when Cutler et al. studied how size affects the antimicrobial activity of a homologous series of alkyldimethylbenzyl ammonium chlorides. They found out that the highest potency is achieved when the alkyl chain has 14 carbons. Block, S.
Disinfection, Sterilization and Preservation;
3rd ed.; Lea & Febiger: Philadelphia, 1983.
Quaternary ammonium compounds are currently widely used as disinfectants. They are surface-active, wide-spectrum antimicrobial agents. QACs are generally known to be more active against Gram-positive bacteria such as S. aureus than Gram-negative bacteria such as
E. coli.
Literally hundreds to thousands of polymeric compounds have been prepared and tested for antimicrobial properties. However, very few polymer compounds with biological activity have been discovered. The only commercially important polymeric biocide is biguanide. Biguanides show a wide spectrum of antimicrobial activity and are much more potent than the related monomers. Davies, A., Bentley, M. Field, B. S.
J. Appl. Bacteriol.,
31, 448-452 (1968).
Biofilms are matrix-enclosed bacterial populations adherent to each other and/or to surfaces or interfaces. Due to the destructive impact of biofilms in such diverse areas such as human physiology, food processing, and marine shipping, there is a great sense of urgency in the scientific community to discover chemical compositions and methods of use to solve biofilm-related problems.
Biofilms in human physiology can withstand host immune responses and are resistant to antibiotics. Antibiotics have proven to be ineffective in the prevention and treatment of biofihm infections particularly associated with biomaterial implants and prosthetic devices. Costerton, et al.,
Behaviour of Bacteria in Bioflims,
ASM News, 55(12):650 (1989); AnWar, et al.,
Effective Use of Antibiotics in the Treatment of Biofilm-Associated Infections,
ASM News, 58(12):665 (1992). Biofilm infections can occur either on dead/inanimate surfaces, such as sequestra of dead bone and medical devices, or on living tissues, as in the case of endocarditis. Biofilms grow very slowly; however, they are rarely resolved by any host defense system, even for those individuals with excellent immune systems. Bacterial colonization on implanted medical devices such as indwelling catheters, cardiac pacemakers, prosthetic heart valves, chronic ambulatory peritoneal dialysis catheters, and prosthetic joints, and the subsequent transformation into invasive infections contribute significantly to morbidity and complications related to implant-centered infections. Clinical studies have shown that even one thousand times the concentration of antibiotic that would typically kill planktonic (free-floating) bacteria fails to kill bacteria aggregated in the form of a biofilm. Costerton, et al.,
Annu. Rev. Microbiol.,
49, 711-745 (1995); Costerton, J. W.
J. Ind. Microbiol.,
15, 137-140 (1995).
Biofilm bacteria are moreover resistant to bacteriophage and to a wide variety of antimicrobial agents used to combat biofouling in industrial environments.
Food processing, for example, can lead to food poisoning through such bacteria as, for example, Salmonella species,
Clostridium perfringens,
Bacillus species,
Staphylococcus aureus,
and
Escherichia coli.
Standard concentrations of various food processing industry standard disinfectants to clean surfaces in the industry is often ineffective thereby contributing to the public health risk factor. Walker, et al.,
Colloids & Surface A,
77, 225-229 (1993).
Biological fouling in the marine environment occurs on a variety of surfaces, including ships hulls, oil and gas installations and piers. Fouling on static structures increases loading forces caused by waves and currents on supports, and impedes inspection and maintenance. Biofilms in tubes and pipes can increase pressure drop and cause clogging. Biofouling on ships reduces their speed and maneuverability, due to the increased drag introduced by biological accumulations, causing increased fuel consumption and maintenance costs. Current marine anti-fouling technology employs biocides such as organotins which are blended into coatings as a preventive measure against growth of microorganisms. However, the ships treated in this manner require the arduous task of relatively frequent treatment. There is considerable interest in developing engineering approaches to modify susceptible surfaces to prevent biofilm formation. Several approaches have been actively investigated including modifying surfaces to minimize bacterial attachment or bacterial growth control through antimicrobial agents. Currently available approaches have not presented a formula for success. Moreover, traditional antibiological warfare agents are known to be very reactive and extremely toxic. Such agents include chlorine, formaldehyde, and peroxygen to destroy and or neutralize the effect of Anthrax spores and other biological entities. Accordingly, there also exists a need for antibiological warfare agents that are nonreactive and are virtually nontoxic to human skin.
Because of their compact structure and the availability of many end groups, dendrimers have attracted attention as possible antimicrobial agents. Zanini et al, Schengrund et al, and Bundle, et al. investigated carbohydrate modified dendrimers as antibacterial agents and using these oligosaccharides for treating and preventing bacterial and viral disease. Zanini, D.; Roy, R.
J. Am. Chem. Soc.,
119, 2088-2095 (1997); Roy, et al,
J. Chem. Soc. Chem. Commun.,
1869-1872 (1993); Schengrund et al, WO patent 9826662, 1998; U.S. Pat. No. 5,962,423, 1999. All these investigators took advantage of the multiple end groups of dendrimers and introduced different carbohydrates onto the dendrimers. These modified dendrimers tend to enhance the carbohydrate-protein binding interactions and can be potent inhibitors for bacterial and viral infections. The carbohydrate chemistry utilizes the specific interaction of a the carbohydrate with the bacteria. The use of these specific interactions limit the application of these carbohydrate dendrimers since different bacteria only respond to different carbohydrates. The quaternary ammonium functionalized dendrimers of the current invention use non-specific interactions with the bacteria and are therefore effective against a wide range of bacteria, spores, yeast, fungi, and mold. Balogh et al. synthesized dendrimer nanocomposites, dendrimers with inorganic silver or silver ions, and tested their antibacterial properties. Balogh, L.
Chen Chris Zhisheng
Cooper Stuart L.
Connolly Bove & Lodge & Hutz LLP
Fubara Blessing
Page Thurman K.
University of Delaware
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