Title: Method and compositions for the control or
eradication of Helicobacter pylori
United States Patent: 6,555,534
Issued: April 29, 2003
Inventors: Costin; James C. (Lower Gwynedd, PA)
Assignee: Medpointe Healthcare Inc. (Somerset, NJ)
Appl. No.: 266095
Filed: March 10, 1999
The use of 4,4-methylenebis (tetrahydro-1,2-4-thiadiazine-1,1 -dioxide)
in the eradication and control of the microorganism Helicobacter pylori in
humans is disclosed.
Description of the Invention
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
Taurolidine occurs as a white to off-white powder having the molecular
formula -- C7 H16 N4 O4 S2.
Taurolidine's general characteristics include acceptable stability in the
solid state when stored at ambient conditions, melting with decomposition at
approximately 170oC. and the following solubility in aqueous
solutions and organic solvents.
Water 1% at 20oC.
Dilute HCl soluble
Dilute NaOH soluble
EtOH sparingly soluble
DMF 1 g in 2 mL/ca.60oC.
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
Phthalimidoethane sulphonylchloride is reacted with ammonia to form
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'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
Much has been published regarding Helicobacter pylori itself. Helicobacter
pylori is approximately 0.85 .mu.m in diameter with an average length of 2.9
.mu.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
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 Chapters in this work
include Chapter four, The Epidemiology of Helicobacter pylori Infection by
D. N. Taylor and M. J. Blaser; Chapter seven, Laboratory Diagnosis and
Handling of Helicobacter pylori, by T. U. Westblom; and Chapter twelve,
Practical Diagnosis of Helicobacter pylori by B. J. Marshall. The history of
the discovery of Helicobacter pylori and its association with gastro
intestinal disease is extensively described in "Marshall's Hunch, " The New
Yorker magazine, pages 64-72, Sep. 20, 1993 and "The Doctor Who Wouldn't
Accept No, " Reader's Digest magazine, pages 120-124, Oct. 1993.
The effect of treatment of Helicobacter pylori Infection on long term
recurrence of Gastric or Duodenal Ulcer is described by David Y. Graham et
al. In Annals of Internal Medicine 1992; 116: No. 9.
Helicobacter pylori has now been shown to be the causative agent for most
instances of chronic gastritis. And, it is now known that, in the absence of
aspirin, non-steroidal anti-inflammatory drugs or hypersecretory states,
this bacteria is directly implicated in the production of peptic ulcer
diseases such as duodenal and benign gastric ulcers. The eradication of
Helicobacter pylori gastritis by antibiotics has been shown to cure peptic
ulcers and prevent recurrence.
Presently, the main therapies employed in the treatment of chronic active
gastritis and peptic ulcer disease include the histamine H2-receptor
antagonists, bismuth compounds, and antibiotics. However, it is generally
accepted that all currently used treatment modalities are clinically
inadequate since post-treatment relapse rates remain unacceptably high. In
addition, several of these therapies are accompanied by significant side
effects. For example, effective antibiotic treatment of Helicobacter pylori
infections requires treatment over an extended duration (4-6 weeks) and
results in the induction of diarrhea and intestinal discomfort. The bismuth
compounds are also known to have a number of significant undesirable side
To date, the preferred treatment has been dominated by the use of
H2-antagonists which result in the suppression of acid and pepsin secretion;
however, post treatment relapse rates are extremely high. Since symptomatic
relief and ulcer healing are the primary aim of treatment, without
indefinite maintenance therapy, it is becoming increasingly apparent that a
mucosal "protective agent " having antimicrobial activity against
Helicobacter pylori, is desirable.
Thus, the medical community has a need for a protective agent which can be
readily utilized in pharmaceutical and/or nutritional formulations. The
present invention fulfills that need.
The method for the eradication or control of the microorganism H. pylori in
accordance with the present invention comprises the step of administering to
a human infected with a gastrointestinal disorder an effective amount of
Taurolidine either alone or in combination with another antibacterial agent
such as metronidazole, ciproflaxin, amoxicillin, amoxicillin-clavulanic
acid, piperacillin, cefoxitin, imipenem and clindamycin.
Taurolidine can be administered prior to, during or after administration of
the additional antibacterial agent. It has been found that by combining
taurolidine with other antibacterial agents the tendency of the
microorganisms to develop resistance to such antibacterial agents is
In general, the compositions of the present invention can be readily
utilized in pharmaceutical and/or nutritional formulations, preferably
formulations which release taurolin quickly in the stomach. The disclosed
medicament may be used alone or in combination with a pharmacologically
and/or nutritionally acceptable carrier and may be in capsule, tablet,
powder or liquid form.
The formulations of taurolidine generally utilized are sterile solutions
containing about 0.5%, 1.0%, 2.0% or about 4.0% taurolidine.
The compositions for the eradication of Helicobacter pylori may take any of
a variety of forms as noted, however, in terms of ability to deliver the
active material to the target site of action, i.e. the stomach and duodenum
(upper small intestine where most ulcers occur) it is preferred to use
tablet, capsule, solution or suspension formulations.
Solid carriers and diluents suitable for use include sugars such as lactose
and sucrose, cellulose derivatives such as carboxymethyl cellulose,
ethylcellulose, methylcellulose, etc., gelatin including hard and soft
gelatin capsules, talc, cornstarch, stearic acid and magnesium stearate.
Suspension formulations may additionally contain benzoic acid, coloring,
natural and artificial flavors, glycerin, kaolin, magnesium, aluminum
silicate, methyl paraben, pectin, purified water, saccharin, sodium
hydroxide and sucrose.
The percentage of taurolidine in the composition can be varied over wide
limits and the quantity of medicament furnished by each individual tablet,
capsule, solution or suspension is relatively unimportant since the
indicated daily dose can be reached by administering either one or a
plurality of capsules, tablets or suspensions.
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