Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-02-02
2003-06-24
Venkat, Jyothsan (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S405000, C424S422000, C424S614000, C424S618000, C424S653000, C424S604000, C424S205100
Reexamination Certificate
active
06582719
ABSTRACT:
1. INTRODUCTION
The present invention relates to combinations of antiseptic and antibiotic agents which exert an antimicrobial effect while deterring, relative to other antimicrobial agents, the development of antibiotic-resistant microorganisms.
2. BACKGROUND OF THE INVENTION
An antiseptic is a substance that kills or prevents the growth of microorganisms, and which is typically applied to living tissue, distinguishing the class from disinfectants, which are usually applied to inanimate objects (Goodman and Gilman's “
The Pharmacological Basis of Therapeutics
”, Seventh Edition, Gilman et al., editors, 1985, Macmillan Publishing Co., (hereafter, Goodman and Gilman”) pp. 959-960). Common examples of antiseptics are ethyl alcohol and tincture of iodine. Alcohol is usually used to clean a subject's skin prior to insertion of a hypodermic needle; tincture of iodine is frequently applied as a first step in wound care, both uses intended to decrease the number of microbes on the skin to prevent invention.
While antiseptics once played a more substantial role in wound management, they are now secondary in importance to antibiotics, chemical substances produced by various species of microorganisms (or synthetic or semisynthetic analogs thereof) that kill or suppress the growth of other microorganisms (Goodman and Gilman, p. 1067). Antibiotics may be administered systemically or locally applied. Since the production of penicillin in 1941, antibiotics have been widely used, with the result that microorganism strains have developed which are resistant to one or more antibiotic. The generation of resistant organisms has created an ever-increasing need for the identification or synthesis of new antibiotics (Goodman and Gilman, p. 1066).
One particularly useful class of antibiotics is tetracyclines, which exert their antibacterial action by binding to microbial ribosomes and preventing protein synthesis (Goodman and Gilman, p.1171). Tetracyclines are primarily bacteriostatic when tested in vitro, and only multiplying microorganisms are affected. They possess antimicrobial activity against a wide variety of microorganisms, including gram-positive and gram negative bacteria, and against some microorganisms, such as Rickettsiae, Mycoplasma, Chlamydia, some atypical Mycobacteria, and ameobae, that are resistant to other classes of antibiotics (Id.). Minocycline, doxycycline, tetracycline and oxytetracycline are tetracycline-class drugs listed in order of decreasing antimicrobial activity (Id.).
The first documented medical use of bismuth occurred in 1773, when it was used in salves. Since then it has been used to combat diarrhea, gastroenteritis, stomach cramps, vomiting and ulcers. It has been used for the treatment of surgical wounds (Bierer, 1990, Rev. Infect. Dis. 12 (Suppl. 1): S3-S8). The antimicrobial effect of bismuth is well known. The reducing effect of bismuth compounds on fermentation by colonic bacteria has been demonstrated both in vitro and in vivo (Leon-Barua et al., 1990, Rev. Infect. Dis. 12 (Suppl. 1): S24-S29).
Bismuth salts have also been shown to have a significant effect on the inhibitory activity of antibiotics. Bismuth salicylate (“BSS”) and bismuth nitrate have been reported to potentiate aminoglycoside activity against gram negative bacteria (Domenico et al., 1991, J. Antimicrob. Chemother. 28:801-810). BSS, bismuth nitrate and bismuth dimercaprol (Bis-BAL), have also been reported to inhibit capsular polysaccharide production by the bacterium
Klebsiella pneumoniae
(Domenico et al., 1991, J. Antimicrobial Chemother. 28:801-810; Domenico et al., 1996, Ann. N. Y. Acad. Sci. 797:269-270). BisBAL has also been shown to have good activity against a wide spectrum of bacteria among the genera Yersinia, Shigella, Salmonella, Pseudomonas, Proteus, Enterobacter, Escherichia, Staphylococci, Helicobacter, and Clostridia (Domenico, 1997, Antimicrob. Ag. Chemother. 41:1697-1703) and to inhibit polysaccharide production in biofilms (Huang and Stewart, 1999, J. Antimicrob. Chemother. 44:601-605). The use of bismuth salts in combination with thiol compounds for the preparation of a composition with anti-infective properties has been described by Domenico, 1999, U.S. Pat. No. 5,928,671. The potentiation of antibiotics by a bismuth salt of pyrrolidone carboxylic acid, resulting in higher tissue levels of the antibiotic was described by Bocher et al., 1977, U.S. Pat. No. 4,064,238. The use of bismuth salts, in combination with an antibiotic and metronidazole for the eradication of
Helicobacter pylori,
a causative agent of duodenal ulcer, has also been described (Borody, 1993, U.S. Pat. No. 5,196,205).
International Application No. PCT/US00/08692, entitled “TRICLOSAN AND SILVER COMPOUND CONTAINING MEDICAL DEVICES” by The Trustees of Columbia University in the City of New York teaches the addition of various antibiotics, including those set forth herein, to combinations of triclosan and silver salts. The use of bismuth salts, as set forth herein, was not disclosed.
3. SUMMARY OF THE INVENTION
The present invention relates to compositions comprising a combination of one or more antiseptic and an antibiotic. It is based, at least in part, on the discovery that such combinations tend to deter the formation of antibiotic-resistant organisms. In preferred, nonlimiting embodiments of the invention, the antibiotic is minocycline and the antiseptic is a chlorhexidine compound, triclosan, or benzalkonium chloride, and in particular embodiments, a silver salt or a bismuth salt is added. Examples of specific, nonlimiting embodiments of the invention include combinations of (i) minocycline, triclosan, and a bismuth salt; (ii) minocycline, a chlorhexidine compound, and a bismuth salt; and (iii) minocycline, benzalkonium chloride, and a bismuth salt. The present invention further provides for articles, such as, but not limited to, medical articles, which have been treated with or which otherwise comprise a combination of antiseptic and antibiotic.
Antibiotics, unlike antiseptics, may be used in relatively high concentrations because they tend to be less toxic to host tissue. The use of higher concentrations may result in longer term efficacy. In contrast, antiseptics typically should be used in lower concentrations, because they are frequently toxic to host tissue. Even at lower concentrations, however, antiseptics may provide cidal action against a wide range of microorganisms. Thus, combinations of antibiotics and antiseptics according to the invention may provide for prolonged antimicrobial effectiveness against a variety of microbes.
4. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compositions comprising combinations of (i) an antibiotic selected from the group consisting of minocycline, rifampin, and norfloxacin; and (ii) an antiseptic selected from the group consisting of biguanide compounds, triclosan, and benzalkonium chloride. In preferred embodiments, such compositions further comprise a salt of bismuth, cerium, or zinc or a silver-containing compound. Such compositions may be incorporated into or onto medical devices to impart antimicrobial activity to the devices. The present invention also provides for methods of using such compositions in the preparation of medical devices.
Biguanide compounds which may be used according to the invention include poly (hexamethylene biguanide) hydrochloride and chlorhexidine compounds. Chlorhexidine is the term denoting the chemical compound 1,6 bis(N
5
-p-chlorophenyl-N
1
-biguanido)hexane). Chlorhexidine compounds include chlorhexidine free base (“CHX”) as well as chlorhexidine salts, such as chlorhexidine diphosphanilate, chlorhexidine digluconate (“CHG”), chlorhexidine diacetate (“CHA”), chlorhexidine dihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acid phosphate, chlorhexidine difluorophosphate, chlorhexidine diformate, chlorhexidine dipropionate
Modak Shanta M.
Sampath Lester A.
Tambe Suhas
The Trustees of Columbia University in the City of New York
Venkat Jyothsan
LandOfFree
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