Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-10
2003-04-29
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S925000, C514S926000, C514S927000, C424S093400, C544S008000
Reexamination Certificate
active
06555534
ABSTRACT:
This invention relates to a method and compositions for the treatment of bacterial infection which reduces or eliminates the presence of bacteria. Moreover, this invention relates to a method and compositions for the reduction or elimination of
Helicobacter pylori.
Specifically, the present invention relates to the use of 4,4′ methylenebis(tetrahydro-1,2,4-thiadiazine-1,2-dioxide) known generically as taurolidine to treat bacterial infections, particularly
Helicobacter pylori
infections.
Taurolidine occurs as a white to off-white powder having the molecular formula — C
7
H
16
N
4
O
4
S
2
.
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 USA 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. patent application Ser. No. 09/151,885 filed Sept. 11, 1998 and 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, elimination of adhesion formation as a result of surgery; U.S. Pat. No. 4,587,268, resorbable aqueous gels; U.S. Pat. No. 4,604,391, prevention of the occurrence of osteitis or osteomyelitis; U.S. Pat. No. 4,626,536, combating toxic proteins or peptides in the blood; U.S. Pat. No. 4,772,468, treatment of bone cavities; and U.S. Pat. No. 4,882,149, directed to methods for filling congenital, surgical or traumatic defects with compositions comprising natural bone mineral having absorbed therein/thereon taurolidine.
Taurolidine's mechanism of action unlike that of known antibiotics is based on a chemical reaction. While not being bound by any theory, during the metabolism of taurolidine to taurinamide and ultimately taurine and water, methylol groups are liberated which chemically react with the mureins in the bacterial cells walls this results in the denaturing of the complex polysacchardide and liposaccharide components of the bacterial cell wall as well as changing the double stranded DNA of the plasmid to a denatured or single stranded DNA.
Taurolidine has been shown to be safe and well tolerated at systemic doses exceeding 40 g/day and cumulative doses up to and exceeding 300 g.
The formulations of taurolidine generally utilized are sterile solutions containing 0.5%, 1.0% or 2.0% taurolidine for irrigation/lavage, wound instillation, or intravenous administration, primarily for the treatment or prevention of peritonitis, sepsis or osteitis/osteomyelitis. In addition, topical surgical gels containing 2.0% to about 4.0% are utilized for the treatment of osteitis/osteomyelitis.
It has long been the goal of the pharmaceutical industry to produce antibiotic medicinal substances that have the power to kill—or at least to arrest the growth of—many disease causing bacteria such as
Helicobacter pylori.
Much has been published regarding
Helicobacter pylori
itself. Helicobacter pylori is approximately 0.85 &mgr;m in diameter with an average length of 2.9 &mgr;m. The microorganism has a smooth coat and four to six polar flagella which are sheathed and have bulbous ends. In fresh cultures this organism appears as a slender, curved Gram-negative rod.
Helicobacter pylori
is readily distinguished from other gastric bacteria and spirochaetes by the absence of axial filaments in its flagella. Furthermore, optimum growth conditions for
Helicobacter pylori
are unusual and help to set it apart from other enteropathogens. For example,
Helicobacter pylori
requires a microaerophilic gas environment (i.e. low oxygen content) to sustain growth.
Helicobacter pylori
appears tolerate a wide range of local pH conditions and is relatively resistant to acid conditions. It is believed that this resistance is due in part to the organism's outer protein structure which contains urease in large amounts resulting in the cleavage of urea naturally present in gastric fluid and hence, the formation of a buffering ammonia layer immediately around the organism.
Although a number of spiral bacteria inhabit the mouth and lower intestinal tract of all mammals, what distinguishes
Helicobacter pylori
is the observation that it is localized almost exclusively to the luminal mucosal surface of the stomach and duodenum and generally is found deep within the gastric pits.
It is the combination of the unusual growth requirements and intestinal location which makes eradication and treatment of
Helicobacter pylori
so difficult. The ideal antimicrobial drug suitable for the successful treatment of
Helicobacter pylori
associated gastritis should exhibit local activity, be stable at low pH values and should be able to readily penetrate the gastric mucosa. These desirable properties of an antimicrobial are not easily accomplished and thus, satisfactory treatment of
Helicobacter pylori
with antimicrobials has yet to be accomplished.
The development of an agent which is effective in the management of
Helicobacter pylori
induced gastritis would fulfill a long felt need. There is an emerging consensus in the field of gastroenterology that
Helicobacter pylori
is a major contributing factor in the development of gastritis and septic ulcer disease. Specifically, the following reference is useful in establishing the background of the present invention:
Campylocacter pylori
, E. A. J. Rauns and G. N. J. Tytgat, Editors, Adis Press lntntl. (1989).
The present invention relates to a method and composition for the eradication of the microorganism
Helicobacter pylori
(formerly referred to in the literature as
Campylobacter pylori
). In its broadest aspect, the present invention is directed to novel compositions which demonstrate antimicrobial activity against
Helicobacter pylori.
Moreover, owing to its chemical mechanism of action with the bacterial cell wall, taurolidine is fully effective against
Helicobacter pylori
which are resistant to other antibiotics. Further, treatment of
Helicobacter pylori
with taurolidine reduces or eliminates the ability of the bacteria to acquire resistance to antibiotic drug treatment.
Peptic ulcers, once thought to result from stress, or excess acidity, or a reduction of the mucosal defense factors in the stomach, are now in a majority of cases considered to be the result of bacterial infection by
Helicobacter pylori
. The mounting evidence to this effect is well documented in
Helicobacter pylori
in Peptic Ulceration and Gastritis, edited by Barry J. Marshall, Richard W. McCallum and Richard L. Guerraut, Blackwell Scientific Publications, Boston, U.S.A. Pertinent Ch
Medpointe Healthcare Inc.
Olstein Elliot M.
Stauffer Raymond E.
White Everett
Wilson James O.
LandOfFree
Method and compositions for the control or eradication of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and compositions for the control or eradication of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and compositions for the control or eradication of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3024322