Note: Descriptions are shown in the official language in which they were submitted.
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A Preparation for Treatment of Non-Infectious Inflammatory Intestinal Diseases
The invention pertains to medicine and can be used for treatment of non-
infectious inflammatory intestinal diseases.
Non-infectious inflammatory intestinal diseases, ulcerative colitis and
Crohn's
disease among them, have been, and still are, a most serious problem in
modern gastroenterology. The worldwide incidence of ulcerative colitis and
Crohn's disease increases every year, and mainly among able-bodied
population, which makes them socially significant diseases.
The similarity between these digestive tract lesions is that at their core
there are
chronic lesions of mucous membrane; and the clinical course proceeds in
phases, with exacerbation periods and remission stages. So far, the actual
ethiopathogenic reason for the onset of both inflammatory processes and their
transition to a chronic form has not been found. On the other hand, the
diseases
differ substantially in terms of macroscopic histological pattern, as well as
the
localization site in the digestive tract.
In the case of ulcerative colitis, inflammation captures solely the large
intestine
mucous membrane, propagating successively from ist distal to proximal portion
and pervading the entire large intestine, including the rectum, in hard cases.
In the case of Crohn's disease, inflammation process can affect any part, from
mouth to anus. With this disease, the most often occurence is combined lesion
of lower portions of the small and large intenstine, with segmented
localization of
lesions, when, next to an affected area, one finds areas with unchanged
mucous membrane.
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For treatment of non-infectious inflammatory intestinal diseases one uses
sulfasalazane and mesalazane - preparations of 5-aminosalicylic acid.
Preparation sulfasalazane is known (Drug Encyclopedia. Register of
Pharmaceuticals of Russia PJIC, Moscow, 000 RLS-2005, 2004, 12th edition, p.
826 - 827). It has anti-bacterial and anti-inflammatory action. In the
connective
tissue of the intestine it breaks down into 5- aminosalicylic acid (5-ASA)
responsible for anti-inflammation properties of sulfasalazane, and
sulfapyridine,
a competitive antagonist of paraaminobenzoic acid, which stops the synthesis
of
folates in microorganism cells and is responsible for anti-bacterial activity.
The
preparation shortcoming in treatment of ulcerative colitis and Crohn's disease
is
the strong dependence on the condition of the intestine normoflora which takes
part in biotransformation of sulfasalazane and the release of 5-ASA, the
active
component, while sulfapyridine, the second component of the preparation,
suppresses bacteria and actually inhibits and stops specific activity of the
preparation. Possibly, this is the reason for a sharp increase in allergic
developments and for liver function disturbance.
Also known is preparation salophalk - tablets covered with a shell soluble in
the
intestine and containing mesalazane - 5- aminosalicylic acid (Drug
Encyclopedia.
Register of Pharmaceuticals of Russia PJIC, Moscow, 000 RLS-2005, 2004,
12th edition, pp. 780-781). The preparation is an anti-inflammatory agent that
inhibits the synthesis of metabolites of arachidonic acid and the activity of
neutrophilic lipooxygenase, inhibits migration, neutrophil degranulation and
phagocytosis, and lymphocytes secretion of hemoglobulins, and binds and
destroys free oxygen radicals. It is indicated for treatment of ulcerative
colitis and
Crohn's disease. Among the preparation shortcomings are acute allergic
developments and disorders of the intestine function and nervous,
cardiovascular and urinary systems, claimed as side effects. Hence,
recommendations to use the preparation only under physician's supervision and
have regular blood tests and urinalyses.
Also known is a pharmaceutical composition for oral administration that
contains
5- aminosalicylic acid (5-ASA) as an active ingredient and is adapted for
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modified release from the shell in order to derive a clinically important
localized
effective profile of 5-ASA by releasing the corresponding amount of 5 -ASA
into
the small and large intestine (patent RF JNk 2181043 C2, MI)K7 A61K 9/22,
A61K 9/16, A61K 1/606, A61P 1/00, published 10.04.2002). Some of the
shortcomings are as follows. For 5-ASA to demonstrate pharmacological activity
a sufficiently active condition of normoflora is necessary along with general
detoxifying action, normoflora taking part in the reaction of 5-ASA
acetylation
and excretion from the intestine. However, the general condition of normoflora
in
ulcerative colitis and Crohn's disease and especially of its anaerobic section
(bifidobacteria and lactobacteria) is sharply inhibited even prior to the
start of a
specific treatment, and must be corrected, especially during periods of acute
attack of the disease.
The invention objective is to create a preparation for treatment of
inflammatory
intestinal diseases that has no above mentioned shortcomings and that also
contains bacteria that are characteristic for normal microflora of the
gastrointestinal tract.
The technical result of the invention is higher efficiency of treatment of non-
infectious inflammatory intestinal diseases and shorter length of treatment.
The technical result is achieved due to the fact that the preparation for
treatment
of inflammatory intestinal diseases that contains 5- aminosalicylic acid or a
substance that breaks down in the body and forms 5- aminosalicylic acid, in
addition also contains a liophylically dried microbial mass of live
bifidobacteria or
lactobacteria, or a mixture thereof, with the following component ratio, g: 5-
aminosalicylic acid or a substance that breaks down in the body and forms 5-
aminosalicylic acid 0.05-1.00 a liophylically dried microbial mass of live
bacteria
105-1010 CFU. The preparation contains bifidobacteria or bifidobacteria
immobilized on a sorbent.
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The preparation contains lactobacteria or lactobacteria immobilized on a
sorbent.
The preparation contains a mixture of bifidobacteria and lactobacteria, or a
mixture of bifidobacteria and lactobacteria immobilized on a sorbent.
As 5- aminosalicylic acid or a substance that breaks down in the body and
forms
5- aminosalicylic acid, the preparation contains mesalazane or sulfasalazane.
Mesalazane or sulfasalazane are in the form of powder or granules.
The preparation components are grouped into two capsules that together form a
single dose, wherein one capsule contains a microbial mass of live bacteria,
and
the other capsule contains mesalazane or sulfasalazane.
Alternately, the components are grouped into two capsules, wherein one capsule
contains a microbial mass of live bacteria and is located inside the second
capsule that contains mesalazane or sulfasalazane. The essence of the
invention is as follows. There are numerous theories and assumptions about the
causes of onset of non-infectious inflammatory intestinal diseases, in
particular,
disturbances of intra-intestinal immune system; autoimmune processes; genetic
susceptibility to action of microbial toxins or to inadequate immune response,
etc.
According to one aspect of the present invention, there is provided a
preparation
for treating non-infectious inflammatory intestinal diseases, said preparation
containing:
= between 0.05-1.00 g of 5-aminosalicylic acid or a substance that breaks
down
in the body and forms 5-aminosalicylic acid, and
= between 105-101 CFU of a freeze-dried microbial mass of live bifidobacteria
or lactobacteria or a mixture thereof immobilized on a sorbent.
The information available in recent years, as well as our research, indicate
that
patients with ulcerative colitis and Crohn's disease have deep
microenvironment
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disturbances in their digestive tract which makes it possible to assume that
at the
core of these intestinal diseases is imbalance of ecosystem "host ¨ host's
microflora". This can also be corroborated by observations of substantial
improvement in patients' condition when they are prescribed specially selected
probiotics that normalize the composition of intestinal microflora.
Microenvironment analysis of contents of the lower part of small intestine in
cases of chronic inflammatory lesions of the digestive tract finds increased
proportion of potentially pathogenic aerobic enterobacteria, bacteroids and
other
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anaerobic gram-negative bacteria, and gram-positive aerobic and anaerobic
cocci. A similar pattern is also found in studies of contents of the large
intestine.
A fundamentally important indicator of reduced colonization resistance of the
digestive tract in cases of chronic intestinal diseases is a sharp decrease of
the
5 number of bifidoflora and lactobacilli, natural antagonists of
potentially
pathogenic microorganisms, in contents of the digestive tract, and increased
proportion of bacteroids, anaerobic gram-positive coccobacilli and aerobic
enterobacteria. The ratio of the number of anaerobes to aerobes in parietal
microflora drops sharply, to as low as 25:1.
The quantitative content of bacteroids, bifidobacteria, eubacteria,
peptococci,
streptococci and enterobacteria, as well as organic acids, in feces of people
with
ulcerative colitis, is substantially different for sick and healthy people.
Comparative studies of content of lactobacilli, bifidobacteria and bacteroids
in
feces of healthy people and people with Crohn's disease during exacerbation
have demonstrated sharp reduction of the number of bifidobacteria in sick
people. Reduction of the number of bifidobacteria was accompanied by a
significant drop of activity of total fecal fl-galactosidase.
Studies that were conducted had demonstrated that preparations containing 5-
ASA or a substance that breaks down in the body and forms 5 -ASA
demonstrate their anti-inflammatory activity after microbial transformation in
the
large intestine. In this, the released 5 -ASA becomes active only as a result
of
bacterial breakdown.
In addition, microflora imbalance in the large intestine plays an important
role in
pathogenesis of nonspecific ulcerative colitis and Crohn's disease, and the
role
of immune disbalances in such diseases has been proven. Bifidobacteria and
lactobcteria that are used are natural and indispensible intestine
inhabitants,
non-toxic, non-virulent and non-toxigenic for people and animals. They have
high
antagonistic activity towards pathogenic and opportunistic microorganisms,
inhibit their adhesion to the mucous membrane of the intestine, promote
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normalization of the gastrointestinal tract activity and body's increased
nonspecific resistence, promote parietal digestion, synthesize aminoacids and
polyvitamins, and have an imunomodulatory effect. According to clinical tests
data, high doses of bifidobacteria (in particular, probifora and
bifidumbacterin
preparations), as well as lactobacteria, or mixtures thereof have a marked
effect
on reparation processes in the large intestine mucous membrane and promote
marked fading of inflammation in it. The use of these bacteria promotes fast
restoration of intestine microbiocenisis and the resulting improvement of
parietal
digestion and absorption processes, and improves immune system functions.
The joint use of normoflora and 5 -ASA makes it possible to substantially
reduce
general tooxic and allergic manifestations and promotes stabilization and
restoration of natural intestine microflora, which in turn leads to increased
5-ASA
efficiency due to syncronous microbial transformation (acetylation) of the
latter.
Contents of 5 -ASA or a substance that breaks down in the body and forms 5-
ASA in the range of 0.05-1.00 g corresponds to a therapeutic dose that is
usually
prescribed for patients for treatment ulcerative colitis or Crohn's disease.
A less than 105 CFU contents of a liophylically dried microbial mass of live
bacteria does not produce a curative effect because, with intestine
microenvironment out of balance, it does not provide proper colonization
activity
and antagonistic efficiency.
A more than 105 CFU contents of a liophylically dried microbial mass of live
bacteria is impractical because it will result in unjustified waste of it and
increase
the cost of treatment.
The use of bacteria immobilized on a sorbent ensures high local colonization
of,
and increases restorative processes in, intestine mucous membranes. As a
sorbent, one can use, in particular, fine activated charcoal or silicon
dioxide.
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As 5 -ASA or a substance that breaks down in the body and forms 5 ¨ASA, one
can use preparations that contain mainly mesalazane or sulfasalazane.
However, one can successfully use other aminosalicylates that are close to 5-
ASA in chemical structure and have a similar mechanism of action,
particularly,
olsalazane, balsalazide, etc.
It is good practice to use mesalazane or sulfasalazane in powder form for
preparing medical microclysters and for rectal administraton, and in granular
form for peroral administration. For convenient administration and to make it
possible to dissolve preparation components in certain gastrointestinal tract
areas, the components can be grouped into two capsules that together form a
single dose, wherein one capsule contains a microbial mass of live bacteria,
and
the other capsule contains mesalazane or sulfasalazane. Alternately, the
components can be grouped into two capsules, wherein one capsule contains a
microbial mass of live bacteria and is located inside the second capsule that
contains mesalazane or sulfasalazane.
The following examples illustrate the invention. Examples 1-6 characterize the
composition of the claimed preparation.
Example 1.
5 -ASA, powder, 0.05 g of liophilized mass of live bifidobacteria, CFU 5x10
Example 2.
5-ASA, powder, 0.10 g of liophilized mass of live bifidobacteria and
lactobacteria,
CFU 10
Example 3.
5-ASA, powder, 0.25 g of liophilized mass of live sorbed lactobacteria, CFU
106
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Example 4.
5-ASA, granules, 0.50 g of liophilized mass of live sorbed bifidobacteria, CFU
5x10
Example 5.
5-ASA, granules, 0.75 g of liophilized mass of live lactobacteria, CFU 108
Example 6.
5 -ASA, granules, 1.00 g of liophilized mass of live sorbed bifidobacteria and
lactobacteria, CFU 5x109
Example 7. Assessment of preparation's safety in animal experiments.
At the preclinical studies stage, assessment of safety of the proposed
formulation and its individual components was conducted in experiments on
white mice. For this purpose, a method used for medicinal immunobiologic
preparations was selected. The study was conducted on mice with the mass not
more than 15 g that, unlike adult mice, are characterized by hypersensitivity
to
the effect of alimentary factors. For five days, observations registered body
mass
changes and any symptoms of a disease. The body mass drop and appearance
of symptoms of a disease or animal death indicate harmful action on mice
organism.
The following substances were subjected to assessment for õsafety": the
probiotic component of the preparation, containing bifidobacteria and
lactobacteria in the amount of at least 108 CFU, and a mixture of the
probiotic
component with sulfasalazane in doses of 50, 100 and 150 mg/kg of the animal
body mass. The study results demonstrated that, taken separately, the
probiotic
component is safe when introduced directly to white mice stomach; the addition
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of sulfasalazane to the probiotic in the dose of 50 and 100 mg/kg had not
affected the safety; increasing the sulfasalazane dose to 150 mg/kg made it
possible to detect harmfulness symptoms (a 10 % reduction of the mice body
mass).
Thus, the preparation dose containing 100 mg of 5 -ASA and at least 10 CFU of
probiotics per kg of animal's body, which is higher than the human therapeutic
daily dose, is well tolerated by animals. Examples 8-10 characterize
preparation's efficiency in treating ulcerative colitis and Crohn's disease.
Example 8.
Patient C, 28 years old.
Clinical diagnosis: Nonspecific ulcerative colitis, overall affection, high
activity,
relapsing form.
In the anamnesis: Duration of the disease - 5 years. Hospitalization during
the
exacerbation period - 40-60 days.
During examination, exacerbation of a moderately severe nonspecific ulcerative
colitis was found. Clinically: stool frequency 4-6 times a day, moderate touch
of
blood; low-grade fever; no cardiovascular system pathology found, cardiac rate
up to 90 beats per minute; ESR - 30 mm/hour, moderate leukocytosis;
insignificant malabsorption; intestinal pain at rest and during palpation.
During endoscopy: diffuse hyperemia; mucous granularity and edema observed;
no vascular pattern; moderate bleeding; multiple erosions; isolated ulcers;
fibrin;
no pus. Based on the data of microbiological studies of feces ¨
microbiocenosis
imbalance: bifidobacteria content reduced to 10 CFU/g, lactobacteria content
reduced to 105 CFU/g, colon bacillus content reduced to 7x106 CFU/g, cocci
forms in the total microorganisms sum increased to 95 % (the norm is not more
than 25 %). During complex treatment, the patient had been given for 21 days a
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preparation containing 4 g/day of 5 -ASA and 5x108 CFU of bifidobacteria on a
sorbent, corresponding to example 4.
Before discharge after the administered therapy, positive dynamics was noticed
¨ remission of nonspecific ulcerative colitis. Clinically: stool frequency per
norm,
5 stool without pathological admixtures; body temperature normal; no
tachycardia;
no intestinal pain. The positive dynamics of the endoscopic view:
insignificant
mucous membrane erythema; sponginess; diffused vascular pattern. C-reactive
protein negative, hemoglobylin content and ESR are within normal limits.
10 Marked positive dynamics based on the data of microbiological studies of
feces:
normal bifidobacteria content (108 CFU/g), normal lactobacteria content (10
CFU/g), increased colon bacillus content (107 CFU/g) compared to data before
treatment, reduced number of cocci forms in the total microorganism sum (50%).
Thus, ulcerative colitis exacerbation was arrested in 21 days. The patient was
discharged in satisfactory condition.
Recommendation: take the preparation containing 5-ASA, while reducing the
daily dose to 1 g, together with sorbed probiotic.
Example 9.
Patient JI., 58 years old. Clinical diagnosis: nonspecific ulcerative colitis,
distal
form (chronic ulcerous proctitis), moderately severe course.
From the anamnesis: has had the disease for 28 years, with exacerbation and
remission periods; always hospitalized during exacerbation; average hospital
stay - up to 40 days. Hemocolitis is usually arrested during the 2nd or 3rd
week
of treatment.
During examination, exacerbation of a moderately severe nonspecific ulcerative
colitis was found.
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Clinically: stool frequency up to 6 times a day, with mucus and blood. Blood
streaks in feces, Low-grade fever; abdominal pain; pain when defecating;
moderately evident changes in the electrocardiogram, tachycardia up to 85
beats
per minute. A 4 kg weight loss over the last six months is noticed. ESR
43mm/hour, moderate leukocytosis; moderately evident malabsorption.
During endoscopy: diffuse hyperemia; evident mucus granularity and edema; no
vascular pattern; moderate evident bleeding; multiple erosions; isolated
ulcers;
fibrin; insignificant amount of pus.
Marked positive dynamics based on the data of microbiological studies of feces
-
microbiocenosis imbalance: bifidobacteria content down to107 CFU/g,
lactobacteria content down to 105 CFU/g.
During complex treatment the patient was receiving a preparation corresponding
to example 5 containing 5 -ASA in the amount of 4 g/day and lactobacteria in
the
amount of 108 CFU.
The characteristic feature of patient's treatment regimen was the fact that
preparation 5-ASA was administered in a single step with lactobacteria.
The treatment course lasted 25 days. Hemocolitis was arrested on the 6th day
of
treatment.
After the course, there is no intestinal pain, stool frequency is within
normal
limits, no pathological admixtures in'stool, body temperature is normal, no
tachycardia.
During endoscopy: insignificant mucous membrane erythema, diffused vascular
pattern. ESR dropped down to 18 mm/hour. Based on the data of microbiological
studies of feces, there are no symptoms of intestinal microcenosis imbalance:
bifidobacteria content 107 CFU/g, lactobacteria content 10 CFU/g.
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The patient was discharged in satisfactory condition, with recommendation to
continue outpatient treatment for 4 months, taking a 1 giday dose of a 5 -ASA-
containing preparation and sorbed bifidobacteria.
Example 10.
Patient P. 30 years old.
Diagnosis at admission: Crohn's disease.
Admitted to the hospital with body temperature under 37.50; complained about
sharp weakness, muscular tonus disturbance, muscular, abdominal and joint
pain, diarrhea and weight loss.
In the anamnesis: no mention of digestive tract diseases, but suspicion of
previous yersiniosis; because of this, the patient underwent comprehensive
checkup for antibodies to various bacterial and viral infectious matter,
including
Yersinias, and campilobacteria, and to candidas. Digestive tract diseases were
ruled out.
Colonoscopy and gastroscopy found gastritis, duodenitis, focal endocolitis,
and
dysbacteriosis.
During examination at the hospital: pale skin and mucous membranes; increased
pulse rate; fever; bloating; moderate pain in the left iliac region; during
profound
abdominal palpation, the sigmoid colon is spasmodic. Diarrhea 4-5 times a day,
shapeless stool with touch of blood , mucus and pus. Leukocytosis and
increased ESR are noticed. A biochemical study recorded reduced concentration
of potassium, sodium and magnesium in blood serum, increased creatine
phosphokinase, and increased saturation percentage of iron, alpha and gamma
globulins and beta 2 microglobulins. Low blood albumin.
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A bacteriological study of feces for dysbacteriosis found reduced quantity of
colon bacillus with normal functional activity, and enterococci,
bifidobacteria and
lactobacteria.
Complex treatment was prescribed, using a preparation corresponding to
example 6 containing 5-ASA in the amount of 4 g/day and 10 CFU of the mixture
of sorbed bifidobacteria and lactobacteria ¨ 1 pack 3 times a day. Treatment
course duration 21 days.
After the treatment, patient's condition improved significantly. Stool
frequency ¨
once a day, with no pathological admixtures; abdominal pain disappeared. A
bacteriological study of feces for dysbacteriosis found evident positive
dynamics.
The number of bifidobacteria and lactobacteria, normal colon bacillus and
enterococci had increased.
Thus, the claimed preparation is efficient in treatment of non-infectious
inflammatory intestinal diseases and makes it possible to reduce the length of
treatment.
