Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-10
2002-02-26
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S223200
Reexamination Certificate
active
06350742
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel antimicrobial compositions and their use. In particular, this invention relates to compositions which contain 4,4′-methylenebis (tetrahydro-1,2,4-thiadiazine)1,1,1′,1′,-tetraoxide and their use in treating infections of the ear, i.e. otitis media and otitis externa.
The chemical and medical literature describes a myriad of compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. In particular, antibacterials include a large variety of naturally-occurring antibiotic, synthetic, or semi-synthetic compounds. They may be classified for example as the aminoglycosides, ansamacrolides, beta-lactams, including penicillins and cephalosporins, lincos-aminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981), both incorporated by reference herein.
The mechanism of action of these antibacterials vary. However, each can be generally classified as functioning in one or more of four ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins in bacteria, which are responsible for cell wall synthesis. On the other hand, quinolones act by inhibiting synthesis of bacterial DNA, thus preventing the bacteria from replicating.
Not surprisingly, the pharmacological characteristics of antibacterials and other antimicrobials, and their suitability for any given clinical use, also vary considerably. For example, the classes of antimicrobials and members within a class may vary in their relative efficacy against different types of microorganisms, and their susceptibility to development of microbial resistance. These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial or other antimicrobial in any given clinical situation can be a complicated analysis of many factors, including the type of organism involved, the desired method of administration, and the location of the infection to be treated.
The pharmaceutical literature is replete with attempts to develop improved antimicrobials, i.e., compounds that have a broader scope of activity, greater potency, improved pharmacology, and/or less susceptibility to resistance development. For example, one group of antimicrobials that has been developed relatively recently for clinical use is the quinolones. These compounds include, for example, nalidixic acid, difloxacin, enoxacin, fleroxacin, norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin, and pefloxacin. See C. Marchbanks and M. Dudley, “New Fluoroquinolones,” 7 Hospital Therapy 18 (1988); P. Shah, “Quinolones,” 31 Prog. Drug Res. 243 (1987); Quinolones—Their Future in Clinical Practice, (A. Percival, editor, Royal Society of Medical Services, 1986; and M. Parry, “Pharmacology and Clinical Uses of Quinolone Antibiotics,” 116 Medical Times 39 (1988).
However, many such attempts to produce improved antimicrobials have produced equivocal results. Indeed, few antimicrobials are developed that are truly clinically-acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology. For example, the quinolones often show reduced, effectiveness against certain clinically important pathogens, for example, gram positive bacteria and/or anaerobic bacteria. The quinolones also have limited water solubility limiting their bioavailability and suitability for parenteral dosing. They may also produce adverse side effects, such as gastrointestinal disturbance and central nervous system effects, such as convulsions. See, M. Neuman and A. Esanu, “Gaps and Perspectives of New Fluoroquinolones,” 24 Drugs Exptl. Clin. Res. 385 (1988); W. Christ et al., “Specific Toxicologic Aspects of the Quinolones,” 10 Rev. Infectious Diseases S141 (1988); H. Neu, “Clinical Use of the Quinolones,” Lancet 1319 (1987); and “Ciprofloxacin: Panacea or Blunder Drug?,” J. South Carolina Med. Assoc. 131 (March 1989).
SUMMARY OF THE INVENTION
This invention provides methods and compositions for the treatment of bacterial infection referred to as otitis media or otitis externa presenting as inflammation of the mucosal lining of the external and/or middle ear usually with exudation which compositions in addition to killing and eradicating pathogens also reduce or eliminate the ability of pathogens to acquire resistance to antibiotic drug treatment. Moreover, this invention relates to methods and compositions for the reduction or elimination of bacteria associated with otitis media and otitis externa.
Specifically, the present invention relates to the use of 4,4′-methylenebis (tetrahydro-1,2,4-thiadiazine)-1,1,1′,1′ tetraoxide known generically as taurolidine to eradicate or control the indigenous microbiota of the ears, namely:
Gram-positive Cocci
Staphylococcus epidermidis
Staphylococcus aureus
Anaerobic micrococci
Streptococcus mitis
undifferentiated
&agr; and &Ugr; streptococci
Streptococcus pneumoniae
Gram-positive Bacilli
Lactobacillus spp.
Aerobic corne bacterium spp.
Aerobic Gram-negative Bacilli
Enterobacteriaceae
Escherichia coli
Enterobacter spp.
Klebsiella spp.
Proteus mirabilis other
Proteus spp.
Morganella morganii
Providencia spp.
Pseudomonas aeruginosa
Alcaligenes Faecalis
Further, the present invention relates to the use of taurolidine to prevent the development of antibiotic drug resistance in the microbiota of the ear.
Taurolidine occurs as a white to off-white powder having the molecular formula C
7
H
16
N
4
O
4
S
2
and a melting point of 154-158° C.
Taurolidine's general characteristics include acceptable stability in the solid state when stored at ambient conditions, melting with decomposition at approximately 170° C. and the following solubility in aqueous solutions and organic solvents.
Water
1% at 20° C.
Dilute HCl
soluble
Dilute NaOH
soluble
CHCl
3
insoluble
EtOH
sparingly soluble
DMF
1 g in 2 mL/ca.60° C.
Acetone
1 g in 120 mL/Boiling
Ethanol
1 g in 130 mL/Boiling
Methanol
1 g in 170 mL/Boiling
Ethyl Acetate
1 g in 200 mL/Boiling
A saturated solution of taurolidine in deionized water has a pH of 7.4. The apparent partition coefficient of taurolidine between octanol and water (buffered at pH 7.2) is approximately 0.13 and would therefore not be predicted to accumulate to any significant extent in fatty tissues.
The synthesis of taurolidine is covered in a number of patents including U.S. Pat. No. 3,423,408; Switzerland No. 482,713 and United Kingdom No. 1,124,285 and is carried out in five stages:
Potassium phthalimidoethane sulphonate is prepared from taurinc, phthalic anhydride, glacial acetic acid and potassium acetate;
Potassium phthalimidoethane sulphonate is then converted to phthalimidoethane sulphonylchloride by chlorination with phosphorous oxychloride;
Phthalimidoethane sulphonylchloride is reacted with ammonia to form phthalimidoethane sulphonamide;
Phthalimidoethane sulphonylchloride is reacted with hydrazine hydrate and in the subsequent hydrazinolysis to form taurinamide hydrochloride; and
Taurolidine is prepared from taurinamide hydrochloride and formaldehyde.
The antimicrobial actions of taurolidine have been described in U.S. Pat. No. 3,423,408 and elsewhere in the literature. In addition, the following United States patents describe various uses for and compositions containing taurolidine: U.S. Pat. No. 4,107,305, treatment of endotoxaemia; U.S. Pat. No. 4,337,251, e
Carter-Wallace Inc.
Clarke Kevin B.
Weddington Kevin E.
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